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Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the natural death of an embryo or fetus before it is able to survive in-dependently.


  • Uterine malformations have been reported to occur in 3–4% of women overall, in 4% of infertile women and in 15% of those who have experienced recurrent miscarriage (March, 1990; Acién, 1997; Grimbizis et al., 2001). Other studies identified in a systematic review to present the prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure (Saravelos et al., 2008) observed higher percentages: 6.7% in the general population, 7.3% in the infertile population and 16.7% in the recurrent miscarriage patients. The corresponding prevalence values in unselected and high-risk populations (Chan et al., 2011) were 5.5, 8, 13.3 and 24.5% in those with miscarriage and infertility. Therefore, common uterine or Müllerian anomalies are important because of their effects on fertility, but mesonephric anomalies, certain obstructive Müllerian malformations and other malformative combinations are particularly important because they cause several clinical symptoms and impact the patient's quality of life, in addition to creating fertility problems. Such complex malformations of the female genital tract are not common (17.3% of all female genitourinary malformations; Acién and Acién, 2007), but they can cause severe gynaecological symptoms and other problems, particularly in young women.
  • Surgical techniques to correct genital malformations depend on the type of anomaly, its complexity, the patient's symptoms and the proper embryological interpretation of the anomaly. Some anomalies may require complex surgery involving multiple specialties; thus, patients should be referred to centres with experience in the treatment of complex genital malformations. Most malformations can be resolved vaginally or by hysteroscopy, but laparoscopy or laparotomy is often needed; however, the approach and procedure must be carefully chosen and planned. Finally, if there are fertility problems (recurrent miscarriages or immature or premature deliveries) or breech or transverse fetal presentation, a uterine anomaly should always be excluded. The entire genitourinary tract must be analysed considering the embryological aspects presented above.
  • Results: No randomized studies were found. For CVS, nine studies fulfilled the inclusion criteria. The overall pregnancy-loss rate was 3.84% (95% CI, 2.48-5.47; n = 4). The rate of pregnancy loss before 20 weeks was 2.75% (95% CI, 1.28-4.75; n = 3) and before 28 weeks was 3.44% (95% CI, 1.67-5.81; n = 3). For amniocentesis, the overall pregnancy-loss rate was 3.07% (95% CI, 1.83-4.61; n = 4). The rate of pregnancy loss before 20 weeks was 2.25% (95% CI, 1.23-3.57; n = 2), before 24 weeks was 2.54% (95% CI, 1.43-3.96; n = 9) and before 28 weeks was 1.70% (95% CI, 0.37-3.97; n = 5). Pooled data from four case-control studies showed a higher risk (2.59% vs. 1.53%) of pregnancy loss before 24 weeks following amniocentesis (relative risk = 1.81; 95% CI, 1.02-3.19). There were no statistically significant differences in reported pregnancy loss between transabdominal and transcervical approaches, use of a single-needle system vs. a double-needle system and single uterine entry vs. double uterine entry in the CVS group. Similarly, in the amniocentesis group, there was no statistically significant difference in fetal loss between the single uterine entry vs. the double uterine entry.
    Conclusion: In the absence of randomized studies, it is not possible to estimate accurately the excess risk following invasive procedures in twins. Currently available data show similar overall pregnancy-loss rates for both amniocentesis and CVS with the excess risk of around 1% above the background risk.
  • The inability of the uterine cervix to retain a pregnancy in the second trimester is referred to as cervical insufficiency. Controversy exists in the medical literature pertaining to issues of pathophysiology, screening, diagnosis, and management of cervical insufficiency. The purpose of this document is to provide a review of current evidence of cervical insufficiency, including screening of asymptomatic at-risk women, and to offer guidelines on the use of cerclage for management. The diagnosis and management of other cervical issues during pregnancy, such as short cervical length, are discussed more in-depth in other publications of the American College of Obstetricians and Gynecologists.
  • What causes a blighted ovum?
    A blighted ovum is the cause of about 50% of first trimester miscarriages and is usually the result of chromosomal problems. A woman’s body recognizes abnormal chromosomes in a fetus and naturally does not try to continue the pregnancy because the fetus will not develop into a healthy baby. This can be caused by abnormal cell division, or poor quality sperm or egg.
    Should I have a D&C or wait for a natural miscarriage?
    This is a decision only you can make for yourself. Most doctors do not recommend a D&C for an early pregnancy loss. It is believed that a woman’s body is capable of passing tissue on its own and there is no need for an invasive surgical procedure with a risk of complications.
    A D&C would, however, be beneficial if you were planning on having a pathologist examine the tissues to determine a reason for the miscarriage. Some women feel a D&C procedure helps with closure, mentally and physically. Others feel like a D&C is an invasive procedure that can make the loss more traumatic.
    • "Blighted Ovum: Symptoms, Causes and Prevention". American Pregnancy Association. April 26, 2012. (Last Updated: 08/2015)
  • Most doctors recommend couples wait at least 1-3 regular menstrual cycles before trying to conceive again after any type of miscarriage.
    • "Blighted Ovum: Symptoms, Causes and Prevention". American Pregnancy Association. April 26, 2012. (Last Updated: 08/2015) (Archived from the original on July 25, 2017.
  • A miscarriage, or early pregnancy loss, is the expulsion of a fetus from the uterus before it has developed enough to survive. Miscarriages are called spontaneous abortions and they occur in 15 percent to 20 percent of all pregnancies. Most miscarriages happen during the first trimester (first 12 weeks) of pregnancy.
    Many miscarriages are caused because of an anatomic or genetic abnormality in the fetus. Therefore, when a fetus is not developing normally, certain hormone levels drop, and the lining of the uterus begins to shed. The pregnancy separates from the uterus and passes out of the body.
    Miscarriage is not caused by the activities of a healthy pregnant woman, such as jumping, vigorous exercise, and frequent vaginal intercourse. Trauma causes miscarriage only very rarely. Stress and emotional shock do not cause miscarriage either.
  • The objectives of the current study were to calculate: (1) the expected rates of miscarriage by gestational week; (2) the cumulative risk of miscarriage; and (3) the remaining risk of miscarriage for gestational weeks five through 20, through a systematic review of the literature. We searched MEDLINE for articles published in English through the end of 2009. References of articles were also searched. Four studies were identified to have the three necessary pieces of information for the proposed calculations: (1) gestational age at study entry, (2) pregnancy outcome; and (3) the gestational age at which the pregnancy outcome occurred. Data were extracted from each study and Life Table Analysis Methods were conducted. Weekly miscarriage rates varied in the early gestational weeks with the highest rate documented at >20 miscarriages per 1000 women-weeks at each week of gestation prior to week 13. By week 14, the rate for all studies became relatively comparable and fell below 10 miscarriages per 1000 woman-weeks at risk and fell even lower through week 20. The cumulative risk of miscarriage for weeks 5 through 20 of gestation ranged from 11 miscarriages per 100 women to 22 miscarriages per 100 women (11-22%). Based on data from comparable study populations, a range of background miscarriage rates by week of gestation for weeks 5 through 20, the cumulative risk of miscarriage, and the remaining risk of miscarriage are presented. Wider variation of miscarriage rates and risks occurred early in gestation (<14 weeks).
  • LONDON (Thomson Reuters Foundation) - Toxic air in India and other South Asian countries could be causing large numbers of miscarriages and stillbirths, scientists said on Thursday.
    A study in The Lancet medical journal estimated nearly 350,000 pregnancy losses a year in South Asia were linked to high pollution levels, accounting for 7% of annual pregnancy loss in the region between 2000 and 2016.
    South Asia has the highest rate of pregnancy loss globally and some of the worst air pollution in the world.
    “Our findings ... (provide) further justification for urgent action to tackle dangerous levels of pollution,” lead author Tao Xue of Peking University said in a statement.
    The study follows a Lancet report last month which linked India’s bad air quality to 1.67 million deaths or 18% of all its deaths in 2019, up from 1.24 million deaths in 2017. [nL4N2J21ZK}
    The analysis found pollution led to chronic obstructive pulmonary disease, respiratory infections, lung cancer, heart disease, stroke, diabetes, neonatal disorders and cataracts.
  • The scientists estimated the mothers’ exposure during pregnancy to concentrations of PM2.5 - tiny particles found in dust, soot and smoke that can lodge in the lungs and enter the bloodstream.
    They calculated that 7.1% of annual pregnancy losses were attributable to pollution above India’s air quality standard of 40 microgrammes per cubic metre (μg/m³), and 29•7% to pollution above the World Health Organization guideline of 10 μg/m³.
    Co-author Tianjia Guan of the Chinese Academy of Medical Sciences said pregnancy loss had mental, physical and economic impacts on women and that reducing miscarriages and stillbirths may lead to knock-on improvements in gender equality.
    India’s cities top global pollution lists with New Delhi, the world’s most polluted capital.
    Factors contributing to the country’s filthy air include industry, vehicle exhaust fumes, coal-fired power plants, building site dust and the burning of crop residue.
  • Objective Observational studies indicate an association between working nights and miscarriage, but inaccurate exposure assessment precludes causal inference. Using payroll data with exact and prospective measurement of night work, the objective was to investigate whether working night shifts during pregnancy increases the risk of miscarriage.
    Methods A cohort of 22 744 pregnant women was identified by linking the Danish Working Hour Database (DWHD), which holds payroll data on all Danish public hospital employees, with Danish national registers on births and admissions to hospitals (miscarriage). The risk of miscarriage during pregnancy weeks 4–22 according to measures of night work was analysed using Cox regression with time-varying exposure adjusted for a fixed set of potential confounders.
    Results In total 377 896 pregnancy weeks (average 19.7) were available for follow-up. Women who had two or more night shifts the previous week had an increased risk of miscarriage after pregnancy week 8 (HR 1.32 (95% CI 1.07 to 1.62) compared with women, who did not work night shifts. The cumulated number of night shifts during pregnancy weeks 3–21 increased the risk of miscarriages in a dose-dependent pattern.
    Conclusions The study corroborates earlier findings that night work during pregnancy may confer an increased risk of miscarriage and indicates a lowest observed threshold level of two night shifts per week.
  • Epidemiological studies have suggested an association between particulate air pollution, increased temperatures, and morbidity related to pregnancy outcomes. However, the roles of desert dust storms and climatological factors have not been fully addressed. The objectives of the present study were to investigate the association between desert dust storms, particulate matter with a diameter ≤10 μm (PM10), daily temperatures, and toxemia of pregnancy and spontaneous abortion in Gaziantep, South East Turkey. The study was conducted retrospectively at emergency department of two hospitals in Gaziantep city. Data from January 1, 2009, to March 31, 2014, were collected. Patients, who were diagnosed with toxemia of pregnancy and spontaneous abortion by radiological imaging modalities, were included in the study. Daily temperature ranges, mean temperature values, humidity, pressure, wind speed, daily PM10 levels, and records of dust storms were collected. A generalized additive regression model was designed to assess variable effects on toxemia of pregnancy and spontaneous abortion, while adjusting for possible confounding factors. Our findings demonstrated that presence of dust storms was positively associated with the toxemia of pregnancy both in outpatient admissions (OR=1.543 95% CI=1.186-2.009) and inpatient hospitalizations (OR=1.534; 95% CI=1.162-2.027). However, neither PM10 nor maximum temperature showed a marked association with spontaneous abortion or toxemia of pregnancy in our study population. Our findings suggest that desert dust storms may have an impact on the risk for adverse pregnancy outcomes such as toxemia of pregnancy. Health authorities should take necessary measures to protect pregnant women against detrimental effects of these storms.
  • Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. There is an increasing body of evidence indicating that PCOS may have significant implications for pregnancy outcomes and long-term health of a woman and her offspring. Whether or not PCOS itself or the symptoms that coincide with PCOS, like obesity and fertility treatment, are responsible for these increased risks is a continuing matter of debate. Miscarriage rates among women with PCOS are believed to be increased compared with normal fertile women, although supporting evidence is limited. Pregnant women with PCOS experience a higher incidence of perinatal morbidity from gestational diabetes, pregnancy-induced hypertension, and preeclampsia. Their babies are at an increased risk of neonatal complications, such as preterm birth and admission at a neonatal intensive care unit. Pre-pregnancy, antenatal, and intrapartum care should be aimed at reducing these risks. The use of insulin sensitizing drugs to decrease hyperinsulinemic insulin resistance has been proposed during pregnancy to reduce the risk of developing preeclampsia or gestational diabetes. Although metformin appears to be safe, there are too few data from prospective, randomized controlled trials to support treatment during pregnancy.
  • Wild-type rubella infection might result in spontaneous abortion, stillbirth, and, of most concern, congenital rubella syndrome (CRS), with its hallmark characteristics of sensorineural deafness, congenital heart defects, microcephaly, learning difficulties, and eye and bone defects. Measles infection in pregnancy might result in substantial maternal morbidity, an increased abortion rate, prematurity, stillbirth, and possibly congenital malformations. The data for mumps infection are not consistent, with some studies showing a possible increased rate of spontaneous abortion.
  • Hepatitis B infection in a pregnant woman might result in severe disease for the mother and possibly an increase in preterm birth; however, it is not associated with increased abortion rates, stillbirth, or congenital malformation.
  • Regarding fertility, Kühnert and Nieschlag conclude that men start to contribute to the reduced fertility of a couple in their late 30s, and to a reduced fecundity in their early 40s. For example, a descriptive study of birth rates in married couples in Ireland before the widespread use of contraception found that the probability of birth decreased for men from 42–43 years of age. A more recent prospective cohort study of 5121 pregnant women in California concluded that the risk of spontaneous abortion increased with increasing paternal age, and found that the association was stronger for first trimester losses, while another prospective cohort study of 23 821 pregnant women (based on the Danish national birth cohort) reported that the paternal age related risk of late fetal death was higher than the risk of early fetal death, and started to increase from age 45 years.It has been suggested that advanced paternal age (>50 years) increases the risk of preterm delivery and low birth weight, although others have found no such effect. Although aneuploidy is the leading genetic cause of pregnancy loss, there is no substantial evidence for an effect of paternal age on the presence of extra or missing chromosomesand the proportion of fetal deaths attributable to advanced paternal age is currently probably small.
  • Couples in New Zealand who have a miscarriage or stillbirth will be eligible for paid bereavement leave under a new law approved by parliament.
    MP Ginny Andersen, who put forward the bill, said it would allow mothers and their partners to "come to terms with their loss" without taking sick leave.
  • Ms Anderson said one in four women in New Zealand have had a miscarriage and she hoped the new provision would give them "time to come to terms with their loss without having to tap into sick leave".
    "Their grief is not a sickness, it is a loss. And loss takes time," she said, adding that New Zealand was "leading the way for progressive and compassionate legislation".
  • Background: Although the relationship between antidepressant use during pregnancy and its adverse effects has been widely investigated, very few studies have evaluated the impact of antidepressant use during pregnancy on the risk of spontaneous abortion. We present an overview of the evidence relating to the association between antidepressant use during gestation and the risk of spontaneous abortion.
  • Results: Fifteen studies met inclusion criteria. The majority of these were prospective cohort studies on tricyclics antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs) use during pregnancy. Overall, in unadjusted analyses, fluoxetine (OR = 2.0; 95% CI = 1.4 - 3.0) and bupropion (OR = 4.1; 95% CI = 1.5 - 11.1) were significantly associated with the risk of spontaneous abortion. However, in adjusted analyses, only paroxetine (OR = 1.7; 95% CI = 1.3 - 2.3) and venlafaxine (OR = 2.1; 95% CI = 1.3 - 3.3) were significantly associated with the risk of spontaneous abortion.
    Conclusions: This review suggests that gestational exposure to antidepressants, especially paroxetine and venlafaxine, can lead to spontaneous abortion.
  • Background: An incomplete miscarriage occurs when all the products of conception are not expelled through the cervix. Curettage or vacuum aspiration have been used to remove retained tissues. The anaesthetic techniques used to facilitate this procedure have not been systematically evaluated in order to determine which provide better outcomes to the patients.
    Objectives: To assess the effects of general anaesthesia, sedation or analgesia, regional or paracervical block anaesthetic techniques, or differing regimens of these, for surgical evacuation of incomplete miscarriage.
  • Main results: We included seven trials involving 800 women. The comparisons revealed a very high clinical heterogeneity. As a result of the heterogeneity in the randomisation unit, we did not combine trials but reported the individual trial results in the 'Data and analysis' section and in the text. Half of trials have unclear or high risk of bias in several domains.We did not find any trial reporting data about maternal mortality. In terms of postoperative pain, PCB does not improve the control of postoperative pain when it is compared against sedation/analgesia or versus no anaesthesia/no analgesia. In the comparison of PCB with lidocaine versus PCB with saline solution, significant differences favouring the group with lidocaine were found in one trial (moderate or severe postoperative pain) (risk ratio (RR) 0.32; 95% confidence interval (CI) 0.18 to 0.59).When opioids were used, postoperative nausea and vomiting was more frequent in two trials comparing those versus PCB. In terms of requirement of blood transfusion, two trials showed conflicting results.
    Authors' conclusions: Particular considerations that influence the choice of anaesthesia for this procedure such as availability, effectiveness, safety, side effects, practitioner's choice, costs and woman's preferences of each technique should continue to be used until more evidence supporting the use of one technique or another.
  • "Therapeutic" bed rest continues to be used widely, despite evidence of no benefit and known harms. In this commentary, we summarize the Cochrane reviews of bed rest and propose an ethical argument for discontinuing this practice. Cochrane systematic reviews do not support "therapeutic" bed rest for threatened abortion, hypertension, preeclampsia, preterm birth, multiple gestations, or impaired fetal growth. This assessment has been echoed in other comprehensive reviews. Prescribing bed rest is inconsistent with the ethical principles of autonomy, beneficence, and justice. Hence, if bed rest is to be used, it should be only within a formal clinical trial.
  • Several lines of evidence suggest that autoimmune mechanisms may influence the reproductive life and fertility of both sexes, commonly manifesting as infertility or pregnancy loss. Part of the controversy that characterizes this assumption derives from the overlooked suspect of autoimmune conditions in the absence of symptoms or the limited physician awareness in a gynecological setting. Numerous autoimmune diseases, including but not limited to systemic lupus erythematosus and anti-phospholipid syndrome, may be associated with infertility and pregnancy loss through different putative mechanisms. First, serum autoantibodies such as anti-phospholipid, anti-thyroid, or antinuclear antibodies may be directly associated with infertility, regardless of the presence of a clinically overt autoimmune disease. Second, autoimmunity may affect all stages of fertility, via ovarian failure, testicular failure, implantation failure, and pregnancy loss. Third, infertility may also be secondary to vasculitis associated with other conditions such as systemic lupus erythematosus and diabetes mellitus. This review article will illustrate and critically discuss the available data on the link between the breakdown of tolerance that characterizes autoimmune diseases and the changes in reproductive life that affect patients in real clinical setting and that often constitute the iatrotropic stimulus.
  • Infertility (defined as the failure to conceive after 12 months of regular sexual intercourses) can be estimated to affect approximately 10% of the couples of child bearing age. On the other hand, recurrent pregnancy loss (RPL) is defined as the loss of two (American Fertility Society) or three (European Society of Human Reproduction and Embryology, and Royal College of Obstetricians and Gynaecologists) pregnancies and occurs in approximately 1% of couples. The causes of infertility commonly encompass anovulation, endocrine dysfunctions, mechanical infertility (commonly following pelvic infections), and unexplained causes (idiopathic). Autoimmune diseases are not considered as a major cause of impaired fertility and are thus commonly overlooked despite the fact that several conditions are associated with infertility or pregnancy loss. In general terms, autoimmune conditions may affect all stages of fertility, from ovarian and testicular failures, to implantation failure and pregnancy loss. Although the contribution of autoimmunity to impaired fertility remains controversial, numerous conditions are associated with or directly cause subfertility, as in the case of anti-phospholipid syndrome (APS), type 1 diabetes mellitus (T1DM), and systemic lupus erythematosus while maternal anti-Ro/SSA and anti-La/SSB autoantibodies cause a complete heart block in the newborn. Our group summarized the prevalence of autoantibodies in a cohort of 269 patients referred for infertility, recurrent pregnancy loss. In the subjects with infertility anti-phospholipid antibodies (aPL, odd ratio, OR 5.11, 95% confidence interval, CI 1.2–25.4) and anti-prothrombin antibodies (OR 5.15, CI 2.1–12.7) were significantly more represented compared to controls. Further, anti-Sacchromycetes cerevisiae (ASCA, OR 3.9, 95% CI 1.5–10.6), anti-prothrombin (OR 5.4, 95% CI 2.4–12.5), and aPL antibodies (OR 4.8, 95% CI 1.2–22.2) were more frequently found in patients with repeated pregnancy loss. Within this group of patients, serum anti-prothrombin and aPL antibodies were particularly associated with late compared to early pregnancy loss. Pertinent to the present discussion, we recognize a tendency to utilize immunomodulatory approaches to enhance fertility, particularly using steroids which may lower the number and killing activity of natural killer cells, and intravenous immunoglobulin (IVIg) in cases of recurrent implantation failure following in vitro fertilization (IVF) or for the prevention of pregnancy loss. Similarly, cytokine modulation can also be used acting on Th2 and Th1 molecules, albeit in opposite ways. The possibility of an autoimmune response to steroid hormones presenting with infertility or pregnancy loss should be considered in this scenario.
  • It is important to bear in mind that some clinical terms can cause great distress and even anger. It is not acceptable to use the term "abortion" for miscarriage, despite its historical clinical prevalence. To the lay person, "abortion" means the elective termination of pregnancy and while they may have no theoretical objections to that procedure, they are likely to be distressed and even angered at its use in their situation. "Miscarriage" (qualified by adjectives such as recurrent, delayed, early, late, etc.) is easily understood and well accepted.
    • Christiansen O (2014). "Recurrent pregnancy loss". Chichester, West Sussex, UK: John Wiley & Sons. pp. 98–99.
  • Despite a history of heavy vaginal bleeding with clots, a proportion of women diagnosed with complete miscarriage, using transvaginal sonography (TVS), have an underlying ectopic pregnancy (EP). We evaluated the need for hormonal follow up in women with history and scan findings suggestive of complete miscarriage. One hundred and fifty-two consecutive women with findings suggesting complete miscarriage at presentation based on their history and TVS were presented to the Early Pregnancy Unit. Serum human chorionic gonadotrophin (hCG) levels were taken at presentation and 48 hours. All women were followed up until hCG was <5 u/L or a pregnancy was visualised on TVS either inside or outside the uterus. Overall, 9 (5.9%) of 152 women with an apparent complete miscarriage had an underlying EP. A diagnosis of complete miscarriage based on history and scan findings alone is unreliable. These women should be managed as 'pregnancies of unknown location' with serum hCG follow up.
  • Up to 30 percent of pregnancies end in miscarriage, defined as pregnancy loss before 20 weeks of pregnancy. As many as half of miscarriages are unexplained, and there are few known risk factors for these pregnancy losses, which can lead to posttraumatic stress disorder, depression, and anxiety.
    Now, a new study led by School of Public Health researchers has found that risk of miscarriage may increase in the summer months.
    Published in the journal Epidemiology, the study investigated seasonal differences in miscarriage risk and found that pregnant people in North America had a 44 percent higher risk of an early miscarriage (within eight weeks of pregnancy) in the summer months—particularly in late August—than they did six months earlier in February. Risk of miscarriage during any week of pregnancy was 31 percent higher in late August, compared to late February. Geographically, the results showed that pregnant people in the South and Midwest, where summers are hottest, were more likely to experience this loss in late August and early September, respectively.
    These results suggest that additional research is needed to understand the potential roles of extreme heat and other hot-weather environmental or lifestyle exposures in unexpected pregnancy loss.
    “Any time you see seasonal variation in an outcome, it can give you hints about causes of that outcome,” says study lead and corresponding author Amelia Wesselink, research assistant professor of epidemiology. “We found that miscarriage risk, particularly risk of ‘early’ miscarriage before eight weeks of gestation, was highest in the summer. Now we need to dig into that more to understand what kinds of exposures are more prevalent in the summer, and which of these exposures could explain the increased risk of miscarriage.”
  • The findings begin to fill a gap in information on seasonal patterns in miscarriage. Previous studies have relied on clinical or fertility data, both of which likely overlook miscarriages that occur early in gestation (and thus, outside of the hospital) and among couples not experiencing fertility challenges.
    While further research is needed to understand whether extreme heat and other specific exposures are causing these seasonal trends, the researchers say clinicians, policymakers, and climate experts can already take action to mitigate these potential risks.
    “We know that heat is associated with higher risk of other pregnancy outcomes, such as preterm delivery, low birth weight, and stillbirth, in particular,” Wesselink says. “Medical guidance and public health messaging—including heat action plans and climate adaptation policies—need to consider the potential effects of heat on the health of pregnant people and their babies.”
  • Depression and anxiety during pregnancy are common, and patients and providers are faced with complex decisions regarding various treatment modalities. A structured discussion of the risks and benefits of options with the patient and her support team is recommended to facilitate the decision-making process. This clinically focused review, with emphasis on the last 3 years of published study data, evaluates the major risk categories of medication treatments, namely pregnancy loss, physical malformations, growth impairment, behavioral teratogenicity, and neonatal toxicity. Nonpharmacological treatment options, including neuromodulation and psychotherapy, are also briefly reviewed. Specific recommendations, drawn from the literature and the authors' clinical experience, are also offered to help guide the clinician in decision-making.
  • The three main diseases of reproduction in cows–contagious abortion (Brucella abortus), trichomoniasis, and vibrionic abortion–can have serious effects on calving percentages and accordingly they ought to be controlled through calf–hood vaccination of heifers against contagious abortion and by strict adherence to approved breeding procedures in the case of the other two diseases.
    • "Beef cattle and Beef production: Management and Husbandry of Beef Cattle". Encyclopaedia of New Zealand. 1966. Archived
  • It is important to note once again that the prohibition of murder and abortion must be appreciated in a therapeutic, not a juridical or punitive light, with which such offenses are often regarded in most Western moral, philosophical, and theological systems: the goal is not to subject the sinner to just punishment, but to bring the sinner through repentance and God’s grace to holiness.
    Because of this perspective the Orthodox Church never endorsed a doctrine of double effect, such as developed in the West, which allowed Roman Catholicism to approve of indirect abortions. The doctrine of double effects holds that when an action produces two effects, one good and one evil, one may nevertheless act, as long as the act is not evil in itself, the good effect is not produced by the bad effect, the evil effect is not intended,, and there is a proportionate reason (more good will be produced than evil). According to the doctrine of double effect, when these conditions are fulfilled, one is held to be juridically innocent In contrast, the Orthodox Church recognizes that close causal involvement in the death of another, whether a guilty or an innocent person, may harm one’s spiritual life. Orthodox Christianity recognizes harms from both involuntary and “justifiable” homicide, including homicide in a just war, both of which incur excommunication not as punishment, but as spiritual therapy (Basil, 1983, Canon 13, pp. 801-802).
    It is in this spiritually therapeutic context that one should understand the absolution of women who miscarry. The absolution expresses the Orthodox Christian healing approach to the involuntary loss of life.
    • H. Trisram Engelhardt, Jr. Orthodox, “Christian Bioethics: Medical Morality in the Mind of the Fathers”, in "Religious Perspectives on Bioethics". Taylor & Francis. Mark Cherry; John F. Peppin (2013). pp.27-28
  • The woman who has suffered a miscarriage is not held to be guilty in a juridical sense, but in need of God’s loving grace. It is within this therapeutic perspective that the Orthodox Church approaches decisions made by women to engage in operations that will also incidentally lead to the abortion of a child (e.g., the removal of a cancerous uterus containing an unborn child), which in Roman Catholic terms would not count as an abortion. In such cases, the spiritual father must help the patient through repentance and love to repair the spiritual damage from the serious evil of involvement in the death of another person.
    • H. Trisram Engelhardt, Jr., “Orthodox Christian Bioethics: Medical Morality in the Mind of the Fathers”, in "Religious Perspectives on Bioethics". Taylor & Francis. Mark Cherry; John F. Peppin (2013), p. 28
  • Pregnant women who live near farms where pesticides are used face a higher risk of miscarriage due to birth defects than unexposed women, according to a study in heavily farmed areas of California. The results, published in the March issue of Epidemiology, are the strongest to date suggesting that at least some pesticides raise the risk of birth defects in humans, experts say. Unlike other chemicals used by industry, pesticides are designed to kill living animals, making researchers particularly concerned that they may harm humans. Earlier studies showed that some pesticides raised the risk of birth defects and fetal death in rats and mice. But studies in agricultural areas have failed to show clearly whether humans face a similar risk, says epidemiologist Irva Hertz-Picciotto of the University of North Carolina, Chapel Hill. Part of the problem is that it's hard to determine exactly who was exposed, to what chemical, and in what amount. Instead, researchers often rely on people's memory of pesticide use--which can be biased--or on average pesticide application data over an entire county, Hertz-Picciotto says.
  • Women who lived within 2 miles of a place where so-called halogenated hydrocarbons were used during the first 2 months of their pregnancy--when fetal organs are formed--were more than twice as likely to have a miscarriage caused by fetal defects. Other common classes of pesticides--organophosphates and carbamates--raised the risk by about 40%. Strengthening the case, the risk was higher if women lived within 1 mile of the farm where the chemicals were applied. While such an epidemiological study can't prove that pesticides cause birth defects, it raises a red flag, Hertz-Picciotto says.
    "I think it's really a step forward," says epidemiologist Andrew Rowland of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. But because most of the women were exposed to several chemicals, it's still not clear which one might be responsible, he adds. The researchers next hope to "home in on which of the pesticides is toxic," Hertz-Picciotto says.
  • The effect of long-term exposure to dirty air on the risk of miscarriage has been analysed previously. Studies from Brazil to Italy to Mongolia found a link, but others failed to do so.
    However, the latest study is the first to assess the impact of short-term exposure to air pollution. It found that raised levels of nitrogen dioxide (NO2) pollution that are commonplace around the world increased the risk of losing a pregnancy by 16%.
    “It’s pretty profound,” said Dr Matthew Fuller, at the University of Utah’s department of emergency medicine and one of the research team. “If you compare that increase in risk to other studies on environmental effects on the foetus, it’s akin to tobacco smoke in first trimester pregnancy loss.” NO2 is produced by fuel burning, particularly in diesel vehicles.
  • Recurrent miscarriage is frustrating for the physician and a heartbreaking experience for the patient. Approximately 5% of couples trying to conceive have two consecutive miscarriages. Despite a thorough study of patients, the aetiology of this common obstetric complication is unknown in 50% of cases. Known causes include abnormal chromosomes, endocrinological disorders and uterine abnormalities. Although antiphospholipid antibodies have been demonstrated in miscarriages, the role played by alloimmune mechanisms remains unclear. New immunological approaches such as natural killer cells, regulatory T cells, tumour necrosis factor α, cell-derived microparticles, leptin, certain glycoproteins and cytokines should be considered. The management of thyroid diseases and immunological disorders is continuously evolving. Several genetic diagnostic procedures such as parental karyotyping and preimplantation genetic screening should probably not be used routinely. Antiphopholipid syndrome and some recurrent miscarriage-related endocrinological disorders can be effectively treated. Finally, new therapeutic approaches and the pleiotropic effects of old ones have led to improved fetal-maternal outcomes.
  • For most women, it is safe to work while pregnant.
    But there is “a slight to modest increased risk of miscarriage” for women who do extensive lifting in their jobs, according to guidelines published this year by the American College of Obstetricians and Gynecologists. The recommendations are intended to inform doctors about best practices.
    Two decades of medical research have established a link between physically demanding work and fetal death, though there is debate about how strong the connection is. Part of the difficulty in measuring the relationship, researchers say, is that it’s impossible to design a study that isolates the impact of heavy lifting versus other risk factors, like pre-existing conditions.
    In a peer-reviewed study from 2013, researchers in Denmark found that the risk of fetal death increased as women lifted heavier objects more frequently. The researchers theorized that lifting and bending could reduce blood flow to the uterus.
    Another possibility, doctors said, is that extreme physical exertion diverts blood from a woman’s womb to her muscles.
    The potential dangers are greatest for women whose pregnancies are already classified as high risk, which is why doctors often advise that they be given easier tasks.
    “When employers ignore these medical recommendations, they are potentially jeopardizing patients’ health,” said Rebecca Jackson, the chief of obstetrics and gynecology at San Francisco General Hospital. “It’s especially bothersome to me that this is occurring for women in strenuous jobs, given that they are at the most risk of injuring themselves or the pregnancy.”
  • Because spontaneous miscarriage and self-managed abortion are medically indistinguishable in most cases, prohibitions on abortion will predictably lead to the investigation and detention of many women experiencing miscarriages as well as those self-managing abortions.
    • Foley Hoag LLP on behalf of the Global Justice Center, Amnesty International USA, Human Rights Watch, National Birth Equity Collaborative, Physicians for Human Rights, Pregnancy Justice, “UN Special Procedures Letter US Abortion Rights”, (March 2, 2023), pp.18-19
  • Editor—Miscarriage is distressing, giving rise to a range of emotional experiences for both the woman and her partner. The aim of medical and nursing staff must be to reduce distress, but the distress may be increased by staff taking the wrong approach or using inappropriate terminology. The lay public tend to interpret an “abortion” as a termination of pregnancy.1 We advise that when women are counselled about miscarriage the word abortion should be avoided.
    The Royal College of Obstetricians and Gynaecologists has a study group on early pregnancy loss, which last year recommended new medical terminology that avoids the word abortion for spontaneous early pregnancy loss. The group suggests using the term “early fetal demise,” but women may still find this term distressing. “Delayed miscarriage” and “silent miscarriage” have been suggested to replace missed abortion. We carried out a search of Medline between January 1993 and November 1997 (table). We searched for the terms spontaneous abortion and miscarriage as textwords in two general medical British publications (British Medical Journal and The Lancet) and four specialist journals (British Journal of Obstetrics and Gynaecology, Journal of Obstetrics and Gynaecology, Ultrasound in Obstetrics and Gynaecology, and Fertility and Sterility).
    This search showed that the word abortion is still widely used in the medical literature to describe spontaneous pregnancy loss. The British journals had a lower use of the word than the overall English language literature; perhaps surprisingly, the use was lower in general journals than specialist journals on reproduction. A suitable term to replace missed abortion may have slowed the change. While “delayed miscarriage” is not a complete description of the pathogenic process neither was “missed abortion.” For the purposes of medical classification, all miscarriages need further description to explain the underlying pathology, such as “anembryonic pregnancy.”
    Medical and nursing professionals may find it difficult to maintain one form of language for patients and another for medical notes. They should use the word miscarriage to describe all spontaneous pregnancy loss both when speaking to patients and when completing medical notes. The language culture cannot be changed without a change in the medical literature. Editors of medical journals should ensure that the word abortion is avoided when spontaneous pregnancy loss is meant. The problem seems to be confined to the English language. In French and German the medical words for termination of pregnancy and miscarriage are completely different.
  • Family and Sick Leave in Taiwan
    Taiwan’s labor laws also extend to parental leave. According to the LSA, women should be provided with eight weeks of maternity leave. If she has been working at the same company for the prior six months, then she is entitled to receive full wages during the entirety of her maternity leave in Singapore.
    In cases where she doesn’t meet this requirement, she is entitled to receive half of her monthly wages. This paid time off also extends to miscarriages. Women who have already given birth are also given several breaks throughout the day for breastfeeding. Men are provided with three days of paternity leave. These laws also cover families who have decided to adopt as well.
    In the event of a death of an immediate family member, employees in Taiwan are entitled to receive up to eight days of leave.
  • A total of 639 spontaneous abortuses collected in a maternity hospital were set up in culture. This sample included 565 unselected consecutive abortuses and 74 selected abortuses ascertained by morphology and/or clinical history. Among these, 339 were incomplete specimens with no recovered embryo or fetus, 110 were anatomically apparently normal and 190 were grossly abnormal. In the unselected series, 565 specimens were cultured and 402 were karyotyped; 215 (53.5%) were chromosomally abnormal. In the selected series, 74 specimens were set up in culture and 45 were karyotyped; 26 (57.7%) had an abnormal karyotype. In all, successful karyotyping was done on 447 abortuses (70%), of which 339 were studied with banding. One or more major chromosome abnormalities were detected in 241 (54%) of the karyotyped cases, 230 of which were numerical anomalies and 11 structural anomalies. Numerical anomalies included primary autosomal trisomies (31% of the total karyotyped), 45,X (10%), triploidy (6.5%), and tetraploidy (1.8%). Of the 22 types of autosomal trisomies possible, all except those for 1, 5, 17, and 19 were identified. An abortus with a 49,XX,+2,+5,+8 karyotype was detected. The excess autosomal material present in the triple trisomic abortus corresponded to 10% of the haploid autosomal complement. Of the 11 abortuses with structural abnormalities, seven were inherited while the other four were sporadic. The survival rate of 45,X conceptuses was estimated to be one in 300.
  • Background: Women with polycystic ovary syndrome (PCOS) are considered to be at increased risk of miscarriage. Since metformin has beneficial effects on the risk factors contributing to first-trimester abortion in PCOS patients, we hypothesized that metformin - owing to its metabolic, endocrine, vascular and anti-inflammatory effects - may reduce the incidence of first-trimester abortion in PCOS women.
    Materials and methods: A prospective cohort study was set up to determine the beneficial effects of metformin on PCOS patients during pregnancy. Two hundred non-diabetic PCOS patients were evaluated while undergoing assisted reproduction. One hundred and twenty patients became pregnant while taking metformin, and continued taking metformin at a dose of 1000-2000 mg daily throughout pregnancy. Eighty women who discontinued metformin use at the time of conception or during pregnancy comprised the control group.
    Results: Both groups were similar with respect to all background characteristics (age, body mass index, waist/hip ratio, follicle-stimulating hormone, luteinizing hormone, estradiol and dehydroepiandrosterone sulfate levels). Rates of early pregnancy loss in the metformin group were 11.6% compared with 36.3% in the control group (p < 0.0001; odds ratio = 0.23, 95% confidence interval 0.11-0.42).
    Conclusions: Administration of metformin throughout pregnancy to women with PCOS was associated with a marked and significant reduction in the rate of early pregnancy loss.
  • When a woman presents with a PUL and a history of heavy bleeding it is tempting to make a diagnosis of complete miscarriage. However, the evidence shows that such cases should be classified as PUL and evaluated further unless a prior ultrasound has confirmed an IUP. In a study of 152 women with such a history, 5.9% were subsequently found to have an underlying EP (Condous et al., 2005b).
    Difficulty also arises in women found to have a slightly thickened or irregular endometrium with a possible small amount of retained products of conception. We know that measurements of endometrial thickness or volume on TVS are not good tests for predicting the finding of chorionic villi at curettage, and so are unreliable for diagnosing an incomplete miscarriage (Sawyer et al., 2007), although the use of power Doppler has been reported as being useful for confirming the presence of significant retained products in the cavity (Casikar et al., 2012). There is currently no consensus on the correct management of these cases. Where no definitive retained products of conception are seen, it would seem appropriate to adopt the safer approach and manage these cases as PUL, thus also avoiding the possibility of curettage in the presence of a potentially viable early IUP. It follows that some units with very high PUL rates may be managing a larger proportion of incomplete miscarriages as PUL because of this diagnostic uncertainty.
  • Methods: This case-control study of 13,865 women draws on data from women's antenatal or postpartum interviews in the Jerusalem Perinatal Study, a population-based cohort derived from 92,408 births in 1964-1976. Case women (n=1,506) reported spontaneous abortion in the pregnancy preceding the interview; they were compared with women reporting live births in their previous pregnancy (n=12,359). Logistic regression was used to adjust for maternal age, maternal diabetes, maternal smoking, history of spontaneous abortions before the index pregnancy, parity at interview, and interval between the index pregnancy and the interview.
    Results: The adjusted odds ratio for spontaneous abortion was 0.59 (95% confidence interval 0.45-0.76, P< .0001) for pregnancies conceived from fathers aged younger than 25 years compared with those from fathers aged 25-29 years. For fathers age 40 years or older the odds ratio for spontaneous abortion was 1.6 (95% confidence interval 1.2-2.0, P=.0003) when compared with the same reference group.
    Conclusion: Increasing paternal age is significantly associated with spontaneous abortion, independent of maternal age and multiple other factors.
  • When a nonviable first-trimester pregnancy is diagnosed, women have the option of waiting for the uterine contents to pass, choosing medical management with medications such as misoprostol (Cytotec), or undergoing dilation and curettage. Without intervention, more than 65 percent of missed abortions and 80 percent of incomplete and first-trimester abortions pass naturally within two to six weeks. Misoprostol 600 to 1,200 mcg vaginally on day 1, with a repeat dose if indicated on day 3, has been proven safe and effective. Success rates approach 95 percent, and women find their experience satisfactory. Surgical management includes vacuum extraction, suction curettage, or sharp curettage with or without dilation. Surgical management is the definitive treatment when other methods fail.
  • Nanda and colleagues reviewed the literature for trials comparing expectant management with surgical treatment for miscarriage. They found five trials with a total of 689 participants.
    Expectant management had higher rates of incomplete miscarriage, need for unplanned surgical treatment, and bleeding, but a lower rate of pelvic infection (relative risk 0.29; 95% confidence interval, 0.09 to 0.87). Rates of infection ranged from 0 to 10 percent. Overall, there were two women in expectant management groups who required blood transfusion. However, rates of hemorrhage greater than 500 mL and bleeding requiring transfusion were not statistically significant between expectant management and surgical treatment groups. Two to 20 percent of women in the expectant management groups needed surgery. Unplanned surgical management usually was attributed to unacceptable pain, bleeding, or patient request. There were no differences in serious adverse events between the expectant management and surgical treatment groups.
    Rates of complete abortion varied by study. In one study, the rate of complete abortion in the expectant management group was 81 percent at less than two weeks and 93 percent at seven weeks. Surgical treatment had a complete abortion rate of 97 percent at less than two weeks; no patients required second procedures. There is no clear indication for routine surgical management; therefore, patient preference should be respected.
  • Obesity has become a major health problem across the world. In the UK, obesity affects one/fifth of the female population (Anonymous, 2001). Maternal obesity has been reported as a risk factor for adulthood obesity in offspring (Parsons et al ., 2001). Obesity may also lead to a poor pregnancy out-come, such as sudden and unexplained intrauterine death (Froen et al ., 2001 ), and in women with polycystic ovary syndrome (PCOS) receiving infertility treatment is associated with an increased risk of miscarriage (Hamilton, Fairley et al ., 1992 ; Wang et al ., 2000 ). However, in the general population there is less evidence for a link between obesity and spontaneous miscarriage (Risch et al ., 1990).
  • Spontaneous miscarriage affects 12-15% of all pregnancies (Zinman et al ., 1996 ). Eighty percent of miscarriages occur before 12 weeks of gestation, and the majority are due to chromosomal abnormalities (Harlap et al ., 1980). Our figures from this study population are consistent with previously published data.
    The risk of miscarriage after the detection of a fetal heart on ultrasound scan is reduced to 5%, except in patients who have had recurrent miscarriages (van Leeuwen et al ., 1993).
    Many factors have been described to increase the risk of spontaneous miscarriage; however, obesity was not found to be a risk factor by Risch et al . (1990) . Recent evidence indicated that obese women undergoing infertility treatment were at increased risk of spontaneous miscarriage (Hamilton, Fairley et al ., 1992 ; Wang et al ., 2000). However, this point has also been controversial (Lashen et al ., 1999 ; Roth et al., 2003).
  • Background: Threatened miscarriage occurs in 10% to 15% of all pregnancies. Vaginal spotting or bleeding during early gestation is common, with nearly half of those pregnancies resulting in pregnancy loss. To date, there is no effective preventive treatment for threatened miscarriage. Chinese herbal medicines have been widely used in Asian countries for centuries and have become a popular alternative to Western medicines in recent years. Many studies claim to show that they can prevent miscarriage. However, there has been no systematic evaluation of the effectiveness of Chinese herbal medicines for threatened miscarriage.
  • Main results: In total, we included 44 randomised clinical trials with 5100 participants in the review.We did not identify any trials which used placebo or no treatment (including bed rest) as a control.The rate of effectiveness (continuation of pregnancy after 28 weeks of gestation) was not significantly different between the Chinese herbal medicines alone group compared with the group of women receiving Western medicines alone (average risk ratio (RR) 1.23; 95% confidence interval (CI) 0.96 to 1.57; one trial, 60 women).Chinese herbal medicines combined with Western medicines were more effective than Western medicines alone to continue the pregnancy beyond 28 weeks of gestation (average RR 1.28; 95% CI 1.18 to 1.38; five trials, 550 women).
    Authors' conclusions: There was insufficient evidence to assess the effectiveness of Chinese herbal medicines alone for treating threatened miscarriage.A combination of Chinese herbal and Western medicines was more effective than Western medicines alone for treating threatened miscarriage. However, the quality of the included studies was poor. More high quality studies are necessary to further evaluate the effectiveness of Chinese herbal medicines for threatened miscarriage.
  • The Bruce effect is awidely studied reproductive phenomenon in rodents in which exposure of pregnant females to unknown males causes termination of the current pregnancy. The Bruce efet has been reported from numerous studies in the laboratory, and one field study with the promiscuous graytailed vole, Microtus canicaudus, failed to support it. We conducted a field study with the monagomous prairie bole, M. orchrogaster, to determine if complete replacement of the male population every 10-14 days affected pregnancy and juvenile recruitment. The mean days to first parturition for control and treatment females were 36.8 and 44.4 days. Fifty-five percent of control females and 33% of treatment females conceived within the first 14 days of the study. All control females and 79% of treatment females successfully delivered at least one litter. These differences between treatment and control population provide minimal support for the Bruce effect when compared with results from laboratory studies. Nulliparous females may have experienced some pregnancy disruption, but not parous females. Removal of mates, rather than exposure to strange males, may have contributed more to the lower reproductive successof treatment females than exposure to strange males. Treatment females, however, had lower juvenile recruitment than controls, which may have been due to infanticide from strange males. Our results are more similar to those of the field study of the gray-tailed vole than predicted, based on laboratory studies of prairie voles.
  • The Bruce effect is a form of pregnancy disruption in mammals in which exposure of a female to an unknown male results in pre- or post-implantation failure (Bruce 1960). Some form of pregnancy disruption has been reported in the laboratory for at least 12 species of rodents, including 7 of the genus Microtus (Microtus agrestis; Clulo and Clarke 1968; Milligan 1976; M. Brandti; Stubbe and Hanke 1994; M. californicus; Heske 1987; M. momtanus; Stehn and Jannett 1981; M. ochrogaster; Stehn and Richmond 1975; Kenney et al 1977; Heske and Nelson 1984; M. pennsylvanicus; Clulow and Langford 1971; Storey and Snow 1987, 1990; Storey 1994; and M. pinetorum; Schadler 1981; Stehn and Jannett 1981). The basic design of these experiments is that a recently inseminated female is exposed directly to an unfamiliar nonsire male, or to its urine or soiled bedding, which in turn causes her to prevent implantation or to abort or reabsorb her embryos. Pregnancy disruption may occur at any time from conception to 17 days post-mating, depending on species and experimental conditions (e.g., Stehn and Richmond 1975; Milligan 1976; Stehn and Jannett 1981; Storey 1994). Variables such as length of exposure, timing of exposure to a strange male sexual experience, and behavior of strange males may all influence the degree of pregnancy failure (e.g., Stehn and Richmond 1975; Millign 1976; Kenney et al. 1977; Schadler 1981; Storey and Snow 1990; de Catanzaro et al. 1999). The overall implication is that some level of exposure to strange males ddisrupts normal pregnancy in female rodents. This response is supposedly adaptive for the male in that termination of pregnancy results in the female becoming estrus within 1-4 days, providing the male with a mating opportunity The benefit to the female is less clear, but if the strange male were to commit infanticide and kill her offspring after parturition, a female could conserve reproductive effort by aborting her current litter and mating with the new male (Labov 1981; Huck et al. 1988; Storey 1994). Thus, pregnancy block or termination of pregnancy may have evolved as a female counter-strategy to infanticide by males (Labov 1980, 1981; vom aal and Howard 1982; Labov et al. 1985l Storey and Snow 1990; Storey 1994).
  • [Republic Act No. 8187]
    Be it enacted by the Senate and the House of representatives of the Philippines in Congress assembled:
    SECTION 1. Short Title - This ACT shall be known aas the “Paternity Leave Act of 1996”. <r> SEC. 2. Notwithstanding any law,rules and regulations to the contrary, every married male employee in the private and public sectors shall be entitled to a paternity elave of seven (7) days with full pay for the first four (4) deliveries of the legitimate spouse with whom he is cohabiting. The male employee applying for paternity leave shall notify his employer of the pregnancy of his legitimate spouse and the expected date of such delivery.
    For purposes of this Act, delivery shall include childbirth or any miscarriage.
    Sec. 3. Definition of Term. - For purposes of this Act, Paternity Leave refers to the benefits granted to a married male employee allowin him not to report for work for seven (7) days but continues to earn the compensation therefor, on the condition that his spouse had delivered achild or suffered a miscarriage for purposes of enabling him to effectively lend support to his wife in her period of recovery and/or in the nursing of the newly-born child.
    SEC. 4. The Seretary of Labor and Employment the Chairman of the Civil service Commission and the Secretary of Health shall, within thirty (30) days from the effectivity of this Act, issue such rules and regulations necessary for the proper implementation of the provisions hereof.
    SEC. 5. Any person, corporation, trust, firm, paternership, association or entity found violating this Act or the rules and regulations promulgated tthereunder shall be punished by a fine now exceeding Twenty-five thousand pesos (P25,000) or imprisonment of not less than thirty (30) days nor more than six (6) months.
    If the violation is committed bya corporation, trust or firm, partnership, association or any other entity, the penalty of imprisonment shall be imposed on the entity’s responsible officers, including, but not limited to, the president, vice president, chief executive officer, general manager, managing director or partner directly responsible therefor.
  • Most miscarriages happen very early in the pregnancy, often before a woman even knows she is pregnant.
    Factors that may contribute to miscarriage include:
    A genetic problem with the fetus
    Problems with the uterus or cervix
    Chronic diseases, such as polycystic ovary syndrome
    Signs of a miscarriage include vaginal spotting, abdominal pain or cramping, and fluid or tissue passing from the vagina. Bleeding can be a symptom of miscarriage, but many women also have it in early pregnancy and don't miscarry. To be sure, contact your health care provider right away if you have bleeding.
    Women who miscarry early in their pregnancy usually do not need any treatment. In some cases, there is tissue left in the uterus. Doctors use a procedure called a dilatation and curettage (D&C) or medicines to remove the tissue.
    Counseling may help you cope with your grief. Later, if you do decide to try again, work closely with your health care provider to lower the risks. Many women who have a miscarriage go on to have healthy babies.
  • Whether pregnant women with insulin-dependent diabetes mellitus have an increased risk of spontaneous abortion is controversial. To address this question, we enrolled 386 women with insulin-dependent diabetes and 432 women without diabetes before or within 21 days after conception and followed both groups prospectively. Sixty-two diabetic women (16.1 percent) and 70 control women (16.2 percent) had pregnancy losses (odds ratio, 0.99; 95 percent confidence interval, 0.67 to 1.46). After adjustment for known risk factors for spontaneous abortion, the rate was still not significantly higher in the diabetic group (odds ratio, 0.91; 95 percent confidence interval, 0.59 to 1.40). Nonetheless, among the diabetic women, most of whom had good metabolic control, those who had spontaneous abortions had higher fasting and postprandial glucose levels in the first trimester than those whose pregnancies continued to delivery (P = 0.01 for fasting glucose levels and P = 0.005 for postprandial levels). In the small subgroup of diabetic women with poor control, who had elevated values for glycosylated hemoglobin in the first trimester, each increase of 1 SD above the normal range was associated with an increase of 3.1 percent in the rate of pregnancy loss (95 percent confidence interval, 0.6 to 5.6). We conclude that diabetic women with good metabolic control are no more likely than nondiabetic women to lose a pregnancy, but that diabetic women with elevated blood glucose and glycosylated hemoglobin levels in the first trimester have a significantly increased risk of having a spontaneous abortion.
    • Mills JL, Simpson JL, Driscoll SG, Jovanovic-Peterson L, Van Allen M, Aarons JH, et al. (December 1988).[ https://pubmed.ncbi.nlm.nih.gov/3200277/ "Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception"]. The New England Journal of Medicine. 319 (25): 1617–23. doi:10.1056/NEJM198812223192501. PMID 3200277.
  • Abortion is described as removing conception products from the uterus before the 20th week of pregnancy and or delivery of a fetus with a weight of less than 500 g. Abortion is either spontaneous or induced. Spontaneous abortion, also known as miscarriage, is one of the most common problems which a woman may encounter during her pregnancy which mostly predominates from hormonal problems, maternal disorders, and chromosomal abnormalities. Lifestyle, diet, smoking, and alcohol are also other important risk factors for miscarriage. A miscarriage is the natural death of a fetus in the womb.
    With nearly 130 million births per year across the world, a 15% risk of miscarriage proposes nearly 23 million miscarriages per year or 44 per min. given that the miscarriages and preclinical pregnancy losses are usually managed at home, the absolute number of miscarriages is significantly higher than reported. Moreover, miscarriage is associated with long-term health problems (such as thromboembolism, cardiovascular disease, and etc.) and psychological consequences (such as bereavement, anxiety, depression, suicide, and etc.). Also, miscarriage is one of the most important causes of maternal death .
  • In the NAME region, the incidence and prevalence rates of spontaneous abortion decreased by 56%, and also the mortality and DALYs rates decreased by 89% between 1990 and 2019. Afghanistan and Sudan had the highest prevalence and incidence rates of spontaneous abortion, and Yemen had the highest death and DALYs rates by ASR among the NAME countries between 1990 and 2019. The highest spontaneous abortion-related DALYs rate was attributed to iron deficiency, and Yemen (29%) had the highest attributed burden to iron deficiency. As recurrent miscarriage is a marker for various obstetric risks in future pregnancies, women should receive post-abortion care. As psychological consequences are common after abortion, effective screening and timely treatment for mental health complications of miscarriage need to be available. At the national and state levels, health policymakers can use the information reported in this study to facilitate comparison of rates among countries, to accelerate research, to develop their health planning, to resource allocation, to improve patient care and policy development, and to decrease the burden of spontaneous abortion.
  • Some studies have shown a higher chance of miscarriage (early pregnancy loss) in older mothers. When considering all women, about half of first trimester miscarriages occur because of a chromosomal abnormality in the fetus. Because these abnormalities increase with maternal age, miscarriage is also more likely.
  • The guideline covers diagnosis of early pregnancy loss, including the use of ultrasound scanning and biochemical testing. Investigations incur costs and the use of serial measurements may delay decision making. The guideline includes guidance on when senior and/or specialist advice should be sought in order to avoid errors and unnecessary delay.
    Treatment for threatened miscarriage has been offered by many clinicians over the years, although it is not freely available to all women. Even though progesterone/progestogen is not licensed for this purpose in the UK, it is commonly prescribed in many countries. The guideline examines the evidence for the risks and benefits of this treatment.
    The clinical and cost effectiveness of expectant, surgical and medical management for miscarriage and surgical and medical treatment of ectopic pregnancy are considered, with reviews looking at both the risks and benefits of each strategy in terms of clinical and psychological outcomes. Cost effectiveness is an extremely important component of any guideline, in order to ensure that the limited resources of the National Health Service are used to maximise health benefits for its users. The final advice and selection of first line treatment takes this into account.
    The guideline does not cover pregnancy after the first trimester (after 12 completed weeks of pregnancy). It also does not deal with unusual conditions that present with pain and bleeding, such as hydatidiform mole, which require a different form of treatment. Similarly, it does not consider recurrent miscarriage, as this requires more specific investigation and management.
    • National Coordinating Centre for Women's and Children's Health (UK) (December 2012). "Ectopic Pregnancy and Miscarriage: Diagnosis and Initial Management in Early Pregnancy of Ectopic Pregnancy and Miscarriage". NICE Clinical Guidelines, No. 154. Royal College of Obstetricians and Gynaecologists. PMID 23638497. Archived
  • Couples who attempt to conceive within three months after losing an early pregnancy, defined as less than 20 weeks gestation, have the same chances, if not greater, of achieving a live birth than those who wait for three months or more, according to a National Institutes of Health study.
    This finding, published today in Obstetrics & Gynecology, questions traditional advice that couples should wait at least three months after a loss before attempting a new pregnancy. The World Health Organization, for example, recommends waiting a minimum of six months between a pregnancy loss and a subsequent attempt.
    “Couples often seek counseling on how long they should wait until attempting to conceive again,” said Enrique Schisterman, Ph.D., chief of the Epidemiology Branch at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and senior author of the study. “Our data suggest that women who try for a new pregnancy within three months can conceive as quickly, if not quicker, than women who wait for three months or more.”
    Previous studies of pregnancy spacing have focused on when women should become pregnant after experiencing a loss, but few have addressed the question of when couples should start trying to conceive.
  • The researchers found that more than 76 percent of the women attempted to conceive within 3 months after losing a pregnancy. Compared to those who waited longer, this group was more likely to become pregnant (69 percent vs. 51 percent) and to have a pregnancy leading to a live birth (53 percent vs. 36 percent). The investigators did not observe any increase in the risk of pregnancy complications in this group.
    “While we found no physiological reason for delaying attempts at conception following a pregnancy loss, couples may need time to heal emotionally before they try again,” said Karen Schliep, Ph.D., a postdoctoral fellow in the NICHD Epidemiology Branch at the time of the study and primary author of the study. “For those who are ready, our findings suggest that conventional recommendations for waiting at least three months after a loss may be unwarranted.”
  • Exposure to common air pollutants, such as ozone and fine particles, may increase the risk of early pregnancy loss, according to a study conducted by the National Institutes of Health. The study appears in the journal Fertility and Sterility.
    Ozone is a highly reactive form of oxygen that is a primary constituent of urban smog. Researchers followed 501 couples attempting to conceive between 2005 and 2009 in Michigan and Texas. The investigators estimated the couples’ exposures to ozone based on pollution levels in their residential communities. Of the 343 couples who achieved pregnancy, 97 (28 percent) experienced an early pregnancy loss — all before 18 weeks. Couples with higher exposure to ozone were 12 percent more likely to experience an early pregnancy loss, whereas couples exposed to particulate matter (small particles and droplets in the air) were 13 percent more likely to experience a loss.
    The researchers do not know why exposure to air pollutants might cause pregnancy loss, but it could be related to increased inflammation of the placenta and oxidative stress, which can impair fetal development. The findings suggest that pregnant women may want to consider avoiding outdoor activity during air quality alerts, but more research is needed to confirm this association.
  • The estimated rate of miscarriage is 15% to 20% in women who know they are pregnant, but as many as half of all fertilized eggs may spontaneously abort, often before the women realize they are pregnant. Women who have had previous miscarriages are at a higher risk for miscarriage. The risk of miscarriage also increases with maternal age beginning at age 30 and becoming greater after age 35.
    • "How many people are affected by or at risk for pregnancy loss or miscarriage?". www.nichd.nih.gov. July 15, 2013. (Last Updated Date: 11/30/2012 Last Reviewed Date: 07/15/2013) Archived
  • In most cases, no treatment is necessary for women who miscarry early in their pregnancy, because the bleeding associated with miscarriage usually empties the uterus of pregnancy-associated tissue. In some cases, however, a woman may need to undergo a surgical procedure called a dilation and curettage (D&C) to remove any pregnancy-associated tissue remaining in the uterus. A D&C is performed if the woman is bleeding heavily or if an ultrasound test detects any remaining tissue in the uterus.
    An alternative to a D&C is the use of a medication called misoprostol that helps the tissue pass out of the uterus. The use of misoprostol has proven to be effective in 84% of the cases studied. Other treatments after a woman miscarries may include control of mild to moderate bleeding, prevention of infection, pain relief, and emotional support. If heavy bleeding occurs, the woman should contact her health care provider immediately.
    • "What are the treatments for pregnancy loss/miscarriage?". www.nichd.nih.gov. July 15, 2013. (Last Updated Date: 11/30/2012 Last Reviewed Date: 07/15/2013) Archived
  • There are ways to lower the risk of general pregnancy complications, but none of them definitely prevent pregnancy loss. Some ways to lower overall risk include:
    *Staying in good health before becoming pregnant and getting regular care during pregnancy
    *Diagnosing any health conditions, such as diabetes or thyroid disorders, and taking steps to manage or treat the condition before getting pregnant
    *Avoiding environmental hazards, such as exposure to radiation, pollution, or toxic chemicals
    *Avoiding alcohol and drugs, including high levels of caffeine in both partners
    *Protecting yourself from certain infections by not traveling to certain areas and by preventing mosquito bites.
  • Symptoms of miscarriage may include vaginal spotting or bleeding; abdominal pain or abdominal cramps; low back pain; or fluid, tissue, or clot-like material passing from the vagina. Although vaginal bleeding is a common symptom when a woman has a miscarriage, many pregnant women have spotting early during their pregnancy because of other factors but do not miscarry. Regardless, pregnant women who have any of the symptoms of miscarriage should contact their health care providers immediately.
    • "What are the symptoms of pregnancy loss/miscarriage?". www.nichd.nih.gov/. July 15, 2013. (Last Updated Date: 11/30/2012 Last Reviewed Date: 07/15/2013) Archived
  • An NICHD study found that women who are at higher risk for pregnancy loss because of two or more previous losses may increase their chances of carrying the pregnancy to term by taking a low-dose aspirin every day if they have high levels of inflammation.
  • Pregnancy loss is the unexpected loss of a fetus before the 20th week of pregnancy. It is sometimes called miscarriage, early pregnancy loss, mid-trimester pregnancy loss, fetal demise, or spontaneous abortion.
    Health care providers use a different term—stillbirth—to describe the loss of a fetus after 20 weeks of pregnancy.
    Pregnancy loss may occur so early that a woman may not know she was pregnant.
    Researchers can only estimate the number of women who experience pregnancy loss, because some losses occur before a woman's pregnancy is confirmed by a health care provider or pregnancy test. But the American College of Obstetricians and Gynecologists estimates that early pregnancy loss is common, occurring in about 10% of confirmed pregnancies.
  • Results: The adolescents and women in both groups were predominantly black and of lower socioeconomic status. Among those who had spontaneous abortions, 28.9 percent used cocaine on the basis of hair analysis and 34.6 percent smoked on the basis of a urine cotinine assay, as compared with 20.5 percent and 21.8 percent, respectively, of the adolescents and women who did not have spontaneous abortions. The presence of cocaine in hair samples was independently associated with an increase in the occurrence of spontaneous abortion (odds ratio, 1.4; 95 percent confidence interval, 1.0 to 2.1) after adjustment for demographic and drug-use variables. However, the use of cocaine as measured by self-reports and by urine analysis was not. The presence of cotinine in urine was also independently associated with an increased risk of spontaneous abortion (odds ratio, 1.8; 95 percent confidence interval, 1.3 to 2.6). Twenty-four percent of the risk of spontaneous abortion could be related to cocaine or tobacco use.
    Conclusions: Cocaine and tobacco use were common in our study population and were associated with a significant risk of spontaneous abortion.
  • First-Trimester Miscarriage
    Miscarriage, or spontaneous abortion, is generally defined as the spontaneous loss of a previable pregnancy. Previability refers to a fetus weighing <500g or at gestational age (GA) <20 weeks
    *Miscarriages are classified according to the GA at which they occur.
    *Preclinical or subclinical miscarriages happen at or before 5 weeks’ GA.
    Clinical miscarriages include the following:
    Embryonic miscarriage occurs at 6 to 9 weeks’ GA or crown rump length (CRL) > 5 mm without cardiac activity.
    *Fetal miscarriage occurs at 10 to 20 weeks’ GA or CRL > 30 mm without cardiac activity.
  • Incidence and Risk
    *Thirty to forty percent of all conceptions result in miscarriage.
    *Ten to fifteen percent of clinically recognized pregnancies end in first-trimester and early second-trimester losses *<20 weeks’ GA).
    *Nearly 80% of sporadic losses occur during the first trimester and typically manifest before 12 weeks’ GA.
    The risk of preclinical miscarriage is estimated as approximately 25% in women less than age 35. Among clinical miscarriages, this risk increases significantly with advanced maternal age (AMA) from 8% to 12% in women under age 35 to as high as 45% in those older than age 40. This increase is thought to be related to the increased risk of aneuploidic pregnancies in older women.
    *Though maternal age probably has the greatest impact, several other factors carry an increased risk of sporadic first or early second trimester clinical miscarriage. See Table 33-1.
    *Previous obstetrical history: Risk of miscarriage increases from 20% to 43% in women with a history of one miscarriage and three or more, respectively.
    Tobacco: Smoking and exposure to second-hand smoke increase the risk.
    *Observational and population-based studies have also implicated the following risk factors: alcohol and illicit drug use, NSAID use, fever, caffeine and low folate levels.
    *Common causes of sporadic losses include the following:
    Chromosomal abnormalities account for approximately 50% of miscarriages.
    * Incidence is inversely related to GA.
  • Miscarriage is defined as a pregnancy failure occurring before the completion of 24 weeks of gestation. Around 10 to 15% of all pregnancies end in early spontaneous first trimester miscarriage. Advancing maternal and paternal age are known to be associated with increasing chance of miscarriage. Other risk factors include being underweight or overweight, smoking and high alcohol consumption. Traditional practice classified miscarriage according to the history and findings on speculum examination but transvaginal ultrasound scan should now be considered the standard test to assess viability of the pregnancy. Assessment of the amount of vaginal bleeding experienced is best made in the context of time taken to saturate a sanitary pad. Changing a pad soaked with blood and clots more than once an hour is an indication of heavy bleeding that requires immediate referral. Following confirmation of a viable intrauterine pregnancy, symptoms may resolve. If the symptoms worsen, or persist beyond 14 days, a repeat referral should be made to the early pregnancy unit for further assessment. If a pregnancy is 12 weeks' gestation and the woman is rhesus negative, she will require anti-D prophylaxis if there are symptoms of bleeding. Expectant management is the first-line approach, and is encouraged for 7-14 days after diagnosis of miscarriage. Most women will miscarry spontaneously during this time and will need no further treatment. It is not appropriate if there are risk factors for haemorrhage, or if the woman is at increased risk from the effects of haemorrhage. Medical management of miscarriage can be offered using misoprostol. Surgical management may be chosen by a woman if she has had a previous adverse or traumatic experience associated with pregnancy.
  • Viral infections during pregnancy have been associated with adverse pregnancy outcomes and birth defects in the offspring; unfortunately, we have limited therapeutic or preventative tools to protect the mother and the fetus during pandemics. Viruses rarely cross the placental barrier, but when the virus does reach the fetus, it can result in severe birth defects such as microcephaly or even fetal death. It has been well established that viral infection of the cells at the maternal-fetal interface can affect placental function, which may result in pregnancy complications such as miscarriage, intrauterine growth restriction (IUGR), or preterm birth (PTB). Furthermore, a growing body of evidence suggests that viral infection of the decidua and/or placenta may result in the production of soluble immune factors that could reach the fetus and might affect fetal development.
  • Data collected from the 2009 influenza H1N1 pandemic revealed that women with H1N1 were more likely to have adverse pregnancy outcomes, such as spontaneous miscarriage and preterm birth.
  • Researchers also identified ZIKV in placentas from miscarriages and IUGR pregnancies, suggesting that ZIKV also affects placental function and could increase the risk of several pregnancy complications
  • Results: Four predominant themes were identified from the experiences of 211 women in the nine studies: 'What I feel', 'Care for me and communicate with me', 'Me, my baby and others' and 'Help me to cope with the future'.
    Conclusions: Early miscarriage is a potentially devastating experience, and the diversity of experiences of women must be reflected in the provision of appropriate and sensitive nursing care.
    Relevance to clinical practice: The study demonstrated a significant training need for nurses and midwives to provide women with individualised care.
  • Overweight women are more likely to miscarry a healthy baby, according to research involving 204 women who had suffered a miscarriage.
    The researchers said the findings back up advice that obese women should lose weight before trying to conceive.
    "The excess miscarriage rate in overweight and obese women is due to the loss of chromosomally normal embryos," said Dr Inna Landres of Stanford University School of Medicine. "It's important to identify elevated BMI [body mass index] as a risk factor for miscarriage and counsel those women who are affected on the importance of lifestyle modification
  • Results: We enrolled 344 women of whom 88 became pregnant (88/344, 25.5%). Half of them had a subsequent live birth (47/88, 53%) and the rest lost their pregnancy (41/88, 46%). The median CD138+ score was significantly lower in the live birth group (P < 0.005) and women with a CD138+ score ≥ 16/hpf had a higher risk of subsequent miscarriage (RR 10.0, 95% CI 2.78-36.02). CD138+ cells count showed a good prediction for subsequent pregnancy loss in high-risk women with an area under the curve of 0.75 (95% CI 0.59-0.82, P = 0.01). A cut-off value of 4-6 cells/hpf offered the best predictive accuracy with higher scores predicting worse reproductive outcome. Our findings are limited by the small event rate and the sample size of our cohort.
    Conclusion: Quantifying CD138+ cells by immunohistochemistry in women with a history of recurrent pregnancy loss is helpful to diagnose chronic endometritis and predict subsequent reproductive outcome.
  • Occupational studies included in this review found that several occupational and non-occupational factors influenced reproductive outcomes. Occupational factors involved were standing, lifting and exposure to chemicals- usually persons who were exposed to noise were exposed to other occupational factors. Important non-occupational factors were mother’s age, mothers weight and height, mother’s weight gain during pregnancy, smoking, education, race and socioeconomic status. Gravidity and parity, and chronic diseases of the mother were also important factors for examination of spontaneous abortion or preterm labour.
  • New multi-disciplinary research on brain-body interactions triggered by stress in early pregnancy has shown that maternal biological responses, including localized inflammation in uterine tissue and sustained depression of progesterone production, challenge the endocrine-immune steady state during pregnancy, leading to serious consequences for the fetal environment. Recent basic science findings and new theoretical development around a "pregnancy stress syndrome" associated with over-activation of the HPA axis warrant a new look at the epidemiological evidence around the age-old question of whether or not stress can actually cause human reproductive failure.
  • Miscarriage is a common complication of pregnancy and often occurs before 20 weeks gestation. It can be a unique, traumatic and distressing experience with the consequential response for women being both physical and psychological. Psychological aspects are often given priority over the physical by health professionals but both are equally important and can be interlinked. Much emphasis is given to inadequacies of care which includes attitudes, lack of information and support. Women are often ignorant about miscarriage and therefore dependent on health professionals for specialist treatment and care. Expectations of support are sometimes difficult to establish and awareness and acknowledgment by others is often lacking. Provision of information is fundamental as is having specialist knowledge and skills to improve experiences while reducing the risk of long term complications such as depression and complicated grief. However, there are many factors to consider and therefore early miscarriage remains complex and ambiguous, and a challenge for all involved.
  • Once your pregnancy has progressed to the fourth month, the risk of complications decreases considerably; miscarriages at this stage, known as late miscarriage, account for less than 25 percent of all miscarriages.
    • Rosenthal, M. Sara (1999). "The Second Trimester". The Gynecological Sourcebook. WebMD. Archived
  • Between the third month and twentieth week of pregnancy, a spontaneous abortion is known as a late miscarriage. The symptoms are similar to the first trimester miscarriage variations. In many cases, a condition known as an "incompetent cervix" is responsible. This is when the cervix dilates prematurely and can't hold in the fetus. If an incompetent cervix is caught early enough, the cervix can be stitched up and the pregnancy can be resumed. Then, at labor, the stitches can be removed and a normal vaginal birth can take place. Some stitching techniques are permanent, however, and a cesarean section is required.
    If the miscarriage is inevitable and can't be prevented, a D & C can be performed up until the twentieth week. A miscarriage after twenty weeks is no longer a miscarriage. It graduates to either a premature birth or, in unfortunate cases, a stillbirth. You'll also need to follow emergency instructions outlined above.
    • Rosenthal, M. Sara (1999). "The Second Trimester". The Gynecological Sourcebook. WebMD. Archived
  • Results: There was no significant association between antidepressant medication exposure and spontaneous abortion (odds ratio [OR], 1.47; 95% CI, 0.99 to 2.17; P = .055). Gestational age and preterm delivery were statistically significantly associated with antidepressant exposure (mean difference [MD] [weeks], -0.45; 95% CI, -0.64 to -0.25; P < .001; and OR, 1.55; 95% CI, 1.38 to 1.74; P < .001, respectively), regardless of whether the comparison group consisted of all unexposed mothers or only depressed mothers without antidepressant exposure. Antidepressant exposure during pregnancy was significantly associated with lower birth weight (MD [grams], -74; 95% CI, -117 to -31; P = .001); when this comparison group was limited to depressed mothers without antidepressant exposure, there was no longer a significant association. Antidepressant exposure was significantly associated with lower Apgar scores at 1 and 5 minutes, regardless of whether the comparison group was all mothers or only those who were depressed during pregnancy but not exposed to antidepressants.
  • Registration responsibilities
    Where a fetus is born before the 24th week of gestation and did not breathe or show any signs of life, there is no provision for the event to be registered. However, the doctor or midwife who attended the delivery will need to issue a certificate or letter for the funeral director, cemetery or crematorium stating that the baby was born before the legal age of viability and showed no signs of life to allow a funeral to proceed, if that is the parents’ wish.
  • Postimplantation as well as preimplantation pregnancy in prairie voles can be terminated by replacing the original stud male with an unfamiliar male. The pregnancy is disrupted by the ensuing male-induced estrus. Females spontaneously abort their litters, become receptive, and successfully breed again 4 or 5 days after introduction of the new male.
  • Abortion may be caused in different ways. Injuries sustained by crowding through doors, hooks from cattle, or chasing by dogs have caused many a ewe to give birth to an immature lamb, usually dead. Ergotized grain or hay, smutty grain or its straw, frozen turnip or beet tops and impure water are other sources of this trouble. Careful management, clean, sound food and pure water are the best preventatives of sporadic abortion. Some of the symptoms are a loss of appetite, dullness and desire on the part of the ewe to isolate herself from the flock. Generally abortion takes place before any symptoms are noticed, but it is occasionally necessary to remove the foetus and placenta lest blood poisoning set in. Both foetus and afterbirth should in all cases be burned, and the uterus flushed out twice a day for several days with a three per cent solution of creolin in warm water.
    Epizootic abortion is caused by a germ allied in the common moulds. It is contagious and spreads rapidly through a flock unless proper precautions are taken. An animal which has aborted should be at once removed from the flock, and the uterus injected with the creolin solution mentioned above. Foetus, afterbirth, etc. should be burned, and the place where the main flock are kept should be thoroughly cleaned. All bedding should be burned and the floors covered with sawdust containing ten percent be weight of crude carbolic acid. The walls and ceilings should be whitewashed with lime and carbolic acid in the proportion of one pound of commercial carbolic acid to each give gallons of lime wash. Rams that have served affected ewes should be disinfected by syringing into the sheath a five per cent solution of creolin, or a 1 to 1,000 solution of bi-chloride of mercury. For this purpose a fountain syringe is the most convenient instrument. Such rams should not be used again for breeding until a considerable time has elapsed.
  • Recent findings: Medical management using misoprostol is effective for the management of miscarriages. The success rate ranged from 84 to 93% depending on the regimen of misoprostol, the duration of waiting period and the types of miscarriage.
    Summary: Miscarriages occur in 10 to 20% of all pregnancies. Surgical evacuation has been used to empty the uterus. Recently, medical treatment using misoprostol has been studied for the management of miscarriage. It avoids surgery and its associated complications. Compared to expectant management, the success rate is higher. Nonsurgical management takes a longer period to reach the endpoint and medical management is associated with side effect of medication. Studies have shown that medical management is safe and acceptable to women. The optimal regimen of medical management, however, is yet to be determined.
  • We always write stories of tragedies because that's how we reach our human depth. How we get to the other side of it. We look at the cruelty, the darkness and horrific events that happened in our life whether it be a miscarriage or a husband who is not faithful. Then you find this ability to transcend. And that is called the passion, like the passion of Christ. You could call this the passion of Frida Kahlo, in a way.
    When I talk about passion, and I'm not a religious person, but I absolutely am drawn and attracted to the power of religious art because it gets at that most extreme emotion of the human experience.
  • A blighted ovum eventually results in miscarriage. Some women choose to wait for the miscarriage to happen naturally, while others take medication to trigger the miscarriage. In some cases, a procedure called dilation and curettage (D&C) is used to remove the placental tissues.
    Most women who've had a blighted ovum go on to have successful pregnancies. If you experience multiple consecutive miscarriages, talk with your doctor or other care provider to identify any underlying causes.
    • Yvonne Butler Tobah, "Blighted ovum: What causes it?". Mayo Clinic. Archived (August 19, 2017)
  • MATERIALS AND METHODS: Retrospective cohort study was performed among women diagnosed with pregnancy in the outpatient clinic at our academic institution from 2015 to 2018. Patients with recurrent pregnancy loss (RPL) were identified utilizing the International Classification of Diseases (ICD) codes. RPL was defined as two or more failed clinical pregnancies. The primary exposure was ‘‘low income, low access to a super-market (LILA)’’, more commonly known as a ‘‘food desert’’. A low-income area was defined by the Department of Treasury’s New Markets Tax Credit (NMTC) program as having greater than 20% of the poverty rate or a median family income of less than 80% of the state-wide or metropolitan area median. Low access was defined the number of households without access to a vehicle and live in an urban area that is half a mile from a supermarket or within a rural area that is twenty miles from the nearest grocery store. Chi-squared analysis was performed with statistical significance (p<0.05).
    RESULTS: RPL was diagnosed in 236 of the 2996 patients (7.9%) included in our study. The demographics of the cohort were 70% African American, 20% Caucasian and 2% Asian American. The majority of the patients (89%) were characterized as living in an urban setting. In our cohort, 61.5% of patients diagnosed with RPL in the outpatient clinic lived in a food desert compared to 47% of patients who continued their pregnancy during the same time period (p-value of 0.008). According to the 2010 Census of Population and Housing Report, 4.2% of the United States population live in a food desert, compared to 13% of Tennessee residents. Food deserts demonstrate a disparity in the availability of resources among varying communities. From our analysis, patients with recurrent pregnancy loss were more likely to live in a food desert compared to the general population.
    CONCLUSIONS: The incidence of RPL in our patient population was higher than the national average of 2-5%. Patients with RPL are more likely to live in a food desert compared to the general population. This effect is likely a reflection of racial and socioeconomic disparities, and this may be a good marker for patients requiring additional treatment or earlier intervention. In the Mid-South, environmental factors may be more influential than previously thought in the setting of RPL
  • Miscarriage
    an unplanned loss of a pregnancy. Also called a spontaneous abortion.
  • [A]s a woman and her eggs age, she is more likely to miscarry, as well as have a baby with genetic problems, such as Down syndrome.
  • Results: The rates of tocolysis (28.6 vs 22.3%), miscarriage (6.0 vs 5.3%), and preterm labor (8.1 vs 4.4%) were significantly higher among nurses than non-nurses. After adjustment for background differences, nurses had significantly higher risks for cesarean section (adjusted OR 1.12 [95% confidence interval (CI) 1.03-1.22]), tocolysis (OR 1.18 [95% CI 1.09-1.29]), and preterm labor (OR 1.46 [95% CI 1.28-1.67]) than non-nurses.
    Conclusions: Nurses are at higher risk for cesarean section, tocolysis, and preterm labor than non-nurses. Occupational exposure related to these adverse pregnancy outcomes should be examined. Strategies to decrease the risks should be developed to improve reproductive health among nurses.
  • The consequence of radiation exposure in fetuses is mostly based on observations rather than based on scientific research. Ethical issues prohibit researching on the fetus. Therefore, most of the data on the impact of radiation on the fetus derives from observations of patients who suffered Japan’s Hiroshima bombing and the Chernobyl nuclear power plant disaster. Based on the observations made from the victims of the high level of radiation exposure, the consequences of radiation exposure can categorize into four broad groups, including pregnancy loss, malformation, developmental delay or retardation, and carcinogenesis. Pregnancy loss most often happens when radiation exposure happens during early gestation (less than two weeks).
  • The effect of radiation exposure during pregnancy also depends on the gestational age of the fetus. The embryo/fetus is most susceptible to radiation during organogenesis (2 to 7 weeks gestational age) and in the first trimester. The fetus is more resistant to the radiation during the second and third trimester. Dose between 0.05 to 0.5 Gy is generally considered safe for the fetus during the second and third trimester while it is considered potentially harmful during the 1st-trimester fetus. Even though the fetus is more resistant to the radiation during the second and third trimester, a high dose of radiation (greater than 0.5 Gy or 50 rad) may result in adverse effects including miscarriage, growth reduction, IQ reduction, and severe mental retardation. Therefore, clinicians and radiologists should counsel the pregnant patient regardless of the gestational age.
  • Fetus death risk reduction is included in the United Nations Sustainable Development Goals. However, little is known about how missed abortion in the first trimester (MAFT) is related to maternal air pollution exposure. We quantify the link between air pollution exposure and MAFT in Beijing, China, a region with severe MAFT and air quality problems. We analyse the records of 255,668 pregnant women from 2009 to 2017 and contrast them with maternal exposure to air pollutants (particulate matter PM2.5, SO2, O3 and CO). We adjust for confounding factors such as sociodemographic characteristics, spatial autocorrelation and ambient temperature. We find that, for all four pollutants, an increased risk of MAFT is associated with rises in pollutant concentrations and the adjusted odds ratios (ORs) of these associations increase with higher concentrations. For example, the adjusted OR of MAFT risk for a 10.0 g m−3 increase in SO2 exposure is between 1.29 and 1.41 at concentrations of 7.119.5 g m−3; it drops to 1.17 below this range and rises to 1.52 above it at higher SO2 concentrations. This means that the risk increase is not linear but becomes more severe the higher the pollutant concentration. The findings provide evidence linking fetus disease burden and maternal air pollution exposure.

"Sharks, rays and abortion: The prevalence of capture-induced parturition in elasmobranchs" (July 12, 2019)[edit]

Adams Kye R, Fetterplace Lachlan C, Davis Andrew R, Taylor Matthew D, Knott Nathan A (January 2018). "Sharks, rays and abortion: The prevalence of capture-induced parturition in elasmobranchs". Biological Conservation. 217: 11–27. doi:10.1016/j.biocon.2017.10.010. S2CID 90834034. Archived from the original on February 23, 2019. Retrieved July 12, 2019.

  • The direct impacts of fishing on chondrichthyans (sharks, rays and chimeras) are well established. Here we review a largely unreported, often misinterpreted and poorly understood indirect impact of fishing on these animals — capture-induced parturition (either premature birth or abortion). Although direct mortality of discarded sharks and rays has been estimated, the prevalence of abortion/premature birth and subsequent generational mortality remains largely unstudied. We synthesize a diffuse body of literature to reveal that a conservative estimate of > 12% of live bearing elasmobranchs (n = 88 species) show capture-induced parturition. For those species with adequate data, we estimate capture-induced parturition events ranging from 2 to 85% of pregnant females (average 24%). To date, capture-induced parturition has only been observed in live-bearing species. We compile data on threat-levels, method of capture, reproductive mode and gestation extent of premature/aborted embryos. We also utilise social media to identify 41 social-media links depicting a capture-induced parturition event which provide supplementary visual evidence for the phenomenon. The mortality of embryos will have implications for elasmobranch populations, and there are limited options to deal with this problem. This review is the first to synthesize available data on capture-induced parturition in sharks and rays, and highlights an important ethical and management issue for fishers and managers deserving of much greater attention.
  • Capture-induced parturition in sharks and rays is by no means a novel phenomenon; there are numerous anecdotal observations in the scientific literature, some of which date to > 200 years ago.
    The phenomenon has so far attracted very little interest, other than sporadic references to the inconvenience it causes when measuring fecundity (e.g. Struthsaker, 1969, Ebert, 1984, Snelson et al., 1988). There seems to be a general lack of awareness among recreational fishers of the occurrence of capture-induced parturition in sharks and rays (see Table A.2). There is also a distinct lack of targeted research into the occurrence and cause of capture-induced parturition, making it difficult for managers to incorporate into by-catch management. Our suspicion is that these casual reports, when viewed as a whole, indicate that capture-induced parturition is a common event with potential impacts on the reproductive capabilities of species. This may lead to effects on recruitment in shark and ray populations.
  • It is therefore surprising that 200 years later the phenomenon of capture-induced parturition remains unstudied and unquantified in any detail, other than sporadic observations and reports. Although it has been noted that fecundity in elasmobranchs is sometimes difficult to estimate because they abort their young on capture (Struthsaker, 1969), we are yet to develop a clear understanding of the frequency, specific cause, and impact of these “abortions”. We know of no studies that have been specifically interested in capture-induced parturition beyond incidentally observing and recording it.
    The phenomenon of capture-induced parturition in elasmobranchs has been noted in the literature under a variety of terms, including ‘abortion’, ‘capture-induced abortion’, ‘spontaneous abortion’, ‘slip’, ‘sudden parturition’, ‘dropping young’ and ‘premature birth’. Given that nothing is currently known about the survival of embryos after the event, ‘abortion’ may not correctly describe the process in all cases, given that some near-term offspring may survive. We propose that “capture-induced parturition” is the most suitable blanket term for the process, with capture-induced abortion most appropriate for cases where complete embryo mortality occurs (Fig. 1; Table 1). Importantly, until mortality estimates for these embryos are determined, application of the precautionary principle (Lauck et al., 1998) suggests that all capture-induced parturition events should be viewed as capture-induced abortions (i.e. all pups are assumed to die). We also propose that ‘spontaneous abortion’ is not an appropriate characterisation given that it ignores the fact that the parturition events are capture-induced, and may not be spontaneous.
  • Stress appears to be a key contributing factor that induces parturition/abortion given that such births have been reported to occur following various methods of fishing, stranding (Williams et al., 2010) and possibly an unsuccessful predation event (Marshall and Bennett, 2010). Parturition has also been observed after administration of anaesthetic (Ferreira, 2013, Silbernagel and Yochem, 2016), injection of quinine (Rall and Zubrod, 1962), during an inter-uterine endoscopy (Carrier et al., 2003) and during a sonogram (Mollet et al., 2002). It remains unclear, however, whether it was these specific procedures or the stress on the animal that induced these parturitions. In fishery capture-induced parturition, common stress-inducing stimuli include physical trauma (e.g. harpoons, netting injuries) or asphyxiation (e.g. caught in mesh net, left on deck). The physical trauma and physiological stress caused by capture is likely to vary with fishing method and the sensitivity of the species involved (Dapp et al., 2015). The nature and magnitude of stress responses are species-specific, and linked to physiology as well as the form and intensity of the stressor (Skomal and Mandelman, 2012). We know that fishing can cause major stress to sharks and their relatives, however the species-specific thresholds that induce parturition remain undetermined.
    Stress-induced parturition events do not appear to be isolated to capture. The fact that they can occur in nature means that the phenomenon may have adaptive significance. The earliest record of abortion in sharks and rays appears in the fossilised embryos of a Devonian chondrichthyan (Delphyodontos dacriformes), with a yolk sac still attached but lacking an adult nearby, dated 318 m.y.a. (Lund, 1980). There is further evidence of abortion occurring in the now extinct Harpagofututor volsellorhinus ~ 318 m.y.a. (Grogan and Lund, 2011). Stress-inducing stimuli that exist in nature may include stranding, predation attempts, toxic dinoflagellate blooms, thermal shock and hypoxia.

"Amniocentesis and chorionic villus sampling for prenatal diagnosis" (September 2017)[edit]

Zarko Alfirevic, Kate Navaratnam, Faris Mujezinovic, (September 2017). "Amniocentesis and chorionic villus sampling for prenatal diagnosis". The Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. 2017 (9): CD003252. doi:10.1002/14651858.cd003252.pub2. PMC 6483702. PMID 28869276.

  • One study compared second trimester AC with no AC (control) in a low risk population (women = 4606). Background pregnancy loss was around 2%. Second trimester AC compared to no testing increased total pregnancy loss by another 1%. The confidence intervals (CI) around this excess risk were relatively large (3.2% versus 2.3 %, average risk ratio (RR) 1.41, 95% CI 0.99 to 2.00; moderate‐quality evidence). In the same study, spontaneous miscarriages were also higher (2.1% versus 1.3%; average RR 1.60, 95% CI 1.02 to 2.52; high‐quality evidence). The number of congenital anomalies was similar in both groups (2.0% versus 2.2%, average RR 0.93, 95% CI 0.62 to 1.39; moderate‐quality evidence).
    One study (women = 4334) found that early amniocentesis was not a safe early alternative compared to second trimester amniocentesis because of increased total pregnancy losses (7.6% versus 5.9%; average RR 1.29, 95% CI 1.03 to 1.61; high‐quality evidence), spontaneous miscarriages (3.6% versus 2.5%, average RR 1.41, 95% CI 1.00 to 1.98; moderate‐quality evidence), and a higher incidence of congential anomalies, including talipes (4.7% versus 2.7%; average RR 1.73, 95% CI 1.26 to 2.38; high‐quality evidence).
    When pregnancy loss after CVS was compared with second trimester AC, there was a clinically significant heterogeneity in the size and direction of the effect depending on the technique used (transabdominal or transcervical), therefore, the results were not pooled. Only one study compared transabdominal CVS with second trimester AC (women = 2234). They found no clear difference between the two procedures in the total pregnancy loss (6.3% versus 7%; average RR 0.90, 95% CI 0.66 to 1.23, low‐quality evidence), spontaneous miscarriages (3.0% versus 3.9%; average RR 0.77, 95% CI 0.49 to 1.21; low‐quality evidence), and perinatal deaths (0.7% versus 0.6%; average RR 1.18, 95% CI 0.40 to 3.51; low‐quality evidence). Transcervical CVS may carry a higher risk of pregnancy loss (14.5% versus 11.5%; average RR 1.40, 95% CI 1.09 to 1.81), but the results were quite heterogeneous.
    Five studies compared transabdominal and transcervical CVS (women = 7978). There were no clear differences between the two methods in pregnancy losses (average RR 1.16, 95% CI 0.81 to 1.65; very low‐quality evidence), spontaneous miscarriages (average RR 1.68, 95% CI 0.79 to 3.58; very low‐quality evidence), or anomalies (average RR 0.68, 95% CI 0.41 to 1.12; low‐quality evidence). We downgraded the quality of the evidence to low due to heterogeneity between studies. Transcervical CVS may be more technically demanding than transabdominal CVS, with more failures to obtain sample (2.0% versus 1.1%; average RR 1.79, 95% CI 1.13 to 2.82, moderate‐quality evidence).
    Overall, we found low‐quality evidence for outcomes when early amniocentesis was compared to transabdominal CVS. Spontaneous miscarriage was the only outcome supported by moderate‐quality evidence, resulting in more miscarriages after early AC compared with transabdominal CVS (2.3% versus 1.3%; average RR 1.73, 95% CI 1.15 to 2.60). There were no clear differences in pregnancy losses (average RR 1.15, 95% CI 0.86 to 1.54; low‐quality evidence), or anomalies (average RR 1.14, 95% CI 0.57 to 2.30; very low‐quality evidence).
  • Second trimester amniocentesis increased the risk of pregnancy loss, but it was not possible to quantify this increase precisely from only one study, carried out more than 30 years ago.
    Early amniocentesis was not as safe as second trimester amniocentesis, illustrated by increased pregnancy loss and congenital anomalies (talipes). Transcervical chorionic villus sampling compared with second trimester amniocentesis may be associated with a higher risk of pregnancy loss, but results were quite heterogeneous.
  • Transcervical chorionic villus sampling may increase the total risk of pregnancy loss compared with a second trimester amniocentesis, mostly because of increased spontaneous miscarriages.
  • Despite relatively large numbers of randomised women (4606) in Tabor 1986, such an increase in total pregnancy loss did not reach statistical difference, with CIs for an excess pregnancy loss ranging from almost 0 to 2%. How robust are these figures, and should they be used for routine counselling? It is unlikely that a trial of similar size and quality will ever be repeated. Therefore, in the absence of other randomised data, written and oral information for women considering second trimester amniocentesis has included the data from Tabor 1986. However, several systematis reviews that added observational data to the randomised evidence have been published since, showing significantly lower complication rates (see Agreements and disagreements with other studies or reviews).
    Second trimester amniocentesis was consistently safer than transcervical CVS, whilst Smidt‐Jensen 1993 (Denmark) showed no clinically significant difference in the pregnancy loss between transabdominal CVS and second trimester amniocentesis. Therefore, one would expect a clear benefit of transabdominal CVS in the 'head to head' comparisons with transcervical CVS. Unfortunately, the data were quite heterogeneous; for example, Smidt‐Jensen 1993 (Denmark) showed expected benefits of transabdominal CVS, but other trials did not. It is likely that operator skill and preferences played an important role in these studies.
  • Somewhat unexpectedly, the preliminary data from the Nicolaides 1994 (King's) and Leiden 1998 trials suggested an important increase in pregnancy loss following early amniocentesis, both before and after fetal viability. However, pooled data from the final reports of these two trials and Sundberg 1997 (Copenhagen) were not conclusive. In order to test the hypothesis that the total pregnancy loss after early amniocentesis is indeed 0.5% higher compared with CVS, around 40,000 women would need to be recruited (power 80%, confidence level 95%). Such a trial is likely to be considered unethical, given the strong possibility of causal relationship between early amniocentesis and talipes (see below).
    The observation that transabdominal CVS appeared safer than transcervical CVS was heavily influenced by the data from Smidt‐Jensen 1993 (Denmark). Increase in pregnancy loss following transcervical procedure was not replicated in four other direct comparisons between transcervical and transabdominal procedures (Bovicelli 1986; Brambati 1991; Tomassini 1988; Jackson 1992). The transcervical approach required multiple insertions more frequently and caused vaginal bleeding in approximately 10% of cases. The subgroup analysis from Smidt‐Jensen 1993 (Denmark) showed no differential effect on the pregnancy loss between transabdominal CVS and mid‐trimester amniocentesis. It would be reassuring if the results achieved by Smidt‐Jensen and colleagues could be replicated by other centres (71% of all procedures in the Smidt‐Jensen 1993 (Denmark) trial were performed by Smidt‐Jensen himself). The results of the systematic review of observational studies were broadly consistent with the randomised data (Mujezinovic 2007).
  • We acknowledge the ethical and potential medico‐legal problems in trying to obtain adequate cytogenetic follow‐up on all randomised women. A higher incidence of abnormal karyotypes is to be expected in the CVS group, because of possible spontaneous loss of pregnancies with abnormal karyotype that occur between randomisation and a mid‐trimester amniocentesis group.
  • For second trimester amniocentesis compared to control, we found high‐quality evidence for laboratory failure, and spontaneous miscarriage, and moderate‐quality evidence for all known pregnancy losses and anomalies.
    For early compared to second trimester amniocentesis, we found high‐quality evidence for laboratory failure, all known pregnancy losses, and all anomalies. We assessed the evidence to be moderate for spontaneous miscarriages, sampling failure, and false negative chromosomal diagnosis after birth.
    For transabdominal CVS compared to amniocentesis, we judged the evidence to be low quality for spontaneous miscarriage, all known pregnancy losses, and perinatal deaths.
    For transcervical compared to transabdominal CVS, we found moderate‐quality evidence for sampling failure, and low‐quality evidence for laboratory failure, and anomalies, and very low‐quality for spontaneous miscarriage, and all known pregnancy losses.
    For early amniocentesis compared to transabdominal CVS, we found moderate‐quality evidence for spontaneous miscarriage, low‐quality evidence for sampling and laboratory failure, all known pregnancy losses, delivery before 33 weeks' gestation, and known false negative after birth results. We only found very low‐quality evidence for anomalies.
  • Mujezinovic 2007 reviewed observational studies that reported complications for transabdominal CVS performed between 10 and 14 weeks' gestation, and genetic amniocentesis performed after 14 weeks' gestation. This review included studies published from January 1995, and reporting data for 100 or more participants. The pooled pregnancy loss rates within 14 days of the procedure were 0.7 (95% CI 0.3 to 1.4) and 0.6 (95% CI 0.5 to 0.7). A more recent systematic review and meta‐analysis by Akolekar 2015 reviewed observational studies published between 2000 and 2014 that reported procedure‐related complications for both CVS and amniocentesis. They only included studies with more than a thousand procedures reported. In order to minimise risk of bias from smaller studies, they used a random‐effects model to calculate risks. This meta‐analysis described weighted pooled procedure‐related risks of miscarriage for procedures performed prior to 24 weeks' gestation of 0.22% for CVS and 0.11% for amniocentesis, which was much lower than previously quoted. There was no clear difference between the procedure‐related risk of miscarriage for either procedure, or to the background risk of miscarriage. The authors of these reviews highlighted concerns with the difficulty of adequate control groups. The meta‐analysis in Akolekar 2015 also found significant heterogeneity. However, it is likely that the estimates that only come from RCTs performed many years ago overestimate the risks.
  • Agarwal 2012 completed a systematic review of observational studies in twin pregnancies to assess the risks of CVS performed between 9 and 14 weeks' gestation, and genetic amniocentesis performed between 14 and 22 weeks' gestation. They included study reports published between January 1990 and May 2011. The overall pregnancy loss rates were 3.84% (95% CI 2.48 to 5.47) for CVS, and 3.07% (95% CI 1.83 to 4.61) for amniocentesis. The authors described an excess pregnancy loss of approximately 1% above the background rate for both procedures. There were no clear differences in pregnancy loss rates between transabdominal or transcervical CVS, or amniocentesis performed with either single or double entry technique. Vink 2012 also conducted a systematic review of observational studies that assessed pregnancy loss rates in women with twin pregnancies undergoing genetic amniocentesis, but included a broader time‐frame for publications (from January 1970 until December 2010). They used random‐effects models to pool procedure‐related loss rates. The authors commented on significant heterogeneity in the literature, but were able to report a pooled pregnancy loss rate before 24 weeks' gestation of 3.5% (95% CI 2.6 to 4.7). Taking into account the pregnancy loss rates before 24 weeks reported by Agarwal 2012 and Vink 2012, the true pregnancy loss rate at this gestation is likely to lie between 2.5 to 3.5%.
  • New methods of prenatal diagnosis should be rigorously evaluated before deciding whether they should be introduced into clinical practice. Measures of outcome must include total pregnancy loss (antenatal and neonatal), detailed description of anomalies, diagnostic accuracy, and women's views of the alternative procedures. Ascertainment bias should be reduced as much as possible, i.e. neonatal assessors should be blinded to the allocated procedure.

“Ferri's Clinical Advisor 2017” (2017)[edit]

Ruben Alvero in Fred F. Ferri (2017). “Ferri's Clinical Advisor 2017”. Elsevier.

  • Basic information
    Spontaneous miscarriage is fetal loss before week 20 of pregnancy, calculated from the patient’s last menstrual period or the delivery of a fetus weighing <500 g. Early loss is before menstrual week 12, whereas late loss refers to losses from weeks 12 to 20.
    Miscarriage can also be classified as incomplete (partial passage of fetal tissue through partially dilated cervix), complete (spontaneous passage of all fetal tissue), threatened (uterine bleeding without cervical dilation or passage of tissue), inevitable (bleeding with cervical dilation without passage of fetal tissue), or missed abortion (intrauterine fetal demise without passage of tissue).
    Recurrent miscarriage involves three or more spontaneous pregnancy losses before week 20. However, in actual practice, most reproductive experts consider two spontaneous pregnancy losses sufficient to initiate an evaluation for habitual or recurrent spontaneous abortion. The definition is somewhat variable depending on the source. *Epidemiology & Demographics
    Incidence: 5% to 20% of clinically recognized pregnancies; 80% of miscarriages occur in the first trimester. Recurrent miscarriage occurs in <1% of couples attempting to have children.
    Distribution of abnormal karyotypes: autosomal trisomy (50%0. Monosomy 45,X (20%), triploidy (15%) tetraploidy (10%), structural chromosomal abnormalities (5%).
    With two or more spontaneous miscarriages, a karyptype can be performed on the products of conception to evaluate for aneuploidy, which may be associated with a balanced translocation in one of the parents, and which has a substantially increased risk for abortion (depending on the actual type of translocation); if the pregnancy is carried to term, it has a 3% to 5% risk for an unbalanced karyotype. In patients with habitual abortion, evaluation for anatomic defects such as uterine septum and for antiphospholipid stnddrome (lupus anticoagulant, beta 2 glycoprotein IgG/IgM, and anticardioplin antibody) IgGIgM should also be obtained.
  • Risk Factors
    Vaginal bleeding, especially >3 d, carried with it a 15 to 20% chance of miscarriage. Diabetes should be controlled to reduce risk.
    Physical findings &Clinical Presentation
    Profuse bleeding and cramping have a higher association with miscarriage than bleeding without cramping, which is more consistent with a threatened miscarriage.
    Cervical dialation with history or finding of fetal tissue at cervical os may be present.
    In cases of missed abortion, uterine size may be smaller than menstrual dating, in contrast to molar gestation, where size may be greater than dates.
  • Etiology
    In a general overview the etiology can be classified in terms of maternal (environmental) and fetal *genetic) factors, with the majority of miscarrriages being related to genetic or chromosomal causes.
    Causes: uterine anomalies (unicornuate uterus risk, 50%; bicornuate or septate uterus risk, 25%-30%); incompetent cervix (iatrogenic or congenital, associated with 20% of mid-trimester losses); diethylstilbestrol exposure in utero (T-shaped uterus); submucous leiomyomas; intrauterine adhesions or synechiae; luteal phase or progesterone deficiency; autoimmune disease such as anti-cardiolipin, beta 2 glycoprotein or lupus anti-caogulant autoantibodies; uncontrolled diabetes mellitus. Rare or controversial vauses include HLA associations between mother and father; infections such as tuberculosis, Chlamydia, and Ureaplasma; smoking and alcohol use; irradiation; and environmental toxins. Most of the literature is observational in nature, which may skew risk factor data.
    Use of fluconazole in pregnancy is associated with a statistically significant increased risk of spontaneous miscarriage.
  • Diagnosis
    *Differential diagnosis
    *Normal pregnancy
    *Ectopic pregnancy
    *Dysfunctional uterine bleeding
    *Pathologic endometrial of cervical lessons
    * All patients with bleeding in the first trimester should have an evaluation for possible ectopic pregnancy.
    * If there are three early, prior pregnancy losses, a workup and treatment for recurrent miscarriage should begin before next conception. If there is a strong history for second-trimester loss, consideration for cerclage should be given if the history is consistent with incompetent cervix (e.g., painless cervical dialation).
    *Many providers will initiate an evaluation for couples who have had 2 previous losses.
    * One unexplained fetal loss beyond 10 wk or 1 birth before 34 wk because of preeclampsia should prompt an evaluation for antiphospholipid syndrome.
  • Laboratory Tests
    *Type and antibody screen are used to evaluate the need for Rh immune globulin.
    *Recurrent pregnancy loss: During the preconception period in patients with habitual abortion, hemoglobin A, anticardiopin antibody, lupus anticoagulant, 20210A beta 2 glycoprotein antibodies, karyotyping, and anatomic evaluation, hysterosalpingography, or saline ultrasonography to assess for uterine septum. With increasing age, oocyte quality is a factor, and some practitioners will perform day 3 of the menstrual cycle FSH and anti-mullerian hormone to assess for diminished ovarian reserve, septate uterus. Progesterone level <5 mg/dl suggests nonviable gestation vs. >25 mg/dl, which suggests a good prognosis.
  • Imaging Studies <
    Transvaginal sonogram (preferred) can be used with menstrual dating and serum quantitative human cchorionic gonadotropin to document pregnancy location, fetal heart presence, gestational sac size, and adnexal pathology.
  • Treatment
    Nonpharmacological Therapy
    Depending on the patient’s clinical status, desire to continue the pregnancy, and certainty of the diagnosis, exptectant management can be considered. In pregnancies <6 wk or ?14 wk, complete expulsion of fetal tissue usually occurs, and surgical intervention such as D&C can be avoided.
    Acute General Rx
    Incomplete miscarriage between 6 and 14 wk can be associated with great blood loss; these patients should undergo D&C.
    In cases of missed abortion, if fetal demise has occurred >6 wk before or gestational age is >14 wk, there is an increased risk of hypofibrinogenemia with disseminated intravascular coagulation. Thus D&C or manual vacuum aspiration should be performed early in the disease course. Consider use of misoprostol (Cytotec) 200 mg PO q6h as an alternative approach if patient desires a less invasive approach.
    Rh-negative patients should be given rhoGAM 50 mcg IM to prevent Rh isoimmunization
  • Pearls & Considerations
    Spontaneous pregnancy loss is recommended as a replacement for the term abortion and to acknowledge the emotional aspects of losing a pregnancy.

“Heavy metals in miscarriages and stillbirths in developing nations” (June 2017)[edit]

Cecilia Neadiuto Amadi, Zelinjo Nkeiruka Igweza, Orish Ebere Orisakew; “Heavy metals in miscarriages and stillbirths in developing nations”, Middle East Fertility Society Journal, Volume 22, Issue 2, June 2017, Pages 91-100

  • Objectives: Cases of miscarriage and stillbirths due to heavy metal poisoning continue to be on the rise in developing nations. In these countries like Nigeria, the menace of miscarriage is not readily linked to heavy metal exposure. This could be as a result of insufficient scientific data available due to poor documentation and inadequate public health education on the consequences of these heavy metals on maternal health. The heavy metals mercury, lead and cadmium are toxicants which have been shown to cross the placental barrier to accumulate in fetal tissues. Methods: For this review, relevant databases were searched for original scientific reports and a total of 100 articles were retained for analysis. Required data was extracted from these studies and their methodology assessed. Results: Miscarriages and still- births were observed from exposure to five heavy metals namely; mercury, arsenic, lead, chromium and cadmium. These heavy metals were associated with increased incidence of miscarriages in developing nations. In Nigeria, women with history of miscarriage had blood lead levels >25 mg/dL during pregnancy with approximately 41.61% increase in miscarriage incidence. Cadmium blood level was found to be 85.96 – 1.09 lg/dl with a 9.50% increase in miscarriage incidence in women exposed to mercury in comparison to the unexposed group. For chromium, a 1.60% increase in the incidence of miscarriage in women exposed to chromium was reported. For cadmium and arsenic, 83.93% and 5.88% increase in incidence were reported respectively. Similar data were obtained for Jamaica (mercury = 7.29 – 9.10 lg/l), Egypt (Cadmium = 1.17%; Lead = 32.33%). Conclusion: Medical practitioners and Toxicologists involved in women health in sub-Sahara Africa SSA should consider if these heavy metals can become additional biomarkers in the diagnosis of miscarriages and stillbirths.
    • p.91
  • In fact both paternal and maternal exposures to environmental toxicants may be associated with fetal death. Occupational exposure is often cited as a risk factor for female fertility, as well as for early pregnancy loss and pre-term delivery. Miscarriage an abrupt end of a pregnancy at a stage where the embryo or fetus is not capable of surviving independently, is the most common adverse pregnancy outcome with aggravating emotional consequences for affected individuals and families. Miscarriage is a critical indicator of embryotoxicity. It is an important outcome for the study of embryotoxic effects of chemicals including environmental contaminants and drugs and a vital end point to track the progress of reproductive health programmes and their impact on maternal health.
    Often times miscarriages are not accounted for and ignored. Maternal and women reproductive health related indicators therefore miss a significant number of unreported pregnancies that are often not seen by health professionals. This significant reproductive health outcome has added a challenge on the paucity of data on miscarriage rates in sub-Sahara Africa. Whereas studies from developed countries report rates of miscarriage in clinically recognised pregnancies, studies of miscarriage in low-income and middle-income countries face additional challenges as most miscarriages occur without any contact with the formal healthcare system and are not registered.
    In Kenya, reviews using regional estimates project the risk of miscarriages and stillbirths in 2007 to be 12.2% and 3.3% per pregnancy, respectively. In a comparison of women with induced abortion, spontaneous abortion and ectopic pregnancy in Ghana, Schwandt and co workers recorded 75% spontaneous abortion. Incidences of miscarriage in women continues to be on the rise across the globe and this is attributable to factors which could be genetic, biological (e.g. bacteria and viruses), social (e.g. stress), lifestyle (e.g. tobacco smoking and alcohol consumption), environ- mental (e.g. exposure to certain chemicals/dangerous gases/heavy metals) etc.
    • p.92
  • In the early part of the 20th century, there were reports of pregnant women occupationally exposed to high levels of lead in England and Hungary. This exposure however was associated with frequent spontaneous abortions, stillbirths, premature births, and neonatal deaths, compared with mothers in occupations unexposed to lead poisoning.
    • p.93
  • Blood lead levels >25 mg/dL during pregnancy have long been recognized to increase the risk of abortion and stillbirths. In fact relatively low- exposure levels have also been found to increase the risk of spontaneous miscarriage. Women with increasing blood lead levels had higher incidences of miscarriages. This hypothesis is consistent with data obtained from two studies carried out in Nigeria. From these studies, women with history of miscarriage had blood lead levels >25 mg/dL during pregnancy. However, data obtained by Ajayi et al. revealed a 41.61% increase in miscarriage incidence while work by Otebhi and Osadolor an increase by 8.9%. In Egypt, studies by Ahmed et al., 2007 revealed a 32.33% increase in miscarriage incidence in women exposed to lead. In another study blood levels of 5—9 mg/dL were associated with an odds ratio for miscarriages of 2.3. At blood levels of 10—14 mg/dL, the odds ratio increased to 5.4 and at blood levels of 15 mg/dL, the odds ratio increased to 12.2.
    • p.94
  • Research has documented that a high incidence of miscarriage in women is associated with a high cadmium level in the body. Furthermore, studies involving animal models examined the effects of cadmium exposure and data generated from these studies confirm the endocrine disrupting property of cadmium. Vaiserman and coworkers demon-strated that cadmium mimicked estrogen effects resulting in the proliferation of both uterine and mammary tissues. Cadmium can mimic the effect of the endogenous oestrogen receptor agonist, oestradiol, which leads to oestrogen receptor activation. While the effects of cadmium on the endocrine system are no longer in doubt, the exact mode of action is still being studied. At the molecular level there appears to be a ‘cross-talk’ between the oestrogen receptors and growth factor receptor. This ‘cross-talk’ appears necessary for estrogen signalling in mammary cells to divide or differentiate. These events are critical for explaining several risk factors including pregnancy related challenges. Data from experimental animals suggest that cadmium mimics estrogenic effects and this leads to the proliferation of both uterine and mammary tissues. Results from in vitro studies have also indicated that cadmium may directly affect hormone-production in steroid hormone- producing ovarian cells.
    • pp.94-95
  • The association between cadmium and miscarriage was investigated in some developing nations such as Nigeria, Sudan and Egypt. Results obtained highlighted that while an increase in miscarriage incidence was observed in Nigeria (83.93%) and Egypt (1.17%), a decrease in miscarriage incidence was observed for the population studied in Sudan (27.32%).
    Cadmium can also inhibit the transcription of LDL-receptor mRNA, which leads to a decrease in supply of cholesterol substrate needed for placental progesterone production. In addition, higher concentrations of cadmium in the body have been indicated to alter the secretory patterns of a number of reproductive hormones, including luteinizing hormone (LH) and follicle- stimulating hormone (FSH).
    • p.95
  • Mercury on its own, does not affect intrauterine growth, however, an increased risk for miscarriage has been documented.
    • p.95
  • Some studies have examined the association of paternal exposure to mercury and an increased risk for spontaneous miscarriage. Women occupationally exposed to elemental mercury vapour had more spontaneous abortions than non-exposed women as shown in another study. In Nigeria, there was a significant increase (q < 0.001) in the mean blood mercury level of pregnant women with history of pregnancy complications compared with the pregnant and non-pregnant women that are without history of pregnancy complications. The association between mercury exposure and miscarriages was investigated in developing countries such as Nigeria and Jamaica, results revealed mercury blood concentration of 85.96 – 1.09 lg/dl and 7.29 – 9.10. lg/l respectively. Another study by Otebhi and Osadolor revealed a 9.5% increase in miscarriage incidence in women exposed to mercury in comparison to the unexposed group.
    According to a study involving women living along the Beni River, Bolivia Brazil, have associated exposure to methylmercury and spontaneous abortion. Findings from this study indicated that women who had losses of pregnancy had high methylmercury levels. Studies have indicated that mercury possesses endocrine disrupting characteristics in that mercury may modulate the physiological levels of reproductive hormones. Furthermore, it has been documented that exposure to mercury can induce female reproductive hormones like estrone and estradiol.
    The umbilical cord blood is known to possess higher mercury levels compared to maternal blood. Furthermore, it is documented that cord blood concentrations of mercury are almost twice those in the maternal blood. This could be further explained by the higher hematocrit, haemoglobin, and plasma albumin levels in fetal blood as compared to maternal blood (which enhances mercury binding in fetal blood cells), but could be more likely to be caused by active mercury transport to the fetus. The toxicity profile of mercury in placenta includes abnormal amino acid transfer, placental oxygen consumption, enzyme activity, hormonal secretion, and membrane fluidity.
    • p.95
  • Occupational chromium poisoning (OCP) is of public health concern. Chromium poisoning could lead to an increased risk of abortion or threatening miscarriage in female workers. In China, 18 epidemiological surveys studying occupational chromium poisoning from 1983 to 2010 with analysis of incidence of abortion associated with occupational Cr (VI), recorded an increased risk of spontaneous abortion or threatened abortion in female workers, compared to the control of non-occupational chromium exposure. ‘‘For female workers with occupational chromium expo- sure, the incidence rate of spontaneous abortion or threatened abortion increased by 5.58% or 6.00%, respectively. So the risk of spontaneous abortion or threatened abortion increased by 2.31 or 20.47 times, respectively, compared to unexposed controls”. A recent study carried out in Nigeria revealed that the incidence of miscarriage or spontaneous abortion increase by 1.60% in women exposed to chromium.
    Chromium is commonly used in its hexavalent form [(chromate, Cr (VI)] in making stainless steel, leather tanning, pigment production, electroplating and in other applications. This hexavalent form exists widely in the environment and can be refined through the process of industrial melting.
    • pp.95-96
  • The association between arsenic exposure through drinking water and spontaneous abortion, stillbirth, and neonatal death in Bangladesh was studied by Milton and coworkers. Data obtained revealed that individuals exposed to arsenic concentrations higher than 50 lg/L via drinking water had a higher risk of spontaneous abortion, stillbirth and neonatal death than subjects exposed to arsenic concentration <50 lg/L. Further studies also have probed the link between arsenic exposure and abnormal obstetric effects, including spontaneous abortion, stillbirths, neonatal death, pregnancy hypertension, and gestational diabetes. Though the majority of studies were conducted in populations of some developing countries like West Bengal, India and Bangladesh, data from other populations were also studied. Research by Ahmad and coworkers concentrated on two separate populations in Bangladesh. Adverse effects in population with elevated arsenic exposures (mean arsenic levels 240 lg/L) were compared with population consuming safe drinking water (arsenic levels <0.05 ppm total arsenic). Eighty percent of tube wells in the exposed village had drinking water arsenic concentrations >50 lg/L. Data obtained revealed a statistically significant (z = 3.2 and p = 0.02) greater proportion of pregnancies ended as normal live births 89.1% and 95.5% of the exposed and non-exposed populations respectively. In addition, significantly higher (p < 0.05) rates of spontaneous abortion (68.8), stillbirths (53.1), and preterm births (68.8) per 1000 births were obtained in the exposed population compared. Data obtained in Nigeria by Otebhi and Osadolor highlighted a 5.88% increase in the incidence of miscarriages in women exposed to arsenic compared to the unexposed group. Arsenic has been shown to possess endocrine disrupting capability and this is further supported by data from chicken embryos which revealed that non-cytotoxic doses of NaAsO2 resulted in the suppression of transcription of the 17b-estradiol-inducible vitellogenin II gene.
    • pp.96
  • Hopenhayn-Rich and group reported high perinatal and neonatal mortality in the mining area of northern Chile in association with arsenic-contaminated water. In Bangladesh, Ahmad and coworkers reported a significant increase in spontaneous abortions, stillbirths, and preterm births.
    • p.96
  • Male-mediated spontaneous abortion remain unreported in man hitherto, nonetheless some facts have emerged to suggest that the welding of stainless steel may be a relevant paternal exposure. Stainless steel fumes (not mild steel), contain hexavalent chromium, inhalation of which trigger pulmonary absorption of hexavalent chromium with autopsy findings of former chromate exposed workers confirming high concentrations of hexavalent chromium in several examined organs. Hexavalent chromium administration in male rodent also impairs the viability of embryos fathered by that male. Increased risk of self-reported spontaneous abortion was previously found in spouses of stainless-steel welders, compared with spouses of non-welders [odds ratio (OR) 2.0, 95% confidence interval (95% CI) 1.1—3.51, but no excess risk was found in the same cohort in analyses based on abortions treated in a hospital, a finding which may be explained by high risk being restricted to early (preclinical) abortions. According to Hjollund et al., 2000, there is an increased risk of early spontaneous abortion for women whose partners are engaged in stainless-steel welding during the cycle in which the woman conceived.
    • p.96
  • Poor nutritional intake in developing countries like Nigeria could also play a role in the aetiology of spontaneous recurrent abortion. In Nigeria, for example, many people live below the one dollar a day mark. This puts pregnant women in a difficult situation where healthy diets needed to sustain mother and fetus becomes inaccessible.
    • p.97
  • Otebhi and Osadolor, 2016 observed a significant increase (q < 0.001) in the blood toxic metals (lead, mercury, cadmium and arsenic) levels in pregnant women with history of pregnancy complications compared with women who are also pregnant but without any history of pregnancy complications. Otebhi and Osadolor, 2016 findings were in agreement with other studies including Ibadan Nigeria, where similar increases were observed to be associated with spontaneous abortion. Elevated serum heavy metals (cadmium and lead) may contribute to recurrent spontaneous abortion.
    • p.97
  • It is thought that in normal pregnancy there is an oxido- reductive balance between activity of pro-oxidative factors, like free radicals, and competence of antioxidative systems, in which Se, Zn, Mn and Cu are present and which are ingredients of enzymes in the first line of defense taking part in expelling free radicals. The enzymatic antioxidants namely super-oxide dismutase, catalase, glutathione peroxidase and glutathione reductase and non-enzymatic antioxidants are influenced by dietary intake (vitamin C, vitamin E, Se, Zn, Mn, Cu, taurine, hypotaurine, glutathione, b-carotene and carotene). Increase of constitutional oxidative stress markers tend to trigger advanced and irreversible state of abortion which does not appear in mild pregnancy disorders. The exaggerated oxidative stress impact adversely on female reproduction and the pathophysiology of miscarriage. Potential toxic metals like lead, cadmium, chromium, mercury, arsenic act by the generation of free radicals — reactive oxygen species (ROS) and reactive nitrogen species (RNS), that may precipitate oxidative stress which has been reported to influence the female reproductive system adversely. There are two plausible theories about the possible pathways of the mechanism of lead induced miscarriages in pregnant women. Firstly, lead can induce excessive production of Reactive Oxygen Species (ROS) which disrupt collagen being a primary target for ROS causing the membrane to lose its elasticity and eventual premature rupture of membrane with its associated risks. With regard to balance in reproductive hormones, lead disrupts the balance in reproductive hormones which is a sacrosanct for the normal progress during the course of pregnancy. Estrogen and progesterone secretion can be affected by lead via increase in luteinizing hormone and follicle stimulating hormone. Exposure to metallo-hormones is ubiquitous since these chemicals are commonly used in trade and commerce and in household products. Their inherent characteristics cause these metallo-hormones to act as ligands and bind to respective hormone receptors which bind to response elements in the target genes to produce undesired downstream effects by regulating gene expression. In man hormones play a key role in regulating cellular activities and gene functions especially the downstream manifestations as estrogenic, anti-estrogenic, androgenic and anti-androgenic effects. These alter the function and expression of important genes. Interference in the hormonal activity of natural hormones by metallo-hormones could manifest into adverse reproductive and developmental effects. Furthermore, Lamadrid-figueroa et al., 2007 cautioned that assessing the influence of genetic polymorphisms of lead binding proteins on the probability of suffering from miscarriage or other reproductive outcomes will be very important to identify groups particularly susceptible to the effects of lead exposure during pregnancy.
    • p.97
  • Given the ubiquity of heavy metals in sub-Sahara Africa and the masked diagnosis of miscarriages in Africa as recently reported in Sudan (24% of known causes and 76% of unknown causes) and whereas majority of clinicians dealing with pregnant women with miscarriages are unlikely to suspect heavy metal toxicity in the etiology due to a general lack of knowledge regarding this subject in the medical community. Furthermore since unique bio-chemical, genetic, and nutritional factors confer different susceptibilities to the effects of toxic heavy metals; thus, cases of miscarriages should be handled on an individual basis. In most part of the world other than sub-Sahara Africa the number of practitioners trained in "functional" or "orthomolecular" medicine is increasing and these practitioners are very familiar with the diagnosis and treatment of problems associated with heavy metal toxicity.
    • pp.97-98
  • The continued negligence and/or ignorance of potential toxic metals in the etiogenesis of miscarriages, still birth has huge socioeconomic burdens in the developing nations especially Sub Saharan Africa SSA where the prevalence rates are feared to be higher than previously thought. It may be worthwhile for toxicologists and scientists in SSA to investigate if these heavy metals can become additional biomarkers in the diagnosis of miscarriages and stillbirths.
    • p.98

“The Amerian College of Obstetricians and Gynecologists, Frequently Asked Questions FAQ 100 Pregnancy, Repeated Miscarriages”[edit]

“The Amerian College of Obstetricians and Gynecologists, Frequently Asked Questions FAQ 100 Pregnancy, Repeated Miscarriages” "Archived copy" (PDF).

  • What is recurrent pregnancy loss?
    Recurrent pregnancy loss is defined as having two or more miscarriages. After three repeated miscarriages, a thorough physical exam and testing are recommended.
    What is the likelihood of having repeated miscarriages?
    A small number of women (1%) will have repeated miscarriages.
    What is the most common cause of miscarriage?
    Most miscarriages (about 60%) occur randomly when an embryo receives an abnormal number of chromosomes during fertilization. This type of genetic problem happens by chance; there is no medical condition that causes it. However, it becomes more common in women of increased reproductive age.
    Are there other genetic problems associated with repeated miscarriages?
    In a small number of couples who have repeated miscarriages, one partner has a chromosome in which a piece is transferred to another chromosome. This is called a translocation. People who have a translocation usually do not have any physical signs or symptoms, but some of their eggs or sperm will have abnormal chromosomes. If an embryo gets too much or too little genetic material, it often leads to a miscarriage.
    Are problems with reproductive organs associated with repeated miscarriages?
    Certain congenital problems of the uterus are linked to repeated miscarriages. Although there are many such disorders, one of the most common that has been associated with miscarriage is a septate uterus. In this condition, the uterus is partially divided into two sections by a wall of tissue. Asherman syndrome, in whichadhesions and scarring form in the uterus, may be associated with repeated miscarriages that often occur before a woman even knows she is pregnant. Fibroids and polyps, which are benign (noncancer) growths of the uterus, also may play a role in recurrent pregnancy loss
    • p.1
  • Can medical conditions increase the risk of repeated miscarriages?
    Women who have certain medical conditions may have an increased risk of repeated miscarriages. Antiphospholipid syndrome (APS) is an autoimmune disorder in which a person’s immune system mistakenly makesantibodies to certain substances involved in normal blood clotting. APS is associated with repeated miscarriages and fetal deaths. Another disease that can lead to miscarriage isdiabetes mellitus. In this disease, high levels of a sugar calledglucose are present in the blood. Women with diabetes, especially those in whom the disease is poorly controlled, have an increased risk of pregnancy loss. Women with a condition called polycystic ovary syndrome also have an increased risk of miscarriage.
    How common is it that a cause for repeated miscarriages cannot be identified?
    In 50–75% of women with repeated miscarriages, no cause can be found for the pregnancy loss. There may be clues about what the problem is, but there is no sure answer.
    What tests and exams are available to help find the cause of repeated miscarriages?
    To help find the cause of repeated miscarriages, your health care professional will ask about your medical history and past pregnancies. A complete physical exam, including a pelvic exam, may be done. You may have blood tests to detect problems with the immune system. Testing may be done to help detect genetic causes of repeated miscarriages. Imaging tests may be considered to find out if a uterine problem is causing repeated miscarriages.
    Is treatment available if the cause of my repeated miscarriages can be identified?
    If a specific cause of your repeated miscarriages can be identified, your health care professional may suggest a treatment that addresses the cause.
    What can be done if I have a chromosome translocation?
    If you have a chromosome translocation, genetic counseling may be recommended. Results of genetic testing can help clarify your options. In vitro fertilization with special genetic testing called preimplantation genetic diagnosis may be done to select unaffected embryos.
    How can problems with reproductive organs be treated?
    Corrective surgery may be able to increase the chances for a successful pregnancy. For example, a septum in the uterus can be removed.
    What treatment is available if I have antiphospholipid syndrome?
    Use of a medication that prevents blood clots, such as heparin, sometimes combined with low-dose aspirin, may be prescribed throughout pregnancy and for a few weeks afterward. This treatment can increase the rates of successful pregnancy in women with this condition.
    What are my chances of having a successful pregnancy if I have repeated miscarriages and no cause is found?
    About 65% of women with unexplained recurrent pregnancy loss have a successful next pregnancy.
    • p.2

"Maternal age and fetal loss: population based register linkage study" (June 2000)[edit]

Anne-Marie Nybo Andersen, Jan Wohlfahrt, Peter Christens, Jørn Olsen, Mads Melbye (June 2000). [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC27416/pdf/1708.pdf "Maternal age and fetal loss: population based register linkage study". BMJ. 320 (7251): 1708–12. doi:10.1136/bmj.320.7251.1708. PMC 27416. PMID 10864550.

  • Overall, 13.5% of the pregnancies intended to be carried to term ended with fetal loss. At age 42 years, more than half of such pregnancies resulted in fetal loss. The risk of a spontaneous abortion was 8.9% in women aged 20-24 years and 74.7% in those aged 45 years or more. High maternal age was a significant risk factor for spontaneous abortion irrespective of the number of previous miscarriages, parity, or calendar period. The risk of an ectopic pregnancy and stillbirth also increased with increasing maternal age.
    Conclusions Fetal loss is high in women in their late 30s or older, irrespective of reproductive history. This should be taken into consideration in pregnancy planning and counselling.
    • p.1708
  • An increasing risk of fetal death, and in particular spontaneous abortion, with increasing maternal age has been observed by several authors. Previous spontaneous abortions and multigravidity are also well known risk factors for spontaneous abortion in subsequent pregnancies. As these factors are highly correlated, it remains to be evaluated what the effect of maternal age is when taking into account a woman’s reproductive history.
    As the association between age and spontaneous abortion reflects both biological mechanisms and forces of selection, the significance of the association is expected to change over time. Decades ago, older pregnant women were mainly those with low fecundity or high parity. At present, many women delay childbearing for social reasons.
    To study the effects of maternal age on fetal loss we derived our data from the population based Danish health registries, which cover the population of Denmark. This allowed us to control for the confounding effects of reproductive history and calendar period.
    • p.1708
  • From 1978-92, a total of 634 272 women had 1 221 546 pregnancies, of which 126 673 ended in fetal loss, 285 022 in an induced abortion, and 809 762 in a live birth (table). The overall risk of fetal loss was 13.5%. The risk of fetal loss according to maternal age at conception followed a J-shaped curve, with a steep increase after 35 years of age (fig 1). More than one fifth of all pregnancies in 35 year old women resulted in fetal loss, and at 42 years of age more than half of the intended pregnancies (54.5%) resulted in fetal loss. After adjustment for induced abortions, the increased risk of fetal loss disappeared in women aged less than 20 years and the increased risk in women aged more than 35 years was at a slightly lower level.
    • p.1709
  • Spontaneous abortion accounted for 80% of fetal losses. The overall risk of spontaneous abortion was 10.9%. A curve was observed for the association between maternal age at conception and spontaneous abortion, which was similar to that for all fetal losses (fig 2). The risk of spontaneous abortion varied from a minimum of 8.7% by the age of 22 years to 84.1% by the age of 48 years or more. When the figures were adjusted for the effect of induced abortion, the risk in women in their teens was similar to those in their early 20s.
    The overall risk of spontaneous abortion leading to admission to hospital increased from 9.3% in 1978-82 to 11.1% in 1983-87 and 12.5% in 1988-92. However, the association between maternal age and risk of spontaneous abortion was not confounded by calendar period or maternal birth cohort.
    • pp.1709-1710
  • The association between spontaneous abortion and age was similar in all strata, although the level increased with increasing number of previous spontaneous abortions. The incidence of spontaneous abortion varied according to a woman’s parity and number of spontaneous abortions in the preceding 10 years; among women aged 25-29 years spontaneous abortion occurred in 8.9% of nulliparous women and 9.3% of parous women without a history of spontaneous abortion, in 12.4% and 11.8% of those with a history of one spontaneous abortion, and in 22.7% and 17.7% of those with a history of two spontaneous abortions. After three or more spontaneous abortions, the proportion of pregnancies ending in spontaneous abortion increased to 44.6% in nulliparous women and 35.4% in parous women.
    In women with no history of spontaneous abortions we found a slightly lower overall risk of spontaneous abortion among nulliparous women than parous women (10.0% v 11.6%). This tendency was found in all strata of age except for women aged 40-44 years. Among women with a history of spontaneous abortion, the reverse tendency was observed; in general, nulliparous women had a higher age specific risk than did parous women (fig 3).
    Under the assumption that only 80% of women with abortions in recognised pregnancies were hospitalised the risk of spontaneous abortion would be: 12-19 years, 13.3%; 20-24, 11.1%; 25-29, 11.9%; 30-34, 15.0%; 35-39, 24.6%; 40-44, 51.0%; and 45 or more, 93.4%.
    • p.1710
  • Our study shows an increasing risk of fetal loss with increasing maternal age in women aged more than 30 years. At 42 years of age, more than half of all pregnancies resulted in a spontaneous abortion, ectopic pregnancy, or stillbirth. The increasing risk of spontaneous abortion was observed in both nulliparous and parous women, regardless of parity, number of previous spontaneous abortions, or calendar period. Thus, although maternal age is highly correlated with parity and reproductive history, our data clearly show a strong and independent effect of maternal age on the risk of spontaneous abortion.
    • p.1711
  • The observed association could be the result of age related changes such as an increase in conceptions that are chromosomally abnormal or decreasing uterine and hormonal function. Also, age might be a surrogate measure of cumulative exposure to unknown factors.
    It could be argued that women at a particularly high risk of spontaneous abortion are overrepresented among pregnant women of high maternal age because of the tendency to carry on in an attempt to achieve the desired number of children. However, we found the same increasing risk of spontaneous abortion with increasing maternal age when restricting the analysis to women with no history of spontaneous abortion in the previous 10 years (women with an average low propensity of spontaneous abortion) and women with a history of live births (women with an average higher degree of achievement of the desired number of live births).
    Alternatively, the increased risk of spontaneous abortion in older age groups could in part be explained by subfertile women reaching a higher average maternal age before achieving a pregnancy. Thus, subfertile women have a higher risk of spontaneous abortion than fertile women.17 Following this argument, however, the effect of maternal age in nulliparous women with no history of spontaneous abortions should be stronger than in women with a history of only live births, which was not observed. In women without a history of spontaneous abortion, we observed a slightly higher risk of spontaneous abortion in parous than nulliparous women.
    • p.1711
  • The estimated risk of fetal loss in pregnancies intended to be carried to term might be slightly biased by the fact that several pregnancies ended in fetal loss before an intended induced abortion. Such cases would wrongly be counted as an intended pregnancy. This bias was found to be particularly relevant to risk estimates in women aged less than 20 years but had only a minor influence on risk estimates in other ages.
    Regan et al and others stated that “as the most predictive factor for spontaneous abortion is a previous spontaneous abortion, the outcome of a woman’s first pregnancy has profound consequences for all subsequent pregnancies.”Our study does not agree with this statement. We found a substantially lower risk of spontaneous abortion among women under 30 years of age with a history of spontaneous abortion in their first pregnancy than among women aged 35 years or more with a history including only live births.
    Our study was based on data from population based registers, with complete information on all pregnancy outcomes leading to hospital admission over a period of 15 years and complete live birth history for all women in the cohort. This rules out biases such as selection related to non-responders and differential misclassification of a woman’s reproductive history.
    Our results were restricted to spontaneous abortions leading to admission to hospital. If the tendency to be admitted was dependent on maternal age, this might confound the association. It is, however, unlikely that a differential referral to hospital could explain more than a minor part of the association. In the hypothetical scenario where all women aged 45 years or more were admitted to hospital and only 80% of women aged 20-24 years were admitted, the risk of spontaneous abortion would be 74.7% and 11.1% respectively instead of 74.7% and 8.9%.
    Another potential problem could be that some induced abortions were recorded as spontaneous abortions. Our study takes advantage of the fact that both conditions are mandatorily reported and that induced abortion before 12 weeks of gestation is legal, available, free of charge, and a widely accepted practice in Denmark. Thus, we assumed that misclassification of induced abortions was minimal, which is supported by other studies.
    • p.1711
  • Our study shows an important increase in the risk of spontaneous abortion and other types of fetal loss among women aged more than 40 years and that the increase is already considerable among those in their 30s. This increase is observed irrespective of a woman’s reproductive history. For society, such findings would indicate that tendencies to postpone pregnancy increase the overall incidence of fetal loss and possibly the costs of health care. On the individual level, information about the increased risk of spontaneous abortion with high maternal age should be part of medical counselling so that it can be taken into consideration in decisions about reproduction.
    • p.1711-1712
  • What is already known on this topic
    Maternal age at conception and history of fetal loss are risk factors for fetal death; these factors are highly correlated
    What this study adds
    Maternal age at conception is a strong and independent risk factor for fetal death, irrespective of previous reproductive outcome, as is a history of fetal loss
    The chance of a successful pregnancy in women aged 40 years or more is poor
    Patients could be counselled more fully about their chance of a successful pregnancy if their age and reproductive history were taken into account
    • p.1712

“Is ambient heat exposure levels associated with miscarriage or stillbirths in hot regions? A cross-sectional study using survey data from the Ghana Maternal Health Survey 2007” (2018)[edit]

Benedict Asamoah, Tord Kjellstrom, and Per-Olof Östergren, “Is ambient heat exposure levels associated with miscarriage or stillbirths in hot regions? A cross-sectional study using survey data from the Ghana Maternal Health Survey 2007”, Int J Biometeorol. 2018; 62(3): 319–330.

  • It is well established that high ambient heat could cause congenital abnormalities resulting in miscarriage or stillbirth among certain species of mammals. However, this has not been systematically studied in real field settings among humans, despite the potential value of such knowledge for estimating the impact of global warming on the human species. This study sought to test the hypothesis that maternal heat exposure during pregnancy in hot regions is associated with increased prevalence of spontaneous abortions or stillbirths and to develop an analytical strategy to use existing data from maternal health surveys and existing data on historical heat levels at a geographic grid cell level. A subsample of the Ghana Maternal Health Survey 2007 was used in this study. This study sample consisted of 1136 women with pregnancy experiences between 2004 and 2007, out of which 141 women had a pregnancy that terminated in miscarriage or stillbirth. Induced-abortion cases were excluded. The linkage between ambient heat exposure and pregnancy outcome followed the epidemiological time-place-person principle, by linking timing of pregnancy outcome with historical data of local area heat levels for each month, as estimated in an international database. Maternal heat exposure level was estimated using calculated levels of the wet-bulb globe temperature (WB GT), which takes in to account temperature, humidity, heat radiation, and air movement over the skin (wind speed). The values we used applied to exposure in the shade or in buildings without cooling (no solar heat radiation) and a standard air movement of 1 m/s. We applied two exposure durations: yearly average and monthly average for second month of pregnancy. In one analysis, we restricted the sample to four regions with time-homogeneous ambient heat. Analysis was made using logistic regression. About 12% of the latest pregnancies ended in either miscarriage (9.6%) or stillbirth (2.8%). The odds ratios indicated 12 to 15% increase (OR crude 1.15, 95% CI 0.92–1.42, and OR age adjusted 1.12, 95% CI 0.90–1.39) in the odds of having a stillbirth or miscarriage with each additional degree increase in WBGT, although this was just outside two-sided statistical significance. The WBGT range was quite narrow (most annual values in the range 24–26 °C, and most monthly values in the range 23–27 °C), which may have hidden any real impacts of high heat levels. The seemingly positive association observed disappeared after adjusting for gravidity. The analyses of the four selected regions indicated 27 to 42% increase in the odds of experiencing miscarriage or stillbirth with every degree increase in WBGT (crude OR 1.42 95% CI 1.00–2.03). This association remained after adjusting for maternal age pregnancy history, although no longer statistically significant (adjusted OR 1.27, 95% CI 0.89–1.81). Environmental heat exposures may be associated with adverse pregnancy outcomes, but this study was inconclusive, possibly because the heat exposure range was small. Historical records of routine observations in existing databases can be used for epidemiological studies on the health effects of heat, although data from properly and purposively designed studies might be more suitable for further


    • p.319
  • In summary, hyperthermia is a well-known teratogen in animals and maternal hyperthermia has been associated with birth defects in human (Edwards 2006; Edwards et al. 2003; Moretti et al. 2005; Van Zutphen et al. 2012). The central nervous system is known to be most sensitive to elevated temperatures (Edwards 1998; Edwards et al. 2003; Graham 2005; Moretti et al. 2005). In human clinical studies, an oral temperature of 37 °C (98.6 °F) is considered normal, and 39 °C (102 °F) is regarded as the threshold for potential damage (Van Zutphen et al. 2012). However, the teratogenicity of heat is dependent on the overlap between the ambient heat elevation and the susceptible stage of development; the type of defect depends on the particular stage of development (Edwards 1998, 2006; Graham 2005; Van Zutphen et al. 2012). Major birth defects may result in miscarriage or fetal death (Parker et al. 2010), as it is known that a large proportion of embryos with neural tube defects expires in the uterus prior to expulsion or delivery (Edwards et al. 1995). Ambient heat in hot regions of the world could therefore induce congenital malformations in humans (especially for outdoor workers, e.g., in agricultural work), resulting in an increased prevalence of spontaneous abortion or stillbirth than would be expected from other causes acting alone, but few empirical investigations in real-world settings are reported in the existing scientific literature. The aim of this study was to use an existing maternal health database to test the hypothesis that maternal heat exposure during pregnancy in hot regions is associated with increased prevalence of spontaneous abortions or still-births, and to develop an analytical strategy to use existing data from maternal health surveys and existing data on historical heat levels at a global grid cell level (Kjellstrom et al. 2017).
    • p.320-321
  • The findings of this study suggest possible association between atmospheric heat exposure and adverse pregnancy out-comes: miscarriage or stillbirth that could be further explored. The likelihood of experiencing a miscarriage or stillbirth increased twofolds with each additional pregnancy, although the effect was not statistically significant after adjustment for possible confounders. The findings are supported by findings from previous studies elsewhere (Strand et al. 2012, 2011).
    • p.325
  • Although we suspect that most malformed fetuses would end up in miscarriage or stillbirth, it is not all miscarriages or stillbirths that are due to malformations. The reverse is also true that it is not all malformations that end up in miscarriage or stillbirth (Edwards et al.; Moretti et al. 2005). Thus, lack of comprehensive data on pregnancy outcomes, including fetal malformations, limited the analysis regarding adverse pregnancy outcomes in this study. Pregnancies that ended in induced-abortions were excluded, since they could not be directly linked to adverse pregnancy outcomes. However, there could be a subsample of women who might have undergone elective termination of the pregnancy upon detection of fetal malformation during pregnancy (Cragan and Khoury 2000)
    • p.327

“Surgery for Family Planning, Abortion, and Postabortion Care” (2015)[edit]

Joseph B Babigumira, Michael Vlassoff, Asa Ahimbisibwe, and Andy Stergachis. (2015). Debas HT, Donkor P, Gawande A, Jamison DT, Kruk ME, Mock CN (eds.). Ch.7 “Surgery for Family Planning, Abortion, and Postabortion Care”. Washington (DC): The International Bank for Reconstruction and Development / The World Bank. doi:10.1596/978-1-4648-0346-8_ch7. ISBN 978-1464803468. PMID 26741012.

  • Incomplete abortion is one of the most common complications of induced abortion, particularly in the case of illegal induced abortion. It occurs when the products of conception have not been fully expelled through the cervix (Bottomley and Bourne 2009). The symptoms and signs of abortion complications—vaginal bleeding, abdominal pain, fever, purulent or foul-smelling vaginal discharge, and shock—are usually present with incomplete abortion. In one study, even after clinical assessments had suggested that no products were retained (in this case, following first-trimester spontaneous abortions, or miscarriages), ultrasounds showed that 45 percent of the women had retained tissue (Alcázar, Baldonado, and Laparte 1995).
  • Regarding the three methods for management of incomplete abortion—expectant, medical, and surgical—a 2005 meta-analysis found that surgical management was more likely to complete uterine evacuation than medical management, which in turn was more effective than expectant management (Sotiriadis and others 2005). However, studies report mixed results regarding the overall advantages and disadvantages of medical versus surgical management of incomplete abortion or miscarriage. One study reported that surgical management resulted in more infections but less pain, a lower chance of retained products, and greater satisfaction than medical management (Niinimaki and others 2006; Niinimaki and others 2009). A Cochrane review found that, compared with expectant management, surgical management reduced the risk of incomplete abortion or miscarriage, need for additional surgery, bleeding, and transfusion despite being less costly; however, the two methods carried similar risks of infection and psychological issues (Nanda and others 2012).
  • Miscarriage. Medical management of miscarriage using the labor-induction medication misoprostol is less costly than expectant management, which in turn is less costly than surgical management of first-trimester miscarriage (You and Chung 2005). However, to treat first-trimester miscarriage or incomplete abortion, medical management is more efficacious and cost-effective (Tasnim and others 2011). Some studies indicate no clear preference concerning the cost-effectiveness of medical versus surgical management but cite other advantages associated with both (Niinimaki and others 2009). Others suggest that either expectant or medical management of first-trimester miscarriage would be more cost-effective than traditional surgical management (Petrou and others 2006). For first-trimester pregnancy loss, surgical management is more cost-effective and more efficacious than medical management when performed in the outpatient setting (Rausch and others 2012). For incomplete or inevitable abortion, medical management is cost-effective and more efficacious (Rausch and others 2012). Among the surgical procedures, MVA is more cost-effective than EVA because it costs less, does not require general anesthesia, and is more suited to LMICs (Tasnim and others 2011).

"Understanding early miscarriage" (January 2017)[edit]

"Understanding early miscarriage". BabyCenter, L.L.C. January 2017. Archived.

  • Sadly, early miscarriages are very common. It’s perfectly possible to have a miscarriage before you even realise you’re pregnant. About half of all fertilised eggs are thought to be lost in the earliest days of pregnancy, before a pregnancy test has been done.
    After a positive pregnancy test, between 10 per cent and 20 per cent of pregnancies end in miscarriage. Most miscarriages happen in the first 12 weeks of pregnancy.
    Miscarriage at any stage of pregnancy can be a terrible blow. Even if it happens very early on in pregnancy, it’s only natural that it comes as a shock. Don’t feel you’re not allowed to grieve over your loss.
  • Early miscarriages usually happen because the embryo is not developing as it should. Chromosome problems are thought to be the most common cause. These problems usually happen for no reason and are unlikely to happen again.
    To develop properly, a baby needs the right number of normal chromosomes. He’ll need 23 from his mum and 23 from his dad. Chromosomal abnormalities can prevent a baby from developing. These abnormalities may happen because there are too many chromosomes or not enough chromosomes, or because there are changes to a chromosome’s structure. In that case, the pregnancy will come to an end at the embryo stage.
    It’s thought that up to 95 per cent of pregnancies with chromosomal abnormalities end in miscarriage.
  • The most common signs and symptoms of miscarriage are vaginal bleeding and strong period-type cramps.
    The bleeding can vary from light to heavy, perhaps with blood clots, and may come and go for a few days.
    Sometimes, symptoms settle down and the pregnancy usually carries on. This is called a threatened miscarriage. There is some, limited evidence that treatment with progesterone may stop a threatened miscarriage from happening. Progesterone is not offered as a routine NHS treatment, but it may be worth asking your doctor about it.
    Unfortunately, though, if a miscarriage is really under way, it will usually take its course.
  • In most cases, a woman’s body will complete the miscarriage naturally. If this happens to you, you won’t usually need further treatment.
    The bleeding is likely to tail off in a week to 10 days and will usually have stopped after two weeks or three weeks.
  • Depending on your stage of pregnancy and whether you are still experiencing symptoms, you should be offered a follow-up appointment two weeks after the miscarriage. This is to check that your body is recovering as it should.
    You may be referred to an early pregnancy unit (EPU) if there’s one near you. There are more than 200 EPUs in the UK, so there’s a good chance you’ll have access to one.
    At the EPU, you may be offered an ultrasound scan and other tests to confirm that the pregnancy has ended.
  • If the bleeding doesn’t tail off or stop after two weeks or so, you may need extra care from hospital doctors. The bleeding may mean there are some pregnancy tissues left in your womb (uterus). This is called an incomplete miscarriage and may need treatment.
    Your doctors are likely to advise one of the following approaches:
    *Expectant management: the bleeding is given up to a week more to settle, without treatment, as long as there’s no sign of infection.
    * Medical management: your doctor will give you medicines to help along completion of the miscarriage.
    *Surgical management: your doctor will perform a minor operation to complete the miscarriage. Doctors call this an SMM, which stands for surgical management of miscarriage.
  • With medical management, you may be offered tablets to swallow or a pessary to insert into your vagina. The bleeding after medical management can be heavy and take longer to stop. But it will mean you don’t have to have surgery, and you should only have to stay in hospital for a short while after your treatment.
    An SMM takes a few minutes and you’re likely to recover quickly. It’s most likely that your doctor will carry out the procedure while you’re asleep under a general anaesthetic.
    Some hospitals offer the option of surgical management with a local anaesthetic, instead of a general. This procedure is called MVA, which stands for manual vacuum aspiration.
    One advantage of surgical management is that bleeding usually stops more quickly afterwards, which may help to ease your distress. It also means there is less chance you’ll have to go back into hospital for further treatment.
    SMM works very well and in most cases no further treatment is needed. Your doctor is particularly likely to recommend SMM if you have heavy bleeding or signs of infection.
  • Deciding whether or not to have treatment and which option to go for is a highly personal decision. Most women prefer to let nature take its course, even if it means they may need treatment later. Others want the miscarriage to be over as soon as possible.
  • You may be surprised that your doctor doesn’t arrange for you to have any special tests after a first miscarriage. The sad fact is that early miscarriage is very common.
    Serious medical problems aren’t usually to blame for an early miscarriage. Most early miscarriages are one-off, so it is very likely that your next pregnancy will be a successful one. For this reason you’re unlikely to be given a follow-up appointment to see a consultant unless you’ve had three early miscarriages in a row.
  • Miscarriage can be traumatic because it takes away all the hopes and dreams that a positive pregnancy test brings. The experience can leave you with overwhelming feelings of loss and grief.
    Losing a baby can be tragic no matter how early in pregnancy it happens, and you will need to allow yourself a chance to recover and grieve.

"Vitamin supplementation for preventing miscarriage" (May 2016)[edit]

Balogun OO, da Silva Lopes K, Ota E, Takemoto Y, Rumbold A, Takegata M, Mori R (May 2016). "Vitamin supplementation for preventing miscarriage". The Cochrane Database of Systematic Reviews. 5 (5): CD004073. doi:10.1002/14651858.CD004073.pub4. PMC 7104220. PMID 27150280.

  • Miscarriage can be caused by a wide range of factors, and determining the aetiology is oMen difficult given the variety of underlying mechanisms potentially responsible. Consideration of the timing of the miscarriage is also important, as diverse causes of miscarriage manifest at different periods of gestation. The most common causes include abnormal chromosomal rearrangements, endocrinological disorders and uterine abnormalities (Garrido- Gimenez 2015). Early miscarriages are mostly associated with chromosomal abnormalities, defective placental development and maternal disease conditions; while late miscarriages are more likely due to structural problems of the uterus and/or cervix such as cervical incompetence. Women experiencing recurrent miscarriage oMen have an underlying medical condition such as autoimmune disease, i.e. systemic lupus erythematosus and antiphospholipid syndrome, or other blood clotting disorders such as hyperhomocysteinaemia (high levels of homocysteine in the blood) or another thrombophilia (Preston 1996). Other risk factors for miscarriage include higher maternal age at conception, multiple pregnancies and a history of previous miscarriage (Baba 2011; Garcıa-Enguıdanos 2002; Hure 2012). Behavioural factors including alcohol consumption (Maconochie 2007), smoking (Baba 2011; Hure 2012), use of illicit drugs (Garcıa-Enguıdanos 2002), and exposure to non-steroidal anti-inflammatory drugs (NSAIDs) around the time of conception are also suggested causes of miscarriage (Li 2003; Nielsen 2001). While several factors may promote miscarriage, for a great proportion of women, no cause can be found.
    In clinical practice, surgical and non-surgical interventions are used in the management of miscarriage. Bed rest, commonly prescribed for preventing miscarriage, is lacking proven benefit (Aleman 2005). Similarly, there is currently insufficient evidence on the benefit provided from the use of uterine muscle relaxant drugs (Lede 2005), Chinese herbal medicine (Li 2012), hormones (Devaseelan 2010; Haas 2013; Lim 1013; Morley 2013), and immunotherapy (Wong 2014).
    • p.9
  • Vitamins are essential nutrients required in the body for numerous functions such as to ensure normal metabolism, physical growth and development as well as to prevent diseases. Based on evidence from observational studies, vitamin supplementation has been advocated for the prevention of miscarriage (Hasan 2009; Maconochie 2007), most commonly folate and B vitamins. Due to consistent associations between pregnancy complications and decreased antioxidant defence and infections, it has been suggested that vitamin supplementation during pregnancy might provide protection against adverse pregnancy outcomes and may influence the risk of spontaneous miscarriage in women.
    • p.9
  • Homocysteine is an amino acid that is involved in several key metabolic processes, vital to ongoing cellular activity of the living organism. The metabolism of homocysteine is facilitated by B vitamins and folate. The concentration of homocysteine in the blood is determined by various dietary factors, including folate, vitamin B6 and vitamin B12. Disturbance of maternal and fetal homocysteine metabolism has been associated with various obstetric conditions including miscarriage (Hague 2003; Nelen 2000), and hyperhomocysteinaemia is considered a risk factor for recurrent early pregnancy loss. Therefore, supplementation with B vitamins and folate may influence the risk of spontaneous miscarriage in women with recurrent miscarriage. Moreover, low serum vitamin B12 concentrations have been reported in women with recurrent miscarriage (Hübner 2008). Evidence on the effect of vitamin supplementation, particularly folic acid, on risk of miscarriage is still conflicting; however the few studies that have adjusted for confounding support a protective effect.
    Oxidative stress is caused by an imbalance between pro-oxidants and antioxidants. Pro-oxidants act either by generating reactive oxygen species (ROS) or by inhibiting antioxidant systems. In living cells, ROS are formed continuously both from biochemical processes occurring in the body and in reaction to external factors. Excessive ROS production may however, overpower the body’s natural antioxidant defence system, creating an environment unsuitable for normal female reproductive processes (Al-Gubory 2010). A recent review of evidence from experimental and observational studies suggests that oxidative stress is an important cause in spontaneous and recurrent miscarriage (Agarwal 2012b; Al-Gubory 2010; Gupta 2007). Adequate maternal antioxidant status before and during pregnancy could prevent and control oxidative stress. Therefore, intake of antioxidant vitamins such as vitamin C and vitamin E may be an important factor to reduce the risk of miscarriage. In a population-based case-control study, vitamin supplementation (including vitamin C), and eating fresh fruits and vegetables daily were associated with reduced risk of miscarriage (Maconochie 2007). Another observational study demonstrated an association between the risk of spontaneous early miscarriage and dietary factors; poor intake of green vegetables, fruit and dairy products coupled with a high intake of fat was associated with a high risk of spontaneous miscarriage (Di Cintio 2001). There is limited information available about the impact of vitamins on the risk of early versus late miscarriage. However, dietary factors could theoretically influence structural abnormalities such as cervical incompetence. There is a growing body of research investigating the relationship between nutrition and placental development, fetal growth, pregnancy outcomes and adult diseases (McMillen 2008; Meher 2015; Wu 2004). Therefore, adequate maternal nutrition, particularly vitamin intake, may be an important factor in preventing spontaneous miscarriage. Currently, little information is available about the most appropriate vitamin type or combination. Similarly, many commercially available vitamin preparations contain a range of combinations of vitamins. Therefore, this review will cover all vitamin types.
    • pp.9-10
  • This is an update of a Cochrane review first published in 2005 and previously updated in 2011. The previously updated review included 28 trials involving 96,674 women (98,267 pregnancies(Rumbold 2011)). Based on available evidence, Rumbold 2011 concluded that taking any vitamin supplements prior to pregnancy or in early pregnancy does not prevent women from experiencing miscarriage or stillbirth. However, there is insufficient evidence to examine the effects of different combinations of vitamins on miscarriage. In the current review, we examined the effect of different vitamin combinations on the risk of miscarriage. The scope of the current update has been restricted to look at miscarriage and miscarriage-related outcomes.
    • p.10
  • Vitamin C supplementation
    The trials involving vitamin C supplementation included the following interventions: vitamin C plus multivitamins versus placebo plus multivitamins (Briscoe 1959; Hans 2010), vitamin C and vitamin E supplementation versus placebo (Chappell 1999; McCance 2010; Poston 2006; Roberts 2010; Rumbold 2006; Spinnato 2007; Xu 2010), and vitamin C alone versus no supplement or placebo (Hemmi 2003; Steyn 2003).
    Primary outcomes There was no difference in the risk of total fetal loss between women receiving:
    1. vitamin C with vitamin E (risk ratio (RR) 1.14, 95% confidence interval (CI) 0.92 to 1.40, seven trials, 18,949 women; Analysis 1.1; high-quality evidence);
    2. vitamin C alone (RR 1.28, 95% CI 0.58 to 2.83, two trials, 224 women; Analysis 2.1);
    3. vitamin C with multivitamins (RR 1.32, 95% CI 0.63 to 2.77, one trial, 406 women; Analysis 3.1);
    compared with placebo or no vitamin C groups.
    Similarly, we found no overall difference in the risk for early or late miscarriage between women receiving:
    1. vitamin C with vitamin E (RR 0.97, 95% CI 0.70 to 1.34, five trials, 15,882 women; Analysis 1.2; moderate-quality evidence);
    2. vitamin C alone (RR 1.17, 95% CI 0.52 to 2.65, two trials, 224 women; Analysis 2.2);
    3. vitamin C with multivitamins (RR 1.19, 95% CI 0.79 to 1.79, two trials, 790 women; Analysis 3.2).
    Secondary outcomes
    There was no difference in the risk of stillbirth for women receiving:
    1. vitamin C with vitamin E (RR 1.24, 95% CI 0.92 to 1.68, seven trials, 18,906 women; Analysis 1.3; moderate-quality evidence);
    2. vitamin C alone (RR 3.00, 95% CI 0.12 to 72.77, one trial, 200 women; Analysis 2.3); <br compared with placebo or no vitamin C groups. We found no difference in the risk of congenital malformations (Analysis 1.4) or adverse effects of vitamin supplementation (RR 1.16, 95% CI 0.39 to 3.41, one trial, 739 women; Analysis 1.5; moderate-quality evidence).
    • p.18-19
  • Vitamin A supplementation
    The trials involving vitamin A supplementation included the following interventions: vitamin A and/or beta-carotene versus placebo (Katz 2000; Prawirohartono 2011; West 2011), vitamin A with or without multivitamins versus multivitamins (excluding vitamin A) or placebo (Fawzi 1998), and vitamin A plus iron and folic acid versus iron and folic acid (Kumwenda 2002; Schmidt 2001; Van den Broek 2006).
    Primary outcomes
    We found no difference in the risk of total fetal loss between women receiving:
    1. vitamin A plus iron and folate (RR 1.01, 95% CI 0.61 to 1.66, three trials, 1640 women; Analysis 4.1; low-quality evidence);
    2. vitamin A alone (RR 1.05, 95% CI 0.90 to 1.23, three trials, 52,480 women; TauY = 0.01, IY = 73% Analysis 5.1);
    3. beta-carotene alone (RR 1.02, 95% CI 0.98 to 1.07, two trials, 51,163 women; Analysis 6.1);
    4. vitamin A or beta-carotene (RR 1.05, 95% CI 0.91 to 1.21, one trial, 17,373 women; Analysis 7.1);
    5. vitamin A with or without multivitamin (RR 0.80, 95% CI 0.53 to 1.21, one trial, 1074 women; Analysis 8.1);
    compared with placebo or no vitamin A groups.
    The heterogeneity in Analysis 5.1 seemed to have been contributed by combining two cluster-randomised trials and one individually-randomised trial. Heterogeniety was no longer present when the individually-randomised trial was excluded. However, this did not

change the conclusion of no significant difference between vitamin A and no vitamin A groups.
There was no evidence of a difference in the risk for early or late miscarriage between women receiving:
1. vitamin A plus iron and folate (RR 0.86, 95% CI 0.46 to 1.62, two trials, 1397 women; Analysis 4.2; low-quality evidence);
2. vitamin A alone (RR 0.98, 95% CI 0.92 to 1.04, one trial, 39,668 women; Analysis 5.2);
3. beta-carotene alone (RR 1.00, 95% CI 0.94 to 1.06, one trial, 39,860 women; Analysis 6.2);
4. vitamin A with or without multivitamin (RR 0.76, 95% CI 0.37 to 1.55, one trial, 1075 women; Analysis 8.2); compared with placebo or no vitamin A groups.
Secondary outcomes
There was no difference in the risk for stillbirth for the following supplementation treatments:
1. vitamin A plus iron and folate (RR 1.29, 95% CI 0.57 to 2.91, three trials, 1640 women; Analysis 4.3; low-quality evidence);
2. vitamin A alone (RR 0.95, 95% CI 0.86 to 1.06, one trial, 39,668 women; Analysis 5.3);
3. beta-carotene alone (RR 1.09, 95% CI 0.98 to 1.20, one trial, 39,860 women; Analysis 6.3);
4. vitamin A with or without multivitamin (RR 1.04, 95% CI 0.60 to 1.79, one trial, 1075 women; Analysis 8.3); compared with placebo or no vitamin A groups. Congenital malformations and adverse effects of vitamin supplementation were not reported by trials included in these analyses.

    • p.19
  • Multivitamin supplementation
    The trials involving multivitamin supplementation included the following interventions: multivitamins with or without folic acid versus no multivitamins or folic acid (Czeizel 1994; ICMR 2000; MRC 1991); multivitamins with or without folic acid versus folic acid (Kirke 1992; MRC 1991; Zeng 2008); multivitamins with or without vitamin A versus vitamin A or placebo (Fawzi 1998); multivitamins versus control (People's League 1942); multivitamins with vitamin E versus multivitamins without vitamin E or control (Rush 1980); multivitamins with iron and folic acid versus iron and folic acid (Bhutta 2009; Fawzi 2007; Osrin 2005; Roberfroid 2008; Rumiris 2006; Sunawang 2009; Summit 2008; Tofail 2008; West 2014; Zagre 2007).
    Primary outcomes
    The risk for total fetal loss was reduced in women supplemented with:
    1. multivitamin without folic acid (RR 0.49, 95% CI 0.34 to 0.70, one trial, 907 women; Analysis 10.1);
    2. multivitamin with/without vitamin A (RR 0.60, 95% CI 0.39 to 0.92, one trial, 1074 women; Analysis 15.1);
    compared with placebo or no multivitamin groups.
    There was no difference in the risk of total fetal loss for the following interventions:
    1. multivitamin plus iron and folic acid compared iron and folate only groups (RR 0.96, 95% CI 0.93 to 1.00, 10 trials, 94,948 women; Analysis 9.1; high-quality evidence);
    2. multivitamins alone or in combination with other vitamins or micronutrients compared with placebo or no multivitamins groups (Analysis 11.1; Analysis 12.1; Analysis 13.1; Analysis 14.1; Analysis 16.1; Analysis 17.1; Analysis 18.1 (random effects; three trials)).
    Similarly, we found no difference in the risk for early or late miscarriage between women receiving the following interventions:
    1. multivitamin plus iron and folic acid compared iron and folate only groups (RR 0.98, 95% CI 0.94 to 1.03, 10 trials, 94,948 women; Analysis 9.2; moderate-quality evidence);
    2. multivitamins alone or in combination with other vitamins or micronutrients compared with placebo or no multivitamins groups (Analysis 10.2; Analysis 11.2; Analysis 12.2; Analysis 13.2; Analysis 14.2; Analysis 17.2; Analysis 18.2 (random effects; three trials)).
    The heterogeneity in Analysis 18.1 and Analysis 18.2 seemed to have been contributed by ICMR 2000, which included women who had previously given birth to a child with an open neural tube defect. When this trial was excluded, the heterogeneity was no longer present.
    Secondary outcomes
    There was evidence of a decrease in the risk for stillbirth among women receiving multivitamin plus iron and folic acid compared iron and folate only groups (RR 0.92, 95% CI 0.85 to 0.99, 10 trials, 79,851 women; Analysis 9.3; high-quality evidence).
    There was no difference in the risk of:
    1. stillbirth (Analysis 10.3; Analysis 11.3; Analysis 12.3; Analysis 13.3; Analysis 14.3; Analysis 16.2; Analysis 17.3; Analysis 18.3); or
    2. congenital malformation (Analysis 10.4; Analysis 11.4; Analysis 12.4; Analysis 13.4; Analysis 14.4; Analysis 18.4) between women receiving multivitamins alone or in combination with other vitamins or micronutrients compared with placebo or no multivitamins groups.
    There were no data available to conduct any analysis for adverse effects of vitamin supplementation.
    • pp.19-20
  • Folic acid supplementation
    The trials involving folic acid supplementation included the following interventions: folic acid with or without multivitamins compared with no folic acid or multivitamins (Czeizel 1994; ICMR 2000; MRC 1991); folic acid with or without multivitamins compared with multivitamins (Kirke 1992; MRC 1991); folic acid and iron compared with iron (Fleming 1968); folic acid and iron compared with no iron or folic acid (Fleming 1986).
    Primary outcomes
    We found no difference in the risk of:
    1. total fetal loss (Analysis 19.1 (random effects; three trials); Analysis 20.1; Analysis 21.1; Analysis 22.1; Analysis 23.1; Analysis 24.1; Analysis 25.1; Analysis 26.1); or
    2. early or late miscarriage (Analysis 19.2 (random effects; three trials); Analysis 20.2; Analysis 21.2; Analysis 22.2; Analysis 23.2; Analysis 24.2; Analysis 25.2; Analysis 26.2);
    between women supplemented with folic acid with or without multivitamins and/or iron compared with no folic acid groups. The heterogeneity found seemed to have been contributed by ICMR 2000, which included women who had previously given birth to a child with an open neural tube defect. Excluding this trial removed the heterogeneity but did not change the conclusion of no difference between the treatment groups.
    Secondary outcomes
    There was no difference in the risk of:
    1. stillbirth (Analysis 19.3; Analysis 20.3; Analysis 21.3; Analysis 22.3 (random effects); Analysis 23.3; Analysis 24.3 (random effects); Analysis 25.3); or
    2. congenital malformations (Analysis 19.4; Analysis 20.4; Analysis 21.4; Analysis 22.4 (random effects); Analysis 23.4; Analysis 24.4 (random effects)) between women supplemented with folic acid with or without multivitamins and/or iron; compared no folic acid groups. There were no data available to conduct any analysis for adverse effects of vitamin supplementation.
    • p.20
  • Antioxidant vitamins supplementation
    The trial involving antioxidant vitamins supplementation included the following interventions: antioxidant with multivitamins compared multivitamins with low antioxidant content (Wibowo 2012).
    Primary outcomes
    In the one trial involving 110 women (Wibowo 2012), there was no evidence of differences between women given antioxidant with multivitamins compared multivitamins with low antioxidant group on early or late miscarriage (RR 1.12, 95% CI 0.24 to 5.29, one trial, 110 women, Analysis 27.1). No other primary or secondary outcomes were reported by this trial.
    • p.20
  • The purpose of this review was to determine the effectiveness and safety of any vitamin supplementation taken by women

pre- or periconceptionally on the risk of miscarriage. In this updated version of the review, we included 40 studies involving 59,094 women from individually-randomised trials plus a further 217,726 women from eight cluster-randomised controlled trials. The results did not provide sufficient evidence to support the use of single vitamin supplementation for preventing total fetal loss or early or late miscarriage. However, stillbirth was significantly lower in women given multivitamin supplementation plus iron and folic acid compared to iron and folic acid alone. Although there was evidence of decreased risk for total fetal loss among women receiving multivitamins without folic acid compared with no multivitamin/folic acid and multivitamin supplementation with/ without vitamin A compared with vitamin A or placebo; these findings occurred in analyses involving one trial each with small numbers of women involved. Also, they include studies where the comparison groups included women receiving either vitamin A or placebo, and thus require caution in interpretation.

    • p.21
  • There are several Cochrane reviews evaluating the effect of single vitamin supplementation during pregnancy on maternal, fetal, neonatal and infant outcomes. Benefits or hazards of vitamin supplementation in pregnancy on total fetal loss and miscarriage have not been or insufficiently investigated. However, our results on secondary outcomes are consistent with finding in the particular publications.
    In the analysis by vitamin type, vitamin C supplementation alone or in combination with vitamin E or multivitamins did not show any effect on total fetal loss, miscarriage, or the secondary outcomes stillbirth, congenital malformation and adverse effects. A review focusing on vitamin C supplementation alone or in combination with other separate supplements on pregnancy outcomes, did not observe effects on stillbirth or congenital malformations which is consistent with our results (Rumbold 2015).
    Supplementing women with vitamin A alone or in combination with iron and folic acid or multivitamins was not associated with changes in fetal loss or miscarriage as well as stillbirth. These findings are consistent with the Cochrane review 'Vitamin A supplementation during pregnancy for maternal and newborn outcomes' (McCauley 2015), which found no difference in the rate of stillbirth for women receiving vitamin A alone compared with placebo/no treatment or vitamin A with other micronutrients compared with micronutrient supplementation without vitamin A.
    In the analysis comparing multivitamin alone or in combination with other vitamins, we found a positive effect of multivitamin supplementation without folic acid compared with no multivitamin/folic acid as well as multivitamin with/without vitamin A compared with vitamin A alone or placebo on total fetal loss. However, these findings resulted from only one study, respectively. Stillbirth was significantly reduced for women receiving multivitamin plus iron and folic acid. This result is consistent with findings in a review assessing the effect of multiple-micronutrient supplementation during pregnancy on maternal, fetal and infant health outcomes (Haider 2015). Here they also reported a significant reduction in the risk of stillbirth. Miscarriage (loss before 28 weeks) was not effected by this intervention.
    Folic acid supplementation with or without multivitamin compared to no folic acid/multivitamin or multivitamin alone did not reduce the risk of total fetal loss, miscarriage, stillbirth or congenital malformations. This in accordance with a review evaluating the effectiveness of oral folic acid supplementation during pregnancy on maternal health and pregnancy outcomes (Lassi 2013). The authors did not observe any effect of folic acid supplementation on stillbirth. Even though miscarriage was included as a secondary outcome, none of the included studies reported on miscarriage. In addition, another review assessed the effects and safety of periconceptional oral folate supplementation for preventing birth defects (De-Regil 2015). There was no effect of folate versus no intervention, placebo or other micronutrients without folate on miscarriage or stillbirth. They investigated the effect of folate supplementation on several congenital malformations and found a 69% reduction in the risk of neural tube defects.
    Antioxidant vitamin supplementation had no effect on early or late miscarriage. The effectiveness and safety of any antioxidant supplementation during pregnancy on the risk of various pregnancy outcomes is explored in the Cochrane review 'Antioxidants for preventing pre-eclampsia' (Rumbold 2008). Our results are in accordance with the results form this review where any antioxidant supplementation compared to control or placebo had no effect on miscarriage or stillbirth.
    • pp.24-25
  • Implications for practice
    There is no evidence to support the prophylactic use of single vitamins to prevent either early or late miscarriages. Supplementing women with multivitamin with or without iron and/or folic acid or vitamin A, may decrease the risk of total fetal loss and stillbirth, Even though there is a positive effect of multivitamin supplementation on pregnancy outcomes, there was insufficient evidence to examine the effect of different combinations of vitamins on miscarriage and miscarriage-related outcomes. Our findings suggest, that no particular vitamin decreases the risk of miscarriage or stillbirth, but the combination of various vitamins may have the potential to positively influence pregnancy outcomes. This could be due to an overall improvement in maternal nutrition and health status, making women more resistant to infections during pregnancy. However, this needs to be investigated further before recommendations on routine multivitamin supplementation to prevent miscarriage can be given.
    Implications for research
    The impact of different combinations of vitamins (i.e. individual vitamins or multivitamin preparations with or without vitamin A and folic acid) on miscarriage and miscarriage-related outcomes is unclear. Any future studies of vitamin supplementation should be high quality and focus on women at high risk of miscarriage. Considerations should include timing of the intervention and trials should assess the most appropriate vitamin type and dosage; to see whether it is beneficial without causing any harms to the mother or fetus and include assessments of any psychological effects and long-term follow-up of mothers and infants. Further, the data in the current review were complicated by differing definitions of miscarriage and so this may be an important issue to consider in any future trials.
    • p.25

"Female behaviour plays a critical role in controlling murine pregnancy block" (May 2009)[edit]

Stuart D. Becker and Jane L. Hurst (May 2009). "Female behaviour plays a critical role in controlling murine pregnancy block". Proceedings. Biological Sciences. 276 (1662): 1723–9. doi:10.1098/rspb.2008.1780. JSTOR 30245000. PMC 2660991. PMID 19324836.

  • Exposure of recently mated female rodents to unfamiliar male scents during daily prolactin surges results in pregnancy failure (the ‘Bruce effect’). Control of nasal contact with male scents during these narrow windows of sensitivity could allow females to maintain or terminate pregnancy, but female behavioural changes specifically during this critical period have not been investigated. We examined the approach or avoidance of familiar stud strain and unfamiliar male scents by recently mated female mice. Females that maintained pregnancy avoided both unfamiliar and familiar male scent during critical periods of susceptibility for the Bruce effect. By contrast, females that did not maintain pregnancy showed a sharp rise in the time spent with unfamiliar male scent during this critical period. Manipulation of the social status of unfamiliar and stud strain scent donors did not affect the likelihood of pregnancy block, although females spent more time with dominant male scents across all time periods. The ability to control the Bruce effect through behaviour during brief sensitivity just before dusk, when females are likely to be in nest sites, provides a mechanism by which females may adjust their reproductive investment according to nest site social stability and likelihood of offspring survival.
  • Exposure of female laboratory mice to the urinary scent of an unfamiliar male within a limited time after mating causes pregnancy disruption and return to oestrus (the ‘Bruce effect’, Bruce 1959; Parkes & Bruce 1961). Since its discovery in mice, pregnancy block has been confirmed in several other murine and microtine rodent species (e.g. Storey 1986; de la Maza et al. 1999; Mahady & Wolff 2002). Pregnancy disruption is triggered by semio-chemicals in rodent urine that are pumped into the lumen of the vomeronasal organ following nasal contact with male scent (Meredith & O'Connell 1979; Luo et al. 2003). This activates a specific vomeronasal neuroendocrine pathway that inhibits prolactin release (Bellringer et al. 1980; Rajendren & Dominic 1993). As prolactin is essential for maintaining luteal function during early pregnancy in rodents (Stormshak et al. 1987), this inhibitory pathway causes luteolysis and hence pregnancy failure. The duration of sensitivity to pregnancy-blocking signals varies between species, ranging from 4 to 5 days post-mating (pre-implantation) in Mus (Parkes & Bruce 1961) up to 17 days post-mating (pre- and post-implantation) in microtine species (Stehn & Jannett 1981).
    The timing of exposure to unfamiliar male scent is critical. Around oestrus, female rodents show daily prolactin surges, increasing to twice daily after mating and peaking approximately 1 hour before the change to light and dark periods (Barkley et al. 1978; Ryan & Schwartz 1980). Pregnancy block occurs only if females are exposed to male scent coincident with two prolactin peaks, at least one during the light phase, while exposure outside these peaks fails to cause pregnancy block (Rosser et al. 1989).
    During the 4–6 hours period after mating, females learn the scent signature of the stud male, with memory formation contingent on mating (Kaba et al. 1989; Brennan et al. 1990). Exposure to the stud male's scent after mating, or to scent from males that are genetically identical to the stud male, fails to disrupt pregnancy (Bruce 1960; Rülicke et al. 2006) and may reduce the likelihood of pregnancy block if females are concurrently exposed to unfamiliar male scent (Kumar & Dominic 1993). Studies commonly define familiar and unfamiliar males according to whether they are from the same or different inbred strain of genetically identical individuals, such as C57BL/6, CBA or BALB/c (e.g. Yamazaki et al. 1983; Rosser et al. 1989; Peele et al. 2003). In addition, others have suggested that socially dominant males may be more likely to trigger pregnancy block, as females that terminate gestation and remate with such animals could reduce the risk to their offspring from infanticidal behaviour by non-stud males (Labov 1981a; Huck 1982).
  • Despite extensive research into the neurophysiological mechanisms and scent stimuli that cause pregnancy block, the functional significance and evolutionary advantage of this response to females under natural conditions remains an enigma (Bronson & Coquelin 1980; Brennan & Peele 2003). A substantial barrier to understanding the natural circumstances of this response is that the laboratory studies generally prevent females from controlling their exposure to male cues, either through the use of small cages or by applying stimuli directly to the female nares. However, females may be able to control their exposure to scents that elicit pregnancy block under more free-ranging conditions, given the very narrow window of sensitivity around dawn and dusk over a few days after mating (when females are likely to be within their nest sites), and the requirement for females to actively contact and pump scents to the vomeronasal organ. This could provide females with a mechanism to terminate investment in gestation and subsequent lactation under particular circumstances, where survival of their offspring is at risk because the nest sites cannot be effectively defended against disturbance from unfamiliar animals (Becker & Hurst 2008).
  • Earlier studies on the behaviour of recently mated females towards male scents are conflicting. Drickamer (1989) found a general avoidance of unfamiliar male scent during the early stages of gestation when wild-derived females were presented with paired samples of soiled male bedding. Conversely, deCatanzaro & Murji (2004) reported attraction of inbred CF1 females to unfamiliar male scent. However, neither of these studies tested females during the sensitive period for the Bruce effect.
    Here, we investigate whether recently mated females control their exposure to male scent cues at critical times for pregnancy block, in relation to whether or not they maintain pregnancy. The implications of female control of scent exposure for the functional significance of the Bruce effect under natural conditions are discussed.
  • This experiment demonstrates that female mice are able to control whether or not gestation is blocked by choosing to, respectively, contact unfamiliar male scent or avoid all male scent at sensitive times for the Bruce effect.
  • As previously discussed, pregnancy block occurs only if females are exposed to male scent coincident with two prolactin peaks, at least one during the light phase, while exposure outside these peaks fails to block pregnancy (Rosser et al. 1989). It was suggested above that the unusual sharp rise in time spent with novel male scents by blocking females, observed 70–75 min before dark, may reflect a specific attraction to novel male scent on reaching a threshold level of prolactin among these females. Rodent prolactin levels have been shown to influence several behaviours that may affect reproductive success, including mating strategy (Schradin 2008), parental behaviour (Storey et al. 2006) and anxiety (Torner et al. 2001). Changes in prolactin through the oestrus cycle have been measured in trunk blood in a limited number of serial sampling studies in mice (Michael 1976; Barkley et al. 1978; Ryan & Schwartz 1980). While these studies confirm that a surge in prolactin occurs approximately 1 hour before dark, in all cases measurements were taken at intervals of 1–2 hours. Thus, it remains unclear about how the observed behaviour of females in the present study might correspond to specific changes in prolactin secretion at a finer temporal scale.
    Female control of exposure to male scent at critical times may help to explain why similar pregnancy-blocking stimuli have produced conflicting results in earlier experiments. Many early studies into the Bruce effect appear to assume that it evolved for male advantage (reviewed by Schwagmeyer 1979), and the presence of a male or his scent are assumed to result inevitably in female exposure (e.g. Bruce 1963; Labov 1981a; Huck 1982). Correspondingly, most experimental designs have attempted to prevent females from controlling exposure to male scent, but this may not have been achieved in some cases. For example, in one study examining how the social status of males influenced their ability to trigger pregnancy block (Labov 1981a), females were housed directly below males, while a similar study (Huck 1982) housed females adjacent to males, separated by mesh. The pregnancy-blocking ability of dominant males was equal to subordinate males in the former study, but more efficacious in the latter. As the former study enforced female proximity to male scent while the latter did not, it is possible that females were able to exert some control over their exposure to male scent in the apparatus used by Huck (1982) but not by Labov (1981a). In addition, in the design described by Huck, the social status of the male scent donor may have influenced the intensity of contamination of the female area with male scent. As dominant males produce copious scent marks throughout their territory, while subordinates do not (Desjardins et al. 1973), contamination of the female area with male scent is likely to have been greater when adjacent to a dominant, rather than a subordinate male. In the present study, male social status had no effect on the likelihood of pregnancy block, supporting the findings of Labov (1981a).
  • Central to many of the arguments for male reproductive advantage in pregnancy block is the assumption that females will remate with the blocking male after terminating their current gestation, but this behaviour has not been demonstrated except in situations of enforced cohabitation (Labov 1981b). Indeed, females able to evade such male-induced reproductive costs are likely to be at a significant evolutionary advantage, and intriguingly, in tests conducted under free-ranging conditions, females maintained pregnancy despite artificial replacement of stud males in their enclosure (Mahady & Wolff 2002).
    The adaptive advantages of a passive female response to male scent have been queried repeatedly (e.g. Bronson & Coquelin 1980; Brennan & Peele 2003), and several authors have proposed hypothetical female advantages for the Bruce effect. These include enabling the female to remate if deserted by the original stud male (Dawkins 1976), avoidance of male infanticide (Labov 1981b; Storey 1986) or post-copulatory mate choice for a preferred stud male (Labov 1981a; Huck 1982; Coopersmith & Lenington 1998; Rülicke et al. 2006).
  • The issue of timing has frequently been overlooked in previous studies, but appears to be of critical importance in the interaction between behaviour and pregnancy block. By altering their exposure to male scent during brief periods of sensitivity, females could choose to maintain or terminate pregnancy in the presence of unfamiliar male scent with minimal impact on normal behaviour at other times. Recently, we proposed that females could use pregnancy block to terminate investment in gestation where risk to offspring survival was increased (Becker & Hurst 2008). Females that maintained pregnancy in the present study avoided the scents of all males during the critical sensitive period for the Bruce effect, regardless of the efficacy of the scents to block pregnancy, by remaining mostly in the central cage. Females that do not explore areas containing male scents during the critical period may avoid accidental exposure to close nasal contact with the scents of unfamiliar males, particularly given the propensity of males to countermark each other, which increases the risk that familiar and unfamiliar scents may be found together.
    Furthermore, the sensitive period, occurring approximately 1 hour before dark (Rosser et al. 1989), coincides with the time females are most likely to be in sheltered nest sites (Refinetti 2004). If females remain within the nest during this sensitive period, their exposure will be restricted to other animals that share their nest through the light phase. Social disruption of maternal behaviour has been suggested as the main factor affecting offspring survival in mice (Peripato et al. 2002). Its importance can be seen in the sharp decrease in pup survival, and hence female reproductive success, in nest sites that cannot be defended effectively, particularly those used by a large number of animals including non-stud males (Southwick 1955). Pregnant females strongly defend their nest sites (Vom Saal et al. 1995), but their ability to do so depends on the physical protection afforded by the site and social pressure to use limited sites of shelter (Wolff 1985; Hurst 1987). The presence of fresh scents from other males, particularly from outside a familiar stable group, would indicate a nest site not defended effectively. Avoidance of male scents would allow pregnant females to avoid settling in such sites and, since pregnancy block occurs only in response to fresh scent (Peele et al. 2003), by the end of the light phase females will have had ample opportunity to exclude males or to leave the nest for an alternative. However, where this is not possible (e.g. because defendable nest sites are limited), females that terminate pregnancy until they can find a more suitable nest will avoid wasted investment, particularly prior to implantation.
  • Thus, rather than providing a reproductive benefit to males as traditionally assumed, the Bruce effect may have evolved solely to female advantage. Investigation of how the apparent stability of nest sites influences the outcome for the maintenance or blocking of pregnancy, and the analysis of remating strategies following pregnancy block, including paternity and the subsequent willingness of females to remate, will be essential to evaluate the advantages and disadvantages of the Bruce effect from both a female and male perspective.

“Superfertility is more prevalent in obese women with recurrent early pregnancy miscarriage” (2015)[edit]

HM Bhandari, BK Tan, S Quenby; [1]ry.wiley.com/doi/full/10.1111/1471-0528.13806 “Superfertility is more prevalent in obese women with recurrent early pregnancy miscarriage”], BJOG, Volume 123, Issue 2, (29 December 2015)

  • Miscarriage remains the most common complication of pregnancy despite many advances in the understanding of early pregnancy. Loss of three or more consecutive pregnancies before 24 weeks of gestation is the most acceptable definition for recurrent miscarriage (RMC) in Europe, but has recently been defined by the American Society for Reproductive Medicine as a disease with two or more failed pregnancies. Despite best efforts to identify the underlying causes for RMC, it remains “unexplained” in the majority of cases. Chromosomal errors appear to be common in the pre-implantation developing embryos, which predispose to increased risk of pregnancy losses. High rates of chromosomally abnormal cells within human embryos mean that the reproductive success is dependent on the endometrial ability to distinguish between normal and abnormal embryos. In vitro studies have provided convincing evidence that perturbation in the bio-sensor function of the decidualised endometrium is an important mechanism underpinning RMC.
  • Our study findings are supportive of the concept that increased female BMI may have a negative in-fluence on the early pregnancy outcome. We found a significant positive correlation between the BMI and first trimester pregnancy losses and anembryonic miscarriages. There were also significantly more first trimester miscarriages in obese women than in normal weight or overweight women with recurrent miscarriage.
  • A study that examined miscarriage type and fetal karyotypes in RMC women found that very early pregnancy losses (anembryonic and embryonic loss with embryo <3 mm) are more likely to be karyotypically normal and embryonic miscarriage (with embryo ≥3 mm) and fetal demise to be karyotypically more likely abnormal.36 It is possible to speculate from our study findings that obesity is likely to be associated with an increased risk of first trimester miscarriages and, in particular, increases the risk of miscarriage of anembryonic pregnancies, which are likely to be karyotypically normal. However, it re-mains uncertain whether BMI may have any significant effect on the embryo loss pattern, and further well-controlled studies are required to analyse their association.
  • It is likely that an alternate mechanism exists in obesity that may be responsible for “biological super-fertility” in obese women. Teklenburg et al. elegantly showed that the endometrial stromal cells transform into biological sensors of embryo quality upon decidualisation. There is a good body of evidence, from in vitro studies, to suggest that inability of the peri-implantation endometrium to mount an adequate decidual response, impairs embryo recognition and selection upon implantation, which leads to shorter TTP intervals and predisposes to RMC. This abnormal phenotype results in an extended window of implantation, which reduces the endometrial ability to be “selective” in response to embryo quality. This concept is consistent with the previously reported association of late implantation of embryos with an increased risk of early miscarriage. The findings from our study may suggest that an obesogenic environment might have a negative influence on the peri-implantation endometrium, which would predispose women to RMC.
  • Our study findings support the concept of “biological superfertility” in women with RMC and present a unique finding that superfertility may be more prevalent in obese women with a history of RMC. Further prospective studies in women with idiopathic RMC are required to confirm the association of BMI, RMC and superfertility. If confirmed, further investigation is required to understand why obesity predisposes to superfertility. It is likely that superfertility may be linked to impaired endometrial development in the peri-implantation period; further research to describe the peri-implantation endometrium in obese women and to study the exact mechanism by which obesity affects the endometrium is required. Clinical trials with therapeutic targets to improve decidualisation and thus reproductive outcome in obese women could hold significant clinical potential.

"Miscarriage: Emotional considerations and support" (October 2004)[edit]

"Miscarriage: Emotional considerations and support". Birth.com.au. October 2004. p. 13.

  • The emotions you experience after the loss of your baby through miscarriage is very personal and as with every life experience, it is unique to the individual. Miscarriage is a relatively common occurrence but this does not mean it is a 'minor' event. The loss you may feel can to some extent be magnified if you have had previous miscarriages and/or have been trying to conceive for a while or were using fertility treatments.
    Many women (and their partners) will describe an array of responses after their miscarriage. Some women will say in retrospect that they 'knew' their baby had gone, even before the signs of miscarriage appeared. Reactions can range from being philosophical and accepting, to very devastated and profoundly affected, perhaps with a sense of failure. It is not uncommon to feel numb and perhaps shocked and in denial that it has happened. Some women will feel guilty because they were unsure about wanting the pregnancy, or perhaps relieved in a sense if the pregnancy was not planned. These can be mixed with overwhelming emotions of sadness, blame, jealousy, heartache, emptiness, disbelief, confusion and anger, in the days, weeks or months that follow. However, whatever your reactions, it is important to remember that there is no wrong or right way to grieve when dealing with your miscarriage.
    You may find that your emotions affect your appetite and ability to sleep. Or you may feel constantly tired and have difficulty concentrating. Some people are physically unwell and less able to cope with life. You may not want to socialise very much, nor be with others (especially pregnant women and parents). These are all very normal reactions to losing your baby. If you feel you are depressed and this continues for a long time, you may need to seek professional help. It is not unusual to relive your grief and experience these feelings again around the time your baby would have been due, or on annual anniversaries after the miscarriage occurred.
    Many women talk about bizarre dreams and/or nightmares after their miscarriage. As examples, the dream may be one of giving birth to your baby and everything being 'all right' or it could be a nightmare where you or a family member faces personal danger and their safety is threatened. For some woman the nightmares are incredibly vivid and their experiences so strong and fearful, they leave them feeling upset or unsettled upon waking. Some women will see a homoeopath for a remedy to help with these feelings.
    Be aware that men and women will tend to grieve very differently and if you are with a partner, each person's emotional reactions to the miscarriage may place an enormous strain on the relationship. The experience may bring you closer together, or you may feel that your partner does not understand your feelings or is unable support you in any way. Many men are concerned with their partner's well being, but find it difficult to express their own feelings and can feel powerless to help. At the same time they can be grappling with their own feelings of grief and loss. Some men feel they need to 'stay strong' and in doing this they suppress their own feelings. It may be that you need to encourage your partner to show how he really feels and to express his grief.
    When a woman experiences more than one miscarriage, each loss can bring up different emotions and reactions. For some, the very possibility of ever having a child, and the dreams and hopes associated with this, can begin to slip away. Feelings of fear, distress and anxiety may grow as the couple start to consider the possibility that perhaps they will never be able to have a baby together.
    Try not to expect too much of yourself at this time. Allow yourself adequate time and space to grieve and make it so that you are only with people you feel comfortable with. It is important to remember that you will recover, but that this will happen in your own way and in your own time. The pain of your miscarriage may never leave you completely, but it will be easier to live with as time passes.
  • Others around you
    Society in general does not cope well with the concept of death 'colliding' with a new baby and birth. For many, miscarriage is still considered a 'private matter', possibly even regarded as taboo and not an appropriate topic to talk about openly. However, change is slowly occurring as more people openly articulate their feelings about their pregnancy loss. This slow shift in attitudes increasingly provides permission for grieving parents to acknowledge their miscarriage and validate the pain they are feeling. For many women and their partners, part of their healing comes from letting others know and sharing their grief, as well as taking advantage of the offers of help, sympathy and support. However, others will feel quite alone in their grief because friends, family and others were not yet aware of their pregnancy.
    In some countries, rituals and ceremonies openly acknowledge the loss of a baby through miscarriage. In Japan, the baby is called 'mizuko' or 'water child' and a ritual by the mother called 'Jizo' helps the baby find another 'pathway into being'. The mother places a statue or offering in a sacred place as a spiritual acknowledgement of her lost child.
    People touched by miscarriage will react in varying ways. One very sad attitude towards miscarriage is the common concept that it is 'low' on a preconceived hierarchy of grief. For some reason, many people view miscarriage as a less acceptable reason to mourn. This can cause women and their partners to suppress their emotions and grieve in silence, often seeming as if the pregnancy and baby never existed. This can add to a deeper dimension of loss and grief. Women bond with their baby as soon as they know they are pregnant, some even before this time while they are trying to conceive. After a miscarriage, many women feel that no one really understands what they are going through.
    It can be of great help if you have close friends and relatives who understand your loss. It is amazing how many others will start to share with you their own experiences of miscarriage (even people who did not previously let you know this had happened for them). This can give you a sense of not being alone and a degree of hope if they have gone on to have a healthy baby. However, being told by others that "It wasn't meant to be.' or "You will have another baby soon.' is not really helpful. It also dismisses the importance of the child you have lost and fails to validate your grieving.
    Going through the process of expressing and exploring your feelings doesn't alter the loss, but it can move the pain into some form of acceptance. When talking with women about past miscarriages (even several years later) it is not uncommon to see how painful and raw their sadness still is, especially if they were not given opportunities to openly deal with their grief at the time.
    The reactions of caregivers at this time can leave a lasting impression. If the professionals you deal with are compassionate, sympathetic and caring, this can make the miscarriage experience much easier to bear. However, if your caregiver comes across as being very matter-of-fact and uncaring (perhaps they are busy and it is true they do deal with miscarriages all the time) this can increase your feelings of anger and resentment. For some women it is enough for them to make arrangements so they do not need to associate with them again in the future.
  • Future pregnancies
    Thinking about having another baby is a very personal decision. You should talk about your feelings with your partner. Some people need time to work through their grief before feeling emotionally ready to 'try again'. For others the question is "Can I try again?' It can often seem an almost unmanageable task to get through those early weeks of pregnancy again, to reach the ultimate goal of having a baby. A few women will be upset that they had endured the weeks of morning sickness and discomforts, only to have to now face the prospect of starting these all over again.
    It is a normal grief reaction to want to 'immediately put things back the way they were' in a sense. This is why many women have an initial reaction to want a pregnancy after miscarriage as soon as possible. While this is OK (and you may find that this is exactly what happens), just try to be aware that you may need to work through the grief of losing this baby, before moving on. A subsequent pregnancy is not a replacement, but a new pregnancy with a new baby, often accompanied by much fear and anxiety that another miscarriage may occur.
    Women who experience one miscarriage are not more likely to experience another (unless they have a medical condition that is likely to cause recurrent miscarriages). Therefore, if there are health concerns or further investigations are recommended because you have had recurrent miscarriages, waiting until these are completed and any findings are discussed with your caregiver may be necessary.
    Up to 95% of women who experience one miscarriage will go on to have a healthy baby with a subsequent pregnancy and up to 75% of women who have had 3 or more miscarriages will have a subsequent normal pregnancy and baby. While these statistics can be reassuring, the thought of another pregnancy can still be daunting, even terrifying for some women.
    Once you are pregnant, feeling anxious and uneasy until the pregnancy is well advanced (or even until the baby is born) is very normal. Often women will try not to consciously bond with their baby until this time and/or avoid telling others about their new pregnancy until they feel more confident. However, it may help to let others know your fears and have someone you trust to share your feelings with. Talking with your caregiver or even seeking professional counselling at this time may be appropriate.

"The History of Talking About Miscarriage" (Retrieved April 26, 2018)[edit]

Blei D. "The History of Talking About Miscarriage". The Cut. (Retrieved April 26, 2018).

  • Exact numbers are hard to parse, but miscarriage is common, occurring in at least one in five pregnancies, the odds rising with age. Chromosomal abnormalities that spell doom for a growing embryo are usually to blame. Once the body realizes the pregnancy won’t develop, nature takes over, rejecting it. Women have, of course, been miscarrying since the beginning of time; stories of miscarriage go back as far as the Hebrew Scriptures. But the ways we talk about miscarriage have changed, especially in recent decades. A woman’s response to losing a pregnancy, however emotional and personal, never takes place in a vacuum.
    After losing her pregnancy at 16 weeks, Dr. Jessica Zucker launched the social-media campaign #ihadamiscarriage to confront the cultural silence around pregnancy loss by encouraging women to share their experiences online. Stories aligned with Dr. Zucker’s movement — and miscarriage more broadly — have cemented an idea in our minds: that women have forever suffered in silence. A Google search returns a slew of headlines: “Women Aren’t Meant to Talk about Miscarriage” (The Guardian); “5 Reasons We Need to Talk about Miscarriage Because a Culture of Silence Isn’t Good Enough” (Bustle); “Breaking the Silence on Miscarriages” (New Republic). When Mark Zuckerberg and Priscilla Chan announced in 2015 that they were expecting a baby girl after suffering three miscarriages, the internet exploded in praise for the couple’s revolutionary candor. The only problem with today’s narrative is that it’s not quite accurate — the cultural silence around miscarriage is relatively new.
  • Shannon Withycombe, a historian and the author of the forthcoming Lost: The Meanings of Miscarriage in 19th-Century America, spent years digging through archives, women’s personal writings, and doctors’ publications. “I found a huge range of responses and interpretations of miscarriage,” she told me. Women expressed “grief, frustration, resignation, relief, and joy. Miscarriage could lead to death and it could be a minor inconvenience.” By the late 19th century, explained Withycombe, as birth control and abortion were becoming illegal in America, there weren’t many ways to limit family size. Losing a pregnancy, in this context, could mean many different things for different women.
    In 1928, Margaret Sanger, the crusader for birth control, published Motherhood in Bondage, a collection of heartrending letters she’d received over the years from women (and some men), all of them desperate to avoid pregnancy. Teeming with accounts of miscarriage, Sanger’s book shows that silence was hardly the cultural norm. “I get pregnant every two or three months and in a few weeks miscarry. I realize it is killing me,” wrote a mother of four. “Soon I’ll be gone and who will see to my little children?” Miscarriage was once synonymous with dangerous hemorrhages and infections, not to mention financially draining medical costs — no wonder women talked about this life-or-death matter. The birth-control movement fought to emancipate women, not just from unwanted pregnancies, but from the burdens of miscarriage.
    That was nearly a century ago, but even as recently as the 1970s, miscarriage was seen as a public-health issue. Historian Leslie Reagan examined changing magazine coverage over the course of the 20th century, and found that the silence of the past is “overstated.” Reagan wanted to know: How and when did miscarriage become a private tragedy? Whereas stories that ran in women’s magazines once framed miscarriage as a medical matter, a blessing (nature doing its work), or a public-health issue, eventually, a different narrative emerged. Even the photos that accompanied these stories prove Reagan’s point: Articles about miscarriage once featured pictures of happy babies and healthy mothers, a promise for the future. Only recently did another image take over the genre: the empty crib, or the sad, isolated woman, sitting alone on her bed.
  • For many women in the 1970s, miscarriage represented the opposite of private tragedy. These women saw it as a call to public action and as such, took matters into their own hands. Lois Gibbs, a stay-at-home mom in Love Canal, New York, convinced her neighbors to help research the effects of living on a former chemical dump. With the help of a volunteer scientist, Gibbs and her community uncovered higher-than-average rates of miscarriage, stillbirth, and crib deaths. In another high-profile case (one of several that decade), Bonnie Hill, a mom and teacher in western Oregon who miscarried in 1975, led a study that suggested links between the spraying of an herbicide in the nearby national forest and rising rates of miscarriage. Spurred to investigate, the EPA eventually banned the Agent Orange–like chemical.
    In February of this year, 31-year-old Sharanda Taylor caused a stir when she showed up at a Richmond, Virginia, City Council meeting carrying a plastic tub containing the embryo she had miscarried. Echoing an earlier generation of women for whom miscarriage was a private heartache and a public health problem, Taylor attributed her loss to unsanitary public-housing conditions, including vermin infestations, which had given her constant stress and anxiety, putting her at greater risk for miscarriage. In Flint, Michigan, where systemic racism has produced a dystopian water crisis, women, doctors, and researchers suspect there are links between a spate of miscarriages and the poisoned water, which has already been tied to dwindling fertility rates and a sharp increase in fetal deaths.
    Today, these stories are unusual. Because by the end of the 20th century, Withycombe told me, something had shifted. “We arrived at silence because of the triumph of reproductive control and the medical triumph of prenatal care,” she said. “We ended up with this narrative that every pregnancy is intended and every pregnancy is successful.” Glimpsing an embryonic heartbeat at six-and-a-half weeks, or a positive pregnancy test just days after a missed period, means that a pregnancy becomes real earlier than ever. “We are so often told that medicine is so advanced, especially in prenatal care and reproductive medicine,” that miscarriage shouldn’t happen, said Withycombe. “Once you miscarry, especially if you haven’t heard the statistics about how common it actually is, it’s easy to think it’s your fault, or that you did something wrong. Which only encourages women to stay silent.”
  • There’s another layer to the recent silence: the anti-abortion movement. By entangling pregnancy loss with abortion, anti-abortion activists have seized on miscarriage as an opportunity to push the idea that life begins at conception, changing the stakes of the conversation. “Most feminists have maintained a studied silence on the topic,” wrote Linda Layne, an anthropologist of miscarriage who suffered seven losses of her own. In her work, she has called for a “new feminist discourse of pregnancy loss” to put an end to the silence, loneliness, and shame.
  • From a medical perspective, miscarriage and abortion are the same, even if the language we use and the emotions associated with the two experiences are not. One key difference: Talking about your miscarriage won’t get you death threats.
    Though in the Age of Trump, a miscarriage will get you punitive policies. As governor of Indiana, Mike Pence signed a law requiring hospitals to bury or cremate every miscarriage, regardless of gestation stage. Last May, Florida governor Rick Scott signed the “Grieving Families Act,” making his state the first to offer death certificates to women whose pregnancies end after 9 weeks and before 20 weeks of gestation. Idaho’s “Unborn Infants Dignity Act,” introduced by Republican lawmakers, does the same. This February, an all-male group of Wyoming Republicans proposed, but ultimately failed to pass, a mandatory “certificate of non-viability.” Nebraska is now debating a “commemorative birth certificate” for any loss before 20 weeks, after which a miscarriage officially becomes a stillbirth. As historian Lara Freidenfelds wrote at the blog Nursing Clio, legislating death rituals is an affront to women. Why can’t women decide how to respond to their own experiences and needs? Equally terrible is that these laws impose emotional uniformity, a narrative of grief “to make a political point about abortion.”
  • Finding the language or the rituals to process the death of a not-yet-human isn’t easy, and narrative of grief can be helpful, when Mike Pence isn’t writing the script. While researching miscarriage, I spoke to several women to ask how they dealt with their losses. I heard stories about a ceremony in the park, gardens planted, online communities, and in-person support groups. One woman simply cocooned herself in bed for a week, blaming the flu. The overwhelming emotion was grief, but I also heard fear, confusion, and ambivalence — a response like my own. One woman whose pregnancy wasn’t intended expressed relief. Another, whose marriage unraveled shortly after, described her loss as a blessing.
    When it comes to miscarriage, any remaining silence should be broken, no doubt, but with the understanding that there’s no one way to talk. History reminds us that a miscarriage can mean different things to different people. Some may see it as a relief or a blessing, right along any grief. Speaking openly about miscarriage means making room for everyone to talk about miscarriage, no matter what they say.

"Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review" (2011).[edit]

Emmy van den Boogaard, Rosa Vissenberg, Jolande A. Land, Madelon van Wely, Joris A.M. van der Post, Mariette Goddijn, Peter H. Bisschop (2011). "Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review". Human Reproduction Update. 17 (5): 605–19. doi:10.1093/humupd/dmr024. PMID 21622978.

    From a total of 14 208 primary selected titles, 43 articles were included for the systematic review and 38 were appropriate for meta-analyses. No articles about hyperthyroidism were selected. Subclinical hypothyroidism in early pregnancy, compared with normal thyroid function, was associated with the occurrence of pre-eclampsia [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.1–2.6] and an increased risk of perinatal mortality (OR 2.7, 95% CI 1.6–4.7). In the meta-analyses, the presence of thyroid antibodies was associated with an increased risk of unexplained subfertility (OR 1.5, 95% CI 1.1–2.0), miscarriage (OR 3.73, 95% CI 1.8–7.6), recurrent miscarriage (OR 2.3, 95% CI 1.5–3.5), preterm birth (OR 1.9, 95% CI 1.1–3.5) and maternal post-partum thyroiditis (OR 11.5, 95% CI 5.6–24) when compared with the absence of thyroid antibodies.
    Pregnant women with subclinical hypothyroidism or thyroid antibodies have an increased risk of complications, especially pre-eclampsia, perinatal mortality and (recurrent) miscarriage. Future research, within the setting of clinical trials, should focus on the potential health gain of identification, and effect of treatment, of thyroid disease on pregnancy outcome.
  • In the general population, miscarriage occurs in ∼15% of all clinically recognized pregnancies and recurrent miscarriage in 1–3% of all couples trying to conceive (Regan and Rai, 2000). Complications later in pregnancy that have been associated with thyroid disorders are pre-eclampsia (incidence 5–10%), preterm delivery (incidence 10–15%) and placental abruption (incidence ∼1%) (Cunningham and Lindheimer, 1992; Ananth et al., 2006).
  • One study reported on the relation between untreated hypothyroidism (determined retrospectively using frozen serum) and miscarriages, showing an increased risk for miscarriage in women with untreated hypothyroidism compared with euthyroid controls (OR 5.78, 95% CI 2.4–14) (Negro et al., 2010). Another study, with 240 patients with subclinical hypothyroidism and 10 518 controls did not show any difference in miscarriage rate (OR 0.69, 95% CI 0.10–5.0) (Cleary-Goldman et al., 2008). Data from 13 studies were included to determine the risk for miscarriage rate in relation to thyroid antibodies (Fig. 3) (Stagnaro-Green et al., 1990; Lejeune et al., 1993; Pratt et al., 1993; Singh et al., 1995; Roberts et al., 1996; Iijima et al., 1997; Rushworth et al., 2000; Sieiro et al., 2004; Ghafoor et al., 2006; Negro et al., 2006, 2007a; Benhadi et al., 2009; Sezer et al., 2009). Data from 12 studies reporting on 966 thyroid antibody positive patients and 7331 controls without thyroid antibodies could be included in the meta-analysis and showed an increased risk of miscarriage in patients with thyroid antibodies (12 studies, OR 3.7, 95% CI 1.8–7.6). Five studies reported on pregnancy outcome after IVF (Supplementary data, Fig. S1b) (Geva et al., 1996; Kim et al., 1998; Muller et al., 1999; Kutteh et al., 1999a; Negro et al., 2007a). In contrast to spontaneous pregnancy, there was no evidence for an increased risk of miscarriage in IVF pregnancies in women with antibodies, compared with women without antibodies (five studies, OR 1.6, 95% CI 0.76–3.5).
    Thyroid function and recurrent miscarriage was studied in one study, with 8 hypothyroid patients and 325 euthyroid controls (Rao et al., 2008). There was no evidence for a difference in risk for recurrent miscarriage between the two groups (one study, OR 7.6, 95% CI 0.92–62). Antibodies in women with recurrent miscarriage were investigated in eight of the included studies, reporting on 460 patients with thyroid antibodies and 1923 antibody-negative controls (Fig. 4) (Roberts et al., 1996; Bussen and Steck, 1997; Kutteh et al., 1999b; Dendrinos et al., 2000; Mecacci et al., 2000; Shoenfeld et al., 2006; Bellver et al., 2008; Iravani et al., 2008). Patients with recurrent miscarriage more often had thyroid antibodies (eight studies, OR 2.3, 95% CI 1.5–3.5). One study could not be included in the meta-analysis, since only the OR was documented and not the exact number of patients in both groups (Mavragani et al., 1999): this study reported an OR for recurrent miscarriage in women with thyroid antibodies of 2.6, with an OR of 2.6 for TPO-Ab and 4.1 for Tg-Ab.
  • The results of this review provide clear evidence for a relationship between the presence of thyroid antibodies or subclinical hypothyroidism on several pregnancy outcome parameters. Subclinical hypothyroidism, compared with normal thyroid function, was associated with the occurrence of pre-eclampsia and showed an increased risk of perinatal mortality. Meta-analyses on the presence of thyroid antibodies showed an increased risk of unexplained subfertility, miscarriage, recurrent miscarriage, preterm birth and post-partum thyroid disease. In contrast to spontaneous pregnancy, miscarriage after IVF was not associated with the presence of thyroid antibodies.
  • This review showed an association between the presence of thyroid antibodies and recurrent miscarriage (OR 2.3, 95% CI 1.5–3.5). Not all individual studies reported showed this association but the meta-analysis was conclusive on this point, showing the additional value of pooled studies compared with individual studies.
    Several hypotheses exist on the causality between thyroid autoimmunity and obstetric complications. The first hypothesis is that the autoimmunity increases the risk for hypothyroidism, owing to the chronic lymphocytic thyroiditis that is associated with the presence of TPO-Ab. The thyroid then may fail to respond adequately to the increased demand for thyroid hormone during pregnancy. The second hypothesis is that thyroid antibodies can be considered an expression of autoimmunity in general and adverse obstetric outcome may be caused by other underlying autoimmune diseases e.g. anticardiolipin antibodies. The third hypothesis assumes that age is more important than the presence of antibodies, since the amount of antibodies increases with aging (Sinclair, 2006) and age in itself is a risk factor for obstetric complications (Dulitzki et al., 1998).The third hypothesis seems the least plausible hypothesis for a number of reasons. The majority of the studies included in this review used age-matched control-groups as a reference to their patients. After exclusion of studies not using age-matched control groups, patients with thyroid antibodies still had an increased risk of miscarriage compared with euthyroid patients without antibodies (OR 5.4, 95% CI 1,8–16; Supplementary data, Fig. S10).
  • We conclude that patients with subclinical hypothyroidism are facing an increased risk of pre-eclampsia and the hitherto under-reported risk for perinatal mortality. The presence of thyroid antibodies in euthyroid patients is associated with unexplained subfertility (which was so far unknown), miscarriage, recurrent miscarriage, preterm birth <37 weeks and post-partum thyroid disease. Special attention in pregnant women at risk for, or diagnosed with, thyroid abnormalities and in non-pregnant patients with a history of recurrent miscarriage is desirable. Therapeutic options and thereby the viability of a standardized screening program remain to be established in the near future.

“Pregnancy and Fetal Loss Reported by Methamphetamine-Using Women”[edit]

Mary-Lynn Brecht and Diane M Herbeck, “Pregnancy and Fetal Loss Reported by Methamphetamine-Using Women”, Subst Abuse. 2014; 8: 25–33.

  • Abstract: To better understand substance use disorder treatment needs of pregnant and parenting women who use methamphetamine (MA), this paper describes pregnancy histories and fetal losses for women who were treated for MA use (N = 153) with reference to a national sample, and describes their drug use, sexual risk behaviors, and mental health status. MA users reported an average of 4.6 total pregnancies and 2.1 fetal losses, whereas women in a general population survey reported 3.2 and 1.2, respectively. Higher numbers of pregnancies and fetal losses were correlated with specific substance abuse and mental health problems including early sexual abuse and cognitive problems. The combination of MA users’ especially high numbers of pregnancies, fetal losses, and rates of risk behaviors suggest high social and health care costs for this population. Prenatal care may provide a vector through which women can be connected to risk reduction interventions and gender-responsive treatment services addressing substance use and mental health needs.
    • p.25
  • In this sample of women with MA-use histories, we see a high average number of pregnancies per woman overall, 44% higher than the national figure, and specifically for African- Americans and non-Hispanic whites. We also see higher average numbers of pregnancies that terminated without a live birth. Furthermore, there was a high rate of late-term fetal loss (2% of pregnancies, representing 4.8% of those pregnancies that ended without a live birth). These high rates are cause for concern, as we see epidemic spread of MA use to previously low-prevalence areas of the US.
    • p.30
  • Our findings also indicate women who had more severe substance abuse problems, used crack/cocaine, had more sexual partners, and had cognitive and/or anxiety problems suffered a greater number of fetal losses than women with-out these problems. Whether fetal losses were the result of spontaneous or induced abortions (not distinguished in this study), the women in this sample may have experienced substantial adverse physical and/or psychological consequences prior to, or due to these losses. Studies have shown that pregnancy loss per se, whether abortion or miscarriage, increases the risk of a range of substance use disorders and psychiatric problems.
    • p.31

"Miscarriage" (Last reviewed: 17 Jun 2023; Last updated: 03 Feb 2023)[edit]

BMJ Best Practice. "Miscarriage". us.bestpractice.bmj.com. Ida Muslim, Jothi Doraiswamy, Acknowledgements. (Last reviewed: 17 Jun 2023; Last updated: 03 Feb 2023)

  • Miscarriage occurs in up to one third of pregnancies.
    Described as threatened, inevitable, incomplete, complete, missed, or recurrent miscarriage.
    Presence of pain, hypotension, tachycardia, and/or anemia warrants exclusion of a life-threatening differential diagnosis such as an ectopic pregnancy.
    Serial serum beta hCG titers and a transvaginal ultrasound scan aid in diagnosis.
    Medical or surgical uterine evacuation is recommended when the pregnancy is no longer viable. The patient may also be offered a choice of conservative management unless there is profuse, heavy, and persistent bleeding.
    The experience of a miscarriage is associated with a psychological impact of varying intensity in the short or long term, or both.
  • Miscarriage is an involuntary, spontaneous loss of a pregnancy before 20-24 completed weeks. The gestational threshold for the definition varies between countries: in the US it is usually 20 weeks (but may vary in different states), whereas in the UK, the Royal College of Obstetricians and Gynaecologists defines it as 24 weeks. After these differing cut-offs, the loss would be defined as a stillbirth. Miscarriage is associated with unprovoked vaginal bleeding with or without suprapubic pain. The commonly used term, abortion, is unpopular with women who are uncomfortable with a suggestion that it follows an intentional attempt to terminate the pregnancy.
  • Key diagnostic factors
    vaginal bleeding with or without clots
  • Other diagnostic factors
    suprapubic pain
    low back pain
    recent postcoital bleed
    uterine structural abnormality
  • Risk factors
    older age
    uterine malformation
    bacterial vaginosis

"Luteal phase defect: myth or reality" (December 2004)[edit]

Bukulmez O, Arici A (December 2004). "Luteal phase defect: myth or reality". Obstetrics and Gynecology Clinics of North America. 31 (4): 727–44, ix. doi:10.1016/j.ogc.2004.08.007. PMID 15550332.

  • Although the diagnosis of luteal phase defect (LPD) has been described convincingly in the research setting, it remains a controversial clinical entity. Apart from many uncertainties that surround the diagnosis of LPD, there is no convincing evidence that LPD is associated with infertility and recurrent abortion. Once diagnosed, the treatment options are empiric and include those that are recommended for unexplained infertility. The efforts to diagnose LPD in patients who have infertility or recurrent abortion are not justified.
  • Recurrent abortion is defined as the loss of three or more consecutive pregnancies before the twentieth week of gestation. This condition may be associated with LPD that is marked by retarded endometrial development in the peri-implantation period.
  • Luteal phase defect (LPD) was described by Jones in 1949; it is characterized by failure to develop fully mature secretory endometrium. This entity is defined as a defect of the corpus luteum to secrete progesterone in high enough amounts or for too short a duration. This results in an inadequate or out-of-phase transformation of the endometrium which precludes embryo implantation. Therefore, LPD is believed to be a cause of infertility and spontaneous miscarriage. Abnormalities of the luteal phase have been found in 3% to 10% of the female population that has primary or secondary infertility and occurs in up to 35% of those who have recurrent abortion.
    As a clinical entity, however, LPD is poorly characterized. LPD may be identified in many women who have proven fertility.

“Famine, social disruption, and involuntary fetal loss: evidence from Chinese survey data” (2005)[edit]

Yong Cai, Wang Feng; “Famine, social disruption, and involuntary fetal loss: evidence from Chinese survey data”, Demography. 2005 May;42(2):301-22.

  • While many studies have attributed miscarriage as an outcome of human biology, largely immune of human social environment, there has also been evidence suggesting the roles of non-biological factors (Carlson and Mourgova 2003; Ellett, Buxton and Luesley 1992; Shapiro and Bross 1980, cf. Wood 1994: 267). In particular, several studies have reported increased level of fetal mortality related to famines and wars (Kang et al. 2001; Rajab et al. 2000; Wynn and Wynn 1993). In this article, we analyze self-reported incidences of miscarriage among Chinese women for over a quarter century's time, and examine the roles of biological as well as social and environmental factors in affecting this adverse outcome of human reproduction.
    • p.1
  • One such view is summarized by Bongaarts: “Based on small differences in intrauterine mortality observed between developed and developing countries, some speculated that intrauterine mortality was relatively invariant among populations, therefore largely caused by biological factors that are independent from social, economic and health factors." (Bongaarts and Potter 1983:124).
    • Footnote 1, p.1
  • A special focus of our investigation is on the effects of two large-scale social and economic disruptions on miscarriage. During the period under our examination, 1955-1987, China not only completed its demographic transition from high mortality and high fertility to low mortality and low fertility, but also experienced several large-scale economic and social crises that are unprecedented in human history. One is the Great Leap Famine of 1959-1961. Past studies have already shown the devastating demographic impacts of this famine both in terms of mortality and fertility (e.g. Ashton et al. 1984; Kane 1987, 1988; Peng 1987), but not on an important factor contributing to a sharply declined fertility level during the famine, which is the increase in intrauterine mortality. The Chinese Cultural Revolution of 1966-1976 is another large-scale social and political shock with profound impacts on the daily lives of the population, but its impact on reproduction has hardly been looked on.
    • p.2
  • As health care and medical technology improves, more and more preterm births can be saved. Such improvements therefore change the classification of miscarriage and stillbirth. For example, a recent WHO publication acknowledges the different definitions of miscarriage used by different countries, and concludes that: “At what gestational age a miscarriage becomes a stillbirth for reporting purposes depends on the policy of the country.” (WHO 2000:165) Most often, the cutoff point for miscarriage is at the end of the second trimester, usually 20 or 28 weeks. This and other differences in the definition often introduce confusion for international comparisons (Kramer et al. 2002).
    • p.3
  • The arrival of two technological tools, hCG (human chorionic gonadotropin) assays and ultrasound machines, have made early pregnancy losses (EPL) detectable. The hCG assays can detect pregnancies within a few days of implantation (Armstrong et al. 1984; Wilcox et al. 1985). Ultrasound technology permits the early diagnosis of pregnancy at about five weeks of gestation age (Nyberg et al. 1983). The clinical and home-use version of hCG assays and ultrasound technology are now widely available in developed countries. In much of the developing world, women continue to rely on traditional

methods to count pregnancy and pregnancy loss.

    • Footnote 2, p.3
  • What makes defining a miscarriage particularly difficult is not just the ending of a pregnancy, but also the beginning of a pregnancy, which can be very ambiguous. Early stage pregnancies are highly difficult to detect in the absence of more recent technological tools. Physical signs of pregnancy, such as missed menses, breast tenderness, amenorrhea, and morning sickness may be recognizable in the 4-6 weeks of gestation age, but a significant proportion of pregnant women lack such signs. The recognition of these signs depends highly on a woman’s self-consciousness. A missed period, for instance, might be perceived as a delayed menstruation. Pregnancy losses are often only recognizable in 6-8 weeks of gestation age with signs such as passage of tissue, opening of the cervix, uterine contractions, or bleeding (Simpson and Carson 1993). Moreover, pregnancy (and pregnancy loss) recognition also depends on the social or cultural definition of what is considered a fetus or a life prior to birth. Difficulties in identifying the start of pregnancy imply that a large number of pregnancies and consequently pregnancy losses in the early stages are not recognized. Due to such difficulties, estimated prevalence of miscarriage varies widely by population, time, and, most often, by data sources.
    • pp.3-4
  • Existing estimates of miscarriage prevalence mostly come from three data sources: prospective clinical studies, hospital records/vital statistics, and surveys. Clinically based prospective studies provide the most accurate estimate of the prevalence of miscarriage, but have limitations for studying socially based miscarriage risk factors, due to the small samples used in such studies. One recent study with a sample of Chinese population reports, for instance, that of 618 pregnancies detected by using the hCG method, 24.6% ended up as early pregnancy losses (EPLs). The majority of these pregnancy losses occur very early in pregnancy. After the sixth and before the 28th week of pregnancy, only 10.5% of pregnancies ended in miscarriage (Wang et al. 2003). Observable miscarriage rate declines quickly further into pregnancy, to about 3-5% of live fetuses beyond the 8th week of pregnancy (Hoesli et al. 2001; Simpson et al. 1987; Sun et al. 2003). In comparison to clinically based studies, studies based on hospital records or vital registrations are large-scale, but they are also subject to underreporting and selection bias. Studies of this type report miscarriage rates ranging from the high of 13.5% in Denmark (Andersen et al. 2000) to the low of 4.5% in the Czech population (10-28 weeks, Carlson et al. 1999). Retrospective surveys of pregnancy and fertility histories provide a third major source for estimating miscarriage at the population level. These surveys have the desirable features of being large-scale and containing more social background information than vital statistics or clinical studies, but they are subject to recall and underreporting errors and culture biases. Miscarriage rates revealed by the World Fertility Survey data in 40 countries ranged from 2.7 to 13.0, with Asian populations mostly at around the 5% level (Casterline 1989a, Table 3).
    • pp.4-5
  • Despite the progress made in the last century on the etiology of miscarriage and related issues, we still do not fully understand the mechanisms of reproduction and miscarriage. While a large number of factors have been suggested as risk factors of miscarriage, only very few are generally accepted. One recent review listed 26 factors and at the same time acknowledged that only two, uterine malformations and chromosomal abnormalities, are being generally accepted (García Enguídanos et al. 2002).
    • pp.5
  • Chromosomal anomaly is the single most important risk factor of miscarriage, accounting for about half of all miscarriages (García-Enguídanos et al. 2002; Simpson and Carson 1993). A number of other health related factors have also been linked to the risk of miscarriage, including uterine anatomic defects, infections, immune diseases, endocrine disorders, trauma, malnutrition, and etc. (García-Enguídanos et al. 2002; Simpson and Carson 1993). Multiple-gestation has also been associated with increased risks of miscarriage, birth defects, and premature birth (Dickey et al. 2002; Glinianaia et al. 2002).
    • pp.5-6
  • The associations between demographic factors, namely the mother’s age, gravidity, length of pregnancy interval, pregnancy history (number of pervious live births and fetal losses), and the risk of miscarriage have long been noticed. Some of them are linked to one or more etiological risk factors listed above. For example, maternal age is positively correlated with the incidence of chromosomal aberrations (Hansen 1986 cf. Garcia-Enguidanos 2002). Others may be due to confounding effects from the selectivity nature of the reproductive process (Andersen et al. 2000 and its critics; Casterline 1989a;

El-Saadani 2000; Leridon 1976, Santow and Bracher 1989). Because maternal age, gravidity, length of pregnancy interval, and pregnancy history are highly correlated, they also pose a challenge to assessing the independent effect of each on the occurrence of miscarriage.
The risk of miscarriage has also been linked to a woman’s behavior and to the social and environmental context a woman lives in. Drug use, caffeine, smoking and drinking and exposure to certain environments have been proposed as risk factors, with some linked to etiological sources. The effects of these behaviors on pregnancy outcomes, however, are also believed to confine largely to pregnancies at late stages (Hoyert 1996; Wood 1994). The use of certain contraceptive methods is suspected to increase the risk of miscarriage, but there is no clear evidence. The relationship between previous induced abortion and miscarriage is also inconclusive.
The role of social/environmental factors in miscarriages has been subject to more debate than that of biological or demographic factors (Casterline 1989b). A number of studies have shown that social/environmental factors, such as race, socioeconomic status, and place of residence, affect the risk of miscarriage (Carlson and Mourgova 2003; Ellett, Buxton, and Luesley 1992; Shapiro and Bross 1980 cf. Wood 1994). The conclusions reached in these studies, however, are far from being conclusive. One primary critique of findings of such nature is that differentials by socioeconomic factors may be interpreted more sensibly as a reporting issue (Casterline 1989a, 1989b). For example, people with a higher level of education may be more self-conscious and thus less likely to miss a miscarried pregnancy, especially during the first trimester. Better access to health care services by women of higher socioeconomic status may also facilitate a higher level of early pregnancy recognition among them.

    • pp.7-8
  • The predominant role of biological factors over that of social factors in determining the risk of miscarriage also suggests that miscarriages are hardly preventable, and that one should not expect to see a drastic change over time in the prevalence of miscarriages. New medical technology and improvement in health care can only result in a gradual decline of miscarriages in the population. Indeed, while considerable variations have been reported across locales, miscarriage rate is also found to be generally stable across time in a specific region (Andersen et al. 2000; Wood 1994).
    • p.8
  • Nutrition has long been argued as probably the most important environmental factor affecting pregnancy outcomes (King 2003). Since pregnancy is a period of increased nutrition needs – fetus growth is totally dependent on maternal organism, one would expect a direct effect from mother’s nutritional intakes during pregnancy on fetal growth (Rosso 1990). Experimental studies on animals have demonstrated an association between maternal malnutrition during pregnancy and abnormal placental growth (Symonds et al. 2001; Symonds et al. 2003; Vonnahme et al. 2003), and between malnutrition during the periconceptional period and a fetus’ health status (Edwards and McMillen 2002). Some scholars have suggested a number of specific mechanisms through which nutritional factors may affect the risk of pregnancy (Di Cintio 2001; Dillion and Milliez 2000; Lumey 1998). Malnutrition may trigger changes in hormones. Medical evidence indicates that progesterone, a steroid hormone produced in the ovary and prepares and maintains the uterus for pregnancy, can be reduced substantially by restricting food intake (Wynn and Wynn 1993). Also, malnutrition can increase stress hormones in the mother and disrupt the growth of the placenta (Scott and Duncan 2002)
    The roles of malnutrition and famine on miscarriage, however, are still a topic subject to debate. Results of the effects of malnutrition and famine on intrauterine mortality in human populations have been inconclusive. Increased levels of fetal wastage were found among poorly nourished Indian women and during the siege of Leningrad in 1942 in the former Soviet Union. A dramatic increase of miscarriage, accompanied by a decline in birth rate and an epidemic of low birth-weight, was also reported in Frankfurt during the period of postwar food shortage (Wynn and Wynn 1993). However, studies of another well-documented war-famine, the Dutch Hunger Winter of 1944-1945, reported no evidence of rising miscarriages (Stein et al. 1975; Stein and Susser 1977).
    • pp.8-9
  • Stress has been suggested to be abortogenic in mice and human populations through their negative effects on the nervous, endocrine and immune system (Arck 2001). It is suggested that any stressful event, “even a relatively mild one, during pregnancy can cause a marked rise in the level of stress hormones in the mother, with serious repercussions for the fetus and neonate” (Scott and Duncan 2002:137). But again, empirical research has not supplied sufficient support to the link between stress and miscarriage. While some studies are able to identify an association between the two (e.g. Arck et al. 2001; Boyles et al. 2000; Joachim et al. 2001; Neugebauer et al. 1996), others fail to do so (e.g. Milad et al. 1998; Nelson et al. 2003). One important reason contributing to such conflicting results is the relatively small samples used in the laboratory-based studies. Another reason lies in the difficulty in measuring stress accurately. Moreover, unlike in animal-based laboratory research settings, stress in human societies does not exist in isolation, but often confounds with other risk factors, such as the use of tobacco, alcohol, or drugs, which makes separating the role of stress difficult.
    One window to understand the role of stress in miscarriage is to study it within non-experimental settings where external factors are known to have resulted in increases in stress level and where other risk factors can also be controlled for. If stress is linked to the level of fetal wastage, large-scale social disruptions such as wars and revolutions should lead to an elevated miscarriage level. In fact, a number of recent studies of the Gulf War of 1991 found that there was an increased level of miscarriage and other adverse pregnancy outcomes in Iraq, Kuwait, Bahrain, and among US veterans (Kang et al. 2001; Rajab et al. 2000). One of the suggested causes of the increase was the stress and anxiety caused by the War. Studies of such nature, however, are still relatively rare in numbers.
    • pp.9-10
  • To sum up, many factors have been proposed as risk factors for miscarriage. The general consensus so far is that early fetal deaths (miscarriages) are likely to involve factors endogenous to the fetus, such as chromosome anomalies, while late fetal deaths (stillbirths) are more likely to be caused by exogenous factors, from either the uterine or the external environment (Wood 1994). With such an understanding, one would expect that the level of miscarriage in different populations should not vary that much, and social environmental factors should not have much impact on miscarriages. Nutrition and stress, in other words, might not be important factors of miscarriage under normal conditions. Whatever effect they may have, however, they are most likely to be seen when magnified during periods of social crisis such as famines or social disruptions.
    • pp.10-11
  • One common source in survey data that complicates the study of miscarriage is the presence of induced abortions and misreporting of induced abortions as miscarriages (Casterline 1989a; Leridon 1976). This is unlikely a problem for the survey data we use here for several reasons. First, the distinction between miscarriage and induced abortion is rather clear in Chinese, and it is unlikely that a respondent might have mixed the two up. Second, while there was a rapid increase in induced abortions in China in the 1970s and 1980s (Wang 1995), there is no parallel increase in miscarriages as shown by our examination later in this paper. Third, while in some populations social pressures may lead respondents to misreport induced abortions as miscarriages, and therefore resulting in higher reported miscarriage rates, this is again not the case in China. Induced abortion is widely used as a birth control method, and there is neither a cultural taboo nor a legal barrier associated with it in the Chinese society.
    • p.13
  • There is a rich literature on whether the observed associations between age, gravidity, length of pregnancy interval and the risk of miscarriage are spurious. For instance,Naylor (1974) suggested that there is an increased risk of miscarriage at higher ages. Leridon (1976) designed a classification method to control for heterogeneity and his results suggested that the risk of miscarriage tended to decline with the number of previous live births, as long as the woman had not yet had a miscarriage (El-Saadani 2000; Leridon 1976).
    • pp.13-14
  • We apply an exchangeable correlation structure to pregnancies from the same mother in our models, following Santow and Bracher’s (1989) argument that “the innate risk (of miscarriage) is invariant with age at least until the mid-thirties.”
    • Footnote 7, p.15
  • From 1955 to 1987, the 411,696 women in our sample had 1,307,427 pregnancies. Among them, 85.3% were live births, 3.1% ended in miscarriage, 1.3% ended in stillbirth, and 10.3% were terminated by induced abortion. Measured as a lifetime experience, 7.6% of all women aged 15 to 57 in 1988 had at least one miscarriage up to the time of survey. Among those who had completed their reproductive career at the time of the survey (aged 45 and above), 14.6% had experienced at least one miscarriage. In Figure 1, we show the trend in miscarriage prevalence reported in the survey for the time period of 1955-1987.
    The overall miscarriage rate, 3.1%, is very low if simply compared with rates based on prospective studies that detect all pregnancies. However, such a level is more consistent with the level of miscarriage in clinical studies for pregnancies after the eighth week, and close to the low end of survey-based estimates found in Asian populations in the World Fertility Surveys, as reviewed earlier. This level of miscarriage prevalence, therefore, should not be interpreted as the true prevalence level of miscarriage in the Chinese population. Rather, it is the reported level of miscarriages by Chinese women in the survey, based on their understanding of what is considered a pregnancy and a miscarriage.
    • pp.16-17
  • A major reason for such a reported low level of miscarriage prevalence in the Chinese population, we believe, is that most respondents only recognized and remembered pregnancies that ended relatively late into pregnancy. As well explained by Leridon (1976:320), miscarriage is a “non-objective” event, since it may: 1) occur without noticing, 2) be hidden from others, 3) be forgotten and 4) be perceived differently in various cultural contexts. In our case, we suspect that the reported low miscarriage rate in our data is most likely due to reasons 1), 3), and 4) above, especially 4). The Chinese perception of what is considered a human life begins rather late in the life course of a pregnancy, and places more emphasis on the social rather than the biological definition. Historically, just as an unborn child was considered a “liquid life” in the Japanese context (LaFleur 1992), a child born in China was not considered a “fully human” until that child was six months or older (Lee and Wang 1999). It is reasonable therefore to entertain the interpretation that for many respondents in the survey, pregnancies that lasted no more than two months were neither recognized as a pregnancy nor its ending interpreted as a miscarriage.
    • pp.17-18
  • Figure 1 also reveals two prominent features in the overall trend of miscarriage reported by Chinese women. First, with few exceptions, the overall risk of miscarriage is relatively stable across such a long time period, at a level of around 3% of all pregnancies. The absence of an increasing trend, at a first glance, relieves to some extent the concern of a serious recall bias in the survey data, which could result in a higher level of miscarriage among more recent pregnancies as they are less likely to be forgotten. It also affirms us that the reporting of miscarriage is not likely to be contaminated by the rising incidents of induced abortion, since abortion rate increased steadily and drastically after the early 1960s (Wang 1995, Scharping 2003). Second, two spikes show up prominently, with the first during the Great Leap Famine of 1959-1961, when miscarriage rate shot up by more than 50 percent, from 3.4% in 1958 to 4.3% in 1959, 4.4% in 1960, and to 4.9% in 1961. The second spike shows up for 1967, the most turbulent year of the Cultural Revolution, when miscarriage rate rose from about 2.9% in 1966 to 3.6% in 1967. We shall investigate the impact of these two spikes on miscarriages following an initial examination of the biological and social risk factors below.
    • pp.18-19
  • Besides some irregularities at the beginning and the end of the age distribution, the relationship between maternal age and miscarriage risk resembles almost a prefect U-shape. Miscarriage rate is high at the very young age, at a level of 5% among pregnancies by the late teens. The risk of miscarriage declines with age, to below 3% for women in the late twenties and early thirties, before rising to 4% in
the late thirties and to over 5% in the mid-forties.
    • p.19
  • Frequencies of miscarriage also vary by other factors. In Table 1, we summarize these patterns of miscarriage by other biological and demographic characteristics of the woman. The relationship between miscarriage and pregnancy order follows a “J” shape, with a reported rate of 3.2% for the first pregnancy, dropping to below 3% for the second and third pregnancies, then rising to 3.9% by the sixth pregnancy. Results in Table 1 also underline a clear pattern of heterogeneity among women with regard to miscarriage. Women who have one previous miscarriage are more than 3.5 times more likely to have

another one compared with those who had no such an experience. The rate of miscarriage increases to more than one miscarriage in three pregnancies for those with four previous miscarriages, and to more than one in every two for those who had five previous miscarriages. In contrast to the clear pattern of miscarriage associated with age, pregnancy order, or previous history of non-live birth, there seems to be no strong association between the number of live birth and the risk of miscarriage. Whereas the risk is higher among those with no previous live birth, the risk of miscarriage does not increase with the number of live birth until the high birth order of six. Higher fertility alone, in other words, does not result in higher risks of miscarriage. The relationship between previous stillbirth or abortion and miscarriage is also not apparent.

    • pp.19-20
  • Women in cities reported a level of miscarriage clearly higher than those in towns and in the countryside: 3.7 versus 3.2 and 3 percent. Higher social status as shown by educational attainment and occupational status shows a similar pattern, with those having higher status reporting higher rates of miscarriage. Whereas the difference among the majority of women in the mid-range of the educational distribution is less pronounced, those at the extremes, with college education or no schooling, reported the highest and the lowest rates: 4.7 versus 3.0 percent respectively. Similarly, those with cadre

occupational status also reported the highest rate of miscarriage, 4.1%, versus only 3% for peasants. These results seem to suggest a systematic pattern of better recognition and recall of early pregnancy and miscarriage among those with higher social status, rather than a pattern of negative impact of social status on miscarriage. In the later part of this paper, we shall return to the examination of social characteristics in more detail.

    • pp.21-22
  • As shown in Figure 1, the otherwise rather stable trend of self-reported prevalence of miscarriage among Chinese women is marked by two pronounced spikes, once during the Great Leap Famine of 1959-1961, and another in 1967, the most intense year of the Chinese Cultural Revolution.
    The Great Leap Famine of China (1959-1961) is the costliest famine ever in human history in terms of human lives lost or postponed. Political blunders during the Great Leap Forward movement that collectivized hundreds of millions of Chinese farmers over a short time period, occasioned by severe weather conditions, resulted in a sharp drop in grain output of about 25% in 1960-61. Between 1958 and 1962, China experienced an estimated 30 million premature deaths and about 33 million lost or postponed births (Ashton et al. 1984; Kane 1988; Yang 1996).
    • p.22
  • The Cultural Revolution of 1966-1976 is another unprecedented and unsettling historical event in recent Chinese history. Though far less costly in terms of population loss compared with the 1959-1961 famine, the effort led by China's supreme leader Mao Zedong to revitalize the Chinese revolutionary cause resulted in widespread conflict, destruction, and turmoil in China. This unprecedented “revolution from within” resulted in an estimated 750,000 to 1.5 million deaths (Walder and Su 2003), removed at one time at least 60% of officials from their offices, and sent down more than twenty million urban youths, government officials, and intellectuals to live in the countryside or in reform camps. The year 1967 is the most intense year of the decade-long social turmoil, marked by power seizure by the Red Guards and armed battles in Chinese cities.
    Unlike the famine, which affected the less privileged population more severely, the Cultural Revolution targeted first and foremost the elite of the Chinese society, those with higher education, higher social status or “bad family backgrounds”. Previous studies have shown the demographic marks in terms of mortality and fertility left by the famine (Ashton et al. 1984; Kane 1987, 1988; Peng 1987). No one to our knowledge, however, has examined fluctuations in miscarriage, which represent both an increased level of (intrauterine) mortality, and contributes to the sharply depressed fertility level, and no one has examined in detail the impact of the Cultural Revolution on demographic outcomes.
    • pp.22-23
  • The effect of the two social crises under examination, the Great Leap Forward Famine and the Cultural Revolution, is clearly shown in Model 1 of Table 3. Compared with the reference level of miscarriage under study (1980-1987), four years stand out with an excess risk in miscarriage by more than 10%.12 In 1959, 1960, and 1961, the reported risk of miscarriage was 31.9%, 32.4%, and 51.6% above the reference years. In 1967, the risk was 15.5% higher. At the same time, after controlling for each other in the same analytical model, patterns of miscarriage associated with biological and demographic factors as those shown in the earlier bi-variate analyses largely remain. The adjusted miscarriage risk by maternal age is still in a U-shape, with the highest risk at the ends of the distribution. The risk of miscarriage goes up with pregnancy order in a linear pattern. Compared with women with their first pregnancies, miscarriage risk among second pregnancies, controlling for a woman’s age and pregnancy history, is 83.5% (measured in relative odds) higher, and by the fifth pregnancy, 1.9 times higher. Meanwhile, history of live birth decreases the risk of miscarriage about 60%; but additional live birth does not reduce the risk of miscarriage.
    • p.24
  • Women with a previous miscarriage experience are also under a much-elevated risk of repeating such an experience. Compared with women with no prior miscarriage history, those with one previous miscarriage is three times as likely to have a miscarriage again, and the risk difference is as large as over six times between a woman with no miscarriage experience and one with three miscarriages. History of stillbirth does not have a significant effect on the risk of miscarriage. History of abortion, contrary to what would be expected, decreases the risk of miscarriage by 23.4%. Risk of miscarriage of multiple-fetus pregnancies is only about 19.2% of that of single-fetus pregnancy, which is just the opposite to clinical observation but makes perfect sense for a survey study: multiple-fetus pregnancies could only be recognized at a late stage of gestation in the absence of medical examination.
    • pp.24-25
  • In Model 2 of Table 3, we include indicators of a woman’s socials status: residence, educational attainment, and type of employment. Overall, after controlling for the time of pregnancy and for biological/demographic risk factors, we observe the same risk pattern as seen in the bi-variate analysis above, namely that women with higher social status reported a higher rate of miscarriage. Compared with women with their household registration in cities at the time of the survey, those in townships on average reported a risk that is 10.4% lower, and in rural areas, 14.4% lower. Compared with illiterate or semi-illiterate women, women with college education reported a risk that is 50.0% higher, and with senior high school education, 25.9% higher. The effects of these two factors are similar to what Casterline (1989b) found in other developing counties. In addition, compared with women in farming, cadres and professionals reported a risk that is 14.8% higher. While the gap between the high and the low educational and occupational groups in miscarriage rate reduces somewhat when all three social factors are taken into consideration, the persistent pattern of high-status/high risk suggests three possibilities: first, such a pattern is an outcome of a systematic recall bias problem, namely that women with higher social status have higher level of awareness and more accurate recall. Second, higher social status may indeed result in a higher risk of miscarriage, with urban and more educated women having a life style and pressure that was more prone to causing miscarriage than for women in the countryside and with less education. Third, the observed pattern could also be the result of a combination of the above two possibilities.
    • pp.25-26
  • Women with higher social status did not always report a higher risk of miscarriage. During the famine years, it was women in rural areas who were hit the hardest, with a much-elevated risk. With interaction terms specifying location and time, we see that the overall impact of famine on miscarriage is no longer statistically significant for 1959 and 1960. Instead, these initial two years of the famine were only devastating for women in rural areas and in townships. Compared with those living in the cities, the risk of miscarriage for the other two groups was over 23% higher in 1959, and over 16% in 1960. By 1961, however, the impact of the famine reached all China, but rural and township areas were still hit harder than cities, with 10% higher risks compared with cities.
    • pp.26-27
  • Similarly, it was women with the highest educational level who reported an increased level of miscarriage during the peak year of the Cultural Revolution. In 1967, while the overall risk of miscarriage rose by about 15%, women with high level of education and those who worked in service and commerce sectors experienced a much elevated risk above the national average. Compared with those with illiterate or semi- illiterate educational level, women with college education reported an additional 126.5% excess in the risk of miscarriage. Though this additional effect has a lower statistical significance level due the small number of college educated women at that time in our sample, it is nevertheless more than suggestive to indicate that the Cultural Revolution, just as the famine, affected segments of the population differently. Another piece of evidence is the 45.0% higher risk among women with occupation reported at the time of the survey in 1988 as working in service and commerce compared with peasants. Though we lack information on occupational status at the time of the Cultural Revolution for these respondents, we can assume a high degree of consistence in social status among these women given the low occupational mobility in China during the time period under our study. As carriers or accused agents of “feudal” and “bourgeois” culture, intellectuals and commerce worker were among the primary targets of the Cultural Revolution.
    • p.27
  • Large-scale social and economic crises leave heavy demographic footprints. In this article, we find that miscarriage, a common adverse reproductive outcome that has been largely associated with biological factors, does not escape from the impact of famine and other social disruptions. Relying on data from a survey that encompasses a large number of pregnancy histories and covers a long time period, including two unusual social disruptions, we are able to examine in detail the influencing factors of miscarriage in China for over a quarter century’s time. The results of our study confirm the biological and demographic patterns of miscarriage shown for other populations, but they fail to lend indisputable support to findings in some earlier studies that miscarriage is associated with the social background of the pregnant women. Our results, that more educated urban women reported a higher prevalence rate of miscarriage than their rural counterparts with less schooling, may well be a function of urban women’s better awareness and recall of pregnancy and fetal loss than of a higher rate of miscarriage. What emerges more indisputably from our analyses, however, is the role of famine and social turmoil in resulting a higher level of miscarriage.
    • p.28
  • The Great Leap Famine of 1959-1961 in China not only led to a massive number of premature deaths, but also a large number of deaths that could not be observed directly from existing population records: prenatal deaths. Whereas earlier studies revealed a sudden dearth in the number of births during the famine years, the precise mechanisms leading to the drastic fertility reduction were not well analyzed. Our study shows that, among other factors, the sharp increase in miscarriages caused by the famine was a direct and important contributing factor to the drastic reduction in fertility during this time period. The impact of the famine on miscarriage was particularly evident among the less privileged segment of the population, those residing in rural and township areas who could not enjoy the same degree of food supply protection as did the urban population from the government.
    • pp.28-29
  • Our study also provides clues to another demographic puzzle in China’s recent history that has so far largely escaped from careful scholarly scrutiny. This is the temporary but pronounced fertility reduction in Chinese cities during the peak years of the Chinese Cultural Revolution. For Chinese urban population as a whole, fertility level, measured by the total fertility rate, dropped by almost 25% during the first two years of the Cultural Revolution, from 3.8 in 1965 to 3.1 in 1966 and to 2.9 in 1967, before bouncing back to 3.8 in 1968. In the capital city of Beijing, fertility dropped from 2.6 in 1965 to 2.4 and 2.2 in 1966 and 1967 respectively, before rising to 2.9 in 1968. In Shanghai, another epicenter of the Cultural Revolution, fertility went down even further, diving below replacement level to as low as 1.36 in 1966 and 1.4 in 1967, before rising back to 2.1 in 1968 (Coale and Chen 1987). The Cultural Revolution interrupted reproduction through multiple ways, by postponing marriage, reducing coitus and therefore conception within marriage, and by increasing the incidences of induced abortion. What this study further reveals is that the drop in fertility was also a result of a rise in involuntary abortion among urban women. The risk of miscarriage rose by more than 15% in 1967 compared with the reference time period. The rise appears to be particularly pronounced if not totally concentrated among urban and highly educated or high social status women who were affected the most by the social movement. Reckoning that there were an even larger proportion of pregnancies loss ended in miscarriage without recognition, this social disruption’s contribution to fertility decline is considerable.
    • pp.29-30
  • Could the two miscarriage spikes revealed in this study be artifacts of selective memory of large historic events? We have several reasons to believe that this is not the case. First, Chinese census and fertility surveys in the 1980s are known for their accuracy of age and date of vital events because people “almost universally know their date of birth” (Coale 1984:18). Second, by integrating pregnancy and birth history in a consecutive order, the survey we rely on in this study to some extend reduced the likelihood of selective memory. Third, if memory is selective, we should see parallel spikes of live birth during these crises years, which is not the case. Fourth, there were other major social and political events in the years between 1955 and 1987, but we do not observe similar miscarriage spikes as those shown here. Fifth and lastly, based on medical research that suggests male fetuses are more venerable to miscarriage than female fetuses, one would expect a decline in sex ratio at birth in the miscarriage epidemic years. The sex ratio at birth for birth cohorts of 1959 (102.8) and 1968 (103.2) was indeed substantially lower than the 23-year mean between 1955 and 1987 (107.0), revealing a disproportional share of male fetus loss, as would be expected from a miscarriage epidemic.
    • p.30
  • How do famines and revolutions result in a higher rate of miscarriage? Our study points to stress as a highly plausible candidate. Whereas in the case of a severe famine, a sudden decrease in nutritional intake for the population may explain the elevated level of miscarriage, this is clearly not the case for the rise in miscarriage during the Cultural Revolution among urban Chinese women, who were certainly well nourished at the time. For both social events, the common factor underlying the increased risk of miscarriage is a much-increased level of social stress, caused either by a severe food shortage, loss of means of livelihood, dislocation, or a massive political turmoil. Our findings based on this large-scale and non-experimental study lend some support to the inconclusive findings derived from small-scale laboratory research that stress plays an important role in the occurrences of miscarriage (e.g. Scott and Duncan 2002).
    • p.31

“Air pollution 'as bad as smoking in increasing risk of miscarriage” (11 Jan 2019)[edit]

Damian Carrington, “Air pollution 'as bad as smoking in increasing risk of miscarriage'”, The Guardian, (11 Jan 2019)

  • Air pollution is as bad for pregnant women as smoking in raising the risk of miscarriage, according to a scientific study. They said the finding was upsetting and that toxic air must be cut to protect the health of the next generation.
  • The effect of long-term exposure to dirty air on the risk of miscarriage has been analysed previously. Studies from Brazil to Italy to Mongolia found a link, but others failed to do so.
    However, the latest study is the first to assess the impact of short-term exposure to air pollution. It found that raised levels of nitrogen dioxide (NO2) pollution that are commonplace around the world increased the risk of losing a pregnancy by 16%.
    “It’s pretty profound,” said Dr Matthew Fuller, at the University of Utah’s department of emergency medicine and one of the research team. “If you compare that increase in risk to other studies on environmental effects on the foetus, it’s akin to tobacco smoke in first trimester pregnancy loss.” NO2 is produced by fuel burning, particularly in diesel vehicles.
  • Fuller was initially alerted to the issue when a family member miscarried during a particularly poor period of air quality in 2016. He said: “That triggered the question in my mind and then I started noticing anecdotally that I was seeing spikes in miscarriage numbers in the emergency department during and after [pollution spikes].”
    Fuller teamed up with the population health scientist Claire Leiser and others to see if the effect was real. They analysed the records of more than 1,300 women who attended the emergency department after miscarriages from 2007 and 2015.
    A woman’s exposure to air pollution at the time of the miscarriage was compared with similar times when she did not miscarry, meaning that age, weight, income and other personal factors were accounted for. The strongest link with a lost pregnancy was the level of NO2 in the seven days before the miscarriage.
    The average seven-day NO2 level across the whole period was 34 micrograms per cubic metre (g/m3), but peaked at 145g/m3. The researchers found an increase in NO2 pollution of 20g/m3 was associated with a 16% rise in the risk of miscarriage.“Many of us think there is an effect [of air pollution] on our health, but to find out there are actual effects on unborn children is very upsetting,” said Fuller.
  • The mechanism by which air pollution could harm a foetus has not yet been established but a likely hypothesis is that the pollutants cause oxidative stress and inflammation.
    Dr Sarah Stock, at the University of Edinburgh and not part of the research team, said: “Air pollution is clearly detrimental to the health of millions of mothers, babies and children worldwide. Measures to reduce the impact of air pollution are crucial to ensure the health of future generations.”
    But she noted that the risk of miscarriage varied substantially with the number of weeks of pregnancy and that the study had not been able to record this information, potentially introducing a bias into the result.
    Leiser said: “If we were able to get the gestation stage that would be a real benefit, to get a sense of when the woman is most at risk. There really needs to be more studies done on this specific issue. But we know enough about air pollution and birth outcomes to say, if you are pregnant, talk to your doctor.”
    The best action is to cut overall levels of pollution in urban areas, said Fuller. However he said women could choose to time their pregnancies to avoid the most polluted times of year. This is winter in Utah and many other places, but will vary depending on local conditions.
    Fuller also said pregnant women could avoid exertion on polluted days and consider buying indoor air filters. “But in the developing world these are luxuries many people can’t afford,” he said.

"Reproductive outcomes in women with congenital uterine anomalies: a systematic review" (October 2011)[edit]

Chan YY, Jayaprakasan K, Tan A, Thornton JG, Coomarasamy A, Raine-Fenning NJ (October 2011). "Reproductive outcomes in women with congenital uterine anomalies: a systematic review". Ultrasound in Obstetrics & Gynecology. 38 (4): 371–82. doi:10.1002/uog.10056. PMID 21830244. S2CID 40113681.

  • Results
    We identified nine studies comprising 3805 women. Meta-analysis showed that arcuate uteri were associated with increased rates of second-trimester miscarriage (RR, 2.39; 95% CI, 1.33–4.27, P = 0.003) and fetal malpresentation at delivery (RR, 2.53; 95% CI, 1.54–4.18; P < 0.001). Canalization defects were associated with reduced clinical pregnancy rates (RR, 0.86; 95% CI, 0.77–0.96; P = 0.009) and increased rates of first-trimester miscarriage (RR, 2.89; 95% CI; 2.02–4.14; P < 0.001), preterm birth (RR, 2.14; 95% CI, 1.48–3.11; P < 0.001) and fetal malpresentation (RR, 6.24; 95% CI, 4.05–9.62; P < 0.001). Unification defects were associated with increased rates of preterm birth (RR, 2.97; 95% CI, 2.08–4.23; P < 0.001) and fetal malpresentation (RR, 3.87; 95% CI, 2.42–6.18; P < 0.001).
    Canalization defects reduce fertility and increase rates of miscarriage and preterm delivery. None of the unification defects reduces fertility but some are associated with miscarriage and preterm delivery. Arcuate uteri are specifically associated with second-trimester miscarriage. All uterine anomalies increase the chance of fetal malpresentation at delivery.
  • Congenital uterine anomalies result from the abnormal formation, fusion or resorption of Müllerian ducts during fetal life, and are present in 1–10% of the unselected population, 2–8% of infertile women and 5–30% of women with a history of miscarriage. The discrepancy in these prevalence rates presumably relates to the application of different diagnostic methods, with variable test performance, and the use of different classification systems to define the abnormalities.
    Normal development of the female reproductive tract involves a series of complex processes characterized by the differentiation, migration, fusion, and subsequent canalization of the Müllerian system. Uterine anomalies result when these processes are interrupted. Müllerian agenesis, characterized by a failure of the Müllerian ducts to develop, results in inability to conceive. At the other end of the spectrum, the arcuate uterus, characterized by a mild concave indentation or contour towards the uterine cavity, is a subtle abnormality often overlooked by healthcare professionals and, when identified, generally is thought to be of minimal clinical significance. The other subtypes of uterine anomalies are positioned between these two extremes; they can be categorized according to the abnormality in the embryological development process, either as unification defects of the Müllerian ducts which result in unicornuate or bicornuate uteri or uterus didelphys, or as canalization defects (subseptate or septate) where there is incomplete resorption of the midline septum.
    All of these congenital anomalies have been implicated as a potential cause of infertility, recurrent pregnancy loss, preterm delivery and fetal malpresentation. It is also generally accepted that the various types of Müllerian anomaly are individually associated with these outcomes in different ways and to variable degrees, with greater effects being evident in women with more profound defects. However, individual studies often yield conflicting results. Previous reviews included studies without control groups or studies that compared their results to historical controls. We conducted a systematic review to evaluate the association between the different subtypes of uterine anomaly and various reproductive outcomes. Our review includes only studies with contemporaneous controls, and is the first to attempt to group the subtypes of uterine anomaly according to the processes of their abnormal embryological development.
  • Six studies reported first-trimester miscarriage as an outcome. Two studies defined first-trimester miscarriage as pregnancy loss before 14 weeks, while Jayaprakasan et al. defined first-trimester miscarriage as pregnancy loss before 13 completed weeks.
    Pooled results from five studies that reported on arcuate uteri showed no significant difference in first-trimester loss when compared with women with normal uteri (RR, 1.35; 95% CI, 0.81–2.26; P = 0.25; Figure S2). There was a moderate level of heterogeneity across these studies, as indicated by an I2 value of 50%. The inconsistency was primarily due to one study in which much higher rates of miscarriage (34%) were seen in the study group.
    Four studies in which canalization defects were described revealed a significant increase in first-trimester miscarriage (RR, 2.89; 95% CI, 2.02–4.14, P < 0.001; I2 = 40%; Figure 3a). Subgroup analysis showed that women with either subtype of canalization defect (subseptate or septate) have an increased risk of first-trimester miscarriage (RR, 2.94; 95% CI, 1.90–4.54; P < 0.001 and RR, 2.37; 95% CI, 1.64–3.43; P < 0.001, respectively).
    Meta-analysis of three studies revealed no significant difference in first-trimester miscarriage between women with unification defects and those with a normal uterus (RR, 2.56; 95% CI, 0.89–7.38; P = 0.08; Figure 3b). However, there was a significantly high level of heterogeneity between the studies (I2 = 78%). This inconsistency may be due to different study populations and duration of the investigation period. Acien and Shuiqing et al. included all women diagnosed with congenital uterine anomalies, regardless of their fertility status, for periods of more than 10 years but Zlopasa et al. included only women who had achieved pregnancies within the 4-year period (1997–2000). Subtype analysis of women with unification defects showed that women with bicornuate and unicornuate uteri were more likely to experience first-trimester miscarriage than those with a normal uterus (RR, 3.40; 95% CI, 1.18–9.76; P = 0.02 and RR, 2.15; 95% CI, 1.03–4.47; P = 0.04, respectively).
  • Five studies reported second-trimester miscarriage as an outcome. Most studies did not define second-trimester miscarriage; however, Acien defined second-trimester miscarriage as pregnancy loss from 14 weeks up to before 22 weeks' gestation and Zlopasa et al. defined it as pregnancy loss from 14 weeks up to before 23 weeks' gestation.
    Pooled analysis of four of these studies revealed a significant increase in second-trimester miscarriage in women with arcuate uteri compared to women with a normal uterus (RR, 2.39; 95% CI, 1.33–4.27; P = 0.003; I2 = 0%; Figure 4).
    Meta-analysis of the four studies that considered canalization defects, revealed no effect on second-trimester miscarriage rates (RR, 2.22; 95% CI, 0.74–6.65; P = 0.15; Figure S3a). However, there was a moderate level of heterogeneity across these studies, with an I2 value of 50%, and a subgroup analysis revealed an association between second-trimester miscarriage and septate uteri (RR, 3.74; 95% CI, 1.57–8.91; P = 0.003).
    Pooled results from the three studies that compared women with unification defects to those with a normal uterus revealed a doubling in the risk of second-trimester miscarriage, but this was not statistically significant (RR, 1.94; 95% CI, 0.92–4.09; P = 0.08; Figure S3b). Subgroup analysis according to the type of unification defect showed that the association was restricted to women with bicornuate uteri (RR, 2.32; 95% CI, 1.05–5.15; P = 0.04; I2 = 0%). Women with uterus didelphys and unicornuate uteri showed a trend towards an increase in second-trimester miscarriage (RR, 1.39; 95% CI, 0.44–4.41; P = 0.58 and RR, 2.22; 95% CI, 0.53–9.19; P = 0.27, respectively). There was no evidence of heterogeneity across these studies (I2 = 0%), nor in the subgroup analyses (I2 = 0%).
  • This is the first systematic review to evaluate the impact of congenital uterine anomalies on reproductive outcome by including only studies that have appropriate control groups and that considered the effect of the sub-types of uterine anomaly. We have shown that women with canalization defects, such as septate and subseptate uteri, appear to have the poorest reproductive performance; in addition to having a reduced conception rate, they are at increased risk of first-trimester miscarriage, preterm birth and fetal malpresentation at delivery. When compared with women with subseptate uteri, women with septate uteri have poorer outcomes throughout the course of pregnancy.
    While the association between canalization defects and suboptimal reproductive performance appears to be accepted generally and supported by the evidence available, the exact etiology and pathophysiological processes underlying infertility and pregnancy loss remain uncertain. It has been suggested that an endometrium overlying the septum is abnormal and thus a poor site for implantation. Therefore, miscarriage is more likely to occur with embryos that implant on septum, possibly because the septum has a disorderly and decreased blood supply which is insufficient to support subsequent placentation and embryo growth. These hypotheses remain to be proven and there is evidence to contradict them. Dabirashrafi et al. found significantly more blood vessels in biopsy samples of uterine septum, and Kupesic found that patients with a vascularized septum had a significantly higher prevalence of early pregnancy failure and late pregnancy complications than those with avascularized septa. Other authors have suggested that miscarriage and preterm birth may result from more frequent or uncoordinated uterine contractionsor a reduced uterine capacity. Both conditions may also explain the increased incidence of fetal malpresentation, although this may simply reflect the anatomical distortion.
    Unification defects, such as the bicornuate, unicornuate and didelphic uterus, do not appear to reduce fertility but are associated with aberrant outcomes throughout the course of pregnancy. The exact effects are, however, dependent on the type of anomaly. Women with bicornuate and unicornuate uteri have an increased risk of miscarriage, preterm birth and fetal malpresentation while women with uterus didelphys seem to have only a modestly increased risk of preterm labor. These findings are consistent with those of previous studies.
    The arcuate uterus, a minor uterine defect considered a normal variant rather than a uterine anomaly by many but not all authors, was specifically associated with an increase in pregnancy loss during the second trimester. Women with arcuate uteri also appear more likely to experience fetal malpresentation.
  • This review makes clear that congenital uterine anomalies are associated with poor reproductive outcome. The exact effect is dependent on the type of anomaly and the outcome being considered. Canalization defects appear to reduce the chance of clinical pregnancy and increase the chance of miscarriage and preterm delivery. These are more profound in cases of septate uteri. Unification defects do not reduce fertility but some defects, in particular bicornuate uteri, are associated with aberrant outcomes throughout the course of pregnancy. Cases of arcuate uteri, often considered an incidental benign finding, are specifically associated with poor outcomes in late pregnancy, i.e. second-trimester miscarriage. All uterine anomalies appear to be associated with an increased incidence of fetal malpresentation at delivery.

"Contributions of the Nurses' Health Studies to Reproductive Health Research" (September 2016)[edit]

Jorge E. Chavarro, Janet W. Rich-Edwards, Audrey J. Gaskins, Leslie V. Farland, Kathryn L. Terry, Cuilin Zhang, and Stacey A. Missmer, (September 2016). "Contributions of the Nurses' Health Studies to Reproductive Health Research". American Journal of Public Health. 106 (9): 1669–76. doi:10.2105/AJPH.2016.303350. PMC 4981818. PMID 27459445.(review)

  • Results. Collection of detailed reproductive history to identify breast cancer risk factors allowed the NHS to document an association between menstrual irregularities, a proxy for polycystic ovary syndrome (PCOS), and increased risk of diabetes and cardiovascular disease. The NHS II found that infertility associated with ovulation problems and gestational diabetes are largely preventable through diet and lifestyle modification. It also identified developmental and nutritional risk factors for pregnancy loss, endometriosis, and uterine leiomyomata. As women in NHS II age, it has become possible to address questions regarding long-term health consequences of pregnancy complications and benign gynecologic conditions on chronic disease risk. Furthermore, the NHS3 and GUTS are allowing new lines of research into human fertility, PCOS, and transgenerational effects of environmental exposures.
  • Some of the crucial design elements necessary to address the primary hypotheses of the Nurses’ Health Study (NHS I) and the Nurses’ Health Study II (NHS II) regarding the etiology of breast cancer have also made it possible to evaluate hypotheses regarding risk factors for benign gynecologic and obstetric pathology, as well as the implications of reproductive history for chronic diseases other than cancer. Because some of the key potential confounders and risk factors for breast cancer are reproductive life events, the collection of detailed information on reproductive history was embedded within the fabric of the NHS I and NHS II from the outset. Furthermore, because collection of data on reproductive life events such as pregnancies (including pregnancies not ending in a live birth), difficulties becoming pregnant, and use of hormonal and other forms of contraception have been prospective and regularly updated, it has been possible for investigators to use these as primary outcomes and exposures in pursuing new avenues of research within these cohorts.
    Likewise, the systematic and periodic collection of key lifestyle characteristics such as diet and physical activity has also allowed the study of these as risk factors for reproductive events. These and other key design features of the NHS that have facilitated reproductive epidemiology research are summarized in Table 1. Over the years, reproductive health research has become a key area of investigation, allowing NHS scientists to make important contributions to areas as varied as androgen excess disorders, fertility and pregnancy loss, common pregnancy complications, endometriosis, uterine fibroids, and the evaluation of long-term health consequences—to offspring and women themselves—of reproductive events.
  • Work in the identification of risk factors for pregnancy loss started with the evaluation of occupational risk factors. Among women participating in a substudy of occupational factors among nurses, it was shown that the risk of spontaneous abortion was elevated among women who were exposed to antineoplastic drugs (odds ratio [OR] = 1.94), sterilizing agents (OR = 1.39), and x-ray radiation (OR = 1.22) during the first trimester of pregnancy. Work schedule characteristics such as night work and long work hours were also identified as risk factors for spontaneous abortion in this cohort.Specifically, compared with women who worked “days only” shifts, women who worked “nights only” during the first trimester had a 60% increased risk of spontaneous abortion and women working more than 40 hours per week during the first trimester had a 50% increased risk of spontaneous abortion compared with women working 21 to 40 hours, even after adjustment for work schedule.
    More recently, attention has shifted to nutritional and lifestyle factors. With data from more than 25 000 pregnancies, NHS II investigators found that the risk of pregnancy loss was elevated in women who were overweight (RR = 1.07), class I obese (RR = 1.10), or class II and III obese (RR = 1.27) before pregnancy compared with normal-weight women. Moreover, losing 4 kilograms or more since age 18 years was associated with lower risk of pregnancy loss (RR = 0.80), particularly among women who were overweight or obese in adolescence.This latter result directly highlighted the vast potential that weight modification before pregnancy could have on the prevention of spontaneous abortion.
    The availability of prospectively collected preconception data on diet and lifestyle factors represents an enormous methodological advantage to advancing this field because it not only avoids some of the problems already highlighted for infertility research, but it also avoids one of the most pervasive methodological difficulties in pregnancy loss research. Specifically, the prospective data collection helps to differentiate lifestyle risk factors predating pregnancy loss from lifestyle factors that changed in response to early pregnancy—particularly nausea, a strong predictor of lower risk of pregnancy loss. As a consequence, contributions regarding dietary factors have been particularly important.
    We have found that higher intake of folate from supplements was associated with reduced risk of spontaneous abortion and stillbirth. Specifically, the adjusted risk difference of pregnancy loss in women who consumed 0 micrograms per day of folic acid compared with more than 730 micrograms per day was 3.1%. Moreover, it was estimated that only 42 women would need to go from between 400 and 729 micrograms per day of supplemental folate (the current recommendation) to 730 or more micrograms per day of supplemental folate to prevent 1 spontaneous abortion from occurring. This study was also the first to find a protective association between folate intake and risk of stillbirth. In a subsequent analysis, it was shown that 3 well-characterized dietary patterns: the alternate Mediterranean Diet, the alternate Healthy Eating Index, and the Fertility Diet, were not associated with risk of pregnancy loss. Secondary analyses, however, suggested that the Fertility Diet, which was the same dietary pattern previously related to lower risk of anovulatory infertility, was inversely related to pregnancy loss in pregnancies occurring shortly after diet assessment.

“Spontaneous first trimester miscarriage rates per woman among parous women with 1 or more pregnancies of 24 weeks or more” (2017)[edit]

Judy Slome Cohain, Rina E. Buxbaum, David Mankuta; “Spontaneous first trimester miscarriage rates per woman among parous women with 1 or more pregnancies of 24 weeks or more”, Pregnancy and Childbirth (2017) 17:437

  • Miscarriages are common among parous women; 43% of parous women report having experienced one or more first trimester spontaneous miscarriages, rising to 81% among women with 11 or more living children. One in every 17 parous women have three or more miscarriages. Depending on her health, nutrition and lifestyle choices, even a 39 year old parous woman with a history of 3 or more miscarriages has a good chance of carrying a future pregnancy to term but she should act expediently.
    • p.1
  • In this population, 43% of women reported a history of 1 or more recognized spontaneous first trimester miscarriages. If underreporting occurred, perhaps due to denial, forgetfulness, and/or miscarriage mistaken for delayed menstruation, the number of parous women reporting spontaneous first trimester miscarriage rate might approximate 50%. The findings show miscarriage to be widespread. This concurs with current research showing about 50% to 60% of miscarriages are the result of random fetal chromosomal abnormalities incompatible with life.
    Advanced maternal age has been documented to be the strongest risk factor for miscarriage, with women over 42 years experiencing 50% miscarriage rates and women aged 45 associated with 75% rates. This was confirmed by our data.
    • p.3
  • Recurrent miscarriage is defined as three or more consecutive miscarriages and is consistently previously reported as affecting 1% of women and was thought to be predictive of high rates of future miscarriage. In contrast to this, 6% of women in this population had three or more recurrent or non-recurrent miscarriages and went on to deliver at least one more child. Regan et al.’s extensive body of work on recurrent miscarriage states: “The most predictive factor for spontaneous abortion is a previous spontaneous abortion. Since the most important predictive factor for spontaneous abortion is a previous spontaneous abortion, the outcome of a woman’s first pregnancy has profound consequences for all subsequent pregnancies”. Regan’s work studies populations of more limited generalizability and ignores maternal age, the most predictive factor for first trimes- ter miscarriage.
    The largest study of recurrent miscarriage concluded that 16% of women will miscarry the next pregnancy after their first miscarriage, 25% of women are expected o have a third consecutive miscarriage after 2 miscarriages, and 45% are expected to have a fourth and 54% are expected to have a fifth. The paper admits that 17% of the repeat miscarriages were not repeat miscarriages but re-admissions for diagnostic follow-up testing. Even if their rates were adjusted to accurately reflect the correct numbers as well as ages of the women, this research is only about recurrent miscarriage rates in the Danish population where miscarriage is routinely treated with dilation and curettage. Dilation and curettage could theoretically increase subsequent recurrent miscarriage due to the 25% rate of adhesions left after a single dilation and curettage, the same as after a single cesarean. To date, the influence of the routine use of dilation and suction vacuum aspiration on subsequent spontaneous miscarriage is unknown.
    • pp.4-5
  • The bulk of published research on recurrent miscarriage concludes that recurrent miscarriage is associated with high rates of subsequent recurrent miscarriage and ‘profound consequences’ is a possible euphemism for inability to produce a live child. Quite the opposite was found in this study. Recurrent and non-recurrent miscarriage were associated with high parity. Eighty-one percent of women with 11 or more living children experienced one or more first trimester miscarriages. About 7% of grand multiparous women with 5 or more children had 3 or more miscarriages and 2% experienced

as many as 5 miscarriages.

    • p.5
  • We looked at possible factors affecting the risk of spontaneous miscarriages in our population: Our data documented a small but significant increase in miscarriage among women who had a history of a previous cesarean. A 2013 review on the subject found insufficient evidence to determine if CS increased the risk of subsequent miscarriage although the risk of miscarriage was increased following CS in the multinomial logistic regression analysis. A possible mechanism to explain increased miscarriage after previous CS could be uterine scarring, the mechanism that was used to explain the doubling of the rate of third trimester unexplained stillbirth after previous cesarean. As would be expected, women with a history of ectopic pregnancy, smoking and BMI ≥30 experienced significantly more first trimester miscarriages.
    The rates of miscarriage among women having fertility treatment were similar to the rates for women not having any fertility treatments. Four thousand four hundred sixty-six (7%) underwent fertility treatment of Ikaclomid, Pergonal, IVF, egg or sperm donation and/or Other but their miscarriage rates were nearly identical to the general population. Perhaps fertility treatment was not associated with higher rate of miscarriage because fertililty treatment often followed a relatively short history of not conceiving rather than a history of miscarriage.
    • pp.5-6
  • 43% of parous women experienced at least one spontaneous miscarriage. Miscarriage directly increases with age as well as parity. The more pregnancies, the more miscarriages are experienced. Grand multiparas have both more children and a higher prevalence of miscarriages. Those with 1–5 miscarriages also had an average of 3 living children, those with 6–16 miscarriages, had an average of 4 living children. Parous women until their late 30s, who have experienced multiple miscarriages, can be counseled that if they keep trying, they will likely carry a pregnancy to term.
    • p.6

“In some states, doctors weigh ‘ruinous’ litigation against proper care for women who have miscarriages" (July 20, 2022)[edit]

Elizabeth Cohen, Danielle Herman and John Bonifield, “In some states, doctors weigh ‘ruinous’ litigation against proper care for women who have miscarriages “, CNN, (July 20, 2022)

  • The same surgical procedure used to remove a dead fetus is also used to remove a living fetus, and doctors in states with strict anti-abortion laws worry they’ll be prosecuted for performing an abortion when they were actually providing miscarriage care.
    “Doctors can’t just rely on the fact that they’re right,” said Dr. Sarah Prager, co-author of an early pregnancy loss practice bulletin for the American College of Obstetricians and Gynecologists. “They could still potentially be sued multiple times and be on the hook for a lot of money.”
  • Stell had her miscarriage in Texas in September, just a few weeks after a strict anti-abortion law went into effect. Since then, in the wake of last month’s US Supreme Court decision to overturn Roe v. Wade, more than a dozen other states have sought to enforce abortion bans or very restrictive policies, according to the Guttmacher Institute, an abortion rights advocacy research group.
    Those laws will have “an enormous chilling effect” on doctors performing miscarriage surgeries even when doctors “are confident that what they’re doing is within the letter of the law,” said Steve Vladeck, a professor at the University of Texas School of Law and a CNN contributor.
  • In its practice bulletin, the American College of Obstetricians and Gynecologists emphasizes the importance of considering patient preference for the three miscarriage treatment options: miscarrying naturally; taking the pills; or having a D&C.
  • While she searched for care, Stell was worried about getting an infection from the dead tissue inside her, which doctors say is a reasonable fear.
    “All kinds of bad things can happen,” said Dr. Lillian Schapiro, an obstetrician-gynecologist who’s practiced for more than 30 years in Atlanta. “She can develop an infection that can make her sterile and never be able to have children again.”
    If a dead fetus stays in the uterus for too long, it can get even worse, Schapiro said, causing a disorder called disseminated intravascular coagulation.
    “Fetal parts break down and get into the mother’s [blood] circulation and can actually cause multi-organ failure and death,” she said.
    According to the practice bulletin from the American College of Obstetricians and Gynecologists, surgery “results in faster and more predictable complete evacuation” of fetal remains compared with letting the miscarriage happen naturally or using mifepristone and misoprostol.
  • Texas Right to Life has heard stories like this one and says it’s all a big “misunderstanding.”
    The group says doctors have been misinformed, and that while the Texas anti-abortion law, known as SB 8, doesn’t define the word “abortion,” another Texas statute says “an act is not an abortion if the act is done with the intent to remove a dead, unborn child whose death was caused by” a miscarriage.
    Doctors say they do understand the law - but that it’s not enough to protect them.
  • “The Texas law pits citizens against citizens,” said Vladeck, the University of Texas legal scholar. “Even worse, I think what it does is, it encourages citizens to spy on each other.”
    If the citizen is wrong – if the court finds, for example, that the doctor performed a surgery for a miscarriage and not an abortion – the doctor still has to pay their own legal fees, as Texas law specifically forbids doctors from recouping fees from plaintiffs.
    “Even for those providers who are confident that what they’re doing is within the letter of the law, they face the specter of potentially ruinous litigation. They can’t stop it. They can’t avoid it. They can’t pre-empt it,” Vladeck said.
  • All it would take to cause the doctor ruin is a citizen who is confused about the difference between an abortion and a miscarriage, or someone who is out for money or someone who has a vendetta against the doctor or the patient.
    “Physicians may be apprehensive about a situation where a woman has a miscarriage and let’s say she has an angry partner and they try to charge the physicians with aiding an abortion,” said Dr. Leah Tatum, a spokeswoman for the Texas chapter of the American College of Obstetricians and Gynecologists.

"Progesterone to prevent miscarriage in women with early pregnancy bleeding: The PRISM RCT" (2020)[edit]

Coomarasamy A, Harb HM, Devall AJ, Cheed V, Roberts TE, Goranitis I, et al. (2020). "Progesterone to prevent miscarriage in women with early pregnancy bleeding: The PRISM RCT". Health Technology Assessment. 24 (33): 1–70. doi:10.3310/hta24330. PMC 7355406. PMID 32609084.

  • Background: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage.
    Objectives: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding.
    Design: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding.
    Setting: A total of 48 hospitals in the UK.
    Participants: Women aged 16–39 years with early pregnancy bleeding.
    Interventions: Women aged 16–39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation.
    Main outcome measures: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective.
    Results: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval –£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation.
    Conclusions: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets.
    • pp.ix-x
  • Miscarriage is a common complication of pregnancy that affects one in five pregnancies. Several small studies have suggested that progesterone, a hormone essential for maintaining a pregnancy, may reduce the risk of miscarriage in women presenting with early pregnancy bleeding.
    This research was undertaken to test whether or not progesterone given to pregnant women with early pregnancy bleeding would increase the number of live births when compared with placebo

(dummy treatment).
The women participating in the study had an equal chance of receiving progesterone or placebo, as determined by a computer; one group received progesterone (400 mg twice daily as vaginal pessaries) and the other group received placebo with an identical appearance. Treatment began when women presented with vaginal bleeding, were < 12 weeks of gestation and were found to have at least a pregnancy sac on an ultrasound scan. Treatment was stopped at 16 weeks of gestation, or earlier if the pregnancy ended before 16 weeks. Neither the participants nor their health-care professionals knew which treatment was being received.
In total, 23,775 women were screened and 4153 women were randomised to receive either progesterone or placebo pessaries. Altogether, 2972 participants had a live birth after at least 34 weeks of gestation. Overall, the live birth rate in the progesterone group was 75% (1513 out of 2025 participants), compared with 72% (1459 out of 2013 participants) in the placebo group. Although the live birth rate was 3% higher in the progesterone group than in the placebo group, there was statistical uncertainty about this finding. However, it was observed that women with a history of one or more previous miscarriages and vaginal bleeding in their current pregnancy may benefit from progesterone. For women with no previous miscarriages, our analysis showed that the live birth rate was 74% (824 out of 1111 participants) in the progesterone group compared with 75% (840 out of 1127 participants) in the placebo group. For women with one or more previous miscarriages, the live birth rate was 75% (689 out of 914 participants) in the progesterone group compared with 70% (619 out of 886 participants) in the placebo group. The potential benefit appeared to be most strong for women with three or more previous miscarriages, who had a live birth rate of 72% (98 out of 137 participants) in the progesterone group compared with 57% (85 out of 148 participants) in the placebo group. Treatment with progesterone did not appear to have any negative effects.

    • p.xxi
  • Objectives
    The Progesterone in Spontaneous Miscarriage study was designed to test the hypothesis that, in women with vaginal bleeding in the first 12 weeks of pregnancy, receiving vaginal progesterone (400-mg pessaries, twice daily) as soon as possible after the identification of an intrauterine gestation sac until 16 weeks of gestation increases the rate of live births at ≥ 34 completed weeks of pregnancy by at least 5% compared with placebo. In addition, an economic evaluation was conducted alongside the trial to assess the relative cost-effectiveness of progesterone compared with placebo.
    • pp.xxiii
  • Results
    A total of 4153 women from 48 hospitals in the UK received either progesterone (2079 participants) or placebo (2074 participants). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group compared with 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% progesterone vs. 75% placebo; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% progesterone vs. 72% placebo; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% progesterone vs. 57% placebo; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004), thus demonstrating a biological gradient by the increasing number of previous miscarriages. A significant post hoc subgroup effect (interaction test p = 0.01) was found when we grouped all participants with any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the occurrence of adverse events.
    For secondary outcomes, there was evidence that progesterone may increase the rate of ongoing pregnancy at 12 weeks (83% in the progesterone group vs. 80% in the placebo group; relative rate 1.04, 95% confidence interval 1.01 to 1.07; p = 0.01). There was no evidence of a difference in the safety outcomes.
    The results of the health economics analysis show that the average cost per participant was £7655 in the progesterone arm and £7572 in the placebo arm, a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval –£559 to £711) between the two arms. The incremental cost-effectiveness ratio of progesterone compared with placebo was estimated at £3305 per additional live birth at ≥ 34 weeks of gestation. These results suggest that progesterone is likely to be perceived by decision-makers as cost-effective.
    Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall. However, an increase in live births was observed in the subgroup of women with early pregnancy bleeding and a history of previous miscarriages. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks.
    • p.xxiv
  • Existing knowledge
    Progesterone in pregnancy
    Progesterone is an endogenous hormone that is essential to achieve and maintain a healthy pregnancy. Progesterone prepares the lining of the uterus (endometrium) to allow the implantation of the early embryo and stimulates glands in the endometrium to secrete nutrients for the embryo. During the first 8 weeks of pregnancy, progesterone is produced by the corpus luteum; however, between 8 and 12 weeks, the placenta takes over the progesterone-producing role and maintains the pregnancy thereafter.
    The physiological importance of progesterone has prompted researchers, physicians and patients to consider progesterone supplementation during early pregnancy to prevent miscarriages. Progesterone supplementation in early pregnancy has been attempted in two contexts: the first is to prevent miscarriages in asymptomatic women with a past history of recurrent miscarriages and the second is to rescue a pregnancy in women who have started to bleed in early pregnancy. Our Progesterone in Recurrent Miscarriage (PROMISE) study, published in the New England Journal of Medicine, addressed the first context. In 2012, the National Institute for Health and Care Excellence (NICE) Clinical Guideline 154 called for a large randomised placebo-controlled clinical trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of threatened miscarriage. In response, the current study was designed to address this question and focuses on the rescue context in women with vaginal bleeding in early pregnancy.
    Burden of disease
    Miscarriage is the most common complication of early pregnancy; one in five clinically recognized pregnancies end in a miscarriage. This has a substantial impact on physical and psychological well-being: research shows that the level of distress associated with miscarriage can be equivalent to that of a stillbirth of a term baby and can induce post-traumatic stress disorder. An estimated 140,000 women per year miscarry in the UK.
    Costs to the NHS
    It is estimated that miscarriage costs the NHS > £350M each year. This value includes the costs of diagnosis (blood tests and ultrasonography), management of miscarriages (expectant, medical or surgical), investigations of causes of miscarriages (e.g. antiphospholipid syndrome, parental karyotype and uterine cavity tests) and hospital inpatient costs. There are also the associated costs of complications following

treatment of miscarriages (e.g. uterine perforation, infection, bleeding or visceral damage) and any long-term health consequences of miscarriages or miscarriage management (including complications of intrauterine infections and adhesions). Furthermore, the societal costs (including days lost from work and out-of-pocket expenses for patients and partners) can be expected to be far greater.

    • Chapter 1, p.1
  • Progesterone in clinical use for threatened miscarriage
    The Progesterone in Spontaneous Miscarriage (PRISM) study was conceived to address the possibility that progesterone therapy in the first trimester of pregnancy may reduce the risk of miscarriage in women presenting with early pregnancy bleeding. We conducted a UK clinician survey (n = 222) in October 2012. In the UK, the majority of clinicians (212 out of 222; 95.5%) do not use progesterone to prevent miscarriage in women with early pregnancy bleeding. The key reason for non-use is the lack of robust evidence. Therefore, it is not surprising that the majority of clinicians (201 out of 222; 91%) called for a definitive trial. We also conducted a survey of international practitioners at the International Federation of Gynaecology and Obstetrics (FIGO) 2012 conference in Rome. Surprisingly, this survey found that the majority of clinicians (61 out of 68; 90%) already use progesterone in women with early pregnancy bleeding, although the vast majority (56 out of 66; 85%) were willing to recruit into a randomised trial, presumably indicating a lack of confidence in the available evidence.
    • pp.1-2
  • Effectiveness of progesterone in threatened miscarriage
    The first trial of progesterone therapy in women with early pregnancy bleeding was published in 1967, and since then six trials have studied this question, which have previously been summarised in a Cochrane systematic review. In 2014, prior to conducting the PRISM trial, we performed a systematic review of trials on the use of progestogens in women with early pregnancy bleeding, and identified seven studies. These studies are listed in Table 1. The seven studies included a total of 744 women. These studies were small and of poor quality, with none reporting the method of allocation concealment. Only three out of seven studies were placebo controlled and five out of seven studies were not blinded. The modified Jadad quality score varied from 1 out of 6 to 3 out of 6. Outcome data were available for miscarriage rates. Individual studies were too small to show an effect, but a meta-analysis of these seven studies (Figure 1) showed a statistically significant reduction in miscarriage rate with progestogen use [relative rate (RR) 0.53, 95% confidence interval (CI) 0.39 to 0.73]. There was no heterogeneity across the studies (I = 0%), suggesting that there was consistency across the studies.
    More recently, a Cochrane review on this question summarised evidence from seven studies (see Table 1). The review found that the studies were small with methodological weaknesses (the largest study had a sample size of 191) but the pooled analysis found a significantly lower risk of miscarriages among women who received progesterone than among those who received placebo or no treatment (risk ratio 0.64, 95% CI 0.47 to 0.87).
    • pp.2-3

  • The existing trials, although small and of poor quality, suggest that there is a benefit in a highly prevalent condition with substantial morbidity and costs. If benefit is confirmed in the PRISM trial, both women and the NHS stand to gain substantially. On the other hand, if progesterone is found to be ineffective (or indeed harmful), treatment with progesterone can be avoided. This is relevant given the common use of progesterone for this indication outside the UK.
    * Progesterone treatment is cheap (£0.68 per 400-mg capsule) and safe, and, if benefit is confirmed, we expect the intervention to be taken up rapidly.
    *There is support for the study among UK and international clinicians. In a UK survey of 212 practitioners, 91% believed that a clinical trial is needed to investigate whether or not giving progesterone to women with threatened miscarriage can reduce the risk of miscarriage. In the international survey, 56 out of 66 (85%) respondents were willing to recruit into a randomised trial on this question.
    *A patient survey supports the study. A patient survey (n = 79) showed that 72% of women would

consider taking part in this study.

    • pp.3-4
  • Specific objectives
    Primary objective
    *The primary objective of the PRISM trial was to test the hypothesis that in women presenting with vaginal bleeding in the first trimester, receiving progesterone (400 mg vaginal capsules, twice daily) as soon as possible after identification of a visible intrauterine gestation sac with a scan until 16 completed weeks of gestation increases pregnancies with live births at ≥ 34 completed weeks by at least 5% compared with placebo.
    Secondary objectives
    *To test the hypothesis that progesterone improves other pregnancy and neonatal outcomes, including gestational age at birth and survival at 28 days of neonatal life.
    *To test the hypothesis that progesterone, compared with placebo, is not associated with serious adverse effects for the mother or the neonate, including chromosomal anomalies in the newborn.
    *To explore differential or subgroup effects of progesterone in prognostic subgroups, including age, fetal heart activity, gestation at presentation, amount of bleeding, body mass index and the number of previous miscarriages.
    To perform a cost-effectiveness analysis, with cost per additional birth over 34 weeks of gestation from an NHS and NHS/Personal Social Services (PSS) perspective. We will also model longer-term outcomes to the extent that the data permit.
    • p.4
  • Results overview
    The PRISM trial found no convincing evidence of a difference in the primary outcome (live birth at ≥ 34 weeks) between the two treatment groups. The number of live births was higher in the progesterone group than in the placebo group (75% in the progesterone group vs. 72% in the placebo group; adjusted relative risk 1.03, 95% CI 1.00 to 1.07), but this difference was not statistically significant (p = 0.08). There was evidence that the effect was dependent on the number of previous miscarriages, with a significant (p = 0.007) treatment by subgroup interaction observed. In women with three or more previous miscarriages, the live birth rate was 72% (98/137) with progesterone, compared with 57% (85/148) in the placebo group (relative risk 1.28, 95% CI 1.08 to 1.51; p = 0.004). A post hoc subgroup analysis exploring the effects in the subgroup of women with any number of previous miscarriages found a significant increase in the live birth rate with progesterone (relative risk 1.09, 95% CI 1.03 to 1.15; p = 0.003). For secondary outcomes, there was some evidence that progesterone increased the rate of ongoing pregnancy at 12 weeks (83% in the progesterone group vs. 80%

in the placebo group; relative risk 1.04, 95% CI 1.01 to 1.07; p = 0.01) and reduced the rate of emergency C-sections (15% in the progesterone group vs. 19% in the placebo group; adjusted relative risk 0.80, 95% CI 0.69 to 0.94; p = 0.006); there was no evidence of a difference in the other outcomes or in the safety outcomes.
Primary outcome results
Overall, 2972 out of 4038 women (74%) experienced a live birth at ≥ 34 weeks’ gestation. The live birth rate in the progesterone group was 75% (1513/2025) and the rate in the placebo group was 72% (1459/2013) (adjusted relative risk 1.03, 95% CI 1.00 to 1.07), a difference that was not statistically significant (absolute risk difference 2.2%, 95% CI –0.4% to 5.0%; p = 0.08).

    • p.22
  • Secondary outcome results
    Secondary maternal outcome: pregnancy outcomes There was evidence to suggest that progesterone increased the rate of ongoing pregnancy at 12 weeks: 1672 out of 2025 (83%) women in the progesterone group and 1602 out of 2013 (80%) in the placebo group remained pregnant at 12 weeks (adjusted relative risk 1.04, 95% CI 1.01 to 1.07; p = 0.01). However, there was no convincing evidence of a reduction in the number of miscarriages, with 410 out of 2025 (20%) women in the progesterone group and 451 out of 2013 (22%) in the placebo group experiencing a miscarriage (adjusted relative risk 0.91, 95% CI 0.81 to 1.01; p = 0.09). The median gestational age at the time of miscarriage was 8 weeks (IQR 7–10 weeks) for both groups. Time from conception to the end of pregnancy for any reason is graphically displayed in Figure 7.
    Other secondary maternal outcomes
    Twenty-nine women in the progesterone group and 22 women in the placebo group gave birth to twins (see Table 7). There was evidence to suggest that women in the progesterone group were less likely to deliver via emergency C-section (15% in the progesterone group vs. 19% in the placebo group; adjusted relative risk 0.80, 95% CI 0.69 to 0.94; p = 0.006). The results of other secondary maternal outcomes appeared similar in

both groups, with no significant differences.

    • pp.22,24
  • Secondary neonatal outcomes
    Overall, the distribution of gestational age at delivery in those women with a live birth was very similar in both groups. Live births were delivered at 38 + 4 weeks on average in both groups. There were 498 (16%) preterm births (< 37 weeks) observed, but the numbers were very similar in both groups (17% in the progesterone group vs. 15% in the placebo group; adjusted relative risk 1.07, 95% CI 0.91 to 1.25; p = 0.42). Birthweights appeared similar across both groups (mean difference –21 g, 95% CI –67 to 25 g; p = 0.37), with no evidence of any differences in the numbers of infants being large or small for their gestational age (plus other covariates listed in Table 7). No differences were noted in other outcomes. Eight neonatal deaths were observed by 28 days in the progesterone group, compared with two in the placebo group (adjusted relative risk 3.84, 95% CI 0.80 to 18.40; p = 0.09).
    Pregnancy-related complications
    Complication rates of antenatal, intrapartum, postpartum and neonatal complications appeared similar for both groups (Table 8). The denominators throughout Table 8 differ across each outcome as they are based on the number of completed responses for that relevant outcome.
    • p.26
  • Subgroup analyses
    The output from the subgroup analyses for the primary outcome of live birth at ≥ 34 weeks can be seen in Table 12 and Figures 7 and 8. All tests for subgroup by treatment group interaction were non-significant

apart from number of previous miscarriages. Here, there was evidence that the number of live births was higher in the progesterone group than in the placebo group (72% in the progesterone group vs. 57% in the placebo group; relative risk 1.28, 95% CI 1.08 to 1.51; p = 0.007) for those who had three or more previous miscarriages. Further post hoc subgroup analysis on the number of previous miscarriages, where the subgroup was split into none compared with ≥ 1 previous miscarriage, suggested that progesterone was effective in those who had ≥ 1 previous miscarriage (75% in the progesterone group vs. 70% in the placebo group; relative risk 1.09; 95% CI 1.03 to 1.15; p = 0.01).
Subgroup analyses for the outcome of miscarriage (at < 24 weeks) can be seen in Table 13. The results were similar to the primary outcome subgroup analyses, with the only evidence of a differential effect observed in the subgroup of number of previous miscarriages. Here, in those with three or more previous miscarriages, there was some evidence that progesterone was effective (23% in the progesterone group vs. 36% in the placebo group; relative risk 0.58, 95% CI 0.40 to 0.83; p = 0.003).

    • p.30-31
  • Results
    A total of 4153 women were recruited to the PRISM trial and randomised to either the progesterone (n = 2079) or the placebo (n = 2074) arm. Among the 4153 women recruited, 30 women withdrew from the trial and 85 women were lost to follow-up. Hence, the base-case primary analysis was conducted for 4038 participants: 2025 in the progesterone arm and 2013 in the placebo arm.
    Outcomes The details of the major outcomes of the trial are presented in Table 15. At the end of pregnancy, 1513 (74.72%) and 1459 (72.48%) women in the progesterone and placebo arms, respectively, had live births after 34 completed weeks of pregnancy. This translates to an effect difference of approximately 2.2% (0.022, 95% CI –0.004 to 0.050). Among women who had live births during the trial period, babies born to 1538 out of 2025 (75.95%) women in the progesterone arm and 1487 out of 2013 (73.87%) women in the placebo arm survived beyond 28 days of birth.
    • pp.40-41
  • Secondary analysis IV (hospital costs for participants with three or more previous miscarriages) We conducted a subgroup analysis of women with three or more previous miscarriages. This included 137 women in the intervention arm and 148 women in the placebo arm. The intervention was more effective, with an additional gain of 15 live births per 100 women, beyond ≥ 34 weeks' gestation. An ICER of £11,606 per additional live birth beyond 34 weeks’ gestation was calculated for this subgroup.
    • p.50
  • Principal findings
    We evaluated the cost-effectiveness of progesterone in preventing miscarriage and leading to a live birth at ≥ 34 weeks of pregnancy in women who presented with bleeding in early pregnancy. Our results

suggest that progesterone is more effective and slightly more costly than placebo. More specifically, progesterone resulted in an additional two live births per 100 women (0.022, 95% CI –0.004 to 0.050) at ≥ 34 weeks of gestation relative to placebo, with an additional cost of £83 (adjusted mean difference £76, 95% CI –£559 to £711) per woman. The additional cost was mainly attributable to the cost of progesterone administration (mean cost £204). The ICER was estimated at £3305 per live birth at ≥ 34 weeks. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks of pregnancy. For potentially acceptable WTP threshold values for an additional live birth, the probability of progesterone being cost-effective for this population group exceeds 90%.
The National Institute for Health and Care Excellence attached a value to an averted stillbirth of 25 QALYs. This assumes that life lost has a typical life expectancy in good health, but when discounting is applied to the expected years in full health, it yields 25 discounted QALYs. To interpret the primary CEA results in relation to QALYs, we used the NICE value (25 QALYs) as a proxy. If we assume that babies born alive at ≥ 34 weeks live in full health and divide the ICER (£3305 per additional live birth) by 25, then the cost per QALY is likely to be £132. If a baby did live in full health for the anticipated life expectancy, then on the basis of this ICER (£132) the intervention is cost-effective. Furthermore, evidence from the NHS Reference Costs schedule indicates that the upper cost quartile of the most expensive delivery is about £15,000, which could go much higher if we allow for the cost of excess bed-days. This further suggests that progesterone intervention is cost-effective.
The ICER for the final end point (secondary outcome) of the trial was £3037 per additional baby surviving beyond 28 days after birth. The intervention was more effective, with a gain of three neonates per 100 women surviving beyond 28 days post partum. A subgroup analysis of women with three or more previous miscarriages led to an increase of 15 live births per 100 women in the intervention group.

    • pp.53-54
  • Comparison with the literature
    To our knowledge, this is the first UK study to investigate the cost-effectiveness of progesterone in preventing miscarriage and achieving a live birth beyond 34 weeks of gestation. A similar study investigated the cost-effectiveness of progesterone in preventing miscarriages in women with a history of recurrent miscarriages and leading to a live birth beyond 24 weeks of gestation.2 The authors reported that the total mean cost of the intervention was £332.17 higher in the progesterone arm than in the placebo arm and an ICER of £18,053 per additional live birth beyond 24 weeks for the base-case analysis, with a cost-effectiveness probability of 50% at this value.
    Implications for policy
    The results of the CEA suggest that progesterone is likely to be considered a cost-effective intervention by decision-makers for women presenting with early pregnancy bleeding (threatened miscarriage) within 12 weeks of gestation.
    • p.54
  • The additional difference in the mean probability of a live birth beyond ≥ 34 completed weeks of gestation was 0.022 (95% CI –0.004 to 0.050), indicating that the progesterone intervention resulted in an additional two live births per 100 women at ≥ 34 weeks.
    • p.54
  • Currently, in the UK, progesterone is not routinely given to women who are at high risk of miscarriage. The results of the CEA suggest that progesterone is likely to be considered cost-effective, particularly for women (with one or more miscarriages) who present with bleeding in early pregnancy.
    • p.55
  • Our large multicentre, double-blind, placebo-controlled, randomised trial showed that vaginal progesterone therapy in the first trimester of pregnancy did not result in a significant increase in the rate of live births at ≥ 34 weeks of gestation in women with early pregnancy bleeding. However, the large sample size of our study allowed investigation of prespecified subgroups, and we found that women with early pregnancy bleeding and a previous history of miscarriages benefited from progesterone therapy. This subgroup effect showed a biological gradient, with those with no previous miscarriages receiving no benefit, those with one or two previous miscarriages receiving some benefit and those with three or more previous miscarriages receiving a substantial benefit. The biological gradient combined with the overall positive direction of effect in the primary analysis gives us confidence in the effects of progesterone in such high-risk women. The findings of the economic evaluation indicate that progesterone is likely to be considered by decision-makers to be cost-effective for any woman with threatened miscarriage, and particularly for women with a history of a previous miscarriage.
    Of the 10 prespecified subgroup analyses, one showed differential effects of progesterone; that is, the effects of progesterone in women with early pregnancy bleeding differed according to the number of previous miscarriages, with a suggestion of benefit in women with ≥ 3 miscarriages. Previous data have indicated a steep and proportionate increase in the loss of chromosomally normal pregnancies (euploid miscarriages) with an increasing number of past miscarriages. Given that the potential benefit of progesterone therapy would be expected to be specific to euploid pregnancies, an increasing level of benefit in women with an increasing number of past miscarriages is consistent with our biological understanding of miscarriage risk. Previous miscarriage history is one of only two stratification or prognostic risk factors (the other being maternal age) stated as useful to identify high-risk patients in the 2017 European Society of Human Reproduction and Embryology guideline on recurrent miscarriage. However, we did not identify this subgroup as of special interest a priori in our SAP, and multiple comparisons were performed (without adjustment for multiplicity); thus, this observation requires further validation.
    • p.57
  • Although there were more live births in the progesterone group than in the placebo group, the trial did not find a statistically significant difference. However, an important subgroup effect by previous history of miscarriage was observed. This subgroup effect is supported by the fact that the risk of a future miscarriage increases proportionately with increasing number of past miscarriages; there is a steep and proportionate increase in the loss of chromosomally normal pregnancies (euploid miscarriages) with increasing number of past miscarriages. It is euploid miscarriages that are likely to be helped by progesterone therapy, and thus an increasing level of benefit in women with an increasing number of past miscarriages is consistent with our biological understanding of miscarriage risk. We found no increase in the risk of congenital anomalies among offspring of women treated with progesterone, although the study was not powered for such rare outcomes.
    • p.58
  • The primary CEA found that the mean total cost per woman was higher in the progesterone group (£7655) than in the placebo group (£7572). Hence, the progesterone intervention led to an additional cost of £76 per woman. The ICER per additional live birth beyond 34 weeks of gestation was calculated as £3305.
    For potentially acceptable WTP threshold values, the probability of progesterone being cost-effective is over 90%. The likelihood of progesterone being cost-effective increased even further for those women with history of repeated miscarriage.
    • p.59
  • In conclusion, our trial did not find an overall benefit of progesterone supplementation, but identified a subgroup effect in high-risk women, defined as those with early pregnancy bleeding and a previous history of miscarriages. In women with early pregnancy bleeding and a history of previous miscarriages, the number needed to treat to gain an additional live birth at ≥ 34 weeks’ gestation is 18 (95% CI 10 to 71). The results of the economic evaluation, which typically adopts a Bayesian perspective for analysis, suggested that progesterone is likely to be considered cost-effective by decision-makers for women presenting with early pregnancy bleeding, and particularly for women with a history of a previous miscarriage. The final conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at and beyond 34 weeks of pregnancy.
    Implications for health care
    On the basis of the results of this study, progesterone therapy in the first trimester does not have a significant benefit in women with early pregnancy bleeding overall; however, our study found that women with early pregnancy bleeding and a previous history of miscarriages benefited from progesterone therapy. A biological gradient of effect was observed, with those women with no previous miscarriages receiving no benefit, those with one or two miscarriages receiving some benefit and those with three or more miscarriages receiving a substantial benefit. Furthermore, the findings of the economic evaluation suggest that administering progesterone to women with early pregnancy bleeding (< 12 weeks of gestation) is likely to be considered good value for money.
    • p.61

"Diagnostic criteria for nonviable pregnancy early in the first trimester" (October 2013)[edit]

Doubilet PM, Benson CB, Bourne T, Blaivas M, Barnhart KT, Benacerraf BR, et al. (October 2013). "Diagnostic criteria for nonviable pregnancy early in the first trimester". The New England Journal of Medicine. 369 (15): 1443–51. doi:10.1056/NEJMra1302417. PMID 24106937.

  • When a woman presents with symptoms of pain or bleeding in early pregnancy, the main diagnostic possibilities are a currently viable intrauterine pregnancy, a failed (or failing) intrauterine pregnancy, and ectopic pregnancy. Serum hCG measurement and pelvic ultrasonography are commonly performed to aid in the differential diagno-sis. At that point, unless a life-threatening situation dictates immediate management, a key question is: “Is there a chance of a viable pregnancy?” (Table 1). This question is central to management decision making in two main clinical contexts: intrauter-ine pregnancy of uncertain viability and pregnancy of unknown location (Table 1). For a woman with an intrauterine pregnancy of uncertain viability, the answer to this question is central in deciding whether to evacuate the uterus. For a woman with a pregnancy of unknown location, the answer plays an important role in deciding whether to initiate treatment for a suspected ectopic pregnancy.
    • pp.1443
  • A pregnancy is diagnosed as nonviable if it meets one of the commonly accepted positivity criteria for that diagnosis, such as the embryonic size at which nonvisualization of a heartbeat on ultrasonography is diagnostic of failed preg-nancy. The positivity criterion for any diagnostic test should depend, in part, on the downstream consequences of false positive and false negative diagnoses. In diagnosing nonviability of an early pregnancy, a false positive diagnosis — errone-ously diagnosing nonviability — carries much worse consequences than a false negative diagnosis — failing to diagnose a pregnancy as nonviable. For either an intrauterine pregnancy of uncertain viability or a pregnancy of unknown location, the consequence of a false positive diagnosis of nonviability may be dire: medical or surgical intervention that eliminates or severely damages a viable pregnancy. This is much worse than the consequence of a false negative diagnosis in women with an intrauterine pregnancy of uncertain viability: a delay (usually by a few days) in intervention for a failed preg-nancy. Likewise, for a pregnancy of unknown location, harming a potentially normal intrauter-ine pregnancy is considerably worse than the possible consequence of a false negative diagno-sis: a short delay in treatment of an ectopic preg-nancy in a woman who is being followed medi-cally and has no ultrasonographically identifiable adnexal mass.
    Thus, the criteria for diagnosing nonviability in early pregnancy should virtually eliminate false positive results. That is, the goal is a specificity of 100%, which yields a positive predictive value of 100% for nonviability, regardless of the prior probability of that diagnosis. We recognize that this goal cannot always be achieved in clinical practice because of the dependence of ultrasonography on the expertise of the operator and because of statistical limitations in ruling out very rare events. However, we are confident that current data allow us to achieve a specificity extremely close to 100%. Although it would be ideal to have both high sensitivity and high specificity, diagnosis of early pregnancy failure requires a focus on the latter at the expense of the former.
    • pp.1443-1444
  • Research in the past 2 to 3 years has shown that previously accepted criteria for ruling out a viable pregnancy, which were based on small numbers of patients, are not stringent enough to avoid false positive test results. Dissemination of this new information to practitioners and the achievement of standardized practice protocols are challenging, because the diagnosis and man-agement of early-pregnancy complications involve physicians from multiple specialties, including radiology, obstetrics and gynecology, emergency medicine, and family medicine. As a result, there is a patchwork of sometimes conflicting, often outdated published recommendations and guide-lines from professional societies.
    • pp.1444-1445
  • The criteria most often used to diagnose pregnancy failure are the absence of cardiac activity by the time the embryo has reached a certain length (crown–rump length), the absence of a visible embryo by the time the gestational sac has grown to a certain size (mean sac diameter), and the absence of a visible embryo by a certain point in time.
    • p.1445
  • Shortly after transvaginal ultrasonography became widely available in the mid-to-late 1980s, several studies sought to determine the cutoff value for crown–rump length above which cardiac activity is consistently visible on transvaginal ultrasonography in a viable pregnancy. The cutoff values identified in these studies were 4 mm and 5 mm. Despite the small number of pa-tients in these studies, a crown–rump length of 5 mm was widely recommended as a positivity criterion for diagnosing failed pregnancy when no cardiac activity is seen.
    Although the raw data from some of these studies suggest that a 5-mm cutoff for crown–rump length has a specificity of 100% and a sensitivity of approximately 50%, a systematic review of the literature concluded that, because of the small numbers of patients, the 95% con-fidence interval for specificity was fairly wide: 90 to 100%. This indicates that there is a sub-stantial likelihood that a 5-mm cutoff can result in a false positive diagnosis of pregnancy failure. It is therefore not surprising that recent studies involving many more patients have described several embryos with a crown–rump length of 5 to 6 mm and no cardiac activity that subsequently proved to be viable. It has also been shown that the interobserver variation in the measurement of crown–rump length is ±15%.
    Thus, a crown–rump length of 6 mm (the upper limit above) as measured by one practitioner may be 15% greater, or 6.9 mm, when measured by another practitioner.These recent studies suggest that it is prudent to use a cutoff of 7 mm (rather than 5 mm) for crown–rump length with no cardiac activity (Table 2) for diagnosing failed pregnancy (Fig. 2A). This would yield a specificity and positive predictive value of 100% (or as close to 100% as can be determined). Because cardiac activity is usually visi-ble as soon as an embryo is detectable, the finding of no heartbeat with a crown–rump length of less than 7 mm is suspicious for, though not diagnostic of, failed pregnancy.
    • p.1445-1446
  • The size of the gestational sac, measured as the mean sac diameter (the average of the sagittal, transverse, and anteroposterior diameters of the sac), increases as pregnancy progresses. A num-ber of studies have examined the cutoff value for the mean sac diameter above which an embryo is consistently visible on transvaginal ultrasonogra-phy in a normal pregnancy. Initial studies involving small numbers of patients put the cutoff value at 16 mm and 17 mm, leading to the widespread use of a mean sac diameter of 16 mm as a positivity criterion for diagnosing failed pregnancy when no embryo is seen. The raw data from these early studies suggest that a 16-mm cutoff for the mean sac diameter has a specificity of 100% and a sensitivity of approximately 50%, but a systematic review of the literature concluded that, because of the small numbers of patients, the 95% confidence interval for specificity is fairly wide: 88 to 100%. A number of studies have described gestational sacs with a mean diameter of 17 to 21 mm and no visible embryo that subsequently proved to be viable pregnancies. In addition, the interobserver variation in the measurement of the mean sac diameter is ±19%, so a diameter of 21 mm (the upper limit above) as measured by one observer may be 19% greater, or 25 mm, when measured by another observer.
    These studies, in combination, suggest that it is prudent to use a cutoff of 25 mm (rather than 16 mm) for the mean sac diameter with no visible embryo (Table 2) in diagnosing failed pregnancy (Fig. 2B and 2C). This would yield a specificity and positive predictive value of 100% (or as close to 100% as can be determined). When the mean sac diameter is 16 to 24 mm, the lack of an em-bryo is suspicious for, though not diagnostic of, failed pregnancy (Fig. S2 in the Supplementary Appendix).
    • pp.1446-1448
  • Not all failed pregnancies ever develop a 7-mm embryo or a 25-mm gestational sac, so it is important to have other criteria for diagnosing pregnancy failure. The most useful of such criteria involve nonvisualization of an embryo by a certain point in time. An alternative approach to predicting pregnancy failure, based on subnormal growth of the gestational sac and embryo, has been shown to be unreliable.
    Nonvisualization of an embryo with a heart-beat by 6 weeks after the last menstrual period is suspicious for failed pregnancy, but dating of the last menstrual period (in a pregnancy con-ceived without medical assistance) is too unreliable for definitive diagnosis of pregnancy fail-ure. The timing of events in early pregnancy — gestational sac at 5 weeks, yolk sac at 51∕2weeks, and embryo with heartbeat at 6 weeks — is accurate and reproducible, with a variation of about ±1∕2 week; this consistency explains the time-related criteria for pregnancy failure listed in Table 2. For example, if the initial ultra-sonogram shows a gestational sac with a yolk sac and a follow-up scan obtained at least 11 days later does not show an embryo with cardiac activity, the diagnosis of failed pregnancy is estab-lished.
    • p.1448
  • Several ultrasonographic findings early in the first trimester have been reported as abnormal. These include an “empty” amnion, an enlarged yolk sac, and a small gestational sac. Criteria for these abnormal findings are presented in Table 2. Because none of these signs have been extensively studied, they are considered to be suspicious for, though not diagnostic of, failed pregnancy.
    • p.1448
  • A false positive diagnosis of nonviable pregnancy early in the first trimester — incorrectly diagnosing pregnancy failure in a woman with an intrauterine gestational sac or ruling out viable intrauterine gestation in a woman with a pregnancy of unknown location — can prompt interventions that damage a pregnancy that might have had a normal outcome. Recent research has shown the need to adopt more stringent criteria for the diagnosis of nonviability in order to minimize or avoid false positive test results. The guidelines presented here, if promulgated widely to practitioners in the various specialties involved in the diagnosis and management of problems in early pregnancy, would improve patient care and reduce the risk of inadvertent harm to potentially normal pregnancies.
    • p.1450

"Spontaneous Abortion – Gynecology and Obstetrics" (Reviewed/Revised Oct 2022)[edit]

Antonette T. Dulay, "Spontaneous Abortion – Gynecology and Obstetrics". Merck Manuals Professional Edition. Reviewed/Revised Oct 2022

  • Spontaneous abortion is pregnancy loss before 20 weeks gestation. Threatened abortion is vaginal bleeding without cervical dilation before 20 weeks in a confirmed viable intrauterine pregnancy. Diagnosis is by pelvic examination, measurement of beta subunit of human chorionic gonadotropin, and ultrasonography. Treatment is usually expectant observation for threatened abortion and, if spontaneous abortion has occurred or appears unavoidable, observation or uterine evacuation.
  • Spontaneous abortion, by definition, is death of the fetus. About 20 to 30% of women with confirmed pregnancies bleed during the first 20 weeks of pregnancy; half of these women spontaneously abort. Thus, incidence of spontaneous abortion is up to about 20% in confirmed pregnancies. Incidence in all pregnancies is probably higher because some very early abortions are mistaken for a late menstrual period.
  • About 10 to 15% of confirmed pregnancies spontaneously abort. As many as 25% of all pregnancies end in a spontaneous abortion during the first 12 weeks of pregnancy. Incidence in all pregnancies is probably higher because some very early abortions are mistaken for a late menstrual period.
  • Etiology of Spontaneous Abortion
    Early spontaneous abortion is often caused by chromosomal abnormalities. Maternal reproductive tract abnormalities (eg, bicornuate uterus, fibroids, adhesions) may also cause pregnancy loss through 20 weeks gestation. Isolated spontaneous abortions may result from certain viruses—most notably cytomegalovirus, herpesvirus, parvovirus, and rubella virus. Other causes include immunologic abnormalities and major trauma. Most often, the cause is unknown.
  • Risk factors for spontaneous abortion include
    *Age > 35
    *History of spontaneous abortion
    *Cigarette smoking
    *Use of certain drugs (eg, cocaine, alcohol)
    *A poorly controlled chronic disorder (eg, diabetes, hypertension, overt thyroid disorders) in the mother
    Subclinical thyroid disorders, a retroverted uterus, and minor trauma have not been shown to cause spontaneous abortions.
  • Symptoms of spontaneous abortion include crampy pelvic pain, uterine bleeding, and eventually expulsion of tissue. Late spontaneous abortion may begin with a gush of fluid when the membranes rupture. Hemorrhage is rarely massive. A dilated cervix indicates that abortion is inevitable.
    If products of conception remain in the uterus after spontaneous abortion, uterine bleeding may occur, sometimes after a delay of hours to days. Infection may also develop, causing fever, pain, and sometimes sepsis (called septic abortion).
  • Pregnancy is diagnosed with a urine or blood beta-hCG test. Ultrasonography is done to confirm intrauterine pregnancy and check for fetal cardiac activity, which is usually detectable after 5.5 to 6 weeks gestation. However, gestational age is often somewhat uncertain, and serial ultrasonography may be required. If cardiac activity is absent and had been detected previously during this pregnancy, fetal death is diagnosed. Alternatively, serial beta-hCG levels that decrease across ≤ 3 measurements are consistent with a failed pregnancy.
  • Assessment is also done to determine the status of the abortion process as follows:
    *Threatened abortion: Patients have uterine bleeding and it is too early to assess whether the fetus is alive and viable and the cervix is closed. Potentially, the pregnancy may continue without complications.
    *Inevitable abortion: The cervix is dilated. If the cervix is dilated, the volume of bleeding should be evaluated because it is sometimes significant.
    *Incomplete abortion: The products of conception are partially expelled.
    *Complete abortion: The products of conception have passed and the cervix is closed (see table Characteristic Symptoms and Signs in Spontaneous Abortions).
  • Missed abortion is suspected if the uterus does not progressively enlarge or if quantitative beta-hCG is low for gestational age or does not double within 48 to 72 hours. Missed abortion is confirmed if ultrasonography shows any of the following:
    Disappearance of previously detected embryonic cardiac activity
    Absence of such activity when the fetal crown-rump length is > 7 mm
    Absence of a fetal pole (determined by transvaginal ultrasonography) when the mean sac diameter (average of diameters measured in 3 orthogonal planes) is > 25 mm
  • Treatment of Spontaneous Abortion
    For threatened abortion, observation
    For inevitable, incomplete, or missed abortions, observation or surgical or medical uterine evacuation
    If the mother is Rh-negative, Rho(D) immune globulin
    Sometimes pain medication
    Emotional support
  • For threatened abortion, treatment is observation, but health care practitioners may periodically evaluate the woman's symptoms or do ultrasonography. No evidence suggests that bed rest decreases risk of subsequent completed abortion.
  • For inevitable, incomplete, or missed abortions, treatment is uterine evacuation or waiting for spontaneous passage of the products of conception. For patients managed expectantly, evacuation is done if excessive bleeding or infection occur or if the products of conception do not pass after about 2 to 4 weeks.
    At < 12 weeks, evacuation may be done with suction curettage or medical management. For medical evacuation, misoprostol (800 mcg intravaginally) is given; if there is no response to the first dose, one additional dose may be given at least 3 hours after first dose and typically within 7 days (1). A dose of mifepristone (200 mg orally) 24 hours before misoprostol administration should be considered if available.
    Evacuation is typically done with dilation and evacuation at 12 to 23 weeks or medication induction at > 16 to 23 weeks (eg, with misoprostol or mifepristone). For dilation and evacuation, the later the gestational age, the greater the likelihood of placental bleeding, uterine perforation by long bones of the fetus, and difficulty dilating the cervix. These complications are reduced by preoperative use of osmotic cervical dilators (eg, laminaria) or by medical induction.
  • If complete abortion is suspected, uterine evacuation is not done routinely. Uterine evacuation can be done if bleeding occurs and/or if other signs indicate that products of conception may be retained.
    Pain medications should be given, as appropriate. Rho(D) immune globulin is given if the mother is Rh-negative.
  • After a spontaneous abortion, parents may feel grief or guilt. They should be given emotional support and, in most cases of spontaneous abortions, reassured that their actions were not the cause. Formal counseling or support groups may be made available if appropriate.

"Becoming Parents and Overcoming Obstacles: Understanding the Experience of Miscarriage, Premature Births, Infertility, and Postnatal Depression" (2013)[edit]

Emanuela Q (2013). "Becoming Parents and Overcoming Obstacles: Understanding the Experience of Miscarriage, Premature Births, Infertility, and Postnatal Depression". Karnac Books. Ch.1 A paradoxical pain: recurrent miscarriage

  • Despite a growing interest in matters regarding pregnancy and infertility, the impact of a woman’s emotional response to the traumatic event of her previous miscarriage during a current pregnancy has received little research attention, although the broader category of stillbirth has been the subject of many studies. The existing literature has identified various emotional states associated with the interruption of pregnancy but seems to lack a deeper understanding of a meaningful connection between them.
    What particularly struck me was the degree of distress and the depth of loneliness that this event, so invisible from the outside but so traumatic and present inside, could elicit in the couples I met. As happens when a couple faces the news of the death of a baby that is already born, the moment of the negative ultrasound result represented the end of all the parents’ unconscious fantasies about their unborn child and the collapse of all their plans, dreams, and hopes for the future of their child and their family: this reality was often faced in total isolation.
    The depth and complexity of the pain and fear of another loss was often touchingly apparent in the couples, even if concealed behin very different individual behaviours and reactions. Talking to these women I became aware of how this experience, which I would call an “invisible loss”, was accompanied by all the manifestations of mourning.
  • Listening to my patients’ stories, the experience of their previous msicarraiges was a subject wich all of them felt the need to share from the first meeting. If, on the one hand, it seemed that they did manage to talk about it, even if only as part of the process of describing their current state, I think that a special urgency to do so originated from the pressing need to share a traumatic event which, in many cases, seemed not to have found a space to be understood at a deeper level; its unknown impact in their internal world may contribute to these women’s difficulty in developing their identity. For almost all of them the first miscarriage was felt as particularly traumatic although they were told that these were things “that could happen, the sense of belonging to a large group did not helped to alleviate the impact of the event. A variable which turns out to be important in mitigating the traumatic effect of the loss of the abby was its predictability. By contrast, the second miscarriage was a relief for some mothers because they felt too ill, but for others the second miscarriage was not only unexpected, but also unexplained. What seemed to emerge from these experiences-which were different even in their similarity-was that it was nota question of how advanced the pregnancy might have been but that when the miscarriage followed a scan during which the baby’s heartbeat had been heard, and after the first movements of the foetus had been felt, the event was accompanied by strong feelings of loss, anger, and shock. The contrast between life and death seemed to be more marked and violent in these ccase: reality destroyed signs of life which had already been clearly experienced.
  • An interesting contribution shows how PTSD (post-traumatic stress disorder) is prevalent in pregnancies following stillbirth. Women were found to be vulnerable to PTSD in the pregnancy subsequent to stillbirth, particularly where conception occurs soon after the loss (Hughes, 2001). A pregnancy or a birth following a miscarriage are not necessarily helpful in processing the grief, and the complexity of the reaction to a loss of this nature cannot be simplistically resolve by a new conception (Lin & Lasker, 1996). In the ight of many studies, in fact, it could be peculated that the emotional feeligns stirred by death were avoided by conception thus inhibiting the mourning process by pregnancy (Lewis, 1979; Lewis & Casement, 1986).
    Wht is certain, however, is that if the subsequent pregnancy results in a new loss, the intensity of grief experienced is increased to a comparable degree. All these feelings influence the new pregnancy and often do not help these mothers to enter into intimate contat with the vital and creative aspects associate with their new conception. In particular, the emotions experience dby the mother also profoundly affect the couple relationship. The previous failures, as well as the uncertainty surrounding the pregnancy and the risk of further miscarriage, are often the ause of tensions in such couples who are forced to live for many months in a state of doubt and uncertainty.
  • Every woman and every couple reacts in a unique and personal way to solitude and pain. But sometimes, in particular in the case of recurrent miscarriages, the trauma of this loss is so profound as to be not only difficult to work on and overcome, but can also compromise the stability of the couple, contaminate a subsequent pregnancy, and undermine a woman’ own identity(see Raphael Leff, Chapter Five). Often the experience of the loss, and the need to cope with uncertainty, are factors associated with unconscious fantasies which render the experience deeply traumatic. The previous losses, and the threat of the loss of the baby during the new pregnancy, undermine the mothers trust in her creative capacities and raise persecutory feelings in relation to internal objects which are felt to distrust her capacity to become pregnancy, to keep the pregnancy, and to give birth.
  • Interesting hypotheses suggest that a relationship is created through chemical and biological messages between the mother and the foetus (Mancia, 1981), and also the observation of the foetus by ultrasound sccaning (Piontelli, 1992), explore the subject of the balance between hereditaryand environmental influences. Clinical experience has taken us increasingly further back, to trace how fundamental the very early stages of a child’s life are for all of its future development: here we have arrives at the age of “minusthree-quarters” (nine months before birth), in that area of pregnancy which is fundamental for preventative purposes.
  • Often the event of a spontaneous abortion tends to pass unnoticed, not only by the people who are emotionally closest to the woman undergoing the experience, but also by nursing and medical staff t protect themselves from the emotional pain and feelings about life and death which are intrinsically part of their work. It is not easy fo medical staff to give special attention to women who present these ailments which interfere with their ability to procreate The common experience was for women to encounter a tendency by staff to iminish the problem, as though it is no less difficult for them to face this “small”, “invisible loss”.

"Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice" (July 1997)[edit]

Everett C (July 1997). "Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice". BMJ. 315 (7099): 32–4. doi:10.1136/bmj.315.7099.32. PMC 2127042. PMID 9233324.

  • Results: 76 of the 89 women with an unwanted pregnancy requested a termination. In the 550 ongoing pregnancies bleeding occurred before the 20th week in 117 (21%), and 67 (12%) ended in miscarriage. The risk of miscarriage was not significantly increased after a miscarriage in the previous pregnancy (11 (15%) women had miscarriage v 55 (12%) women who had not had miscarriage) who had previously had a live birth). Of the 117 women with bleeding, 64 were not admitted to hospital by the general practitioner; 42 of these women had an ultrasound examination at the health centre and 19 subsequently miscarried at home. In hospital 41 of 46 women who miscarried had evacuation of the uterus.
    Conclusions: Bleeding occurred in one fifth of recognised pregnancies before the 20th week and over half of these miscarried. Treatment of women with miscarriage at home means current statistics on miscarriage in Britain are missing many cases.
    • p.32
  • No statistics about miscarriages are published in Britain except the hospital episode statistics, which report only on hospital admissions in England. Bleeding in early pregnancy is common. It occurs in a fifth of all pregnancies and with a miscarriage rate of about 15% represents appreciable morbidity in the community. Previous reports on the incidence of miscarriages (spontaneous abortions) in early pregnancy have been carried out on selected groups of women in hospital clinics. No published study could be found about the incidence of bleeding in pregnancy, and the only prospective community study of miscarriages was done in Hawaii. Retrospective studies after delivery have been shown to be unreliable because of the problem of recall.
    • p.32

  • The risk of having a second successive miscarriage after a previous miscarriage was not significantly increased in the 74 women who had miscarried previously (15%, 95% confidence interval 8% to 25%) compared with that for women who had had other outcomes.
    • p.32-33
  • In this community cohort study the miscarriage rate was 12%, which is comparable with previous reports ranging from 11% to 16%.These figures do not include reports on unsuspected early pregnancy loss, which vary from 8% to 22% or the further 10% of women who do not contact any health professional after a miscarriage.
    Regan et al reported a risk of miscarriage of 19% in women who had had a previous miscarriage compared with 5% in nulliparous women or those who had had a live birth, but this fourfold increase has not been confirmed by other authors. Selection bias might have occurred in Regan and colleagues’ group of 407 volunteers as women whose previous pregnancy had ended in a miscarriage accounted for half of the sample compared with 10.5% (1687/16 015) in a report by Naylor and Warburton and 13% (74/550) in this study.
    • p.33
  • The national incidence of miscarriages has never been published by the Office for National Statistics. The Department of Health collects general practitioner item of service claims for miscarriages (FP24/GMS2), and the number of these ranged from 46 440 to 98 640 a year (average 73 230) in England and Wales between 1991 and 1995. The figure would be larger if general practitioners had also recorded unbooked pregnancies under eight weeks’ gestation.
    (Ian Hughes, personal communication) The Birmingham Research Unit of the Royal College of General Practitioners has 53 general practices throughout England and Wales which report by electronic link on a population of 323 739 (D M Fleming, personal communication). In 1993 they recorded a rate of 55.8 miscarriages/10 000 women aged 15-44. This extrapolates to 60 134 miscarriages among the 10 769 000 women in England and Wales. This total excludes those women admitted directly to hospital and those in whom the diagnosis was delayed. In my study there were 67 miscarriages and 449 registerable births representing 14.9 miscarriages/100 births. Extrapolation to the 675 000 births in England and Wales suggests that there were 70 000-90 000 miscarriages during 1993, assuming a 12.2% miscarriage rate. However, many problems exist with such extrapolations, and the estimate cannot be relied on.
    There would be an equal number of pregnancies that survived after some bleeding in early pregnancy. Hospital admissions for bleeding in England only are reported in the hospital episode statistics and averaged 51 000 during 1989-95: the equivalent figure for England and Wales would be 54 000 (Suzanne Dunn, personal communication). Assuming that there are 70 000-90 000 miscarriages a year about 14 000- 40 000 (23-40%) women are not included in the current Department of Health statistics and would have been cared for at home.
    • p.33
  • In the absence of any official statistics many thousands of women who miscarry may be excluded from important health planning processes. It may also be important to monitor miscarriage rates if environmental influences are capable of altering miscarriage rates.
    • p.34

"Updated and revised nomenclature for description of early pregnancy events" (November 2005)[edit]

Farquharson RG, Jauniaux E, Exalto N (November 2005). "Updated and revised nomenclature for description of early pregnancy events". Human Reproduction. 20 (11): 3008–11. doi:10.1093/humrep/dei167. PMID 16006453. </smll>

  • The commonest early pregnancy complication of spontaneous miscarriage occurs in approximately 15–20% of all pregnancies, as recorded by hospital episode statistics. The actual figure, from community-based assessment, may be up to 30%, as many cases remain unreported to hospital (Everett, 1997). The great majority occurs early, before 12 weeks gestational age and fewer than 5% occur after identification of fetal heart activity (Brigham et al., 1999). Second trimester loss, between 12 and 24 weeks, occurs less frequently and constitutes <4% of pregnancy outcomes (Ugwumadu et al., 2003). The clinical assessment of every pregnancy loss history requires clarification of pregnancy loss type and accurate classification, whenever possible.
    The traditional grouping of all pregnancy losses prior to 24 weeks as ‘abortion’ may have had pragmatic origins, but it is poor in terms of definition and makes little sense. The term abortion is also confusing for the patient. She may not realize that (spontaneous) abortion is not a termination of pregnancy because ‘medical abortion’ or ‘legal abortion’ is used in the same way.
    Increasing knowledge about early pregnancy development, with the more widespread availability of serum β HCG measurement, the advent of high-resolution ultrasound and a clearer description of gestational age at pregnancy loss make for a more sophisticated assessment of miscarriage history but also help the couple’s awareness from as early as 5 weeks of gestation. The advent of these important information milestones has not been fully realized or incorporated into clinical event description for article publication.
    The emergence of early pregnancy units (EPUs) in many hospitals has addressed the need for a dedicated clinical area for the diagnosis of miscarriage and patient support at a distressing time (Twigg et al., 2002). With the establishment of an EPU network, it becomes more important that a standardized diagnostic classification system be employed for accurate and reproducible reporting of ultrasound findings and clinical outcomes, so that direct comparisons between units can be readily understandable for both research and audit purposes.
  • [T]here are limits to ultrasound resolution of normal early pregnancy development. Recent advice concludes that a diagnosis of an empty sac (previously named ‘anembryonic pregnancy’, ‘early embryonic demise’ or ‘embryo loss’) should not be made if the visible crown–rump length is less than 6 mm, as only 65% of normal embryos will display cardiac activity (Royal College of Radiologists/Royal College of Obstetricians and Gynaecologists, 1995). Repeat transvaginal ultrasound examination after at least a week, showing identical features and/or the presence of fetal bradycardia, is strongly suggestive of impending miscarriage (Chittacharoen et al., 2004). The possibility of incorrect dates should always be remembered by the alert clinician. In addition, it should be remembered that when the fetus has clearly developed and the fetal heart is absent, the term ‘missed abortion’ should be replaced by ‘delayed miscarriage’ (Hutchon and Cooper, 1997).
  • There has been a plea to classify pregnancy losses according to the gestational age at which they occur and detail the event; for example, in the case of fetal demise at 8 weeks, to define it as fetal death at 8 weeks’ gestational age. In this way, possible pathophysiological mechanisms may be postulated and studied. Historically, clinicians have grouped all pregnancy losses that occur at a gestational age prior to theoretical viability under the umbrella of ‘abortion’.
    Between 1% and 2% of fertile women will experience recurring miscarriage (RM) (Stirrat, 1990). Recently, among researchers in the field of RM, it has been recognized that the classification of pregnancy loss is more complex as the developing pregnancy undergoes various important stages, and different pathology at the time of pregnancy loss is exhibited at these different stages. As the majority of RM cases following investigation are classified as idiopathic (Stirrat, 1990), it is generally accepted that within the idiopathic group there is considerable heterogeneity and it is unlikely that one single pathological mechanism can be attributed to their RM history. Furthermore, there is considerable debate about cause and association as the exact pathophysiological mechanisms have not been elucidated. Current research is directed at theories related to implantation, trophoblast invasion and placentation, as well as factors which may be embryopathic.
  • For randomized controlled trials of treatments, it is essential to have a clear classification of pregnancy loss type for both fetal and very early loss events. In addition, there is a strong argument for mandatory karyotyping of all pregnancy losses to exclude a lethal trisomy karyotype or triploidy. This is because, irrespective of treatment intervention, pregnancy loss has occurred and may have been described as a ‘false’ treatment failure. Recent papers testify to the high rate of abnormal chromosome type when pregnancy loss has occurred (Bricker and Farquharson, 2002; Levine et al., 2002; Stephenson et al., 2002; Philip et al., 2003; Morikawa et al., 2004).

“Applying Scientific Rationale to the Current Perceptions and Explanations of Massage and Miscarriage in the First Trimester” (2023)[edit]

Sarah Fogarty, Ruth Werner, Joanna L James; “Applying Scientific Rationale to the Current Perceptions and Explanations of Massage and Miscarriage in the First Trimester”, Int J Ther Massage Bodywork. 2023 Mar 1;16(1):30-43.

  • Miscarriage is a relatively common occurrence, impacting 8–15% of clinically recognised pregnancies, and up to 30% of all conceptions. The public perception of the risk factors associated with miscarriage does not match the evidence. Evidence indicates that there are very few modifiable factors to prevent miscarriage, and the majority of the time little could have been done to prevent a spontaneous miscarriage. However, the public perception is that consuming drugs, lifting a heavy object, previous use of an intrauterine device, or massage can all contribute to miscarriage. While misinformation about the causes and risk factors of miscarriage continues to circulate, pregnant women will experience confusion about what activities they can (and cannot) do in early pregnancy, including receiving a massage.
    Pregnancy massage is an important component of massage therapy education. The resources that underpin pregnancy massage coursework consist of educational print content that includes direction and caution that massage in the first trimester, if done ‘incorrectly’ or in the ‘wrong’ location, can contribute to adverse outcomes such as miscarriage. The most common statements, perceptions and explanations for massage and miscarriage cover three broad areas: 1) maternal changes from massage affects the embryo/fetus; 2) massage leads to damage of the fetus/placenta; and 3) aspects of the massage treatment in the first trimester initiate contractions.
    The goal of this paper is to use scientific rationale to critically consider the validity of the current perceptions and explanations of massage therapy and miscarriage. Whilst direct evidence from clinical trials was lacking, considerations of physiological mechanisms regulating pregnancy and known risk factors associated with miscarriage provide no evidence that massage in pregnancy would increase a patient’s risk of miscarriage. This scientific rationale should be addressed when teaching pregnancy massage courses.
    • p.30
  • Despite much folklore to the contrary, no published evidence suggests that massage causes miscarriage. However, many massage textbooks and a number of the massage trade publications include some direction and caution that massage in the first trimester, if done ‘incorrectly’ or in the ‘wrong’ location can be harmful or risky.
    • p.31
  • The most common cause of miscarriage is chromosomal/genetic abnormalities, leading to ~50% of spontaneous miscarriages. Genetic abnormalities most frequently occur due to aneuploidy—when the chromosomes fail to separate properly during cell division—meaning that some cells have extra copies of a particular chromosome while others have none.The exact causes of aneuploidy are not well understood, although increased maternal age (>35 yrs) is the greatest risk factor. The remaining 50% of spontaneous miscarriages are attributed to failures of early placental development. As causes of miscarriages resulting from impaired early placentation are difficult to define or diagnose, these are often referred to as ‘unexplained’ miscarriages.
    A number of factors are associated with a higher risk of miscarriage. Several of these are modifiable including heavy alcohol use, smoking, and weight (both obesity and being underweight), although it is important to note that recent evidence has highlighted a genetic component to weight, making obesity less modifiable for some individuals. Of particular relevance to the massage field, an association between higher levels of maternal stress and an increased risk of spontaneous miscarriage has been reported, although findings in this area are not consistent. Non-modifiable risk factors associated with an increased risk of miscarriage include increasing maternal and paternal age, non-treated subclinical hypothyroidism, and high or very high levels of morbidity. However, it is important to highlight that these risk factors are associations, and clear causative mechanistic links between fetal and placental factors leading to spontaneous miscarriage (aneuploidy, impaired placental development), and maternal risk factors associated with higher rates of spontaneous miscarriage at a population level are not well defined.
    • pp.31-32
  • The general aetiological factors for recurrent miscarriage are similar to spontaneous miscarriage including genetic, endocrine, anatomical, and immunological abnormalities. However, the difference is that here miscarriages occur more often than is the result of random chance, meaning that there is likely a consistent underlying maternal physiological factor involved. Like spontaneous miscarriage, genetic abnormalities play a role in recurrent miscarriage, although these make up a smaller proportion of overall cases as the ‘random chance’ of aneuploidy is unlikely to occur in three consecutive pregnancies. However, overall higher rates of blastocyst aneuploidy combined with an impaired ability of the decidua to sense embryo quality may mean that a higher rate of abnormal embryos implant, leading to a greater rate of clinically detectable miscarriages, rather than implantation failure/infertility. Non-random genetic components also likely play a role in recurrent miscarriage, with higher rates of balanced translocations in the parental genomes compared to the general population, and a familial association. Finally, despite the number of known contributing factors discussed above, almost half of cases of recurrent miscarriage remain unexplained. Supportive care plays an important role in improving outcomes for recurrent miscarriage patients. This involves a combination of medical support (i.e., working with a medical professional to identify possible causes and potential avenues of treatment, and enabling increased ultrasound monitoring of further pregnancies), as well as non-medical supportive care such as listening and understanding what women are feeling, experiencing supportive care from family, friends, and peer groups, and relaxation tools to manage stress. Importantly for massage therapists, some women indicated that massage for relaxation was a preference for inclusion in non-medical supportive care.
    • pp.32-33
  • Concern: Maternal circulatory changes from massage in the first trimester affect the fetus. Both increasing and decreasing blood flow to the uterus during a massage have been postulated to increase the risk of miscarriage.
    Scientific evidence and rationale: We are aware of no studies that have directly measured changes in uterine blood flow (for example by uterine artery Doppler ultrasound) during or after massage. For most of pregnancy, maternal blood flow to the surface of the placenta is important to deliver sufficient nutrients and oxygen to the baby.
    When considering how massage may affect uterine/placental blood flow, there are two key considerations. First, during the first trimester (when most miscarriages occur), placental trophoblast cells invade the uterus and form significant ‘plugs’ in the vessels closest to the placenta (the spiral arteries), which prevent significant maternal blood flow to the placenta, meaning that the placenta/fetus normally develop in a low oxygen environment in early pregnancy, and this is important for pregnancy success. Secondly, the larger vessels in the uterus also undergo dramatic remodelling, doubling in size by mid-pregnancy and, from the second trimester (when the ‘plugs’ break down), these vessels play a rate-limiting role in controlling blood flow to the placenta. This process is driven by hormones released from the placenta, which allow the vessels to remain dilated, enabling a 15-fold increase in blood flow to the uterus across pregnancy. The extent of these combined normal physiological changes, and their regulation by multiple placenta-driven mechanisms, means that it is highly unlikely that small increases in systemic muscle tissue oxygenation and muscle tissue blood volume induced by massage would significantly impact utero-placental blood flow. However, we consider the two main concerns (increased or decreased flow) specifically below.
    Concern 1: Decreased blood flow to the uterus from massage techniques. It is stated that massage techniques may increase the risk of miscarriage by increasing the blood flow to other areas of the body, leading to a decrease in blood flow to the uterus.
    Scientific evidence and rationale: Redirection of blood flow to skeletal muscle and an increase in heart rate also occurs during exercise (to a greater extent than massage), and maintenance of a moderate exercise programme is recommended throughout pregnancy and is not associated with changes in uterine blood flow or an increase in miscarriage rates. Furthermore, in the first trimester, plugging of the uterine spiral arteries means that blood flow to the placenta is very limited at the time many miscarriages occur, and low levels of blood flow to the placenta at this point are, in fact, important for a healthy pregnancy.
    Concern 2: Increased blood flow during a massage might be harmful. Massage therapists have raised concerns that the dramatic increase in blood flow that occurs during a massage could increase the risk of miscarriage.
    Scientific evidence and rationale: Massage induces small increases in skeletal muscle tissue oxygenation and muscle tissue blood volume. However, no evidence shows that these changes in systemic blood flow have a significant impact on utero-placental blood flow. Early increases in blood flow to the developing placenta would indeed be potentially damaging; however, multiple mechanisms exist to protect against this. In the event that uterine blood flow was increased in the first trimester, this would be prevented from reaching or damaging the placenta via the plugging of the spiral arteries. Abnormal increases in uterine blood flow at this time can also bypass the placenta via arterio-venous shunts in the uterus upstream of the plugged spiral arteries.( This mechanism acts like the overflow of water from a dam, providing a low resistance alternate pathway for blood flow that mitigates against dangerously high pressures or volumes of flow reaching the placenta.
    • pp.34-35
  • Scientific evidence and rationale: No evidence shows that massage in the first trimester can lower hormone levels (hCG, progesterone and or oestrogen), either as a result of the massage itself, or due to secondary ‘physical stress’ caused by

the massage.

    • p.35
  • Concern: Pain during a massage elevates blood pressure, respiration and heart rate.
    Scientific evidence and rationale: Acute pain elevates blood pressure, and increases heart and respiration rates. However, there is no evidence that transient increases in any of these factors increase miscarriage risk. Indeed, such changes are routinely observed when pregnant women undertake moderate exercise, which is not contraindicated in pregnancy, and is not associated with increased miscarriage rates. Data on women with chronically elevated blood pressure also suggests that this is not an independent causative factor of miscarriage (although it is associated with obesity, a known risk factor), further reducing concerns around transient increases in blood pressure during massage.
    • p.35
  • Concern: Hormones released in response to pain during massage negatively affect the fetus.
    Scientific evidence and rationale: In response to acute pain the body releases hormones including endorphins, enkephalins, oxytocin, and cortisol, some of which have analgesic effects. Interestingly, during pregnancy higher levels of estrogen enhance this hormonal pain response and, as a result, many chronic pain conditions improve in pregnancy. There is no evidence that physiological levels of endogenous opiates (endorphins and enkephalins) increase the risk of miscarriage. Indeed, endorphins are released in response to both exercise and pain, and exercise has not been shown to have a negative impact on pregnancy. Baseline plasma oxytocin levels vary considerably between pregnant women and across pregnancy, and no causative link between altered oxytocin levels and miscarriage has been established.
    • p.36
  • The mechanism of miscarriage and initiation of labour are slightly different. In miscarriage, fetal death leads to inflammation and the gestational sac is expelled from the body, whereas the mechanism of initiation of labour involves a cascade of inflammatory mediators and changes in the uterine muscle cells to allow them to talk to each other and synchronise contractions. Acupuncture is hypothesised to initiate the onset of labour at term as “acupuncture neuronal stimulation may increase uterine contractility either by central oxytocin release or by parasympathetic stimulation of the uterus”. The effectiveness of acupressure at term to stimulate uterine contractility to initiate labour has shown no evidence of benefit compared to sham controls nor when compared to usual care. The differing mechanisms between miscarriage and the initiation of labour and the lack of evidence of benefit for acupressure to initiate labour at term suggest that it is unlikely that massage of muscle tissue around or over an acupressure point in the first trimester will initiate the onset of labour.
    • pp.38-39
  • We can find no study that has specifically investigated the safety of massage during the first trimester using robust methodology. This paper is not determining the safety of massage during pregnancy, but rather uses scientific rationale to critically examine common statements about first trimester massage and miscarriage. This paper considers massage as administered by a trained professional massage therapist and does not include the use of massage devices such as massage guns. The paper focuses on massage and natural conception and does not address IVF or other medical fertility treatments where the rate of miscarriage can be slightly higher and where other physiological factors and mechanisms are involved.
    • p.39
  • Overall, whilst direct evidence from clinical trials is lacking, considerations of physiological mechanisms regulating pregnancy and known risk factors associated with miscarriage provide no evidence that massage in pregnancy would increase a patient’s risk of miscarriage. Conversely, if a client perceives massage as relaxing, this could aid their mental health, in turn having positive effects on stress hormone levels. Pregnant people are often bombarded with information about what they can and cannot do, which can cause them considerable anxiety about being a ‘good mother’ and ‘protecting their baby’, and massage practitioners and health professionals should not further increase this emotional burden by making unsubstantiated claims about the risk of massage in pregnancy. Educational facilities who teach pregnancy massage should include this scientific rationale content when addressing massage and miscarriage.
    • p.39

“Handbook of early pregnancy care” (2006)[edit]

Steven R. Goldstein in Condous, George; Tom Bourne, eds. (2006). “Handbook of early pregnancy care”. London: Informa Healthcare. pp. 28–29.

  • Miscarriage is a term often used interchangeably with complete miscarriage by the lay public and even medical professionals. A better term for the healthcare professional involved in an Early Pregnancy Unit is ‘early pregnancy failure’. Any chapter entitled ‘The diagnosis of miscarriage’ has to begin with some housekeeping by defining varying terms that are often confuse. The definitions used in clinical practice are unsatisfactory and need to be rationalized. Some reflect the clinical presentation and others the findings on ultrasonography. Some miscarriages will be obvious because of the presence of pregnancy products in the cervix or vagina. In reality, prior to an ultrasound scan, in most cases the problem can only be classified as ‘bleeding and pain in early pregnancy’. An accurate diagnosis will only be possible in most cases after an ultra-sound scan and in some following the measurement of serial levels of serum hCG However for the sake of completeness the following are commonly used definitions.
    • p.27
  • Threatened miscarriage: Clinically if women present in the first trimester with vaginal bleeding with or without lower abdominal pain (cervical os is closed) they are labeled as a ‘threatened miscarriage’. This very common problem requires an ultrasound scan to establish the viability of the pregnancy.
    Complete miscarriage: Clinically the products of conception have totally passed; the cervix is likely to be closed on examination; bleeding and cramping should have diminished. A transvaginal ultrasound scan (TVS) demonstrates a thin endometrial thickness (often defined as <15 mm). These women should be treated as a pregnancy of unknown location *(PUL) if they have not had a previous scan to confirm the location. Follow-up serum human chorionic gonadotrophin (hCG) levels should be performed to confirm the outcome of pregnancy failure.
    Incomplete miscarriage: Clinically partial passage of the products of conception, bleeding and cramping is variable; characterized by an open cervical os on physical examination. Products of conception may be seen in the cervical os or vagina. TVS demonstrates heterogenous material within the endometrial cavity. In most cases the condition does not require dilation and curettage (D&C) and if managed expectantly will have 90% successful resolution.
    Early embryonic demise (previously termed an anembryonic pregnancy or blighted ovum: If the uterus contains an empty gestational sac of ?20 mm on TVS, this almost certainly represents early embryonic demise, however an interval scan in 7 days or for the findings to be checked by a second operator is recommended if there is any doubt.
    Early fetal demise (previously termed missed miscarriage): This isa failed pregnancy of up to 12 weeks; definitively non-viable but not yet passed. If the CRL is at least 6 mm and there is no fetal cardiac activity or if the crownrump length is ? 6 mm with no change at the time of a repeat scan 7 days later, this is classified as early fetal demise. This is sometimes treated expectantly, medically or electively removed by D&C. (This often depends on gestational age, the size of pregnancy as well as the availability of resources and the woman’s preference.)
    • Definitions, pp.27-28
  • Risk factors include advancing maternal age, previous failed pregnancy, smoking, moderate to heavy alcohol use, cocaine, NSAIDs/aspirin (by interference with prostaglandins), fever, caffeine (dose related, questionably secondary to cytochrome P450 enzyme activation) and low folate.
    The aetiology of pregnancy failure is complicated and could be the subject of an entire chapter. Suffice to say that it can be associated with chromosomal abnormalities Pregnancies associated with trisomy 21, 18 and 12 are the most likely to survive. All other trisomies end in early pregnancy failure. Congenital anomalies are also a source of pregnancy failure. Maternal endocrinopathies, especially diabetes, and haemohlobin A1C levels at conception correlate with risk of pregnancy failure. Other related conditions includeuterine abnormalities (adhesions, septae and submucous fibroids). Accute or chronic maternal illness and/or infection can result in early pregnancy failure. Thrombophilia as well as auto-immune disorders are controversial as to their role, if any, in early pregnancy failure and recurrent miscarriage in particular.
    Our modern understanding of early pregnancy and its failure results from firstly the ability to detect minute levels of serum hCG, secondly lessons learned from the assisted reproductive technologies and finally from the improved resolution available using TVS. SerumhCG is produce by trophoblastic tissue. It is detectable 8 days post conception. Erroneously it is still referred to by some as a ‘beta subunit’ or simply ‘beta’ to distinguish it from the alpha subunit shared with TSH and other molecules. Most current tests however measure the intact hCG molecule. Over-the-counter home pregnancy tests will turn positive at or around the time of the missed menses at a level of 25 IU/L. Serum hCG normally rises by a minimum of 66^ every 48 hours although it often doubles in that period of time. A total of 15-20% of ectopic pregnancies will follow a normal doubling time of hCG. These are the ones that will usually end up with an embryo and/or heart beat in an extrauterine location. Most normal early pregnancies are seen on TBS once the serum hCG level is ?1000 IU/L. Thus there may be a variable but lengthy period of time from when woman can diagnose a pregnancy event with a home pregnancy test and when one will first be able to visualize it.
    TVS provides a degree of image magnification that is as if we were performing ultra-sonography through a low power microscope (‘sonomicroscopy’). Prior to the vaginal probe, ultrasonography was a tool mainly of the obstetrician. Early equipment had barely enough resolution for limited functions such as placental localization, establishing fetal lie, and to perform measurements of gestational age based on parameters such as the biparietal diameter and crown-rump length.
    Several decades of conventional wisdom taught us that ‘25% of all pregnancies will experience bleeding in the first trimester and of those half will miscarry’. Such women were often told to go home, put their feet up and that they had a 50/50 chance of the pregnancy continuing. Although these statistics are very close to accurate, modern practice allows us to tell such women much more. The outcome, however, will usually remain the same.
    Biochemical pregnancy has been defined as a pregnancy detected by assays of serum hCG but one that has failed before it can be clinically recognized (as bleeding then occurs or around the time of the expected menses.). Wilcox et al. studied 221 women attempting to conceive by measuring daily hCG levels by radioimmunoassay. Twenty-two per cent of pregnancies detected by assay were lost prior to clinical recognition. However, of these, 35% became clinically pregnancy the next cycle, 65% clinically pregnant by the third cycle and 83% by the sixth cycle. Such a chemical pregnancy is an excellent prognostic sign indicating that the woman is ovulatory, has tubal patency ( at least on one side), has a fertile partner and is herself capable of capacitating her partner’s semen.
    Now that women have the ability to clinically recognize their own pregnancies by the time of their missed menses, a more appropriate definition of chemical pregnancy would be one in which loss occurs prior to the onset of the embryonic period.
    • Risk Factors and Aetiology For Pregnancy Failure, p.28-29
  • Numerous authors have looked at the role of chromosomal abnormalities in these embryonic losses. One study looked at 144 spontaneous miscarriages by obtaining direct preperations of chorionic villi. Seventy per cent had abnormal chromosomes of which 64% were autosomal trisomies, 9% polyploidy, 7% monosomy X ad 6% structural rearrangements.
    Errors of gonadogenesis during meiosis will result in autosomal trisomies. Errors of fertilization can result in triploidy from dispermy. Errors of the first division of the zygote result result in tetraploidy or mosaicism. None of these would be expected to bea repetitive event except in the very rare instances of balances translocations or inversions in one parent
    The other 30% of non-chromosomal early pregnancy failures will include uterine abnormalities, infectious agents (T strain mycoplasmas), maternal alcohol, maternal smoking,, molecular genetic abnormalities with normal karyotypes, possibly autoimmune factors, and questionably luteal phase defects.
    Some authors’ have suggested that karyotyping chorionic villi obtained at the time of curettage for failed pregnancies prior to spontaneous passage can serve a valuable clinical role. The presence of abnormal chromosomes gies the parents a definitive diagnosis as to why the pregnancy failed and may obviate the need for further investigation. Karyotyping a failed pregnancy that produces normal chromosomes can potentially result in the search for various other causes without the couple first having to go through a subsequent failed pregnancy.
    The natural history of pregnancy failure in the general population has long been of interest to clinicians Simpson et al. found that most losses although not clinically encountere until after 8 weeks actually occur prior to 8 weeks. Spontaneous passage of products of conception actually occurs 1-4 weeks after an embryo loses its viability. It is very important that women understand that rarely is physical activity on the day of spontaneous passage the aue of pregnancy loss. Such an event means that the pregnancy had usually been non-viable for more than 1 week.
    Another study looked at 232 women with no bleeding prior to the first visit. All women had a TVS as the initial visit and at all subsequent visits up to 12 weeks. The latest anatomical landmark visualized using ultrasonography was recorded. There were 200 births, 27 embryonic losses and give fetal losses. These authors looked at loss rates subsequently in the embryonic period based on the anatomical landmark achieved. Thus, if a pregnancy developed to the stage of visualizing a gestational sac, there was still a subsequent loss rate in the embryonic period of 11.5%. If the pregnancy developed a yolk sac visible on ultrasound, the subsequent loss rate in the embryonic period was 8.5%. The development of an embryo to over 5 mm was associated with a 7.2 loss rate in the embryonic period. Embryos of more than 1 cm had a subsequent loss in the embryonic period of 0.5% The authors did report a 2.4 loss int eh fetal period due to factors such as an incompetent cervix, severe maternal infection and abnormalities of placentation. This is an contrast with the 70% of embryonic losses that are thought to be chromosomal.
    • Embryonic Losses, p.29

“Miscarriage Among Flight Attendants” (Mar 26, 2015)[edit]

Barbara Grajewski, Elizabeth A. Whelan, Christina C. Lawson, Misty J. Hein, Martha A. Waters, Jeri L. Anderson, Leslie A. MacDonald, Christopher J. Mertens, Chih-Yu Tseng, Rick T. Cassinelli, II, and Lian Luo; “Miscarriage Among Flight Attendants”, Epidemiology. 2015 Mar; 26(2): 192–203.

  • Background—Cosmic radiation and circadian disruption are potential reproductive hazards for flight attendants.
    Methods—Flight attendants from 3 US airlines in 3 cities were interviewed for pregnancy histories and lifestyle, medical, and occupational covariates. We assessed cosmic radiation and circadian disruption from company records of 2 million individual flights. Using Cox regression models, we compared respondents (1) by levels of flight exposures and (2) to teachers from the same cities, to evaluate whether these exposures were associated with miscarriage.
    Results—Of 2654 women interviewed (2273 flight attendants and 381 teachers), 958 pregnancies among 764 women met study criteria. A hypothetical pregnant flight attendant with median firsttrimester exposures flew 130 hours in 53 flight segments, crossed 34 time zones, and flew 15 hours during her home-base sleep hours (10 pm–8 am), incurring 0.13 mGy absorbed dose (0.36 mSv effective dose) of cosmic radiation. About 2% of flight attendant pregnancies were likely exposed to a solar particle event, but doses varied widely. Analyses suggested that cosmic radiation exposure of 0.1 mGy or more may be associated with increased risk of miscarriage in weeks 9–13 (odds ratio = 1.7 [95% confidence interval = 0.95–3.2]). Risk of a first-trimester miscarriage with 15 hours or more of flying during home-base sleep hours was increased (1.5 [1.1–2.2]), as was risk with high physical job demands (2.5 [1.5–4.2]). Miscarriage risk was not increased among flight attendants compared with teachers.
    Conclusions—Miscarriage was associated with flight attendant work during sleep hours and high physical job demands and may be associated with cosmic radiation exposure.
    • p.1
  • The commercial aircraft cabin environment is the work-place of approximately 168,000 flight personnel in the United States, including pilots, copilots, and 93,100 flight attendants, of whom 84% are female. The International Agency for Research on Cancer (IARC) estimates 250,000 aircrew worldwide are monitored for radiation exposure; US airline crew are not currently monitored. Reproductive problems among female flight attendants have been reported since the 1960s, including adverse pregnancy outcomes and menstrual irregularities. Workplace exposures of concern include cosmic ionizing radiation and circadian rhythm disruption. Galactic cosmic radiation generates secondary and tertiary radiation at aircraft altitudes, including neutrons and energetic photons (IARC-known human [group 1] carcinogens). Solar particle events (transient solar surface eruptions) are another source of cosmic radiation exposure. Flying across time zones or working during normal sleep hours can affect reproductive hormones with circadian regulation. These exposures are different from those of other occupational groups exposed to terrestrial radiation or shift work. We evaluated the risk of miscarriage among flight attendants and a comparison group of teachers and assessed whether cosmic radiation, circadian disruption, and other occupational exposures were associated with miscarriage.
    • pp.1-2
  • Occupational exposures among flight attendants were first considered one at a time (Table 3). Model 8 provided evidence of an association between higher levels of absorbed radiation dose (≥0.1 mGy) and miscarriage in weeks 9–13 (OR = 1.7 [95% CI = 0.95–3.2]). Higher Standard Sleep Interval travel (≥15 hours) was associated with miscarriage during the first trimester (model 15 = 1.5 [1.1–2.2]). Associations were not observed for higher numbers of time zones crossed and miscarriage. When exposure metrics were evaluated 2 at a time (models 16–24), we observed increased odds of miscarriage for Standard Sleep Interval travel ≥15 hours (models 21 and 24). The models also show a modest cosmic radiation–miscarriage association (models 18 and 21). Flight attendants who did not fly during the pregnancy had higher odds of miscarriage compared with actively flying flight attendants with low occupational exposures.
    High physical job demands were a risk factor for miscarriage (OR = 2.5 [95% CI = 1.5– 4.2]). We performed additional modeling adjusted for age and parity with the components of the composite metric: standing/walking, bending at the waist, lifting, and pushing/pulling, as defined in eTable 2 (http://links.lww.com/EDE/A862). Among these job-demand components, standing and walking for more than 8 hours/day (1.8 [1.2–2.8]) and bending at the waist more than 25 times/day (2.0 [1.1–3.5]) were risk factors for miscarriage.
    • pp.6-7
  • In this study, we found associations between miscarriage in flight attendants and occupational exposure to circadian disruption and physical job demands. We also found evidence of an association between cosmic ionizing radiation during pregnancy and miscarriage among flight attendants, although the association was modest and may have been affected by multicollinearity with circadian disruption metrics. We initially evaluated other approaches to exposure metrics, including continuous and quartile cutpoint metrics for radiation and circadian disruption. Many of these earlier models exhibited strong signs of collinearity and diminished evidence of association between the metrics and miscarriage. The analyses we present with “high–low” exposure metrics, especially Standard Sleep Interval travel, were the least influenced by multicollinearity between radiation and circadian disruption metrics and best able to describe the effects of separate metrics.
    Evidence from atomic bomb survivor studies suggested a 50 mGy threshold for adverse reproductive outcomes in humans; however, lower x-ray exposures have been associated with miscarriage in nurses (1 or more hours a day self-reported exposure) and veterinarians (more than 5 self-reported films/week). Flight attendants’ prepregnancy exposure rates were also low compared with the 50 mGy threshold, but generally higher than during their first trimester; half had estimated annual doses between 0.7 and 2.0 mGy (effective dose = 1.8–5.8 mSv) prior to pregnancy. These studies suggest that the most

highly exposed flight attendants, nurses, and veterinarians may be at increased risk for reproductive and other health effects.

    • p.7
  • We found an increased risk of miscarriage in flight attendants who flew 15+ hours during their home-base sleep hours. This is a new finding; however, it is consistent with reports of adverse reproductive outcomes associated with night or rotating shift work. Time zones crossed and radiation metrics were highly correlated, but we attempted to separate the etiologic contributions of circadian disruption and radiation by including our other circadian metric, Standard Sleep Interval travel, in a 2-exposure model with simplified exposure levels. Both time zones crossed and Standard Sleep Interval travel are related to a circadian biomarker, the day-to-day variance in overnight melatonin excretion. Standard Sleep Interval travel may be the better circadian metric for flight crew studies, but it considers only flight time and not commuter or other personal time, and it, therefore, probably underestimates disrupted sleep.
    • pp.7-8
  • Although occupational environmental tobacco smoke exposure was a risk factor in single- exposure analyses (OR = 1.8 [95% CI = 1.2–2.6]), we did not adjust for it when evaluating the association of miscarriage with radiation and circadian rhythm disruption (Table 4). Environmental tobacco smoke was a likely proxy exposure for Standard Sleep Interval travel prior to the airlines’ comprehensive smoking ban on long international overnight routes. Further, active smoking during the pregnancy was rare (4%) and did not meet criteria for confounding in our study because the rates of miscarriage among active smokers (26%) were comparable to those among nonsmokers (21%) (likelihood ratio P = 0.55). Environmental tobacco smoke exposure has generally been associated with later adverse reproductive outcomes rather than with miscarriage.
    • p.9

“Emergency Care: A Textbook for Paramedics” (2005)[edit]

Greaves I, Porter K, Hodgetts TJ, Woollard M (2005). "Emergency Care: A Textbook for Paramedics”. London: Elsevier Health Sciences. ISBN 978-0-7020-2586-0.

  • The most frequent cause of vaginal bleeding with or without abdominal pain early in pregnancy is miscarriage.
    • p.505
  • Approximately 1-=15% of confirmed pregnancies end in miscarriage. This occurs most often at either 8 weeks or 12 weeks from the first day of the LMP. There are several postulated causes of miscarriages, but most are due toa genetic defect in the fetus or to uterine abnormalities. Many threatened miscarriages may settle spontaneously and lead to a normal pregnancy and subsequent delivery of a normal infant. Miscarriage may, however, cause significant uterine bleeding, resulting in hypovolaemic shock.
    • pp.505-506
  • Terminology
    Any form of miscarriage is stressful and distressing experience not only for the mother but also for the father. It is important not to make the situation worse by using the term abortion. There are a number of different types of miscarriage, although these cannot always be distinguished without vaginal examination. Clearly the prognosis is better with threatened abortion and it is important not to be overspecific about prognosis (either in terms of inappropriate reassurance or unnecessary pessimism) unless it is absolutely clear that the products of conception have been lost.
    Threatened miscarriage
    In threatened miscarriage, vaginal bleeding is associated with cramping abdominal pain; the cervix remains closed and pregnancy may progress normally.
    Incomplete miscarriage
    In incomplete miscarriage, vaginal bleeding may be heavy, the cervix is open and abdominal pain is caused by uterine contractions, which have begun to expel the products of conception.
    Complete miscarriage
    In complete miscarriage the products are completely expelled through an open cervix. The symptoms usually then settle.
    • p.506
  • Symptoms and signs
    The patient may be known to be pregnant or admit to being late with a period. There may be a history of previous miscarriage; she will be complaining of vaginal blood loss an may have lower abdominal cramping pain.
    There may be obvious external signs of vaginal bleeding associated with varying degrees of shock. Measurement of pulse, blood pressure and respiratory rate is mandatory.
    Most women will naturally be anxious at the prospect of a miscarriage and gentle handling and reassurance are very important during the initial assessment and transfer to hospital for more detailed examination and management and ultrasound scanning, to confirm pregnancy and determine the viability of the fetus.
    • p.506
  • Miscarriage Timing 5-12 weeks, abdominal pain central and cramping, relation to bleeding, follows, vaginal bleeding frank may be heavy, haemodynamic status shock rare
    • Table 51.1, p.506

“Air pollution exposure during pregnancy and spontaneous abortion and stillbirth” (Sep 25, 2018)[edit]

Alexandra Grippo, Jun Zhang, Li Chu, Yanjun Guo, Lihua Qiao, Jun Zhang, Ajay A. Myneni, Lina Mu; “Air pollution exposure during pregnancy and spontaneous abortion and stillbirth”, Rev Environ Health. 2018 Sep 25; 33(3): 247-264.

  • The developing fetus is particularly susceptible to environmental pollutants, and evidence has shown adverse effects of air pollutants on pregnancy and birth outcomes. Pregnancy loss, including spontaneous abortion (miscarriage) and stillbirth, is the most severe adverse pregnancy outcome. This review focuses on air pollution exposure during pregnancy in relation to spontaneous abortion and stillbirth. A total of 43 studies are included in this review, including 35 human studies and eight animal studies. Overall, these studies suggest that exposure to air pollutants such as particulate matter (PM), carbon monoxide (CO) and cooking smoke may be associated with higher risk for stillbirth and spontaneous abortion. PM10 exposure during an entire pregnancy was associated with increased risk of spontaneous abortion, and exposure to PM2.5 and PM10 in the third trimester might increase the risk of stillbirth. CO exposure during the first trimester of pregnancy was associated with an increased risk of spontaneous abortion and exposure during the third trimester was associated with an increased risk of stillbirth. Cooking smoke was found to increase the risk of stillbirths, and the evidence was consistent. Insufficient and conflicting evidence was found for various other pollutants, such as NO2 and SO2. Studies did not show clear evidence for associations between pregnancy loss and others pollutants such as heavy metals, organochlorine compounds, PAH and total dust count. Further research is warranted to better understand the relationship between air pollution exposure and pregnancy loss.
    • pp.1-2
  • Pregnancy loss is the most severe adverse pregnancy outcome, but understanding around the cause of fetal death is limited. Detrimental effects of environmental pollution on spontaneous abortion and stillbirth have been previously suggested with exposure to magnetic fields, parental smoking and environmental tobacco smoke. However, the relationship between air pollution and pregnancy loss has not been well studied.
    Spontaneous abortion, or miscarriage, is considered the most common and severe complication of early pregnancy, with an incidence of 17-22% of all recognized pregnancies. The true rate of pregnancy loss is difficult to determine, and some authors have suggested 20-40% of all losses may occur before clinical detection. In 2009, the WHO reported that 2.6 million stillbirths occurred worldwide, and more than 7200 stillbirths occur every day. Several potential causes of stillbirth have been reported as umbilical cord accidents, congenital anomalies, placental abruption and smoking during pregnancy. In the last 10 years, literature has been emerging on the topic of air pollution and pregnancy loss, however, the evidence has not been reviewed systematically.
    • pp.2-3
  • Out of the seven studies that focus on PM exposure throughout the entire pregnancy and spontaneous abortion, four provide strong evidence that there is an association between exposure to PM throughout the entire pregnancy and increased risk of spontaneous abortion. A prospective cohort found a significant increased hazard ratio of 1.13 per interquartile range increase for PM2.5 and spontaneous abortion throughout the entire pregnancy. Two retrospective cohorts found significant increased AORs of 5.05 and 2.59 with spontaneous abortion for w >56.72 μg/m3 PM10 vs. ≤56.72 μg/m3 PM10. Both studies had recruited around 400 participants from fertility clinics. One time series study reported a 20% increased risk of spontaneous abortion per 10 μg/m3 increase in PM10 exposure [adjusted risk ratio (ARR) = 1.20, 95% confidence intervals (CI) 1.08–1.34]. A case-control study failed to confirm the association with PM10, but suggested that TSP exposure in the first 14 weeks of pregnancy during the heating period (December to May) has a doubled risk of spontaneous abortion [adjusted odds ratio (AOR) = 2.04, 95% CI: 1.01–4.13]. Although evidence on PM10 and spontaneous abortion is strong, the limited data on PM2.5 exposure warrants more research in this area.
    • p.4
  • The only available epidemiological evidence on the association between exposure to cooking smoke and spontaneous abortion is from a case-control study conducted in Sri Lanka. This study reported that compared to women who carried a viable fetus, those who had miscarriages (defined as partial or full expulsion of fetus ≤28 weeks of pregnancy) during the second trimester were 283% more likely to be exposed to cooking smoke (from burning firewood) during their pregnancy. While this study provides suggestive evidence on the association between cooking smoke and spontaneous abortions, these results should be interpreted with caution as they are based on a low case-yield. Smoke from burning biomass fuels contains many pollutants including particulate matter, carbon monoxide and polycyclic aromatic hydrocarbons. Additional evidence from future studies is necessary to determine how this mixture of pollutants can influence the risk of spontaneous abortions.
    • p.5
  • Six studies were conducted, of which one reported a positive relationship between NO2 exposure and spontaneous abortion, with estimated small magnitude. The case-control study from Iran found a 4% increase in spontaneous abortion among those exposed to higher concentrations of NO2, compared to those exposed to lower concentrations of NO2 (AOR = 1.04, 95% CI: 1.02–1.05). A prospective cohort in the United States reported an 18% increase on spontaneous abortion for those individuals in the top 90th percentile of annual average daily traffic exposure compared to the bottom 75th percentile, in which the main pollutant analyzed was NO2 (AOR = 1.18, 95% CI: 0.87–1.60). However, the other four studies failed to support the above findings. These results are inconclusive, suggesting more studies need to analyze this association.
    • p.6
  • Two case-control studies found significant associations between sulfur dioxide exposure and spontaneous abortion. A study from Croatia found frequencies of spontaneous abortion were lower when the local coal power plant was closed compared to when the power plant was open (p < 0.05), and a study from China found fetal loss within 14 weeks was associated with exposure to SO2 (AOR = 19.76, 95% CI: 2.34–166.71). These results suggest a strong relationship between sulfur dioxide exposure and spontaneous abortion.
    • p.6
  • Only three studies analyzed carbon monoxide exposure and spontaneous abortion, and the results are conflicting. A case-control study from Iran found a 95% increase in spontaneous abortions in cases compared to controls (AOR = 1.95, 95% CI: 1.50–2.55), but a time series study found no association between spontaneous abortion and exposure to carbon monoxide, and a prospective cohort found null results. These studies produced inconclusive results, suggesting more studies need to be done in this area.
    • p.6
  • Four studies examined the effect of ozone on spontaneous abortion, with three producing strong results. A time-series study from Italy found a 34% increased risk of spontaneous abortion per 10 μg/m3 increase in ozone (AOR = 1.34, 95% CI: 1.26–1.42). A case-control study from Iran found a 10% increased risk of spontaneous abortion in cases exposed to ozone compared to controls (AOR = 1.10, 95% CI: 1.06–1.13). A prospective cohort found a 12% increased risk of spontaneous abortion per interquartile range increase in ozone throughout the entire pregnancy (HR = 1.12, 95% CI: 10.7–1.17). Another time series study produced null results. These results suggest an association between ozone and spontaneous abortion, but more studies are needed to investigate this association.
    • p.7
  • Overall, three studies examined the effects of other pollutants not mentioned above on spontaneous abortion risk. One cross-sectional study from Brazil examined the association between different levels of heavy metals and organochlorine compounds and risk of spontaneous abortion, but no significant results were found. A second cross-sectional study was conducted in Egypt which examined the association between total dust count, suspended dust concentration, and respirable dust concentration, with a significant correlation for respirable dust count (r = 0.72, p < 0.05). A case-control study from China observed a 35% increased risk of missed abortion among women whose maternal blood BaP-DNA level showed evidence of PAH exposure (AOR = 1.35, 95% CI: 1.11–1.64). A missed abortion is where the embryo has died but a miscarriage has not yet occurred.
    • p.7
  • Overall, two cross-sectional studies from Finland and two cohort studies from China examined the association between occupational pollutants and risk of spontaneous abortion. One cross-sectional study examined spontaneous abortion risk in an industrial community. Pollutants that were examined included sulfur dioxide, hydrogen sulfide and carbon disulfide. An increased rate of spontaneous abortion was found for women employed in rayon textile and paper products jobs (10.3 and 16.7, respectively, p < 0.10). Another occupational cross-sectional study from Finland examined the association between solvents, automobile exhaust fumes, PAH, chemical exposures, metals, textile dust and spontaneous abortion risk, however, no association was found. A retrospective cohort study from Shanghai, China examined the miscarriage risk among women textile workers. Pollutants that were measured included cotton dust, wool dust, silk dust, synthetic fibers, mixed fibers, solvents, acids and bases, resins, lubricants and metals. Women exposed to synthetic fibers had an 89% increased miscarriage risk (AOR = 1.89, 95% CI: 1.20–3.00) and women exposed to mixed fibers had a 231% increased miscarriage risk (AOR = 3.31, 95% CI: 1.30–8.42) compared to those women who were unexposed. A retrospective cohort study from Beijing, China showed a 190% increased risk of spontaneous abortion among those exposed to petrochemicals compared to those unexposed to petrochemicals (AOR = 2.9, 95% CI: 2.0–4.0).
    • p.8
  • Overall, we found eight animal studies for this review, from which seven studies provide strong evidence that air pollution causes both spontaneous abortion and stillbirth. Animals that were analyzed in these studies included sows, mice and cattle. Pollutants analyzed included CO, PM10, NO2, benzo(a)pyrene, diesel exhaust particles, H2S, SO2, and volatile organic compounds. Both short- and long-term exposures were included due to a shorter life span.
    Two studies in particular observed a dose-response relationship with exposure to air pollutants and spontaneous abortion. A study found that as the ambient level of CO increased from 150 ppm, 200 ppm, 250 ppm, 300 ppm, to 350 ppm for 48–96 h, overall stillbirths rates were 0.0%, 6.7%, 34.8%, 42.3%, and 80.0%, respectively. Although 48–96 h is a much shorter exposure window than compared to the human exposure window, we decided to include it in this review due to the limited number of animal studies, and the study can at least provide certain useful evidence. Another study observed pregnant mice exposed to levels of diesel exhaust particles ranging from 0.3, 1.0, to 3.0 mg/m3, with abortion rates of 9.1%, 10.0%, and 16.7%, respectively.
    Mice exposed to PM10 and NO2 showed a decreased fertility as higher numbers of live-born mice were born in the clean chamber compared to the polluted chamber (median = 6.0 and 4.0, respectively, p-value = 0.037). A study examining the effects of benzo(a)pyrene on rats found that out of eight females fed benzo(a)pyrene, there was one successful birth and eight unsuccessful births. Of the eight females fed benzo(a)pyrene, five became pregnant and only one gave birth. The female that gave birth had four pups, of which two were stillborn. The remaining pregnant females did not give birth, indicating spontaneous abortion or fetal absorption, while three out of the six female controls became pregnant and all three females delivered healthy litters. Another study observed pregnant sows in Poland that were exposed to high levels of CO. In the first group of sows that experienced carbon monoxide poisoning, 28/28 aborted. In the second group 26/28 aborted, in the third group 25/28 aborted, and in the group of unexposed sows none aborted. Another study that focused on carbon monoxide poisoning in sows found 28% of piglets were stillborn in the first CO poisoning incident, and 52.9% were stillborn in the second CO poisoning incident. Waldner et al. conducted two animal studies focusing on exposure in cows from the oil and gas industry and birth outcomes. The first study with 23 herds of cattle investigated a natural gas leak from a pipeline and calf mortality found null results. The other study showed that the risk of spontaneous abortion and stillbirth was 2.6% for cows with higher exposure to oil- and gas-production facilities compared to those who were less exposed. Overall, the animal studies included in this review provide supporting evidence that pollutants such as CO, diesel exhaust particles, benzo(a) pyrene and pollutants from oil and gas production lead to an increased risk for spontaneous abortion and stillbirth.
    • pp.8-9
  • The biological mechanisms behind particulate matter and spontaneous abortion and stillbirth are not well understood. It has been hypothesized that particulate matter may impair reproductive health in women by: [1] affecting the placental interface between the mother and the fetus by compromising delivery of maternal blood and nutrients to the placenta, impairing embryo development; [2] contributing to oxidative stress through oxidative activities of combustion-derived particles adversely affecting the embryo in its earliest stage of growth, which can lead to DNA damage and inflammation; [3] escaping phagocytosis by alveolar macrophages and translocating to extrapulmonary organs due to the high respiratory deposition of ultrafine particles; or [4] increasing concentration of DNA adducts, which may lower the efficiency of the transplacental function, resulting in decreased fetal health ultimately leading to stillbirth. The exposure to the fetus at different periods of development may have differing effects because of differences in physiologic maturity of the fetus. While many pathways between PM and spontaneous abortion and stillbirth have been proposed, none have been proven.
    • p.9
  • One reason for the limited number of data on air pollution and spontaneous abortions is partially due to data collection. Women can have a spontaneous abortion before they even realize they are pregnant, resulting in a large portion of unrecognized spontaneous abortions. In developing countries, spontaneous abortion and stillbirth are still a major health problem, with much of the data underreported or unreliable. Another issue is the definition of the outcomes. Every country, or state in the United States, has their own definition of what constitutes a spontaneous abortion and stillbirth. The various definitions make it difficult to compare the results across the studies. Some studies included in this review presented associations between pollutant exposure during individual trimesters and stillbirths. Considering that women could be exposed to pollutants for only a short period during third trimester; at least some stillbirths occurring during this period could be attributed to an acute exposure to these pollutants. For example, Mendola et al. showed that acute (1 week before delivery) exposures to ozone could increase risk of stillbirths. On the other hand, findings from studies on the associations between third trimester exposure to pollutants and stillbirths should be interpreted with caution because of the lack of specificity in quantifying the exposure period before the occurrence of stillbirth outcome.
    • p.10
  • [T]he evidence presented in this review suggests various air pollutants as a risk factor for spontaneous abortion and stillbirth. Consistent results were observed for PM10 exposure and spontaneous abortion, and for PM10 and PM2.5 exposure in the third trimester and increased risk of stillbirth. Exposure to cooking smoke also produced consistent and strong results with increased risk of stillbirth. Exposure to SO2 and CO showed inconsistent results. Pollutants such as heavy metals, organochlorine compounds, PAH, and total dust count produced no evidence. More evidence is needed.
    • pp.10-11

“Post-conception heat exposure increases clinically unobserved pregnancy losses” (21 January 2021)[edit]

Tamás Hajdu & Gábor Hajdu; “Post-conception heat exposure increases clinically unobserved pregnancy losses”, Nature, Scientific Reports, volume 11, Article number: 1987 (2021) Published: 21 January 2021

  • Evidence of the relationship between temperature during pregnancy and human embryo mortality is limited. Most importantly, the literature lacks causal estimations and studies on early pregnancy losses. Here, we estimate the impact of early pregnancy temperature exposure on the clinically unobserved pregnancy loss rate. We use administrative data of clinically observed pregnancies from more than three decades for Hungary. We apply an empirical approach that allows us to infer the impact of temperature on the clinically unobserved pregnancy loss rate from the estimated effects on the clinically observed conception rate. The results show that exposure to hot temperatures during the first few weeks after the conception week increases the clinically unobserved pregnancy loss rate, whereas exposure to colder temperatures seems to decrease it. Importantly, the temperature induced changes represent changes in the total number of pregnancy losses rather than a compositional change between clinically observed and clinically unobserved pregnancy losses.
    • p.1
  • The Earth’s climate is rapidly warming. The projected changes have prompted numerous studies on the impact temperature has on natural and human systems. A large body of rapidly growing research focuses on the impact of temperature and climate change on human mortality. Nevertheless, the evidence concerning the impacts on embryo mortality is still limited. Most previous papers have investigated the relationship between ambient temperature and the risk of late foetal death (stillbirth), while only a few studies have analysed the association of temperature exposure with miscarriage risk. One of the main shortcomings of these papers is the lack of causal evidence. Furthermore, due to obvious data limitations, the largest share of pregnancy losses that occur in the early period of pregnancy, namely, clinically unobserved pregnancy losses, are ignored.
    Human embryo mortality between fertilization and birth is high. The most reliable estimations range from 40 to 67%. Most of these pregnancy losses remain clinically unobserved. The share of conceptions lost before clinical recognition is estimated to be between 20 and 60%. A primary cause of this sizeable uncertainty is that embryo mortality from fertilization to implantation is undetectable by any technology. Furthermore, most post-implantation losses occur before the pregnancy becomes clinically recognized. Many early embryo losses are caused by genetic abnormalities, although environmental and behavioural factors may also play a role. As most pregnancy losses are clinically undetected, we also have to assess clinically unobserved pregnancy losses to completely understand the impact of in utero temperature exposure on human embryo mortality.
    • p.1
  • We find that early pregnancy temperature exposure to an additional hot day (mean temperature >25 °C) increases the clinically unobserved pregnancy loss rate by 0.22 pregnancy losses per 100,000 women aged 16–44 years, compared with a day with a mean temperature of 15–20 °C (Table 1). The effects of exposure to days with temperatures of 20–25 °C or 10–15 °C are basically identical to those of exposure to a day with a temperature of 15–20 °C. The coefficients of colder temperature bins are negative, but some of them are not different from zero at the 95% significance level, and the point estimate for the coldest temperature bin is especially close to zero. In general, the impact of temperature exposure during the first 6 weeks of the pregnancy (excluding the conception week) seems to be non-linear. Hot days increase the clinically unobserved pregnancy loss rate, whereas colder days seem to decrease it, but the latter impacts are not particularly different from each other. Our findings are in line with the results of other mammalian studies.
    • p.2
  • Using administrative data and applying a novel empirical approach, we provide evidence that exposure to hot temperatures during the first few weeks of pregnancy increases the clinically unobserved pregnancy loss rate. This increase in the clinically unobserved pregnancy loss rate means a “net” increase in total pregnancy losses rather than a compositional change between clinically observed and clinically unobserved pregnancy losses. In other words, early pregnancy exposure to hot temperatures decreases the chance that a pregnancy ends in a clinically observed outcome (live birth, induced abortion, miscarriage/stillbirth) and increases the chance of an early (clinically unobserved) embryo loss.
    We find that each additional > 25 °C day during the early pregnancy period causes an increase of 0.22 pregnancy losses in the clinically unobserved pregnancy loss rate, which reflects an increase of 0.09% to 0.52%, depending on the assumption regarding the share of conceptions that are lost before clinical recognition. The impacts are especially high during the first few weeks after the conception week, whereas they become practically zero after the sixth week, which is in line with the fact that the longer the pregnancy is, the higher the likelihood of clinical recognition.
    Most previous papers have examined the association between ambient temperature and stillbirths, which is typically defined as foetal death after the 20th/28th pregnancy week and constitutes a very small fraction of pregnancy losses. They analysed the impacts during different periods of pregnancy. Therefore, a direct comparison of our estimations with these studies is difficult. While previous studies have found that temperature during the later periods of the pregnancy is associated with late foetal losses, our study provides the first estimate of a causal relationship between early pregnancy temperature exposure and the clinically unobserved pregnancy loss rate that covers the majority of pregnancy losses.
    • pp.4-5
  • This paper provides important implications for the wider literature as well. Our estimations provide evidence that early pregnancy temperature exposure changes the composition of foetuses that survive to live birth (“culling” effect). Therefore, the subsequent birth cohort represents a selected sample of conceptions. The selection is unlikely to be random, but it is likely to remove foetuses with below-average health. Several papers have aimed to estimate the “scarring” effect of in-utero temperature exposure on health at birth and found that exposure to heat reduces birth weight. Our results imply that these estimations are very likely to be biased towards the opposite direction (biased upwards) due to selection in utero. Estimations of the impacts of temperature exposure during early pregnancy should be especially affected. Indeed, the most reliable estimates show that the effect of first trimester exposure to a hot temperature on birth weight is much weaker than the effect of exposure to a hot temperature during the second and third trimesters , which is consistent with a selection-induced upward bias, although other factors may also play a role. More importantly, our empirical approach offers a tool that can be used for the estimation of a corrected scarring effect. Calculating the conception rate based on pregnancies ending in live births and regressing it on the post-conception exposure yields an estimation of the extent of the culling effect. With a further assumption of the average difference between the birth weight of the observed new-borns and the birth weight of the “culled” foetuses, a bias-corrected estimation of the scarring effect can be obtained.
    • p.5

“The Gulf oil spill, miscarriage, and infertility: The GROWH Study” (January 2018)[edit]

Emily W. Harville, Arti Shankar, Leah Zilversmit, and Pierre Buekens; “The Gulf oil spill, miscarriage, and infertility: The GROWH Study”, Int Arch Occup Environ Health. 2018 Jan; 91(1): 47–56.

  • Results—77 (5.1%) women reported postponing pregnancy due to the oil spill, which was more common in those with high contact with oil or overall high exposure (aOR 2.92, 95% CI 1.31– 6.51). An increased risk of miscarriage was found with any exposure to the oil spill (aOR, 1.54, 95% CI 1.17–2.02). Fertility issues were more common in the overall most highly exposed women (aOR 1.88, 1.19–2.95), when the data were limited to those with pregnancies before and after. However, no particular aspect of oil spill exposure was strongly associated with the outcomes, and effects were almost as strong for pregnancies prior to the oil spill.
    Conclusions—The oil spill appears to have affected reproductive decision-making. The evidence is not strong that exposure to the oil spill was associated with miscarriage or infertility.
    • p.1
  • Overall risk of miscarriage was lower for pregnancies after the spill, although this was likely due partly to the relatively large number of currently pregnant women – when women with ongoing pregnancy were excluded, the protective effect disappeared (aOR 0.89, 0.66–1.20). An increased risk of miscarriage was found with any reported exposure to the oil spill (aOR 1.54, 1.17–2.02), an effect that was similar or stronger when limited to those with pregnancies before and after the spill (aOR 1.79, 1.25–2.55), or which occurred within two years of the spill (table S1, aOR 1.87, 1.12–3.12 and 2.56, 1.37–4.79 for those with both a pre- and post-oil spill pregnancy). No specific aspect of oil spill exposure (income, contact, trauma, etc.) could be identified as a stronger predictor than any other. However, reported exposure to the oil spill was also associated with miscarriage in pregnancies prior to the oil spill (aOR 1.64, 1.06–2.54; table 4). No significant interactions indicating stronger effects on pregnancies after the oil spill.
    • p.5
  • In this study of the 2010 Gulf oil spill, few aspects of oil spill exposure were associated with miscarriage or infertility. In a few cases, general indicators of exposure were associated with these outcomes; this could be a chance finding given that multiple comparisons were conducted (given approximately 10 indicators of exposure, at least one or two chance associations would be expected across the miscarriage and infertility analyses). Still, the size of the association is consistent with the size of the effects seen in previous studies indicating associations between psychological or economic stress and miscarriage or infertility (Bruckner et al. 2016; Lynch et al. 2014). Stress could affect conception and miscarriages through behavioral pathways, such as reduced frequency of intercourse or increased smoking by a woman (controlled for, though residual confounding is a possibility) or her partner, and hormonal or immunological changes (Ferin 1999; Kwak-Kim et al. 2014; Whirledge and Cidlowski 2013). Overall, however, the effect of the oil spill on risk of

miscarriage was similar in pregnancies pre- and post-oil spill, suggesting minimal effects.
No associations were found with reported direct contact with oil. We are not aware of any studies that have examined the relationship between oil spills and miscarriage or infertility specifically, although petroleum production has been a source of concern under other circumstances (Colorado Department of Public Health and Environment 2014; Schlanger 2014; Xu et al. 1998) Evidence is inconsistent for effects on miscarriage or fertility for the three major types of environmental pollutants associated with the spill: VOCs, metals, and PAHs (Bukowski 2001; Duong et al. 2011; Wigle et al. 2008)(Detmar et al. 2006; Hertz- Picciotto 2000; Hombach-Klonisch et al. 2005; Wu et al. 2010). There is little evidence on the human reproductive effects of dispersants, a major public concern; animal studies are mixed in their conclusions (Pollino and Holdway 2002; Rowe et al. 2009; Van Scoy et al. 2012; Wooten et al. 2012). Overall, however, the lack of effect was not surprising given the fairly low levels of exposure and the mixed evidence for effects of related toxicants on the outcomes studied.

    • p.6
  • This study provides some moderate evidence for a combined effect of behavioral, social, and economic effects of the oil spill on miscarriage or infertility, but no particular evidence for effects of chemical exposure. Future studies should focus on identifying chemical signatures that can be directly related to oil spill exposures, and attempting to understand mechanisms by which social or economic stressors might affect reproductive success.
    • p.7

"Effects of metformin on early pregnancy loss in the polycystic ovary syndrome" (February 2003)[edit]

Daniela J. Jakubowicz, Maria J. Iuorno, Salomon Jakubowicz, Katherine A. Roberts, John E. Nestler (February 2002). "Effects of metformin on early pregnancy loss in the polycystic ovary syndrome". The Journal of Clinical Endocrinology and Metabolism. 87 (2): 524–9. doi:10.1210/jcem.87.2.8207. PMID 11836280.

  • Polycystic ovary syndrome is the most common form of female infertility in the United States. In addition to poor conception rates, pregnancy loss rates are high (30–50%) during the first trimester. We hypothesized that hyperinsulinemic insulin resistance contributes to early pregnancy loss in the syndrome, and that decreasing hyperinsulinemic insulin resistance with metformin during pregnancy would reduce the rate of early pregnancy loss.
    We conducted a retrospective study of all women with polycystic ovary syndrome who were seen in an academic endocrinology clinic within the past 4.5 yr and who became pregnant during that time.
    Sixty-five women received metformin during pregnancy (metformin group) and 31women did not (control group). The early pregnancy loss rate in the metformin group was 8.8% (6 of 68 pregnancies), as compared with 41.9% (13 of 31 pregnancies) in the control group (P < 0.001). In the subset of women in each group with a prior history of miscarriage, the early pregnancy loss rate was 11.1% (4 of 36 pregnancies) in the metformin group, as compared with 58.3% (7 of 12 pregnancies) in the control group (P = 0.002).
    Metformin administration during pregnancy reduces first-trimester pregnancy loss in women with the polycystic ovary syndrome.
  • POLYCYSTIC OVARY SYNDROME is the most common form of female infertility in the United States, and it affects 5–10% of women of reproductive age. In addition to difficulty conceiving, women with polycystic ovary syndrome are at increased risk of miscarriage after either spontaneous or assisted conception. Rates of early pregnancy loss, defined as miscarriage during the first trimester, are reported to be 30–50% in women with polycystic ovaries or the polycystic ovary syndrome, which is 3-fold higher than the rate of 10–15% reported in retrospective studies for normal women. Keeping in mind that these were retrospective case studies of clinically recognized pregnancies, the true miscarriage rates for both women with polycystic ovary syndrome and normal women were likely underestimated. Conversely, 36–82% of women with recurrent early pregnancy loss are reported to have polycystic ovary syndrome.
    Previous studies have suggested that women who hypersecrete LH, a frequent feature of the polycystic ovary syndrome, are at increased risk for miscarriage after either spontaneous or assisted conception. However, it was recently reported that suppression of endogenous LH release before conception, in women with elevated circulating LH concentrations and a history of recurrent miscarriage, did not improve the live birth rate. Other reported risk factors for early pregnancy loss in the polycystic ovary syndrome include obesity and elevated serum androgen concentrations. Obesity is characterized by insulin resistance with compensatory hyperinsulinemia (i.e. hyperinsulinemic insulin resistance), and a recent study implicates hyperinsulinemia as an independent risk factor for early pregnancy loss.
  • Because metformin has beneficial effects on several risk factors for miscarriage in the polycystic ovary syndrome (namely: hyperinsulinemic insulin resistance, hyperandrogenemia, and obesity), we hypothesized that decreasing hyperinsulinemic insulin resistance with metformin during pregnancy in women with the disorder would reduce the rate of early pregnancy loss. To test the hypothesis, we conducted a retrospective study of all women with polycystic ovary syndrome who were seen in an academic endocrinology clinic within the past 4.5 yr and who became pregnant during that time. Specifically, we compared the pregnancy outcomes of the women who became pregnant while taking metformin and remained on metformin throughout pregnancy vs. the pregnancy outcomes of the women who did not take metformin during pregnancy.
  • When women with polycystic ovary syndrome finally achieve pregnancy (often after a long, arduous, and expensive course of fertility treatments), they are faced with the distressing prospect of a substantially increased risk for miscarriage during the first trimester. The findings of this study support the hypothesis that decreasing hyperinsulinemic insulin resistance, with metformin, in women with the polycystic ovary syndrome, decreases the rate of early pregnancy loss. When metformin was administered throughout pregnancy to women with the disorder, the rate of early pregnancy loss was decreased dramatically, compared with women who had not received metformin (8.8% vs. 41.9%). The early pregnancy loss rate of 8.8% in the metformin group is especially remarkable, given that the historical miscarriage rate for these same women, when they had not been treated with metformin, was 70.6%.
    The early pregnancy loss rate in the control group (41.9%) is comparable with the 30–50% rate described in the literature for women with polycystic ovary syndrome or polycystic ovaries. In contrast, the rate of early pregnancy loss of 8.8% in the women treated with metformin is similar to the rate of 10–15% reported for clinically recognized pregnancies in normal women, suggesting that metformin treatment removed any independent risk for early pregnancy loss conferred by the disorder itself. Moreover, our results are similar to those of a pilot study, which recently reported an early pregnancy loss rate of 11% in 19 women with polycystic ovary syndrome treated throughout pregnancy with metformin.
    Women with polycystic ovary syndrome often have a history of recurrent or habitual (2 or more) abortion, and women with a history of habitual abortion seem to be at an even greater risk for early pregnancy loss than primigravida women with the disorder. Therefore, it is noteworthy that the women with a history of habitual abortion who were treated with metformin experienced only a 11.8% rate of early pregnancy loss (i.e. an 80% decrease in the rate of early pregnancy loss, when compared with the 58.3% observed in comparable women who did not receive metformin).
  • Metformin administration may have decreased the rate of early pregnancy loss by several potential mechanisms. Elevated serum androgen concentrations have been reported to be a risk factor for early pregnancy loss in the polycystic ovary syndrome, and the women who received metformin had serum free T levels, at 6–10 wk of pregnancy, that were 57% lower than those in the women who did not receive metformin. This finding is consistent with a case reported by Sarlis et al., in which a woman with hyperthecosis and elevated serum T concentrations during pregnancy responded to metformin therapy with a marked reduction in circulating T and delivered a healthy, nonvirilized baby girl.
    In addition, mechanisms other than androgen reduction may also have played a role in metformin’s apparent effects to protect against miscarriage. For example, metformin’s salutary effects may have been related directly to its action to improve insulin sensitivity in the polycystic ovary syndrome . A recent study implicates insulin resistance as an independent risk factor for early pregnancy loss in women with polycystic ovary syndrome, and a report suggests that hyperinsulinemia adversely affects endometrial function and the periimplantation environment by decreasing expression of glycodelin and IGF binding protein-1. Glycodelin may play a role in inhibiting the endometrial immune response to the embryo, and IGF binding protein-1 seems to facilitate adhesion processes at the fetomaternal interface.
  • In summary, administration of metformin to pregnant women with polycystic ovary syndrome throughout pregnancy was associated with a marked and significant reduction in the rate of early pregnancy loss. This beneficial effect of metformin administration was also noted in affected women with an established history of miscarriage. Except for a single baby born with achondrodysplasia, metformin was not associated with any adverse fetal outcomes. The findings of this retrospective study of a single endocrine clinic’s clinical experience suggests that a randomized placebo- controlled trial is warranted to confirm metformin’s action to decrease the rate of early pregnancy loss in women with polycystic ovary syndrome.

"Evidence-based management of recurrent miscarriages" (July 2014)[edit]

Yadava B. Jeve and William Davies (July 2014). "Evidence-based management of recurrent miscarriages". Journal of Human Reproductive Sciences. 7 (3): 159–69. doi:10.4103/0974-1208.142475. PMC 4229790. PMID 25395740.

  • Spontaneous miscarriage is a major loss for all pregnant women. It affects 1% of all women. The incidence of spontaneous miscarriage may be much greater than is clinically recognized. Spontaneous miscarriage occurs in 12% to 15% of all pregnancies. Thirty percent pregnancies are lost between implantation and sixth week. Maternal age and previous miscarriages increases risk of subsequent miscarriages. The management of recurrent miscarriages is an unsolved problem; up to 50% of cases of recurrent losses will not have a clearly defined etiology. The investigations and management of recurrent miscarriages is one of the most debated topics. This review is aimed to provide evidence based approach to manage recurrent pregnancy loss. This review is structured to be clinically relevant.
    • p.159
  • Recurrent miscarriages are defined as three or more consecutive miscarriages. The Practice Committee of the American Society for Reproductive Medicine defines recurrent pregnancy loss as by two or more failed clinical pregnancies. The risk of recurrent spontaneous miscarriage is much higher in patients with previous losses. The risk of miscarriage after two consecutive losses is 17% to 25% and the risk of miscarrying fourth pregnancy after three consecutive losses is between 25% and 46%. The risk gets worse with increasing maternal age. The evidence suggests higher frequency of spontaneous miscarriages amongst subfertile couples and a higher prevalence of subfertility in women with recurrent spontaneous miscarriages when compared with the general population.[5] Self reported losses by patients may not be accurate. In one study, only 71% of self reported clinical pregnancy losses could be verified in hospital records.[6] It is important to define pregnancy as a clinical pregnancy documented by ultrasonography or histo pathological examination (Evidence level IV).
    • p.160
  • The prevalence of chromosome abnormalities in women facing a single sporadic miscarriage is to be 45%. Approximately 50% to 60% of early spontaneous miscarriages are associated with a chromosomal anomaly of conceptus. Most common abnormality is aneuploidy, with autosomal trisomy accounting for more than 50% of chromosomally abnormal abortuses. A strong family history of recurrent miscarriage or genetic anomaly suggests a parental karyotypic abnormality, and a chromosomal analysis of the affected partner is appropriate in the primary evaluation. Chromosomal analysis of the miscarriage offers an explanation in at least 50% of cases. Parental karyotyping is not predictive of a subsequent miscarriage. Routine karyotyping of couples with recurrent miscarriage is not recommended. Cytogenetic analysis may be performed on products of conception to avoid unnecessary evaluation and treatment and because an aneuploid conceptus indicates a somewhat greater likelihood of success with a subsequent pregnancy (Evidence Level III).
    • p.160
  • Women with recurrent pregnancy loss have a 3.2% to 6.9% likelihood of having a major uterine anomaly and 1.0% to 16.9% chance of having an arcuate uterus. Ultrasound is quick, readily available, economical, and lacks radiation. 2D US can only identify about half of the congenital uterine anomalies present, but it has very low false positive rate. Some authors consider that this combination of hysteroscopy and laparoscopy can be the gold standard in evaluating congenital uterine anomalies. However, these are invasive tests. Three dimensional ultrasound by experienced hands is a more accurate than two dimensional ultrasound and equal to MRI at assessing uterine anomaly. Sonohysterography is a noninvasive, cost effective method with 95% accuracy in identifying uterine anomalies. MRI is a highly sensitive and specific method available because of its superior ability to reliably visualize complex uterovaginal anatomy. Two dimensional ultrasound can be used as an initial screening tool. Combined hysteroscopy and laparoscopy, sonohysterography, MRI, and 3D US can be used for a definitive diagnosis (Evidence level II).
    • p.160
  • Bacterial vaginosis is a risk factor for preterm delivery and a strong risk factor for late miscarriages. Vaginal swabs should be considered as screening tests during pregnancy in high risk women with previous history of late miscarriages. TORCH test is not recommended (Evidence level II).
    • p.160
  • Antiphospholipid syndrome (APS) is the only proven thrombophilia that is associated with adverse pregnancy outcomes. Five to fifteen percent of women with recurrent miscarriage have clinically significant antiphospholipid antibody titres, as compared with 2% to 5% of unselected obstetrical patients. Antiphospholipid syndrome (APS) is an autoimmune disease with the presence of antiphospholipid autoantibodies (aPL) formed against the person’s own tissues. These autoantibodies interfere with coagulation. Recurrent pregnancy loss will test positive for antiphospholipid antibodies (aPLs), the actual reported range varies between 8% and 42%. Laboratory testing for aPL Abs should generally be limited to patients who present with the thrombotic and/or the pregnancy manifestations of the disorder. Weak positive test results for aPL immunoassays are unlikely to have any clinical significance. The two assays that were preferred were the dilute Russell viper venom time (dRVVT) panel, which is widely used in clinical laboratories and is believed to be specific for detecting LA in those patients at high risk of thrombosis, and an LA insensitive aPTT. Testing positive for aCL Abs does not necessarily mean that a patient has APS. The positive test may be triggered by a preceding infection, such as syphilis, Lyme disease, EBV, CMV, HIV, and hepatitis C virus. These patients do not have LA or elevated Abs against β2GPI. Anti β2GPI immunoassays are more specific but less sensitive for APS than aCL Ab assays. The antiphospholipid syndrome should be diagnosed only when two tests performed 12 or more weeks apart are positive (Evidence level I). International Consensus classification criteria for diagnosis of the antiphospholipid syndrome is based on the presence of at least one of the clinical criteria and one of the laboratory criteria. Laboratory criteria includes the presence of Lupus anticoagulant (LA) or Anticardiolipin (aCL) antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer Anti β2 glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA. Clinical criteria include vascular thrombosis or pregnancy morbidity. One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, severe pre eclampsia or

eclampsia, or recognized features of placental insufficiency before 34 weeks gestation and three or more unexplained consecutive spontaneous abortions before the 10th week of gestation are features of pregnancy morbidity. The presence of any one of these clinical features plus abnormal laboratory test diagnose antiphospholipid syndrome (Evidence level I). When a patient has the clinical appearance of APS but negative standard aPL assay results, there is possibility of seronegative APS. Noncriteria tests such as aCL and anti β2GPI IgA Abs and antiphosphatidylserine Abs may help to clarify the picture[28] (Evidence level II) Ruffatti showed that pregnant women with APS reported that patients with triple aPL Ab positivity (ie, positivity for LA, aCL, and anti β2GPI Abs) and/or previous thromboembolism had an increased likelihood of poor neonatal outcomes than patients with double or single aPL Ab positivity and no thrombosis history. However, other study showed that lupus anticoagulant is the primary predictor of adverse pregnancy outcome in aPL associated pregnancies (Evidence level III).

    • pp.160-161
  • Inherited Thrombophilia: Antithrombin activity, Protein C activity, Protein S levels, Factor V Leiden (F5), and/or prothrombin G20210A (F2)
    Inherited thrombophilias such as factor V Leiden mutation, prothrombin gene mutation (PT 20210A), and deficiencies of natural anticoagulants protein C, protein S, and antithrombin are associated with recurrent miscarriage. The existence of a causal role for heritable thrombophilia and pregnancy failure is controversial. A combination of risk factors, including multiple inherited thrombophilic defects are associated with secondary hypercoagulable states. Case–control studies have shown a modest association (odds ratios of 2 to 3) between recurrent miscarriage and thrombophilias such as the factor V Leiden mutation and the prothrombin G20210A mutation. This

association is stronger for fetal deaths, such as stillbirths after 20 weeks’ gestation, than for recurrent early losses.
Many other large prospective cohort studies have not shown significant associations between thrombophilias and sporadic pregnancy loss. However, the strength of the association between inherited thrombophilia and recurrent miscarriage is not very strong, and more importantly, no evidence indicates that the use of anticoagulants improves the chance of live birth in these women. A disadvantage of testing patients with a VTE for thrombophilia is the high costs of testing. Thrmbophilia testing should not be performed routinely in women with recurrent miscarriage except in the context of scientific studies (Evidence level I).

    • p.161
  • M T H F R ( E C 1 . 5 . 1 . 2 0 ) is a key enzyme in one carbon metabolism. The enzyme catalyzes the conversion of methylenetetrahydrofolate into 5 methyltetrahydrofolate, the predominating circulating form of folate. MTHFR gene polymorphisms are commonly associated with hyperhomocysteinemia. Thus, hyperhomocysteinemia is considered as a risk factor for neural tube defects (NTD) and recurrent embryo loss. Homocysteine levels vary, depending on an individual’s state when measured (intake of folic acid, vitamin B12); therefore, it is difficult to achieve representative results. Mild hyperhomocysteinaemia has been identified as a risk factor for arterial disease and venous thrombosis. The evidence is conflicting on hyperhomocysteinaemia as a risk factor for recurrent miscarriage. Therefore, testing for MTHFR mutation is not a part of routine evaluation for recurrent miscarriage. (Evidence level II).
    • p.161
  • The test is not recommended as routine investigation for recurrent miscarriage currently has little evidence to support it (Evidence level III). It is argued that thromboelastography identifies a proportion of women with recurrent early miscarriages who are in a pro thrombotic state outside of pregnancy.
    • p.161
  • Polycystic ovaries (PCO) is the most commonly identified ultrasound abnormality amongst women with recurrent miscarriages. The prevalence of PCO is 40% among women with recurrent miscarriage; however, polycystic ovarian morphology is not predictive of pregnancy loss amongst ovulatory women with recurrent miscarriage conceiving spontaneously. The ultrasound diagnosis of PCO in women with a history of recurrent miscarriage does not necessarily predict a poor outcome in subsequent pregnancy and therefore it is not recommended (Evidence level III).
    It has been reported that hypersecretion of basal LH with or without polycystic ovaries is a risk factor for miscarriage. Women with elevated LH, a frequent feature of the polycystic ovary syndrome, are at increased risk for miscarriage after either spontaneous or assisted conception. However, suppression of endogenous LH release before conception, in women with elevated circulating LH concentrations and a history of recurrent miscarriage, did not improve the live birth rate. Neither an elevated serum luteinizing hormone concentration (>10 IU/l) nor an elevated serum testosterone concentration (>3 nmol/l) was associated with an increased miscarriage rate.
    Insulin resistance plays a significant role in recurrent pregnancy loss. Insulin resistance can be independent of polycystic ovarian status. Women with a history of recurrent miscarriage are at an increased risk for insulin resistance during the first trimester of a new pregnancy. Recent meta analysis concluded that insulin resistance is associated with the susceptibility to recurrent miscarriages, and it may contribute to the occurrence of recurrent miscarriages. Therefore, insulin resistance might be one of the direct causes that lead to recurrent miscarriage.
    • p.161-162
  • The shortened luteal phase has been associated with pregnancy loss but the assessment and interpretation of a putative luteal phase defect is problematic. The use of histological and biochemical endpoints as diagnostic criteria for endometrial dating are unreliable (Evidence level III).
    • p.162
  • Evaluation for diabetes is advised with clinical suspicion. Glycated hemoglobin test is advised to screen diabetes. The best test is the oral glucose tolerance test (OGTT), but it is the most expensive, is inconvenient. Fasting plasma glucose would miss people with impaired glucose tolerance. Glycated hemoglobin does not require fasting, and may be the best compromise (Evidence level III).
    • p.162
  • Thyroid Function Tests and Thyroid antibody (Thyroid Peroxidase Antibody TPO) Tests: Recurrent miscarriages are associated with clinical and sub clinical thyroid disorders. Thyroid function tests are recommended based on clinical history while evaluating miscarriages. Evidence is controversial about role of TPO antibodies. Pregnant women with subclinical hypothyroidism or thyroid antibodies have an increased risk of recurrent miscarriage. TPO antibody screening is not recommended (Evidence level II)
    • p.162
  • A significant proportion of recurrent pregnancy loss is associated with immune aetiologies. Various mechanisms are suggested. Peripheral natural killer (pNK) and uterine NK (uNK) cells have been associated with reproductive failure. Abnormally functioning immunocompetent cells, including natural killer (NK) cells, in the endometrium, are thought to be responsible and treatment trials including oral prednisolone and intravenous immunoglobulins are now underway. Peripheral immunological dysfunction is observed with recurrent miscarriage. Chronic histiocytic intervillositis is a rare type of placental pathology that is associated with reproductive loss. It is considered to be an immunologic origin. Many studies have suggested that women with recurrent miscarriages have signs of generally exaggerated inflammatory immune responses both before and during pregnancy and signs of breakage of tolerance to autoantigens and fetal antigens. There is neither an adequate standardization of counting uterine NK cells nor consensus as to what constitutes an abnormal level. The prognostic value of measuring pNK or uNK cell parameters is uncertain. Further evidence is required to confirm or

refute the role of NK cell assessments as a predictive test for screening women who may benefit from immunotherapy. No immunological test is currently recommended in the recurrent miscarriage work up (Evidence level I).

    • p.162
  • Sperm samples from recurrent pregnancy loss couples have an increase in their sperm DNA fragmentation. Meta analysis showed a significant increase in miscarriage in patients with high DNA damage compared with those with low DNA damage. The associating sperm quality with recurrent pregnancy loss emphasizes the importance of evaluating male factor by tests. Several different tests are available, but no consensus has yet been reached as to which tests are most predictive. Among terminal uridine nick end labeling assay (TUNEL), sperm chromatin structure assay (SCSA), sperm chromatin dispersion (SCD), and alkaline Comet assays, the alkaline COMET assay showed better prediction for male infertility. A chromosomal abnormality was found in 15.2% men with azoospermia and in 2.3% nonazoospermic men. Male factors abnormality is a significant cause for recurrent pregnancy loss after assisted conception. The number of azoospermic men who needs to be screened to prevent one miscarriage is 80–88 and the number need to screen is 315–347 in the nonazoospermic group. Although there is some evidence of association between DNA defragmentation and recurrent miscarriage, well designed prospective studies are needed before using these tests in clinical practice. Routine testing for spermploidy (e.g. fluorescence in situ hybridization [FISH]) or DNA fragmentation is not recommended (Evidence level II).
    • p.162
  • A cause for recurrent miscarriage can be identified approximately 50–60% of the time. There is tremendous psychological impact of recurrent miscarriage. Psychological support in the form of frequent discussions and sympathetic counseling are crucial to the successful evaluation and treatment of the anxious couple. When no etiologic factor is identified, no treatment started at 60% to 80% fetal salvage rate still may be expected. Therefore, couples with unexplained recurrent miscarriage should be offered appropriate emotional support and reassurance (Evidence level III). Obesity, cigarette smoking, alcohol use, and moderate to heavy caffeine use may be associated with sporadic miscarriage, but its association with recurrent miscarriage is uncertain. Cigarette smoking has been suggested to have an adverse effect on trophoblastic function and is linked to an increased risk of sporadic pregnancy loss. The Cochrane review concludes that any vitamin supplements prior to pregnancy or in early pregnancy do not prevent women experiencing miscarriage or stillbirth. Lifestyle modification and stress reduction should be emphasized by pointing out that a healthier lifestyle, free from tobacco, alcohol, illicit drugs, and undue stress cannot hurt and may significantly improve the couple’s chances for a successful pregnancy (Evidence level III).
    • p.163
  • In vitro fertilization (IVF) plus prenatal genetic testing is a suggested strategy in the management of couples with chromosomal abnormalities and recurrent miscarriages. It is proposed as a faster method of conceiving a live child than natural conception, at least for translocation carriers with recurrent miscarriages. However, this evidence is being questioned. Systematic reviews showed that there is no conclusive evidence to support prenatal genetic screening for unexplained recurrent miscarriages as well as structural chromosome abnormality. The new technologies such as trophectoderm laser assisted blastocyst biopsy and molecular karyotyping via whole genome amplification and either comparative genomic hybridization (CGH) or single nucleotide polymorphism (SNP) arrays helped to revitalize the concept of preimplantation genetic screening. The evidence from these newer technologies is awaited. Because of the lack of evidence, assisted conception with preimplantation genetic screening as a treatment of recurrent miscarriage is not recommended (Evidence level II).
    • p.163
  • Almost 65% to 85% of patients with bicornuate or septate uteri have a successful pregnancy outcome after metroplasty. However, 59.5% of the patients with such anomalies have a successful subsequent pregnancy without surgery, with a cumulative live birth rate of 78.0%. Further evidence is needed to recommend metroplasty surgery in these women (Evidence level II). The clinical management of pregnancy loss patients with Asherman syndrome/intrauterine synechiae, uterine fibroids, and uterine polyps is also controversial, and there is no conclusive evidence that surgical treatment reduces the risk of pregnancy loss. Minimally invasive surgeries are the better option for the treatment of structural defects. Cervical incompetence is treated with cervical encirclage; however, the CERVO trial demonstrated no added benefit of circlage. Trans vaginal Ultrasound examination in subsequent pregnancy is indicated with history of midterm loss due to cervical incompetence, The current data suggest that emergency cerclage is associated with a longer latency and period better pregnancy outcomes when compared with bed rest. (Evidence level III). The accuracy of cervical length in predicting preterm delivery is relatively poor. Compared to the McDonald technique, the Shirodkar technique was more effective in prolonging pregnancy in patients with singleton pregnancies undergoing ultrasound indicated cerclage (Evidence level III). Cerclage, vaginal progesterone, or pessary are equally efficacious in the prevention of preterm birth in women with a short cervix detected on sonogrphy at the midtrimester in singleton gestation (Evidence level II).
    • p.163
  • Treatment of asymptomatic abnormal vaginal flora and bacterial vaginosis with oral clindamycin early in the second trimester significantly reduces the rate of late miscarriage and spontaneous preterm birth in a general obstetric population (Evidence II).
    • p.163
  • It is generally agreed that maternal endocrine disorders (e.g. diabetes, thyroid dysfunction) should be evaluated and treated. Though elevated LH is associated with increased risk of miscarriage suppression of LH secretion with GnRH agonist prior to ovulation induction yielded no difference in outcome. Hyperprolactinemia may be associated with recurrent pregnancy loss through alterations in the hypothalamic pituitary ovarian axis, resulting in impaired folliculogenesis and oocyte maturation, and/or a short luteal phase. Normalization of prolactin levels with a dopamine agonist improved subsequent pregnancy outcomes in patients with recurrent pregnancy loss Hyper prolactinemia is treated with dopamine agonist. Thyroid disorders can be treated medically to achieve euthyroid status and medications should be modified with pregnancy appropriately. There is lack of consensus regarding the definition of a normal upper limit of TSH. A consensus is emerging that TSH values more than 2.5 mIU/L are outside the normal range.
    Thyroid hormone requirement in early pregnancy is higher. The aim is to maintain baseline TSH < 2.5 mU/L. Some evidence suggests association of raised thyroid (TPO) antibodies with recurrent miscarriage. Levothyroxine 50 μg daily for the women with raised TPO antibodies with normal TSH is suggested intervention. Observational study suggest TPO Ab positive status does not have a prognostic value regarding the outcome of a subsequent pregnancy, and empirical thyroxine therapy in those who tested positive did not seem to improve outcome. The thyroid antibodies and levothyroxine study (TABLET) study is a randomized controlled trial of the efficacy and mechanism of levothyroxine treatment on pregnancy and neonatal outcomes in women with thyroid antibodies. This study will help to find the role of thyroxin treatment for women with normal thyroid function tests but raised thyroid peroxidase antibody (TPO). Until robust evidence is available, thyroxine treatment is not recommended in raised thyroid antibody status with normal thyroid function tests (Evidence level III).
    • pp.163-164
  • The progesterone act as immmunomodulator and it shift from proinflammatoryTh 1 cytokine responses to anti inflammatory Th 2 cytokine response which is more favorable and pregnancy protective. Dihydrogesterone is a potential immunomodulator, it produces progesterone induced blocking factors (PIBF) which is protein produced by pregnancy lymphocyte following exposure to progestorene. PIBF inhibits cell mediated cytotoxicity and natural killer cell activity. Thus, it is immunoprotective for pregnancy. Administration of progesterone to women with sporadic miscarriages is ineffective. However, in patients with three or more consecutive miscarriages immediately preceding their current pregnancy, empiric progestogen administration may be of some potential benefit. A large multicenter study called promise study (http://www.medscinet.net/promise) is currently underway to assess the benefit of progesterone supplementation in women with unexplained recurrent miscarriages. Most commonly used regime is micronized progesterone tablets 400 mg daily. The route of administration may be either vaginal or oral. The argument for use of progesterone is that there is no evidence of harm and some evidence of benefit, although not coming from huge multicentric trials. The decision should be based on clinician’s discretion until strong evidence is available to recommend routine use (Evidence level III).
    • p.164
  • Data on the use of metformin to decrease the chance of miscarriage are contradictory as no adequately powered trials have been published. Insulin resistance is an independent risk factor for spontaneous miscarriage in spontaneous pregnancy. Patients with insulin resistance should be advised to improve their insulin sensitivity through lifestyle change or medical intervention before infertility treatment to reduce their risk of spontaneous miscarriage. Nonrandomized studies

have shown that the reduction in insulin levels with metformin in insulin resistant individuals may reduce miscarriage risk by restoring normal hemostasis and improving the endometrial milieu[104,105] Metformin is not recommended as a treatment of recurrent miscarriage (Evidence level III).

    • p.164
  • Low doses of acetylsalicylic acid and low molecular weight heparin (LMWH) are the best solution in women suffering from recurrent spontaneous miscarriage. This treatment combination of low dose aspirin and low molecular weight heparin reduces the miscarriage rate by 54%. The role of low molecular weight heparin and aspirin treatment specifically for the prevention of recurrent miscarriage remains controversial. The meta analysis showed the combination of unfractionated heparin and aspirin confers a significant benefit in live births. However, the efficacy of low molecular weight heparin plus aspirin remains unproven as LMWH data were based on only two trials. These trials were criticized as studies were not blinded and the randomization procedure had been criticized in one of the trials and inclusion criteria were very different. Third trial showed no significant difference in live birth rate with LMWH treatment versus aspirin or a combination of both versus aspirin in women with recurrent miscarriage. A small trial showed comparable results with LMWH plus aspirin as an alternative to unfractionated heparin and aspirin in the management of recurrent miscarriage secondary to APS. The consensus is combination of low molecular weight heparin and aspirin is superior to aspirin alone in achieving more live births. Therefore, it is recommended treatment for recurrent miscarriages with antiphospholipid syndrome (Evidence level I). Glucocorticoids should not be given in antiphospholipid antibodies syndrome without connective tissue disorder. Low dose prednisone is given when lupus is present and with the advice of rheumatologist. Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. Women with a history of thrombosis in whom the antiphospholipid syndrome or a heritable thrombophilia is diagnosed should receive an appropriate dose of unfractionated heparin or low molecular weight heparin (Evidence level I). A third trial could not find that heparin/aspirin was better than aspirin alone.
    • p.164
  • Role of anticoagulation therapy in the treatment of recurrent miscarriages with hereditary thrombophilia is debatable. Few studies suggested low molecular weight heparin therapy during pregnancy may improve the live birth rate of women with second trimester miscarriage associated with inherited thrombophilia. However, there is currently no evidence supporting treatment, because observational research is hampered by poor methodology or inconsistent results. Recent meta analysis showed that the use of LMWH in women with inherited thrombophilia with recurrent pregnancy loss is not indicated. Women with thrombophilia should be followed closely without routine prophylactic low molecular weight heparin other than for prevention of venous thromboembolism in limited circumstances (Evidence level I).
    • p.165
  • High dose folic acid (5 mg) and vitamin B12 (0.5 mg) once daily has been reported to reduce levels of homocysteine; however, a randomized controlled trial on the effect of variable doses of both vitamins on pregnancy has yet to be conducted. High dose folic acid is considered with women with high BMI and diabetes. There is no evidence to support usage of 5 mg folic acid from pre pregnancy stage purely to reduce the risk of recurrent miscarriage (Evidence level III).
    • p.165
  • Activators and inhibitors of the fibrinolytic system are frequently abnormal in recurrent miscarriage. Plasma levels of tissue factor activity, thrombomodulin activity, and procoagulant phospholipids were significantly higher in recurrent miscarriage group. Clinical evaluation of recurrent miscarriage does not include investigating fibrinolytic anomalies. It is limited to the research interest.
    • p.165
  • Both organ specific and systemic autoimmunity are associated with an increased prevalence of recurrent miscarriage. Immune modulating therapies have been mooted as potential therapeutic strategies. There is no specific immunological test or clinical method, which will predict the need for treatment. Mechanisms of possible efficacy of high dose of intravenous immunoglobulin

therapy for recurrent miscarriage may include enhancement of CD94 expression and subsequent suppression of NK cell cytotoxicity. Evidence does not support routine use of intralipid therapy. The Cochrane review analyzed various strategies including paternal cell immunization, third party donor leukocytes, trophoblast membranes, and intravenous immune globulin. None of these interventions proved beneficial over placebo in improving the live birth rate. This Cochrane review has been widely criticized for not making the necessary sub analyses between primary and secondary recurrent miscarriage. Meta analysis showed that IVIG increased the rates of live birth in secondary recurrent miscarriage, but there was insufficient evidence for its use in primary recurrent miscarriage. There is risk of possible complications such as undesirable immune responses and the possibility of transmitting infectious diseases like cytomegalovirus. The risk of transmitting infections disease with intravenous immunoglobulin is extremely small. Most recent systematic review and meta analysis concludes that NK cell analysis and immune therapy should be offered only in the context of clinical research. The current recommendation is immunotherapy should not be advised. (Evidence level II)

    • p.165
  • Unexplained recurrent miscarriage
    * Psychological support: Stress itself is a risk factor for

miscarriage and recurrent miscarriage is a stressful condition so that the vicious cycle can be broken by strong psychological support. Women should be reassured for a successful future pregnancy with supportive care. (Evidence level III)
* Aspirin 75 mg OD: Evidence is debatable. There is paucity of evidence to make any recommendation on aspirin for treating recurrent miscarriage in women without antiphospholipid syndrome. Few RCT suggested clear benefit of using aspirin for such women. Recent trial failed to support any role of Aspirin in unexplained recurrent miscarriage. Aspirin helps in improving uterine perfusion. Aspirin is useful in many undiagnosed implantation failure patients. However, in the absence of strong evidence, routine use of Aspirin is not recommended (Evidence level II)

  • Progesterone: Meta analysis of 4 randomized trials and only 132 women in total showed a statistically

significant reduction in miscarriages. Further, the evidence is awaited before making recommendation on use of progesterone in explained miscarriage. (Evidence level III)

  • LMWH: Use of LMWH to prevent miscarriage is not recommended in the absence of antiphospholipid

syndrome (Evidence level II)

  • Human chorionic gonadotrophin (hCG): Recent Cochrane review failed to find quality evidence to

support use of hCG for preventing miscarriage. A well designed randomized controlled trial of adequate power and methodological quality is required. Therefore, the use of hCG is not recommended (Evidence level II)

  • Steriods: The effect of prednisolone therapy for some women with recurrent miscarriage may be due to altered endometrial angiogenic growth factor expression and reduced blood vessel maturation.[132] The role is mostly limited to recurrent miscarriage with known connective tissue disorders. Rheumatologic advice should be taken with patients diagnosed having recurrent pregnancy

loss and connective tissue disorder. The results from the Prednisolone Trial are awaited; it is a randomized controlled trial of prednisolone for women with idiopathic recurrent miscarriage and raised uNK cells in the endometrium. There is no robust evidence to recommend steroid use for unexplained recurrent miscarriage (Evidence level III)

  • Immunoglobulins: IVIG administration for treatment of recurrent miscarriage is not justified outside the context of research as discussed earlier (Evidence level II)
  • Intravenous intralipid solution: No evidence of benefit with use of intralipid. Well controlled, large scale, and confirmatory studies required before it can be recommended for routine use[118,120] (Evidence level III)
  • p.165-166
  • Recurrent miscarriage is one of most the widely researched areas in medicine. Recurrent miscarriage may be the first presentation of some of the hematological or endocrine disorders. Many investigations such as genetic thrombophilia screening are not based on strong evidence. The management of unexplained miscarriage is a challenge. Role of aspirin and low molecular weight heparin is

controversial in genetic thrombophilias. Any form of immunotherapy is not recommended until further evidence is available. We look forward for results of various ongoing multicentre trials to produce an answer.

    • p.166

“Immunohistochemical Evaluation of CD3, CD4, CD8, and CD20 in Decidual and Trophoblastic Tissue Specimens of Patients with Recurrent Pregnancy Loss” (2022 Feb 28)[edit]

Dimitrios Kavvadas, Sofia Karachrysafi, Pinelopi Anastasiadou, Asimoula Kavvada , Stella Fotiadou, Angeliki Papachristodoulou, Theodora Papamitsou, Antonia Sioga; “Immunohistochemical Evaluation of CD3, CD4, CD8, and CD20 in Decidual and Trophoblastic Tissue Specimens of Patients with Recurrent Pregnancy Loss”. Clin Pract. 2022 Feb 28;12(2):177-193. doi: 10.3390/clinpract12020022. PMID: 35314592; PMCID: PMC8938768.

  • Recurrent miscarriages affect up to 5% of couples. CD3+ (T-lymphocytes), CD4+ (helper T-lymphocytes), CD8+ (cytotoxic T-lymphocytes), and CD20+ (B-lymphocytes) cells may participate in the pathophysiology of recurrent pregnancy loss (RPL). The aim of this study was to investigate the complicity of these molecules in RPL. The experimental specimens were obtained from 20 females who underwent miscarriages in the first gestational trimester, while the control group’s specimens consisted of 20 females who proceeded with voluntary pregnancy termination during the same period. Tissue samples were taken from the decidua basalis, decidua parietalis, and trophoblast (placental chorionic villi) and were studied using immunohistochemical methods. Monoclonal antibodies were used against CD3, CD4, CD8, and CD20 cells. The lymphocyte levels in the decidua parietalis displayed profound disparities among the two groups. The decidua basalis and trophoblast exhibited almost the same disparities regarding positive CD cells. The comparison of CD4+ and CD8+ cells in the endometrial tissue revealed a significant difference between the two groups of study. The analysis uncovered a strong relationship between RPL and the presence of CD3+, CD4+, CD8+, and CD20+ cells in the decidua parietalis tissue. The number of positive T cells was decreased in the decidual basalis and chorionic villi, proving that their absence significantly disrupts the balance of the immunological environment.
  • Recurrent pregnancy loss (RPL) is described as the occurrence of two or three repeated abortions, prior to the 20th week of pregnancy. The frequency of RPL is approximately 1–2%, affecting 5% of couple. There are numerous risk factors, mainly metabolic and anatomic, accompanied by systematic abnormalities and infections. To this date, even though there are a plethora of studies regarding the etiologic factors of RPL, the full comprehension of the immune dysregulation that causes miscarriages seems to be elusive.
    Leukocytes are a significant component of the human endometrium of the female reproductive system. Their numbers increase to 10% of stromal cells, in the proliferative phase. Prior to the phase of implantation is the secretory phase, in which 20% of endometrial cells are leukocytes. In early pregnancy, the proportion of leukocytes increases to 30% of the decidual cells. This indicates their implication in RPL.
  • CD4 (cluster of differentiation 4) cells are glycoproteins, which are located on the surface of immune cells, more specifically on the surface of Th (T-helper) cells, monocytes, macrophages, and dendritic cells. CD8 (cluster of differentiation 8) cells are transmembrane glycoproteins, which function as coreceptors of the TCR (T-cell receptor). Class I proteins of the MHC have the capacity to bind CD8 cells and TCRs. Darmochwal-Kolarz et al. studied the variations in the lymphocyte phenotype of women with unexplained pregnancy losses in comparison with healthy ones. They found that the number of CD4+ T-lymphocytes and CD8+ T-cells was significantly higher in patients with recurrent pregnancy loss.
    The CD3 antigen is expressed mostly in T-lymphocytes and less in other cells, e.g., Purkinje cells, macrophages, and Hodgkin and Reed–Sternberg cells. It is expressed not only in the early maturation of T-lymphocytes but also in the pre-thymocyte cortical stage and is located within the perinuclear space of the cells. Mengyang Du et al. gathered blood samples from RPL cases and observed that, in the peripheral blood of these women, CD3+ T-cells were significantly increased in comparison with a control group consisting of women with a normal pregnancy. The risk of miscarriage was increased proportionally to the augmentation of women with the level of CD3+ cells. However, the miscarriage risk did not appear to further increase when the level of CD3+ T cells exceeded 67.84%
  • In an investigation undertaken with RPL patients, levels of CD45+, CD56+, CD16+, CD3+, CD8+, and CRTH2+ cells were similar to those in control groups. No significant difference in lymphocyte subset numbers or percentages was noted between patients whose later pregnancy was successful and those whose later pregnancy was unsuccessful.
  • In recent years, studies have attempted to figure out the relationship between regulatory T-cells and RPL cases. It is widely believed that these cells play a vital role in establishing and maintaining the maternal–fetal immune tolerance.
    Taking into account that nearly 50% of RPL cases are still classified as unexplained, we performed this immunohistochemical study in order to contribute to the scientific community with more knowledge on the matter. Our hypothesis was based on the immunological profile of RPL. Thus, we studied the markers CD3, CD4, CD8, and CD20 and their implication in RPL. We expected a significant expression of immune cells in the endometrial tissues of women with recurrent miscarriages in the first trimester of gestation, compared to those with a normal early pregnancy until termination. Regardless of the comparative outcome, we consider whether or not specific cells contribute to the pathophysiology of unexplained recurrent miscarriages.
  • The CD3 antigen expression in the decidua parietalis (DP) of the miscarriage experimental group (EG) was moderate in all RPL cases. This finding demonstrates an immunological activity in the decidual part lining the uterus. The CD3 antigen expression was weak to moderate in 15 decidua basalis (DB) specimens. No CD3 antigen expression was observed in the chorionic villi of this group.
    Negative CD3 antigen expression was observed in the decidua parietalis and chorionic villi of the control group (CG). Interestingly, the only CD3 positive expression was detected in the decidua basalis. The part of the endometrium that participates with the chorion in the formation of the placenta exhibits the same immunological response between the control and the RPL cases.
  • The expression of the CD4+ antigen was weak to moderate in the DP, DB, and chorionic villi of the RPL cases.
    The CD4+ antigen expression was negative in the DP of the electively abortion cases (CG). Surprisingly, the CD4 expression was positive in the DB and chorionic villi of the control group. It seems that these specific villi that grow from the chorion to provide the maximal contact area with maternal blood are immunologically activated. Additionally, the fact that the expression in the decidua parietalis was significantly different in comparison to the rest of the sites (DB and trophoblast) among our RPL and control group was an unexpected finding.
  • The CD8+ antigen expression in the decidua parietalis of the RPL specimens was low in 5 cases, moderate in 10 and strong in 5 cases. Apart from the immunological expression, the positive CD8 cells that were found near the vessels revealed mild vascularization in the decidua parietalis. The decidua basalis and trophoblast were negative in all the RPL cases.
    Most of the electively abortion specimens were CD8 negative. The majority of the chorionic villi and DB specimens were marginally stained positive. A significant observation emerges by comparing Figure 5 and Figure 6; among the two groups, only RPL cases were positively CD8+stained and only in the decidua parietalis.
  • CD20+ antigen expression was almost similar to CD8+, as described above. More specifically, decidua parietalis was moderately stained in the majority of the RPL specimens. In the decidua basalis and trophoblast, CD20+ expression was negative in all the RPL specimens.
    Regarding the control group, the CD20 antigen expression was negative in all specimens. Once more, in terms of antigens’ expression, significant differences were observed in the decidua parietalis of the RPL and control cases.
  • There were significant differences between the experimental and control group regarding the expression in the decidua parietalis.
    There are also disparities in the decidua basalis among the miscarriage and control group. B-lymphocytes cells detection appeared to be identical in the DB of the two groups. <br Similarly, in the chorionic villi of the RPL cases, the intensities of CD4+ and CD8+ were decreased in comparison to the control group. Additionally, no significant differences were observed.
  • Summarizing the above analysis, statistically significant differences among the two groups were mainly found in the decidua parietalis. The decidua basalis and chorionic villi (trophoblast) displayed similar behavior regarding the expression of the studied markers, with CD4 and CD8 presenting considerable differences.
    More precisely, significant disparities were observed among the two groups regarding the expression of CD3 markers in the decidua parietalis, while in the DB and trophoblast, the results were the same.
    Regarding CD4 expression, there were significant differences among the two groups in every site of tissue examination (DP, DB, and trophoblast). It is worth mentioning that in the DP, the variation among the results was even more intense than the inconsistencies found in the DB and trophoblastic tissues.
    Furthermore, CD8 antigen expression displayed profound disparities among the two groups in the examined endometrial tissues.
    Finally, CD20 antigen expression appeared to be identical in the DB and trophoblastic cells of each group, while in the DP, the differences were quite significant. It is noteworthy that the expression in the DP displayed inconstancies in every CD cell case of this study.
  • The immunological environment of early pregnancy is rather complicated, especially between the RPL and abortion cases, which consisted of the experimental and control group of the present experiment. This study aimed to comparatively evaluate placental tissues received from the two distinguished groups. However, one should be cautious regarding the control group, as elective termination may not be able to provide a realistic depiction of the normal maternal-fetus environment. Regarding the immunohistochemical investigation, the present experiment made an attempt to correlate the imbalance of CD3, CD4, CD8, and CD20 levels, and the dysregulation of the immune system in the endometrial tissue, with the RPL pathogenesis (up to 80% of RPL cases). This study provides a comprehensive comparison of the CD3+, CD4+, CD8+, and CD20+ levels, in the decidua (both basalis and parietalis) and the chorionic villi, among women with RPL and women who electively terminated their pregnancy. Significant differences on the expression of the studied markers were found in the decidua parietalis.
  • To begin with, the miscarriage group samples presented a significantly higher expression in all the CD3 cells that were studied, in comparison to the control group samples (p-value < 0.00001). The moderate CD3 expression found in the EG is in agreement with Du et al.. These results differ from Kolanska K et al., who did not observe significant disparities on the CD3+ levels, among the experimental and control group. However, the fact that the present miscarriage group appeared to have a positive expression of CD3 in the decidua parietalis supports the hypothesis that the risk of miscarriage phenomena increases proportionally to the augmentation of the CD3+ levels in the mothers’ peripheral blood. Given the current data—that maternal adaptive immune cells display a more activated phenotype in the decidua parietalis than the decidua basalis —there is a strong indicator that increased CD3+ cells in the DP may contribute significantly to the occurrence of RPL phenomena. In addition, Quinn K et al. has shown that the DP has a significantly higher ratio of T-regulator cells expression in comparison to the DB.
    Likewise, there was a significant expression of CD4+ cells in the decidua parietalis of all RPL cases. The CG samples were negative (p-value < 0.00001). This particular finding arouses suspicion regarding the implication of CD3+ and CD4+ presence in the decidua parietalis tissues and their participation to RPL phenomena. There is suspicion that the strong CD4+ expression in the decidua parietalis is in accordance with the CD4+ positive serum levels in mothers’ peripheral blood, since they were observed to be particularly high in several RPL cases. Contrary to the decidua parietalis, the expression of CD4+ in the decidua basalis and chorionic villi displayed an interesting variety of distribution. In most specimens, the control group demonstrated a moderate staining, while the experimental group appeared with low intensity (p-value = 0.00046). According to Li et al. and Inada et al., the percentage of CD4+ positive cells was lower in the decidua samples of early recurrent miscarriage patients, comparing to women with a normal early pregnancy. These interesting studies were in full accordance with the CD4+ levels found in the DB of our experimental and control group samples. This particular discovery leads us to the conclusion that T-cells in the decidua basalis and chorionic villi, are essential for a normal early pregnancy. In addition to that—according to Logiodice et al.—CD4+ T-cells that were presented in the decidua of women who experienced a successful pregnancy were producing IL-4 (Interleukin), whereas in women with RPL, there was no IL-4 production. In the present study, we did not investigate the expression of CD25 for Treg-cells; thus, the aforementioned findings raise the question for further immunohistochemical analyses.
    Furthermore, there were conspicuous disparities of CD8+ levels in the decidua parietalis among the two groups (p-value < 0.00001). One should definitely wonder whether the strong CD8+ antigen expression—similar to the DP of our EG samples—stands as an accomplice to the immune dysregulation, which leads to a potential pregnancy loss. The zero presence of CD8+ positive expression in the CG specimens strengthens the above hypothesis. According to further experiments, Darassejeze et al. found that the prolonged activation of CD8+ cells was directly linked to the augmentation of miscarriage rates on rats. The aggregated positive expression near decidual vessels in our EG samples comes into full accordance with the conclusions of Russel et al.. Despite these results, Lachapelle et al. observed that the percentage of endometrial CD8+ T-Lymphocytes was significantly decreased in RPL cases. Our findings were quite similar to the aforementioned observation, since there was zero positive CD8 T-cells in both decidua basalis and chorionic villi of our EG samples. The control group’s results strengthen these findings, as a significant percentage of CD8+ T-cells was found, which is expected for a normal pregnancy to occur (p-value < 0.00001). Moreover, Johnsen G et al. suggested that the absence of CD8+ in the decidua basalis, could be involved in further complications, such as the development of acute atherosis—a common spiral arterial lesion in preeclampsia. The analysis of the presence of CD8+ T-cells seems to be a rather controversial issue, as one could be led to contradictory results, depending on the site of study.
  • Recurrent miscarriages are associated by some studies with increased numbers of CD20+ lymphocytes. In our experiment, an intense staining in the DP of the EG samples was found, contrary to the CG samples, where there was no expression. This antithesis establishes fundamental evidence of the strong relationship between RPL and the presence of CD3+, CD4+, CD8+, and CD20+ cells in the decidua parietalis (p-value < 0.00001).
  • Based on prominent studies, there should not be any T- or B-cell expression observed in placenta tissues. The present immunohistochemical study did not observe any expression regarding the studied markers in the decidua parietalis of the electively terminations (control group). However, the control group exhibited notable differences in the decidua basalis and trophoblast, which was not expected based on the aforementioned study. There is an implication that some CD4 subsets minimize the embryotoxic state of other CD4 subsets; thus, it should be furthered studied. Some other CD4 subsets initiate inflammatory processes through many cytokines. However, even in this case, there is a fragile balance that is crucial for placentation and early pregnancy. For instance, even though TNF-a (induced by a CD4 subset) is the main culprit for several immunopathologic complications, it has been reported to have a protective role regarding the fetoplacental regulation. Unfortunately, our study is limited to the subset analysis. It seems that CD4(+)CD25(+) Treg-cells are essential in the induction and maintenance of the essential immune-tolerance of normal pregnancy. The CD4 levels in our study are intriguing and rather thought-provoking, especially regarding the control group. Additionally, several studies have shown that positive functional regulatory T-cells are decreased in the decidua basalis and chorionic villi of the RPL cases. Our conclusive data were in full accordance to them and provided even more evidence regarding the CD+ levels in the DB and how they may affect the immunological regulation, which could lead to a miscarriage. The lower intensity of CD4+ and CD8+ in trophoblast and decidua basalis seems to negatively affect the course of a normal pregnancy, perhaps due to a significant reduction of the maternal immune tolerance. Regarding the CD20 cells, apart from the soaring levels in decidua parietalis, there was no significant difference in the decidua basalis and chorionic villi among the two groups. Positive T-cells were found in the decidua parietalis, displaying a more activated phenotype, with a higher intensity of staining, in comparison to those isolated from the DB and the trophoblast. This is a rather interesting outcome, as the decidua parietalis is not located in the maternal–fetal connective interface, and one would definitely not expect to find more activated T-cells there (at least not compared to the DB). This enacts as a proof of correlation among RPL cases and the increased levels of T-cells in the DP.
    Finally, despite the contradiction, it should also be mentioned that there are several cases, e.g., Bohlmann et al. and Michimata et al., which did not observe a significant relationship between altered endometrial immunity and the RPL cases. Although the main culprits regarding immune dysregulation are known, the specific details that lead to RPL are still elusive. It is interesting that a study conducted among women with unexplained miscarriages and healthy fertile women with successful pregnancies revealed elevated CD4 lymphocytes in patients with recurrent pregnancy loss. This study was not performed using electively terminations as controls; thus, despite the fact that we agree on the expression on RPL cases, it is not feasible to apply a proper comparison. Regardless of the methodological differences, each research is significant as it contributes on the elucidation of the immunological imbalance of early pregnancy. After all, despite so many remarkable studies, RPL remains an “unexplained” phenomenon to almost half of the cases.
  • The clinical approach of the RPL depends on the pathogenesis of each condition. Chromosomal causes, anatomical abnormalities, clotting disorders, and hormonal and immunological causes must be investigated as a priority, as there are specific treatments for each condition. In order to understand the mechanisms of the unexplained RPL, researchers should collect as many data as possible regarding the immunological response when such phenomena occur. Thus, more experimental studies should be conducted. Immunization and maternal antibodies’ “behavior” might hold the key not only for setting a diagnosis but also for preventing pregnancy loss. There are several widely used and available algorithms assisting clinicians on the evaluation of each condition and offering possible explanation to parents suffering from miscarriages. However, these algorithms come with painstakingly evaluation that put pressure not only on the couple but on the healthcare system as well. Diagnosis and possible treatment should be based on the causal factors of the RPL. Therefore, clarifying the “picture” of the immunological reaction in the developmental tissue environment (e.g., decidua, trophoblast, etc.) might assist in the development of improved and rigorous algorithms for diagnosis and even new therapeutic interventions.
  • Generally, it seems that the immunological balance between mother and fetus is rather sensitive and volatile. Despite our exclusion criteria and the hypothesis (RPL vs. electively termination cases), there are many unknown factors that may affect the results. However, the study adds extra knowledge regarding the importance of distinguishing the sites of immunohistochemical evaluation, as the decidua parietalis presented conspicuous dissimilarities in comparison to the DB and trophoblast. Hopefully, with more studies, we will be able to narrow down the factors and utterly comprehend the process of immune dysregulation that leads to RPL.
  • In conclusion, in this study, we have performed an immunohistochemical experimental analysis of CD3, CD4, CD8, and CD20 markers on the decidual and trophoblastic tissue specimens of RPL cases and electively terminated pregnancies. The samples of the two groups differ significantly regarding the antigen expression levels. The uniqueness of the present experimental research lies not only in the studied markers, but also in the distinguish evaluation for each tissue site (decidua parietalis, decidua basalis, and chorionic villi). The analysis revealed a strong correlation among RPL and the presence of CD3+, CD4+, CD8+, and CD20+ cells in the decidua parietalis. Positive T-cells were decreased in the decidua basalis and chorionic villi of the RPL cases. This study suggests that the decidua basalis and decidua parietalis should be analyzed further by distinct immunohistochemical evaluation in each tissue site, as there is a strong indication that they do not act collectively regarding the immunological regulation during pregnancy. After proper clinical evaluation and status classifications, further studies on women may elucidate the unexplained RPL and lead from the diagnosis to the prevention.

“Adverse effects of exposure to armed conflict on pregnancy: a systematic review” (2017)[edit]

James Keasley, Jessica Blickwedel, and Siobhan Quenby; “Adverse effects of exposure to armed conflict on pregnancy: a systematic review”, 'BMJ Glob Health. 2017; 2(4): e000377.

  • Exposure to armed conflict has manifold implications for both military and civilian populations. Prenatal stress has detrimental effects on both obstetric outcomes, fetal development and the development of an individual later in life. As well as causing stress to the mother, armed conflicts can decimate local infrastructures making it increasingly difficult to access antenatal and general healthcare. The present review is particularly salient in light of the many ongoing current conflicts. It examines the impacts of exposure to armed conflicts on the pregnancy outcomes.
    Methods A thorough literature search was carried out on three databases using MeSH and truncation terms. 13 studies were included in the final analysis relating to mothers exposed to armed conflicts since 1990. results The studies include data from 1 172 151 patients: mothers from Libya, Bosnia, Herzegovina, Israel, Palestine, Kosovo, Yugoslavia, Nepal, Somalia, Iraq, Kuwait and Afghanistan. There is evidence of an increased risk of mothers giving birth to babies of low birth weight as reported in nine included studies. All have a degree of bias, with four at lower and five at higher risk of bias, either not adjusting for confounders or not employing robust measures of exposure to conflict. Further evidence suggested an increase in the incidence of miscarriage, stillbirth, prematurity, congenital abnormalities, miscarriage and premature rupture of membranes among mothers exposed to armed conflict.
    • p.1
  • Stillbirth was measured in five studies. Of these, only one demonstrated a significant increase in the rate of stillbirth (p<0.01); this was shown in relation to contact with specific chemical exposures in the 1990–1991 Gulf War such as smoke from oil well fires, exhaust fumes from kerosene heaters and generators, diesel fumes, mustard gas and food contaminated with smoke, oil or other chemicals. This study was among those with the lowest risk of bias. Three studies, two with higher risks of bias and another with a low risk of bias, showed no significant difference in the rates of stillbirth when considering exposure to armed conflict. The Pavlinac et al study even showed significant decreases in the overall rates of stillbirth among all singleton births. This study also demonstrates that there was a significant increase in still-births among mothers who had preterm births (p<0.001).
    • p.4
  • The results suggest that exposure to armed conflict increases the incidence of adverse outcomes in pregnancy. The extent to which this is the case cannot be easily quantified. The most convincing evidence suggests that the incidence of low birthweight infants increases with maternal exposure to armed conflict. Four of the nine studies reporting this significant relationship between exposure to armed conflict and low birth weight have been assessed to have a relatively low risk of bias. The effect sizes from the other five studies, however, may have a higher risk of bias due to the lack of adjustment for confounders and limited data on measures of exposure to conflict. In addition, there is some more limited evidence supporting increased rates of miscarriage, prematurity, stillbirth, premature rupture of membranes and congenital abnormalities.
    • p.5

“Injuries to Pregnant Occupants in Automotive Crashes” (1998)[edit]

Kathleen DeSantis Klinich, Lawrence W. Schneider, Jamie L. Moore, and Mark D. Pearlman; “Injuries to Pregnant Occupants in Automotive Crashes”, Annu Proc Assoc Adv Automot Med. 1998; 42: 57–91.

  • Firm statistics on fetal loss resulting from automotive trauma are not available because fetal death certificates do not record recent maternal involvement in crashes as a potential cause of death. In addition, since miscarriage occurs in 10-20% of all pregnancies in the early part of pregnancy, only deaths to fetuses over 20 weeks gestational age are legally defined and recorded. However, based on the frequencies of pregnancies and crash involvement of the general population, it has been estimated that between 1500 and 5000 fetal losses occur each year in the United States as a result of maternal involvement in automotive crashes (Pearlman 1997). Additional uncounted adverse fetal outcomes occur as well, as many children grow up disabled as a result of injuries sustained in utero. Even if a fetus survives, complications arising from early emergency delivery of a premature fetus (such as low birth weight and neonatal respiratory distress syndrome) can lead to long-term negative consequences for the child.
    • p.57
  • Placental abruption is the most common cause of fetal loss in automotive crashes. It occurs in 1 to 5% of minor severity crashei‘during pregnancy and from 20 to 50% of severe crashes during pregnancy. The injury occurs when the placenta detaches from the uterine wall, disrupting the supply of oxygen and nutrients to the fetus. Partial abruptions can also occur, with the possibility of the pregnancy continuing successfully depending on the degree of placental separation from the uterus. The interface between the placenta and the uterus is considered to be weaker than either the uterus or the placenta, and therefore

usually fails before either the uterus or placenta fails.

    • p.67
  • Uterine rupture and lacerations are rare during pregnancy, occurring in less than 1% of pregnant trauma cases (Pearlman 1990). Injury to the uterus in automotive accidents occurs almost exclusively during pregnancy (compared to any other time) because it is much larger, extends outside the pelvic cavity, and is filled with fluid. While uterine rupture is very rare, the likelihood of fetal death with such an injury is near 100%.
    Uterine injury is often reported in the literature as resulting from direct loading from the seat belt. While this may occur, it can also occur to unbelted women who are directly loaded by the steering wheel or instrument panel. Some cases report uterine damage directly beneath the area of seatbelt loading.
    • p.68
  • A review of injuries specific to pregnant motor vehicle occupants illustrates the following points regarding pregnant occupants involved in automotive crashes.
  • All nine cases involving maternal death resulted in fetal death, and eight of these women were unbelted. Thus, the most basic way to protect the fetus is to protect the mother through proper use of belt restraints.
  • While placental, uterine, and fetal injuries may occur with properly belted occupants, the majority of the cases involving these injuries are to unrestrained occupants.
  • The distinguishing characteristic of the cases with completely positive fetal outcomes was proper restraint use by the mother.
  • 65% of the cases with direct fetal injury also involved placental injury, as did 63% of the cases with uterine injury. Thus, reducing the likelihood of placental abruption is likely to reduce the probability of uterine and direct fetal injury as well.
  • All pregnant women involved in crashes, even minor ones, should immediately seek medical attention. In most cases with fetal loss, the mother sustained only minor or no other injuries other than placental, uterine, or fetal damage.
  • The anatomy of pregnant women while seated in automotive posture poses a unique challenge to restraint designers because of difficulty positioning the lap belt and close proximity to the steering wheel and airbag module.
    The information presented in this paper will be used to guide the development of the second-generation pregnant crash dummy. A key goal of the next-generation design is to assess the likelihood of placental abruption, the leading cause of fetal death in crashes.
  • p.74

“Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group” (March 2015)[edit]

A.M. Kolte, L.A. Bernardi, O.B. Christiansen, S. Quenby, R.G. Farquharson, M. Goddijn, M.D. Stephenson on behalf of the ESHRE Special Interest Group, Early Pregnancy, “Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group”, Human Reproduction, Volume 30, Issue 3, March 2015, Pages 495–498

  • Abstract: Pregnancy loss prior to viability is common and research in the field is extensive. Unfortunately, terminology in the literature is inconsistent. The lack of consensus regarding nomenclature and classification of pregnancy loss prior to viability makes it difficult to compare study results from different centres. In our opinion, terminology and definitions should be based on clinical findings, and when possible, transvaginal ultra-sound. With this Early Pregnancy Consensus Statement, it is our goal to provide clear and consistent terminology for pregnancy loss prior to viability.
    • p.495
  • Introduction
    The lack of a consistent and generally accepted terminology, and strict definitions of adverse pregnancy outcomes, makes it difficult to compare scientific results from different research groups in early pregnancy. In this Consensus Statement from the ESHRE Special Interest Group, Early Pregnancy, we present our recommendations for pregnancy terminology and definitions for adverse pregnancy outcome before viability. We aimed to provide a clear, consistent and widely applicable terminology for early pregnancy research.
    • p.495
  • What is a pregnancy loss?
    Under normal, non-neoplastic conditions, human chorionic gonadotrophin (hCG) is exclusively produced by the syncytiotrophoblast. It follows logically that a pregnancy loss is the spontaneous demise of a pregnancy, which has been confirmed by at least two positive b-hCGs in the

serum or urine.

    • p.495
  • Non-visualized pregnancy loss
    Any pregnancy loss, which has not been confirmed ultrasonically or histologically, should be classified as a non-visualized pregnancy loss, irrespective of the time passed since the last menstrual period or clinical presentation.
    If the pregnancy has been diagnosed only by either serum or urine b-hCG, and the serial results decrease to negative, the pregnancy loss should be termed a biochemical pregnancy loss. We recommend against the use of the term ‘chemical pregnancy loss’ since it is a biological process. When transvaginal ultrasound evaluation fails to determine the localization of a pregnancy, it is initially classified as a pregnancy of unknown location (PUL). With further evaluation, final outcomes of PULs can be categorized into ectopic pregnancy, intrauterine pregnancy, resolved PUL or treated PUL. Resolved PUL is defined as decreasing b-hCG to negative, either spontaneously or after uterine evacuation without chorionic villi on pathology. Treated PUL is defined as a PUL treated medically (usually with methotrexate). Major efforts have gone into the classification of PULs and their final diagnoses, the scope of which is beyond this paper (Barnhart et al., 2011).
    We discourage the use of terms like ‘preclinical miscarriage’ (Macklon et al., 2002) as it is ambiguous and assumes the pregnancy is within the uterine cavity. If a woman does not seek medical assistance in the course of a pregnancy loss, except for confirmation of pregnancy with a urine or serum b-hCG, biochemical pregnancy loss is the most appropriate term, unless tissue is passed and confirmed histologically.
    • pp.495-496
  • Intrauterine pregnancy loss
    Though fetal growth rates may vary according to various maternal characteristics (van Uitert et al., 2013), in normal pregnancies, early embryonic development is relatively uniform and, therefore, we can use developmental milestones identified on transvaginal ultrasound (Doubilet et al., 2013). Failure to meet these milestones can be useful in determining gestational age at the time of miscarriage, making ultra- sound findings an important component of early pregnancy evaluation (Farquharson and Stephenson, 2010).
    For intrauterine pregnancy demise before 10 weeks of gestation, we recommend the term early miscarriage comprising anembryonic (empty sac), yolk sac and embryonic miscarriages.
    The term early miscarriage covers all three types of intrauterine pregnancy losses, as described above. Clinically, patients may benefit emotionally from knowing when the pregnancy demise occurred, based on ultrasound findings (Nikcevic ́ et al., 2007). For research purposes, these more detailed descriptions of intrauterine pregnancy losses may lead to a better understanding of the pathophysiology, and developmental-age specific causation.
    We recommend the abandonment of the old fashioned term, blighted ovum, as it is poorly defined in the literature (Goldstein, 1990). Patients prefer the word ‘miscarriage’ rather than ‘(spontaneous) abortion’ because of its lay person’s connotation (Silver et al., 2011). Physicians as well as patient organizations have advocated this change for decades (Gardner, 1972; Beard et al., 1985; Harison, 1986; Pridjian and Moawad, 1989; Chalmers, 1992; Hutchon and Cooper, 1998; Cameron and Penney, 2005; Farquharson et al., 2005; Jutel, 2006; Silver et al., 2011; Moscrop, 2013), but ‘spontaneous abortion’ is still used in scientific literature. In the journal Human Reproduction, at least 11 papers using the term ‘spontaneous abortion’ have been published between 1 January 2013 and June 2014, despite the preference of the journal to use the term ‘miscarriage’.
    At the end of the seventh developmental week, which equates to the end of the ninth gestational week, organogenesis is complete; this heralds the end of the embryonic period and the beginning of the fetal period. We recommend that a fetal demise of at least 10 weeks of gestation, and before the fetus could survive ex utero, is termed a fetal miscarriage. Since factors associated with early miscarriage and fetal miscarriage may differ, a clear distinction between these types of miscarriages should be made. Traditionally, the distinction between ‘early’ (first trimester) and ‘late’ (second trimester) miscarriage has been at 12 weeks of gestation; to our knowledge this has been based on neither ultrasound findings nor biological processes.
    Therefore, striving to base terminology and definitions on human development, we recommend the use of ‘early’ and ‘fetal’ miscarriage, based on ultrasound findings, as described above. This will move research forward, leading to an understanding of why pregnancy loss occurs at specific developmental milestones.
    • pp.496-497
  • Recurrent pregnancy loss
    Recurrent pregnancy loss is a heterogeneous reproductive problem, with multiple aetiologies and contributing factors. As such, evaluating and treating women with this condition is a complex task, and research

in the field is no less daunting. The definition of recurrent pregnancy loss is debated, ranging from two clinical miscarriages, not necessarily consecutive, according to the American Society for Reproductive Medicine (ASRM) (ASRM Practice Committee, 2013) and a joint International Committee for Monitoring Assisted Reproductive Technology and World Health Organization glossary (Zegers-Hochschild et al., 2009), to three consecutive pregnancy losses (not necessarily intra-uterine) as defined by both the European Society for Human Reproduction and Embryology (Jauniaux et al., 2006) and the Royal College of Obstetricians and Gynaecologists (RCOG Green Top Guideline, 2011).
In the latest ASRM Practice Committee Opinion on the definition of recurrent pregnancy loss, a pregnancy is defined ‘as a clinical pregnancy documented by ultrasonography or histopathologic examination’ (ASRM Practice Committee, 2013). However, we recently showed that for women with idiopathic RPL, defined as three or more consecutive pregnancy losses before 12 weeks’ gestation, non-visualized pregnancy losses (biochemical pregnancy losses and/or resolved and treated pregnancies of unknown location) had the same prognostic impact for future live birth as a clinical miscarriage (Kolte et al., 2014). Therefore, non-visualized pregnancy losses should be included in the definition of recurrent pregnancy loss.

    • p.497
  • Recurrent pregnancy loss or recurrent miscarriage?
    With the above-mentioned terminology in mind, we recommend the term recurrent pregnancy loss be used to describe repeated pregnancy demise, and the term recurrent miscarriage be used when all pregnancy losses have been confirmed as intrauterine miscarriages, by ultrasound or histology. In research literature, the (mean or median) number of pregnancy losses and/or miscarriages should always be mentioned. As mentioned, the definition of recurrent pregnancy loss and recurrent miscarriage is controversial, but it is our opinion that the accurate reporting of clinical data is the first step towards an evidence-based definition of recurrent pregnancy loss.
    • p.497
  • Conclusions
    In order to make meaningful comparisons between scientific studies, it is paramount that definitions are adequately described and adhered to. Whenever possible, pregnancy losses should be classified into at least groups of non-visualized pregnancy losses, early miscarriage, fetal miscarriage, ectopic pregnancy, stillbirth or neonatal death. Furthermore, we strongly advise researchers and clinicians to clearly describe the type of pregnancy loss, and additionally, gestational age, number of pregnancy losses, and relevant details of ultrasound measurements.
    This Consensus Statement should bring us closer to using clear, consistent and widely applicable terminology for early pregnancy research.
    • p.497

"Environmental exposure to endocrine-disrupting chemicals and miscarriage". (September 2016)[edit]

Krieg SA, Shahine LK, Lathi RB (September 2016) "Environmental exposure to endocrine-disrupting chemicals and miscarriage". Fertility and Sterility. 106 (4): 941–7. doi:10.1016/j.fertnstert.2016.06.043. PMID 27473347.

  • Establishment of early pregnancy is the result of complex biochemical interactions between the decidua and blastocyst. Any alteration in this chemical dialogue has the potential to result in adverse pregnancy outcomes including miscarriage. Sporadic miscarriage is the most common complication of pregnancy and can be caused by multiple factors. While the most common cause of miscarriage is genetic abnormalities in the fetus, other contributing factors certainly can play a role in early loss. One such factor is environmental exposure, in particular to endocrine-disrupting chemicals, which has the potential to interfere with endogenous hormone action. These effects can be deleterious, especially in early pregnancy when the hormonal milieu surrounding implantation is in delicate balance. The purpose of this paper is to review the current evidence on the role of environmental toxins in reproduction.
    • p.941
  • Sporadic miscarriage, the loss of an embryo or fetus before 20 weeks of pregnancy, is the most common complication of pregnancy, affecting approximately 15% of all clinically recognized pregnancies. A much larger percentage of pregnancies are impacted if preclinical losses are included. Of these clinical pregnancy losses, a large majority occur during the first trimester. A majority of these first trimester losses are secondary to genetic abnormalities in the conceptus. However, sporadic, euploid losses do occur. Risk factors for pregnancy loss include but are not limited to advanced maternal age, hormonal imbalances, immunological interactions, and uterine anatomic abnormalities. Certainly, lifestyle factors such as tobacco smoke and alcohol usage are generally well accepted as contributing causes of miscarriage. Exposure to other chemicals such as endocrine disruptors, heavy metals, or occupational chemicals has also been implicated in miscarriage. The sensitivity of embryonic tissue or fetal tissue to such compounds is far greater than that of adult tissue. This is in part because of the small size and totipotent nature of many of the cells in the embryo or fetus. A single insult at these early stages of development can have deleterious effects on development.
    Not only can environmental toxins impact the developing embryo, there is also a potential for alteration of the endometrium of pregnancy, that is, the decidua. Successful implantation requires a complex biochemical dialogue to occur between the blastocyst and decidua. These early interactions allow for implantation to occur and ultimately for establishment of pregnancy. Environmental alteration of these early uterine events can also disrupt an early pregnancy or potentially result in miscarriage or other adverse pregnancy outcomes. In particular, abnormal hormone signaling pathways could potentially affect not only the ability of a blastocyst to implant in the endometrium but also the ability of the decidua to communicate with fetoplacental unit in a normal way. Multiple industrial contaminants have the potential for endocrine disruption; these chemicals can impact the ability to become pregnant and sustain a healthy pregnancy. Other environmental contaminants have also been implied to have a causal effect on pregnancy loss; these include radiation exposure, heavy metals, agricultural chemicals, and industrial solvents. Given the scope of this review, our discussion will be limited largely to endocrine-disrupting chemicals (EDCs). EDC exposure may represent an additional cause(s) of sporadic or recurrent loss.
    • p.941
  • Early human studies of DDT suggested a possible correlation with cancer in general. However, with time, reproductive disorders became apparent. Similar to the bird population, human population declines were secondary to reproductive failures. In vitro studies have shown that DDT has estrogenic activity. Dichlorodiphenyl dichloroethene (DDE), a metabolite of DDT, has been shown to be an androgen receptor antagonist. The reproductive repercussions of DDT use have been multiple; these include a suggested role in decline in sperm counts, increase in time to conception, and even intrauterine growth restriction. Spontaneous abortion has been correlated with DDT exposure in multiple studies. Given the stability of DDT and its metabolites (in particular DDE), it is possible to correlate serum levels with pregnancy history. Most human studies on miscarriage and DDT have correlated DDT or DDT metabolites with pregnancy outcomes. Some studies show limited impact of DDT on miscarriage. These studies are limited by the timing of collection of samples and the timing of observation of pregnancy losses. In these studies, DDT and/or its metabolites were measured in blood or serum that was collected after the pregnancies had completed. The levels of DDT would have the greatest impact during the pregnancy, that is, during the exposure to the fetus. In addition, many of the samples were collected in the postpartum period when women were nursing their infants. Since breast feeding decreases the DDT levels in the serum, levels could be lower than what they were in pregnancy. In addition to timing of sample collections, many pregnancy losses could have gone unaccounted for since these studies are retrospective in nature. Only prospective studies that collect samples and data throughout menstrual cycles and detect early preclinical losses with bhCG levels can account for all the pregnancy losses associated with high levels of serum DDT.
    However, these studies have been in patients with lower serum levels of DDT or DDE. Several studies have shown that there is also an increase in spontaneous miscarriage at higher concentrations of DDE (>15 μg/L).
    • pp.941-942
  • While many have questioned the impact of BPA upon fertility, development, and adult disease, the focus of this review will be upon miscarriage. It is known that mice exposed to BPA have a lower number of implantation sites. In fact, when mice are exposed to BPA during pregnancy, their offspring have abnormal endometrial stromal signaling pathways. BPA has also been shown to result in thinner endometrial lining in human studies, further supporting a negative impact on the deciduae. BPA has been associated with an increase in aneuploidy oocytes in murine studies, which could also be a cause of miscarriage. BPA has been shown in several animal models to affect oocyte meiosis, leading to aneuploidy. A similar result has been found in human oocytes during culture. This increase in oocyte aneuploidy can certainly lead to miscarriage. In fact, a recent study by Lathi and coworkers demonstrated a statistically significant increase in both euploid and aneuploid losses in patients in the fourth quartile of urinary BPA concentration. The relative risk of loss for sporadic miscarriage was 1.97 (95% CI, 1.08–3.59) and for recurrent loss was 3.33 (95% CI, 1.04–10.71) in the highest quartile of serum BPA concentration. Similarly, another group has demonstrated an increase in idiopathic miscarriage in patients with higher urinary BPA levels, but the sample size was small (n = 45) and there was no fetal karyotyping performed. Shen and coworkers found that a higher urinary BPA level is associated with recurrent miscarriage with an OR of 3.91 (95% CI, 1.23–12.45) in the 0.4–0.93 μg/g Cr group and an OR of 9.34 (95% CI, 3.06–28.44) in the .93 μg/g Cr group adjusting for confounding factors; however, these samples were not collected during pregnancy for the miscarriage group. Taken together, BPA has been shown in laboratory models to increase the risk of miscarriage at the level of both the endometrium and the oocyte. These molecular changes as a result of BPA exposure do appear to confer an increased risk of miscarriage in patients with higher BPA accumulation. These preliminary data suggest a critical need for larger epidemiological studies to confirm an association between BPA exposure and miscarriage.
    • pp.942-944
  • Dioxin exposure in pregnancy has been associated with fetal loss and low birth weight in rodents and monkeys. PCB exposure has also been associated with a developmental syndrome involving hydronephrosis, cleft palate, and thymic atrophy in mice. Monkeys exposed to PCBs have an increased number of miscarriages and higher rates of fetal demise. Human studies generally show similar findings. One example of PCB toxicity is Yusho oil disease. In 1968 in western Japan, rice oil was contaminated with PCBs and other dioxin-related compounds. As a result over 1,900 people presented with clinical symptoms including acne-like eruptions, pigmentation changes, eye discharge, and paresthesias. More than 500 people died as a result. The levels of PCBs and dioxins remained elevated for a prolonged period of time in these individuals. In a study done by Tsukimori et al., a statistically significant increase in miscarriage was noted, with OR ranging from 1.6 (95% CI, 1.1–2.33) to 2.52 (95% CI, 0.92–6.87) depending on the type of PCB measured. This study included interviews with 214 women (512 pregnancies) regarding pregnancy outcomes over 36 years; these patients had also had blood levels of PCBs measured. Other groups have shown an increase in low birth weight and growth restriction in this population. The Yusho oil incident is not isolated; similarly the Yu-sheng accident and Vietnamese exposure to Agent Orange have shown an increase in spontaneous abortion. After an explosion at a chemical factory in Seveso, Italy, that involved dioxin, no increase in miscarriage after evaluating pregnancy outcomes in 510 women was observed. This could be explained by different concentrations of dioxin, PCBs, and dibenzofurans in these exposures and the timing of exposure.
    • p.944
  • There are conflicting data regarding Agent Orange and risk of spontaneous abortion. While many studies have been limited by small sample size or inadequate exposure, the data are inconsistent. Most studies have evaluated paternal exposure; however, studies of exposed Vietnamese women have shown an increase in miscarriage and premature deliveries. Larger studies have found a trend toward increased risk of spontaneous abortion in wives of veterans with low exposure but not at high exposure levels. A larger cross-sectional study of 281 workers exposed to TCDD during production of Agent Orange, showed primary outcomes of increase in stillbirth, spontaneous abortion, and sex ratio. In this study no increase was seen in any of these outcomes. However, this study was vulnerable to recall bias, and it occurred over a time period when early pregnancy tests were not available (1950–1960s), so early losses would not be captured.
    While PCBs represent a large class of chemicals, it appears from largely retrospective studies that they are associated with an increase miscarriage and other adverse reproductive outcomes. Further longitudinal studies are needed to further understand the reproductive repercussions of PCB use not only on pregnancy complication but also on the effect on offspring.
    • p.944
  • Phthalates have been associated with developmental abnormalities of the male reproductive system, miscarriage, endometriosis, and low sperm counts. The mechanism by which phthalates cause adverse reproductive outcomes includes P-like effects; in fact, di-(2-ethyl)phthalate (DEHP) has been modeled in silico to interact with the P receptor. Other studies have shown in vitro that some forms of phthalates activate the PPARs and ultimately decrease aromatase activity. These possible P-like effects and decrease in aromatase activity have been theorized to contribute to adverse reproductive outcomes. In rat models, multiple studies have shown ovarian toxicity stemming from DEHP exposure. While rodent studies may be suggestive of human health risks, they allow the observation of titrated effects. Administration of DEHP to female rats has shown a decrease in serum E2 levels and an increase in anovulation. Histologically, these rats showed cystic follicles with abnormal granulosa cells and smaller follicle size. In human studies of patients undergoing IVF, a lower number of mature oocytes are found in patients with higher phthalate concentrations. These patients are also found to have lower implantation rates. In the mouse endometrium, titrated phthalate dosages are found to cause abnormal gene expression of ERα, PR, and E-cadherin. These gene products are important for normal implantation, and, concordantly, these mice had a lower number of implantation sites. In rodents that did become pregnant, a decrease in the number of litters, litter size, and proportion of live-born offspring was observed after DEHP exposure. Another form of phthalate, di-n-butyl phthalate, was found to confer an increase in midpregnancy miscarriage in rats. Chronically high exposure levels associated with manufacture have been linked to miscarriage and lower fertility rates in humans. Similarly, in humans, elevated urinary concentration of the phthalate monoethylhexyl phthalate around the time of conception was associated with an increase in miscarriage, with an OR of 2.87 (95% CI, 1.09, 7.57) in the highest quartile of exposure. Mu and coworkers also found an increase in miscarriage rates after measuring eight different urinary phthalate metabolites, dividing patients into four different quartiles of exposure. Participants falling into the first and fourth quartile of exposure had an increase in miscarriage.
    • p.945
  • Environmental contaminants have been suggested to play a role in spontaneous miscarriage. The focus of this review was limited to endocrine disruptors. This group of chemicals, which are able to interact with hormone receptors, is known to impact wildlife, laboratory animals, and humans. Some of the effects on wildlife are profound, including marked decreases in population, inability to reproduce, physical changes in the reproductive organs, birth defects, and miscarriage. These exposures may occur in the workplace, from ingesting contaminated food, while receiving medical treatment (i.e., IV tubing), or from the pesticides/herbicides used in agriculture or for pest control. Many of these exposures are cumulative and as a result can be bioconcentrated in the food chain.
    The reproductive outcomes impacted by endocrine disruptors are many, but the focus of this review paper is on miscarriage. Many studies have shown a dose-dependent increase in miscarriage with these endocrine disrupters. There are some considerations when interpreting these data. Many of these studies rely on small sample sizes and often rely on recall of pregnancy history. These are obvious confounders in interpreting the data. That being said, many of these compounds are extremely stable, allowing researchers to measure serum or urinary levels reliably.
    These studies suggest that women of reproductive age should exercise caution in exposure to these endocrine disruptors. Unfortunately, these compounds are ubiquitous in the environment and are often difficult to avoid. One concern with the ubiquitous nature of these chemicals is that many of these studies could be confounded by the presence of multiple chemicals. Ideally, multiple endocrine disruptors would be assayed for, permitting an assessment of the actual compound(s) causing an effect. Also there is the potential that these EDCs could behave in a synergistic manner, exacerbating a preexisting effect. These studies show the need and importance of more prospective studies of adequate sample size and design so that we can understand the full extent of the impact of these hormone-like compounds on the establishment and maintenance of pregnancy.
    • p.945

"13 Things To Know About Grief After Miscarriage or Loss" (May 16, 2013)[edit]

Kate Kripke, "13 Things To Know About Grief After Miscarriage or Loss". Postpartum Progress. May 16, 2013. Archived

  • Losing a baby though miscarriage, elective termination, stillbirth, childbirth, after a NICU stay, SIDS, or any other time is, without a doubt, one of the most difficult experiences that a parent will ever endure. There are no words to explain the depth of despair that a parent goes through when attempting to understand the shift that occurs when all hopes and expectations suddenly drop out from underneath anything stable.
    It is an experience that many will never need to make sense of and also one that many others will swim through unexpectedly. It is tragic and drastic and totally and completely unfair and yet thousands upon thousands of families find themselves in this position each year. Here is what we know:
    * Approximately 15-20% of confirmed pregnancies end in miscarriage.
    * In the US, the rate of stillbirth is documented as 1 in 160-200 pregnancies.
    * In the US, the rates of SIDS affects between 5,000-7,000 infants every year.
    * In the US, approximately 11,300 infants die within 24 hours of their birth each year.
  • So, if you are one of these women, here is what I want you to know:
    1. Some women who lose babies through miscarriage are able to move through this loss freely, while others feel deep despair at this loss. There are no “shoulds” in this. No right way to feel. If you feel strong and grounded and ready to move forward after a miscarriage that is totally valid. If you feel deep loss and grief then that, too, is appropriate. No one gets to tell you how you feel except you.
    2. Any time a body goes from being pregnant to not being pregnant, there is a significant shift in hormones that can affect brain chemistry. Postpartum depression, anxiety, and other mood disorders can affect a mom regardless of the point at which a baby is delivered. You are likely in a position where you need to process through grief while also having a vulnerable brain chemistry. This can make the experience of healing feel impossible for many.
    3. Grief is a normal process and includes a shifting of emotions such as denial, anger, bargaining, depression, and acceptance. Grief felt after the loss of a baby from miscarriage or other event is not necessarily depression and while there may be some overlap, it should not be treated as such. If you feel angry one day and dissociated from your loss the next, this is normal.
    4. If you are not aware of a shifting through the stages of grief and continue to feel debilitated by your suffering, there may be an element of clinical depression or anxiety that needs to be addressed. “Healthy” grief moves, but sometimes it can develop into relentless depression that requires more specific treatment. Many moms will experience depression that includes feelings of guilt, shame, self-doubt, and sometimes suicidal ideation. Regaining a sense of self, hope, and trust is important to one’s healing after a loss such as this.
    5. Identity shifting is a huge piece of the postpartum experience for every new parent, and yet moms who lose their babies are not able to show the world their mother-ness. If you feel like a mom, and yet are not able to participate in the experiences that the mothers around you are included in, know that this is a shared experience and that, whether or not the world can see this, we value you as a mother too.
    6. Loss can often beget feelings of loss. Many women who lose their babies become suddenly afraid of losing everything else, be it their sanity, other relationships important to them, their faith in the world, or any hope for the future. Many, many women who go through this loss feel a deep need to grab onto other things in their life for fear of losing those, too. If this is happening to you, let those close to you know.
    7. Relationships with spouse/partner, family, and friends will be impacted by your loss. It is important to be aware of the tendency to isolate during this time. Receiving appropriate support will be imperative in your healing and there may be work to do in relearning your relationships given this new reality. If you are unable to get the support that you need from loved ones, reach out to a therapist who can help.
    8. While you desperately want your spouse/partner to understand what you are going through, he/she may not. People grieve differently. Often, losing a baby is a very different experience for a mother than it is for her partner, as she was the one who felt the development of this baby and feels, still, the physical loss as her body adjusts to no longer being pregnant. Give space for your own process as well as your partner’s.
    9. You are likely to learn who your truest friends are during this time. Some people’s insecurities and fears around loss and tragedy may interfere with their ability to be there for you. It is entirely appropriate for you to spend time with those who are able to give you what you need, and to take distance from those who do not.
    10. It is normal to feel triggered into sadness and despair when you least expect it. You may find reminders in the places where you least intend them to be. Seeing other pregnant women, babies, holidays and anniversaries, playgrounds, doctor’s offices, advertisements for baby-related items all may bring you to tears even when you feel strong. This is normal.
    11. People don’t always know what to say. Many of you will want desperately to talk about your babies, to bring them to life through your words and memories, to make room for them in conversation and in your experiences. Some people will worry that bringing your baby and your loss in conversation will be upsetting to you. It is helpful to let the people in your life know what you need.
    12. Just because you are ready to feel whole again, are healing, and may decide to have more children, this does not mean that the baby who you lost is forgotten. Regaining strength does not mean that you have “moved on” and will no longer think of what might have been. Your pregnancy and your baby will always be a part of you. However, you deserve to be well and the feeling that you must keep grieving in order to stay faithful to your baby will not serve you. Finding a way to honor your pregnancy or your baby through ritual or event is often a lovely way of incorporating that being into your life as you move forward.
    13. And finally, find others who have experienced something similar. As mentioned so many times on this blog, community is imperative and I am certain that there are others out there who can offer you the kind of solace, strength, and integrity that you will need as you continue to heal.

“Miscarriage: worldwide reform of care is needed” (May 1, 2021)[edit]

“Miscarriage: worldwide reform of care is needed”, The Lancet, Volume 397, ISSUE 10285, P1597, (May 01, 2021)

  • Globally, an estimated 23 million miscarriages occur every year. Despite the personal toll involved, many miscarriages—defined as the loss of pregnancy before viability—are managed in relative isolation. Private grief and misconceptions—eg, the belief that miscarriage can be caused by lifting heavy objects, or that there are no effective treatments—can lead to women and their partners feeling at fault or managing alone. Similarly, in the health-care system and broader society, the continuing conviction that miscarriages are unavoidable and the requirement, enshrined in many national guidelines, that women must have recurrent miscarriages before they are eligible for investigation or intervention has created a pervasive attitude of acceptance of miscarriage, urging women to “just try again”. This mindset underestimates, and risks dismissing, the personal physical and mental consequences of a miscarriage. It has also affected the availability and quality of care that women receive after a miscarriage and does not accurately reflect the evidence on management.
  • Miscarriage is common, affecting one in ten women in their lifetime. The Series sets out clear risk factors for miscarriage: increasing age (both of men and women), body-mass index, and being of Black ethnicity. Alcohol, smoking, air pollution, pesticides, persistent stress, and night shift working also have some association with miscarriage. For women who have early pregnancy bleeding and a history of miscarriages, the Series concludes that there is high-quality evidence showing vaginal micronised progesterone increases livebirth rates. Where this treatment is unsuccessful, all providers should be able to manage miscarriages expectantly, medically with mifepristone and misoprostol, and surgically with manual vacuum aspiration kits. The provision of these interventions must be made a priority in all settings, including low-income and middle-income countries, where they are often unavailable.
    Although most women who have a miscarriage will go on to carry a baby to term without complications, previous miscarriage is associated with a higher risk of preterm birth, fetal growth restriction, and other obstetric complications in subsequent pregnancies. Previous miscarriage is also associated with a higher risk of long-term health problems for women, including cardiovascular disease, venous thromboembolism, and mental health complications. These associations challenge the belief that miscarriage is a single event without wider repercussions, and the Series gives a more nuanced and graduated understanding of miscarriage, which is long overdue.
    The Series authors propose a graded model of care, where after one miscarriage women should have their health needs evaluated and be provided with information and guidance to support future pregnancies. If a second miscarriage occurs, women should be offered an appointment at a miscarriage clinic for a full blood count and thyroid function tests and have extra support and early scans for reassurance in any subsequent pregnancies. After three miscarriages additional tests, including genetic testing and a pelvic ultrasound, should be offered. This model represents a substantial move away from the current fragmented system of care, with barriers to access, and better reflects the significant mental and physical event that miscarriage is to many people. Reviewing the evidence on miscarriage, however, shows that the low priority afforded to miscarriage has resulted in a deficiency of high-quality epidemiology, and trials for management and prevention that should be available to guide practice and guidelines. This is especially true in low-income settings, where most miscarriages happen.
  • For too long miscarriage has been minimised and often dismissed. The lack of medical progress should be shocking. Instead, there is a pervasive acceptance. Not all miscarriages could be avoided, but the insidious implication that miscarriage, like other women's reproductive health issues, including menstrual pain and menopause, should be managed with minimal medical intervention is ideological, not evidence based. This Series should catalyse a major focus on miscarriage for the medical research community, for service providers, and for policy makers. The era of telling women to “just try again” is over.

"New insights into mechanisms behind miscarriage"(June 26, 2013)[edit]

Larsen, Elisabeth Clare; Christiansen, Ole Bjarne; Kolte, Astrid Marie; Macklon, Nick (June 26, 2013). "New insights into mechanisms behind miscarriage". BMC Medicine. 11 (1): 154. doi:10.1186/1741-7015-11-154. ISSN 1741-7015. PMID 23803387.

  • Sporadic miscarriage is the most common complication of early pregnancy. Two or three consecutive pregnancy losses is a less common phenomenon, and this is considered a distinct disease entity. Sporadic miscarriages are considered to primarily represent failure of abnormal embryos to progress to viability. Recurrent miscarriage is thought to have multiple etiologies, including parental chromosomal anomalies, maternal thrombophilic disorders, immune dysfunction and various endocrine disturbances. However, none of these conditions is specific to recurrent miscarriage or always associated with repeated early pregnancy loss. In recent years, new theories about the mechanisms behind sporadic and recurrent miscarriage have emerged. Epidemiological and genetic studies suggest a multifactorial background where immunological dysregulation in pregnancy may play a role, as well as lifestyle factors and changes in sperm DNA integrity. Recent experimental evidence has led to the concept that the decidualized endometrium acts as biosensor of embryo quality, which if disrupted, may lead to implantation of embryos destined to miscarry. These new insights into the mechanisms behind miscarriage offer the prospect of novel effective interventions that may prevent this distressing condition.
  • The term ‘miscarriage’ is applied to many complications of early pregnancy, and it is important to be clear on terminology. In 2005, the European Society of Human Reproduction and Embryology (ESHRE) introduced a revised terminology regarding early pregnancy events. A pregnancy loss that occurs after a positive urinary human chorionic gonadotropin (hCG) or a raised serum β-hCG but before ultrasound or histological verification is defined as a ‘biochemical loss’. In general, these occur before 6 weeks of gestation. The term clinical miscarriage is used when ultrasound examination or histological evidence has confirmed that an intrauterine pregnancy has existed. Clinical miscarriages may be subdivided into early clinical pregnancy losses (before gestational week 12) and late clinical pregnancy losses (gestational weeks 12 to 21). There is no consensus on the number of pregnancy losses needed to fulfill the criteria for recurrent miscarriage (RM), but ESHRE guidelines define RM as three or more consecutive pregnancy losses before 22 weeks of gestation. Although the above-mentioned terminology is widely used, it is also acknowledged that it is not always clinically useful. Indeed, a recent paper has proposed classification according to developmental periods in gestation.
    Clinical miscarriage is both a common and distressing complication of early pregnancy. In recent years, progress in the fields of cytogenetics and immunogenetics and a greater understanding of implantation and maternal-embryo interactions has offered new insights into the possible causes of this condition, and opened up new avenues for research into its prevention and treatment. In this article we review the key mechanisms thought to underlie miscarriage, and discuss emerging concepts in this field (Table 1).
  • Human reproduction is characterized by its inefficiency. Prospective cohort studies using sensitive and specific daily urinary hCG assays in women trying to conceive have demonstrated that only around one-third of conceptions progress to a live birth. An estimated 30% of human conceptions are lost prior to implantation and a further 30% following implantation but before the missed menstrual period, that is in the third or fourth week of gestation. These are often termed preclinical losses (Figure 1). Finally, the incidence of early clinical pregnancy loss is estimated to be 15% of conceptions with a significant variation according to age. Thus, the incidence ranges from 10% in women aged 20 to 24 years to 51% in women aged 40 to 44 years. Late losses between 12 and 22 weeks occur less frequently and constitute around 4% of pregnancy outcomes.
  • The pregnancy loss iceberg: an overview of the outcome of spontaneous human conceptions. It is estimated that 70% of conceptions are lost prior to live birth. The majority of these losses occur prior to implantation or before the missed menstrual period, and since they are not revealed to the woman they are termed preclinical. In the pregnancy loss ‘iceberg’, they are therefore below the ‘waterline’. Figure reproduced with permission from Oxford University Press.
  • Compared to sporadic miscarriage the prevalence of RM is considerably lower irrespective of whether biochemical losses are included or not. If only clinical miscarriages are included the prevalence is 0.8% to 1.4%. If, however, biochemical losses are included the prevalence is estimated to be as high as 2% to 3%. Since the incidence of RM is greater than would be predicted by chance, it is considered to represent a disease entity defined by a series of events, with a number of possible etiologies.
  • It is a generally accepted assumption that sporadic pregnancy losses occurring before an embryo has developed represent a ‘physiological’ phenomenon, which prevents conceptions affected by serious structural malformations or chromosomal aberrations incompatible with life from progressing to viability. This concept is supported by clinical studies in which embryoscopy was used to assess fetal morphology prior to removal by uterine evacuation. Fetal malformations were observed in 85% of cases presenting with early clinical miscarriage. The same study also demonstrated that 75% of the fetuses had an abnormal karyotype. Fetal chromosomal aneuploidies arising from non-inherited and non-disjunctional events are common. Indeed, in a recent study using comparative genomic hybridization to study the chromosomal complement of all blastomeres in preimplantation human embryos, more than 90% were found to have at least one chromosomal abnormality in one or more cells. The clinical implications of minor, mosaic and possibly ‘transient’ aneuploidies remain unclear. However, while most fetuses with severe developmental defects will die in utero some aneuploidies can be compatible with survival to term. The most commonly encountered is trisomy 21, although 80% of affected embryos perish in utero or in the neonatal period. In most cases, the extra chromosome is of maternal origin and caused by a malsegregation event in the first meiotic division. The risk of this increases with maternal age and may be considered to be a biological rather than pathological phenomenon.
    Although fetal chromosomal aberrations may be identified in 29% to 60% of cases in women with RM, the incidence decreases as the number of miscarriages increases suggesting other mechanisms as a cause of the miscarriage in RM couples with multiple losses.
  • A chromosomal abnormality in one partner is found in 3% to 6% of RM couples, which is ten times higher than the background population. The most commonly encountered abnormalities include balanced translocations and inversions that do not have any consequences for the phenotype of the carrier, but in pregnancy there is a 50% risk of a fetus with an unbalanced chromosomal abnormality that can result in a miscarriage. This risk is influenced by the size and the genetic content of the rearranged chromosomal segments. Whether or not to screen couples with RM for chromosomal abnormalities remains a topic of debate. The argument for performing this costly analysis is to optimize the counseling of RM couples with respect to any subsequent pregnancy and to avoid the birth of a child with congenital defects and mental handicaps due to an unbalanced karyotype by offering appropriate prenatal diagnostic screening.
    The case against offering routine karyotyping for couples with RM rests primarily on the findings of a large index-control study with a mean follow-up period of 5.8 years. This study showed that carrier couples with at least two previous miscarriages had the same chance of having a healthy child as non-carrier couples with at least two miscarriages (83% and 84%, respectively), and more importantly a low risk (0.8%) of pregnancies with an unbalanced karyotype surviving into the second trimester. Current clinical guidelines do recommend parental karyotyping as part of the evaluation in RM couples with a high risk of carrier status but only if maternal age is low at the second miscarriage, or if there is a history of two or more miscarriages in first degree relatives.
    Some clinicians recommend in vitro fertilization with preimplantation genetic diagnosis (PGD) as a treatment option in RM couples with carrier status in order to replace euploid embryos only. This may be beneficial in couples with coexisting infertility, but in couples with proven fertility the live birth rate seems to be comparable or maybe even higher after spontaneous conception including PGD.
  • It has long been an enigma how the implanting embryo and trophoblast escape maternal immunological rejection in the uterus in spite of carrying allogeneic proteins encoded by paternal genes. A series of mechanisms regulating maternal immune recognition and fetal antigen expression has been suggested to prevent the rejection of the majority of pregnancies, but these may cause RM when they fail.
    Since reproductive success is of utmost importance for the survival of a species, it is likely that redundant mechanisms have developed to prevent immune rejection of the embryo, and only when several mechanisms fail in a woman will RM will occur. This complexity continues to feed the ongoing controversy regarding which immunological factors play a role in the pathogenesis of RM.
    There is general agreement that a series of autoantibodies such as anti-phospholipid, anti-nuclear and anti-thyroid antibodies can be found with increased prevalence in RM patients and may display a negative prognostic impact. However, in humans there is no proof that the antibodies per se harm the pregnancy; they may simply be markers of a predisposition to disruption of immunological self-tolerance and proinflammatory responses in these women. In contrast, a study found that pregnant mice injected with human IgG from a patient with anti-phospholipid antibodies significantly increased fetal resorption rate and reduced fetal weight while simultaneous treatment with antibodies blocking activation of the complement cascade completely prevented fetal resorptions and growth retardation. In this and similar studies it was also found that mice deficient in various complement factors were resistant to fetal injury induced by injection of the anti-phospholipid antibodies. This indicates that at least in mice, anti-phospholipid antibodies may exercise their harmful effect on pregnancies through immunological mechanisms (complement activation) rather than through a direct procoagulant effect. There is some, however, weaker evidence that anti-phospholipid antibodies also induce complement activation in humans with antiphospholipid syndrome.
  • A series of studies have reported that increased concentrations of proinflammatory or T helper cell type I cytokines or increased frequencies of subsets of natural killer (NK) cells in the blood can be found during euploid sporadic miscarriage and in women with RM but it is debated whether measurements of these biomarkers in peripheral blood reflect conditions at the fetomaternal interface. There is some evidence that uterine NK cells regulate angiogenesis in the non-pregnant endometrium and therefore may also play a role for implantation and early pregnancy but a systematic review of relevant studies did not find peripheral blood or uterine NK cell density or activity to be predictive for pregnancy outcome in patients with RM.
    The most convincing evidence for the importance of the immune system in miscarriage and RM comes from genetic/epidemiologic studies showing that genetic biomarkers of possible importance for immunologic dysregulation in pregnancy are found with increased frequency in women with RM and display a negative impact on the prognosis. Examples of such genetic biomarkers are maternal homozygocity for a 14 base-pair insertion in the human leukocyte antigen (HLA)-G gene, maternal carriage of HLA class II alleles predisposing to immunity against male-specific minor histocompatibility antigens found on male embryos, specific maternal NK cell receptor genotypes in combination with fetal HLA-C genotypes that may be associated with aberrant maternal NK cell recognition of the trophoblast and maternal mannose-binding lectin binding genotypes predisposing to low plasma levels of mannose-binding lectin, which may be of importance for release of cytokines and clearance of apoptopic trophoblast cells.
  • Thrombophilic factors predisposing to thromboembolic events are associated with both sporadic miscarriages and RM and can be hereditary or acquired. It is suggested that the association is caused by an increased risk of thrombus formation in the nascent placental vessels resulting in placenta infarctions. Hereditary factors include deficiency of antithrombin, protein C and protein S or carriage of the factor V Leiden or factor II (G20210A) gene mutations. Acquired factors include the presence of anti-phospholipid antibodies, lupus anticoagulant or anti-cardiolipin antibodies, which are deemed to be present when identified in repeated samples taken 3 months apart and outwith pregnancy. Hyperhomocysteinemia can be both hereditary and acquired. There is some evidence from two non-blinded randomized controlled trials that treatment with low-dose heparin and aspirin during pregnancy increases the chance of live birth in RM patients with anti-phospholipid antibodies. There is no evidence that anticoagulation therapy will improve the prognosis for RM patients with hereditary thrombophilias or no thrombophilia factors at all, and results from relevant ongoing randomized controlled trials are awaited (for example, the ALIFE2 study). Therapy with high-dose folate will lower plasma homocysteine levels but there is no evidence from clinical trials whether this decreases the risk of a new miscarriage.
  • The prevalence of hypothyroidism with or without underlying thyroid autoimmunity is significant among fertile women in fertile age. There is evidence that thyroid dysfunction and thyroid autoimmunity is associated with infertility and pregnancy loss both in the situation where the woman is euthyroid with thyroid antibodies and in a thyroid antibody negative woman with an elevated level of thyroid stimulating hormone (TSH). According to a recent meta-analysis of 38 studies, the presence of antibodies against thyroperoxidase (TPO-Ab) increased the risk of sporadic miscarriage with an odds ratio of 3.73 (95% CI 1.8 to 7.6) as well as RM (OR 2.3, 95% CI 1.5 to 3.5). In a large prospective study including pregnant thyroid antibody negative women, a TSH level within the normal range but higher than 2.5 mIU/L in the first trimester, nearly doubled the risk of a miscarriage. However, the true significance of thyroid dysfunction and the value of its correction in improving outcomes in RM remains unclear.
    Polycystic ovarian syndrome (PCOS) is a common endocrine disorder of reproductive-age women. PCOS may be associated with ovulatory disorder and miscarriage when fertility is desired. Using strict criteria the prevalence of PCOS among women with RM is estimated to be 8.3% to 10%. The mechanisms behind an increased miscarriage risk in women with PCOS remains partly unclear. The current view is that the main cause may be the associated obesity, which is dealt with in the section describing lifestyle factors.
  • Sperm DNA integrity is essential to reproduction, and measurement of sperm DNA fragmentation (SDF) was therefore first introduced as an additional tool in predicting male infertility. Indeed there is a correlation between low semen quality and high SDF levels, but at present much controversy exists with regard to cut-off levels, which assay to use, and the clinical relevance of the tests in assisted reproductive technologies.
    In contrast, there is a documented link between DNA damage in sperm and miscarriage. A recent meta-analysis including 16 studies found a highly significant increase in miscarriage rate in couples where the male partner had elevated levels of sperm DNA damage compared to those where the male partner had low levels of sperm DNA damage (risk ratio = 2.16 (1.54, 3.03, P <0.00001). Due to variation in study characteristics, the authors have subgrouped the included studies according to whether raw or prepared semen was analyzed, and according to which type of assay was used to determine sperm DNA damage. A consistent and significant association with miscarriage was found regardless of which semen preparation was used while the strongest association as regards assays was found in a test quantifying sperm DNA damage directly by incorporating a labeled enzyme into single and double-stranded DNA breaks.
  • In a study comparing fertile sperm donors with couples who have unexplained RM, an assay was used that both measured DNA damage directly and also distinguished between single-stranded and double-stranded DNA damage. The study showed that 85% of the RM couples had a profile with high values of double-stranded DNA damage compared to only 33% among fertile sperm donors, suggesting a specific paternal explanation in these otherwise unexplained cases.
  • Recent in vitro studies of embryo-decidual interactions have demonstrated that decidualized stromal cells act as a biosensor for embryonic derived signals and appear capable of ‘selecting’ embryos for implantation on the basis of their quality. The first study to demonstrate the biosensor function of decidualized endometrial stromal cells (ESC) showed that coculture with an arresting human embryo elicited a reduction in the production of key cytokine regulators of implantation including interleukin (IL)-1β, heparin-binding epidermal growth factor-like growth factor (HB-EGF), IL-6, and IL-10. These findings provided the first experimental evidence to support the hypothesis initially put forward by Quenby et al. that some women with RM may be allowing embryos of poor viability to implant inappropriately. In other words, women who experience RM may not be rejecting healthy embryos, but rather permitting embryos of low viability to implant long enough to present as a clinical pregnancy before rather than being lost as a preclinical biochemical pregnancy.
    The hypothesis that endometrial selectivity to embryo quality may be disrupted in women with RM has found support from a number of other studies. Women with RM have been shown to express lower levels of endometrial mucin 1, an antiadhesion molecule that contributes to the barrier function of the epithelium. Moreover, ESCs of women with RM show an abnormal response to decidualization in vitro, manifest by attenuated prolactin (PRL) production and prolonged and enhanced prokineticin 1 expression. It has been proposed that this may result in a prolonged ‘window’ of receptivity to implantation, but a reduction in the selective functions of the decidua.
    If women with RM are less selective to embryos implanting, then it would be expected that they would report shorter intervals between pregnancies. This has indeed been demonstrated in a retrospective cohort study of 560 RM women, which showed a significantly greater proportion to have time-to-pregnancy intervals of 3 months or less compared with fertile control subjects.
    Further experimental evidence supporting low endometrial selectivity or ‘super receptivity’ in women with RM has come from studies of stromal cell migration in vitro. Recently it has been shown that ESC migration occurs around the time of embryo implantation and may promote implantation by encapsulation of the conceptus. In timelapse imaging studies covering a period of 48 h, ESC migration was clearly depicted at the site of embryo implantation. Moreover, the ESCs showed migration around the embryo suggesting an active role for ESCs in the implantation process.
    Migration (scratch) assays have provided further evidence for altered embryo selectivity in women with RM. In a recent study, the directed migration of decidualized ESCs from normal fertile and RM women in the presence or absence of a high-quality or low-quality (chromosomally abnormal 3PN) embryo was observed. The migration of ESCs from normal fertile women was totally inhibited in the presence of a low-quality embryo. However, the migration behavior of ESCs from women with RM was similar in the presence of both low-quality and high-quality embryos. In addition, in the presence of AC-1 M88 trophoblast cell-line-derived spheroids, the migration of ESCs from women with RM was enhanced compared to the normal fertile ESCs. These observations suggest that ESCs from women with RM have an increased migratory potential in response to trophoblast signals and are more receptive (and thus less selective) for low-quality embryos than normally fertile women.
  • The clinical significance of these findings remains to be clarified, but failure of embryo selection may represent a single pathological pathway responsible for both euploidic and aneuploidic pregnancy losses. Brosens and Gellersen have noted that given the high proportion of chromosomally abnormal preimplantation human embryos, this concept predicts that the likelihood of euploidic pregnancy failure increases with the number of miscarriages. This has indeed been shown to be the case.
    This novel concept requires further elucidation and confirmation, but a growing body of evidence supports the notion of an active, selective decidual phenotype, which if disrupted may result in reproductive failure. Novel therapeutic options may thus be developed that can correct defects in selectivity, preventing inappropriate implantation of embryos of low viability and sparing women the severe stress caused by recurrent clinical miscarriage. Alternatively, in vitro fertilization and PGD may improve outcomes in this context as in vitro embryo selection would increase the chance of a viable embryo implanting. However, the efficacy of PGD in treating women with recurrent miscarriage due to translocations is unclear, and further studies are required.
  • An accepted cause of recurrent pregnancy loss is uterine malformations that may be acquired or congenital. The latter include didelphic, bicornuate, arcuate, and septate uteri. In a recent systematic review including 89,861 women, the prevalence of all congenital uterine malformations was 5.5% (95% CI 3.5 to 8.5) in an unselected population and 15.4% (95% CI 10.3 to 23) among women with ≥3 miscarriages. In another review comprising 3,805 women the meta-analysis showed that a septate uterus increased the rate of a first trimester miscarriage significantly when compared with women with normal uteri (RR = 2.89; 95% CI 2.02 to 4.14). The role of septal resection is being debated. Non-controlled studies suggest a positive effect on pregnancy outcome but we still lack prospective randomized trials.
  • hCG is a glycoprotein composed of two subunits, α and β. Increasing amounts are secreted from the syncytiotrophoblast with increased gestation in the first trimester and bind to luteinizing hormone (LH)/hCG receptors on the corpus luteum preventing it from regression.
    It is well known that early miscarriage is normally associated with low or suboptimally increasing hCG levels. The association between low hCG production and miscarriage can be interpreted in two ways: (1) the trophoblast growth may be delayed due to embryonal aneuploidy, immune or thrombophilic disturbances and low hCG production is a secondary phenomenon, or (2) the fetoplacental unit may secrete inadequate hCG due to a primary failure of the trophoblast to produce hCG, which will result in inadequate progesterone production and resulting embryonal death. Whereas the former condition in theory would not benefit from external hCG supplementation the latter condition may be treatable with external hCG or progesterone.
    If the theory that some miscarriages are due to a primary failure of the trophoblast to produce hCG, the cause could be genetic. The β subunit of hCG is coded by four closely linked duplicate chorionic gonadotropin β (CGB) genes on chromosome 19, with CGB5 and CGB8 being the most active. There is an association between levels of mRNA hCG-β transcripts in trophoblast tissue and plasma hCG levels and the levels of hCG-β mRNA seem to be lower in tissue from RM than from normal first trimester pregnancies or ectopic pregnancies. Specific polymorphisms in the promoter region of the CGB5 gene that may enhance hCG-β transcription have been found with lower prevalence in RM than in fertile couples suggesting that some miscarriages in RM couples may be caused by polymorphism in the CGB genes. Couples with such polymorphisms may be those who would benefit from hCG supplementation, but this must be tested in prospective trials.
  • Recently, evidence has been presented suggesting that epigenetic disruptions may lie behind some instances of early pregnancy loss. During implantation embryos undergo demethylation and remethylation of DNA, which is crucial to their further development and health. In a study comparing methylation in embryos from medically terminated pregnancies with those from spontaneous losses, the villi derived from embryos lost in early pregnancy were found to express lower levels of DNA methyltransferase 1, an enzyme involved in maintaining methylation.
    However, whether or not this is a causal rather than associated phenomenon with miscarriage remains to be elucidated. Numerous candidate genes associated with a small increase in the risk of early pregnancy loss have so far been described. The relative risk of miscarriage attributed to the carriage of most of these genetic polymorphisms is modest, dependent on the clinical and genetic background of the patients and screening for the polymorphisms is therefore not clinical useful.
  • Women experiencing sporadic as well as RM often have many questions regarding lifestyle factors. Although pregnant women are advised to refrain from alcohol a national Danish birth cohort study including nearly 100,000 pregnant women showed that 45% had some level of alcohol intake. Even small amounts of alcohol increased the risk of a miscarriage significantly and further, the results suggested that the risk increased in a dose-related manner. Thus, the adjusted hazard ratio for a first trimester miscarriage was 1.66 and 2.82 when having 2 to 3.5 drinks per week and >4 drinks per week, respectively. In contrast to alcohol consumption, coffee drinking in pregnancy is fully acceptable in many countries. Another Danish study has looked into the association between miscarriage and coffee intake. Only in cases where mothers were drinking more than seven cups of coffee a day could the authors demonstrate an increased risk of miscarriage (adjusted hazard ratio 1.48 (95% CI 1.01 to 2.17)).
  • Smoking-related complications in late pregnancy are substantial and well documented. In contrast, data are sparse and conflicting when it comes to smoking and miscarriage. As such, a recent review reports an increased risk of pregnancy loss among smokers whereas a large prospective study including 24,608 pregnancies could not demonstrate an association between smoking and miscarriage.
  • There are many pregnancy-related complications associated with obesity, including miscarriage. A meta-analysis from 2008 including primarily studies on infertile populations showed significantly increased miscarriage rates when women with a body mass index (BMI) ≥25 kg/m2 were compared to women with a BMI <25 kg/m2. This tendency has also been demonstrated in women with RM although it must be emphasized that a significantly increased risk of another miscarriage was demonstrated only in obese women; that is, BMI ≥30 kg/m2. Interestingly, a logistic regression analysis showed that after advanced maternal age, increased BMI was the most important risk factor in predicting another miscarriage in women with RM.
    A recent systematic review including 5 retrospective studies, 1 prospective study and a total cohort of nearly 30,000 women has investigated the relation between miscarriage rates and obesity (BMI ≥28 or 30 kg/m2) after spontaneous conception. Indeed, they also found a significant association both as regards sporadic and RM implying an urgent need for prospective studies to assess the value of reducing BMI.
  • Reproductive failure is a common complication in early pregnancy, with up to two-thirds of all fertilized oocytes not producing live births. Thus, a large number of conceptions either fail to implant or are categorized as biochemical pregnancies and clinical miscarriages. Although, the incidence of karyotypic abnormalities in the parents is low this high rate of early losses is most certainly connected to a high frequency of sporadic karyotypic abnormalities in the products of conception. In couples experiencing RM, however, a parental chromosomal anomaly is found ten times more frequently than in the background population and whether these couples should be offered PGD or await prenatal invasive diagnosis once a spontaneous pregnancy has been established is a matter under debate. Soon, sequencing of the entire fetal genome from free fetal DNA in the maternal circulation will be a standard procedure and will hopefully have the potential to increase our understanding of embryonic causes of both sporadic and RM.
    Biomarkers associated with predisposition to thrombophilia or autoimmunity can be found with increased prevalence in women with RM and affect the prognosis negatively, but it is still unclear to what extent anticoagulation and immune modulation therapies can improve pregnancy outcome in these cases. Recent studies have highlighted the importance of genetically determined differences in capacity for hCG production and in markers of sperm DNA damage.
    The emerging role of the endometrium as a biosensor of embryo quality, which may be less discerning in some women, also provides a novel mechanism underlying RM that merits further study. Sporadic miscarriage can be seen as representing nature’s quality control system, preventing embryos with severe abnormalities in most cases from progressing beyond the peri-implantation period. Should this quality control be disrupted, such embryos may be allowed to establish implantation long enough to present as clinical pregnancy before failing, resulting in recurrent clinical miscarriage. Clearly, if an embryo is of high quality, then having a less selective endometrium will not have clinical consequences, and an ongoing pregnancy may ensue. Consistent with this, most women with RM will achieve an ongoing pregnancy if they persist in trying.
    However, other concurrent medical conditions outlined in this article may prevent the ready establishment of ongoing pregnancy. Recent and ongoing research is clarifying the varying mechanisms underlying the very distressing condition of RM and offer new opportunities for developing effective interventions.

"Relationship between threatened miscarriage and gestational diabetes mellitus" (August 2018)[edit]

Hee Joong Lee, Errol Norwitz, and Banghyun Lee;

(August 2018). "Relationship between threatened miscarriage and gestational diabetes mellitus". BMC Pregnancy and Childbirth. 18 (1): 318. doi:10.1186/s12884-018-1955-2. PMC 6080503. PMID 30081861. 
  • Both threatened miscarriage and gestational diabetes mellitus (GDM) are common complications of pregnancy. However, only one pilot study has reported that these complications are not related. We aimed to investigate whether threatened miscarriage is one of the risk factors of GDM.
  • Results
    The proportion of women who experienced threatened miscarriage was significantly lower in the GDM group than in the normal group (adjusted odds ratio (OR), 0.38; 95% confidence interval (CI), 0.18–0.78). It was significantly lower in the maternal hyperglycemia group (borderline GDM and GDM groups) than in the normal group (adjusted OR, 0.66; 95% CI, 0.47–0.91). The proportion of women who experienced threatened miscarriage was also significantly lower in the GDM group than in the normal (adjusted OR, 0.35; 95% CI, 0.17–0.70) and borderline GDM groups (adjusted OR, 0.46; 95% CI, 0.22–0.94). Moreover, the proportion of women who experienced threatened miscarriage significantly decreased according to the severity of glucose intolerance (adjusted OR, 0.94; 95% CI, 0.76–1.16).
    This study demonstrates that threatened miscarriage is associated with decreased risk of GDM and the severity of glucose intolerance in Korean women. Additional studies are warranted to understand the pathophysiologic mechanisms that might exist between these frequent complications of pregnancy.
  • Threatened miscarriage, which is defined as any vaginal bleeding that occurs during the first half of a pregnancy, occurs in an estimated 14–20% of all pregnant women (14.8% in Korean women). Approximately 50% of women who experienced threatened miscarriage eventually suffer miscarriages. Bleeding that originates from the uteroplacental vessels between the chorionic membrane and the uterine wall is often considered to be the most common cause of vaginal bleeding in threatened miscarriage. Depending on the severity of bleeding, miscarriage can occur. Many studies have reported that threatened miscarriage is associated with an increased risk of adverse obstetric outcomes, such as antepartum hemorrhage, preterm delivery, cesarean delivery, preterm premature rupture of membrane (PPROM), pregnancy-induced hypertension, preeclampsia, placenta previa, and placenta abruption, and adverse perinatal outcomes, such as perinatal death, small-for-gestational-age (SGA) infants and low birth weight.
  • Progesterone is essential for establishment and maintenance of pregnancy. Low progesterone levels are associated with an increased risk of first trimester miscarriage. Recently, some studies reported that progesterone therapy during early pregnancy in women with threatened miscarriage may reduce pregnancy loss and the risk of adverse obstetric and perinatal outcomes. Insulin resistance in pregnancy normally increases during the second and third trimesters. Several studies in rats, mice, and adipocytes have reported that progesterone induces insulin resistance by multiple mechanisms during pregnancy. The use of 17-alpha hydroxyprogesterone caproate for preterm delivery prevention is associated with an increased risk of developing GDM. Therefore, we hypothesized that women with threatened miscarriage possess lower levels of progesterone throughout pregnancy than those without threatened miscarriage. As a result, women with threatened miscarriage may have less insulin resistance during the second and third trimesters of pregnancy than those without threatened miscarriage, followed by a lower risk for glucose intolerance.
  • The proportion of women who experienced threatened miscarriage was significantly lower in the GDM group than in the normal group with or without adjusting for confounding factors (adjusted odds ratio (OR), 0.38; 95% confidence interval (CI), 0.18–0.78; P = 0.009). It was also significantly lower in the maternal hyperglycemia (borderline GDM and GDM groups) group than in the normal group (adjusted OR, 0.66; 95% CI, 0.47–0.91; P = 0.013). The amount of bleeding and the number of bleeding episodes in women who experienced threatened miscarriage were not different between the groups.
    Threatened miscarriage showed significant associations among the normal, borderline GDM, and GDM groups. The proportion of women who experienced threatened miscarriage was significantly lower in the GDM group than in the normal group with or without adjusting for confounding factors (adjusted OR, 0.35; 95% CI, 0.17–0.70; P = 0.003). The proportion of women who experienced threatened miscarriage was also significantly lower in the GDM group than in the borderline GDM group with or without adjusting for confounding factors (adjusted OR, 0.46; 95% CI, 0.22–0.94; P = 0.034). Moreover, the proportion of women who experienced threatened miscarriage significantly decreased according to the severity of glucose intolerance with or without adjusting for confounding factors (adjusted OR, 0.94; 95% CI, 0.76–1.16; P < 0.001).
  • In this case-control study, we found that the women who experienced threatened miscarriage had a significantly decreased risk of GDM in current pregnancies. This finding was observed in the comparison between the normal and GDM groups, between the normal and maternal hyperglycemia (borderline GDM and GDM groups) groups, and among the normal, borderline GDM, and GDM groups. Moreover, threatened miscarriage showed an inverse correlation with the severity of glucose intolerance. Our data supported our initial hypothesis that low progesterone levels in women with threatened miscarriage might be associated with a low increase in insulin resistance during the second and third trimesters of pregnancy, followed by a low incidence of glucose intolerance. Our findings potentially aids in understanding these common complications of pregnancy. However, future prospective, large-scale studies are necessary to explore the relationship between threatened miscarriage and GDM.
    A prospective pilot study based on a small population with a very low incidence of GDM [threatened miscarriage vs normal pregnancy, 3/69 (4.3%) vs 11/564 (2.0%), respectively] reported no relationship between threatened miscarriage and GDM. By contrast, our study (normal pregnancy vs GDM with or without borderline GDM) retrospectively showed relatively lower incidences of GDM and maternal hyperglycemia (borderline GDM and GDM) in women who experienced threatened miscarriage. However, in a large-scale retrospective study involving women who received intramuscular high-dosage progesterone therapy (the total accumulated dose was ≥500 mg) due to threatened miscarriage in the second and third months of pregnancy, the incidence of GDM was slightly higher in women with threatened miscarriage [37/532 (6.95%)] than in women with normal pregnancy [1141/21,054 (5.42%)], but it was not statistically significant. In the same study, threatened miscarriage was not associated with an increased risk of adverse obstetric and perinatal outcomes, such as preterm delivery, hypertensive disorders in pregnancy, placenta previa, placenta abruption, live births, and low birth weight, compared with normal pregnancy. These findings demonstrate that the risks of common adverse obstetric and perinatal outcomes of threatened miscarriage were affected by progesterone therapy. In particular, considering the effect of progesterone therapy, we speculate that threatened miscarriage in the previous study might be associated with a low risk of GDM, which corresponded with the results of our study that showed inverse correlation between threatened miscarriage and GDM.
  • Intrauterine hematoma is detected in 18–39% of pregnant women who experience threatened miscarriage. It is associated with an increased risk of adverse obstetric outcomes, such as preterm delivery, pregnancy-induced hypertension, preeclampsia, placental abruption, and SGA, through mechanisms that are similar to those that result in threatened miscarriage. In the present study, the incidence of intrauterine hematoma (50.5%) in women with threatened miscarriage was higher than that described in previous reports. Moreover, the incidence of intrauterine hematoma decreased in women with GDM and maternal hyperglycemia (borderline GDM and GDM) compared with the normal women, in accordance with the risk of threatened miscarriage.
    The amount of vaginal bleeding during pregnancy is a subjective measurement. Consequently, distinguishing between light and heavy vaginal bleeding has not been effective. In our study, although the data did not reach statistical significance, GDM and maternal hyperglycemia (borderline GDM and GDM) occurred less frequently in women with heavy bleeding than in women with light bleeding. They also occurred less frequently in women with higher bleeding levels (≥3) than in women with lower bleeding levels (≤2), which is in accordance with the risk of threatened miscarriage.
  • In this retrospective study, we demonstrated that GDM was less frequently observed in Korean women who experienced threatened miscarriage showing inverse relationship between threatened miscarriage and the severity of glucose intolerance. Further research is recommended to confirm these relationships and to evaluate the pathophysiologic mechanisms that interplay between these common obstetric complications. We believe that these interesting findings will help improved care for women with adverse obstetric outcomes.

"Maternal recurrent pregnancy loss is associated with an increased risk for long‐term neurological morbidity in offspring" (January 1, 2019)[edit]

Paz Levy, Dorit; Wainstock, Tamar; Sheiner, Eyal; Sergienko, Ruslan; Landau, Daniella; Walfisch, Asnat (January 1, 2019). "Maternal recurrent pregnancy loss is associated with an increased risk for long‐term neurological morbidity in offspring". Developmental Medicine & Child Neurology. 61 (1): 91–97. doi:10.1111/dmcn.13976. ISSN 0012-1622. PMID 30058166. S2CID 51863388.

  • A population-based cohort analysis was performed, including all singletons born between 1991 and 2014 at a single regional tertiary centre. Neurological morbidity up to age 18 years (including cognitive, motor, and psychiatric disorders) in children born to mothers with and without a history of RPL was compared. Cumulative neurological morbidity incidence was compared with survival curves and a Weibull multivariable survival model to control for follow-up time and relevant confounders.
    A total of 242 187 deliveries met the inclusion criteria during the study period, 5% (n=12 182) of which were in mothers with RPL. Epilepsy and developmental disorders were significantly more common in the group with RPL (0.95 vs 0.74/1000 person-years [p=0.009] and 0.22 vs 0.09/1000 person-years [p<0.001]). The survival curves demonstrated significantly higher cumulative incidences of epilepsy and developmental disorders in the group with RPL. The multivariable model exhibited an independent association between maternal RPL and childhood epilepsy (adjusted hazard ratio 1.23; 95% confidence interval 1.01–1.50) and developmental disorders in the offspring (adjusted hazard ratio 2.41; 95% confidence interval 1.60–3.64).
    A history of maternal RPL appears to be independently associated with long-term neurological morbidity of the offspring.
  • Recurrent pregnancy loss (RPL), reported in 0.5% to 3% of couples trying to conceive, is now defined as two or more successive abortions before 20 weeks from the last menstrual period. In contrast to sporadic early pregnancy losses, the majority of which result from chromosomal abnormalities, RPL has a recognizable source in up to 50% of cases, other than the embryonic genetic make-up. Possible aetiologies for RPL include parental or embryonic chromosomal abnormalities, maternal background medical disorders (classically endocrine or autoimmune), congenital or acquired thrombophilias, toxic environmental exposures, and local uterine abnormalities.
    Females with a history of RPL have been found to be at an increased risk for preterm delivery and lower newborn infant Apgar scores, both are independent and established risk factors for long-term neurological morbidity in the offspring. However, some common pathological pathways raise the possibility that a history of RPL may be independently associated with neurological childhood morbidity of the offspring.
    Females with a history of RPL were found to have an increased risk for different long-term morbidities, including cardiovascular morbidities, possibly due to an inherent systemic or a genetic aberration. A proposed underlying aetiology for this association involves less endothelium-independent vasodilatation related to both RPL and other morbidities later in life. Endothelial dysfunction may cause placental hypoperfusion, leading to fetal hypoxia or placental oxidative stress and inflammation, which may result in prenatal brain injury and cerebral palsy, a sequence already reported in rats born preterm. It is therefore possible that vascular aberrations in the uterine microenvironment, not necessarily leading to an abortion, impact fetal development and neurogenesis, and potentially disrupt the long-term cognitive or motor development of offspring to mothers suffering from RPL.
    Several exposures have been shown to be associated with both maternal RPL and neurological development of the intrauterine exposed offspring. Examples include maternal environmental exposure to bisphenol A, reported to be associated with RPL, as well as with emotional disorders (depression and anxiety) learning and attention deficits, and conduct disorders during childhood. Another example involves imbalanced thyroid activity, a well-established aetiology for RPL. Thyroid malfunction was found to insult the typically developing brain cells immigration early in embryonic development. Indeed, abnormally low or high maternal free thyroxin concentrations during pregnancy was found to be associated with lower child IQ and grey matter volume. A recent example of a shared aetiology for RPL and offspring neurological development was published by our group and is related to maternal diabetes. Gestational diabetes exposure appears to be an independent risk factor for long-term neurological morbidity in the offspring and specifically to autism. Others support this association.
    These observations raise the possibility of a real and independent association between RPL and offspring neurological outcome, perhaps due to an abnormal intrauterine environment or maternal systemic illness. This association has not been previously studied. We therefore aimed, in the present study, to investigate the association between maternal background of RPL and the long-term neurological (including cognitive, motor, and mental) health of surviving children, up to the age of 18 years.
  • During the study period 242 187 deliveries met the inclusion criteria. Five per cent of the cohort (n=12 182) composed of the exposed group (mothers with RPL). The rest of the cohort (n=230 005) constituted the comparison, or ‘no RPL’, group.
    Demographic characteristics and immediate perinatal outcomes of the different groups are presented in Table 1. Pregnancies involving a history of RPL were more likely to occur in older mothers (31y and 3mo [standard deviation {SD} 5y and 9mo] vs 28y [SD 5y and 7mo]; p<0.001), with higher rates of hypertensive and diabetic disorders of pregnancy (6.4% vs 4.9% [p<0.001] and 9.4% vs 4.8% [p<0.001] respectively), and maternal hypothyroidism (1.4% vs 1%; p<0.001). Deliveries in the exposed group were more often preterm (9.8% vs 6.3%; p<0.001) and via Caesarean section (18.7% vs 13.2%; p<0.001). Rates of labour induction, sex of the offspring, and mean birthweight were comparable between the groups. Preterm deliveries occurred in 6.4% of the study population (mean 34.8wks [SD 1.8]). Of them, 1.6% occurred before 28 weeks of gestation, 14.3% between 29 to 33 weeks, and 84.2% after 34 weeks’ gestation. Very early preterm delivery was significantly more prevalent in the group with RPL (p=0.02).
    The incidence density of long-term neurological-related hospitalization in offspring, according to maternal RPL history, is shown in Table 2. Total neurological morbidity up to the age of 18 years was slightly more common among children born to mothers with RPL, but this finding did not reach statistical significance (2.26 vs 2.02/1000 person-years; HR 1.12, 95% confidence interval [CI] 0.99–1.27). However, rates of epilepsy and developmental disorders were significantly higher in the exposed group (0.95 vs 0.74/1000 person-years [HR 1.28, 95% CI 1.06–1.54] and 0.22 vs 0.09/1000 person-years [HR 2.38; 95% CI 1.59–3.55] respectively).
    The survival curves demonstrated significantly higher cumulative incidences of epilepsy and developmental disorder-related hospitalizations (Fig. 1a,b; log-rank p=0.009 and p<0.001 respectively).
    The Weibull multivariable parametric survival model of long-term epilepsy and developmental disorders in offspring (up to the age of 18y) according to maternal history of RPL is presented in Tables 3 and 4. The model adjusted for multiple confounders, including follow-up time, maternal clusters (sibling), maternal ethnicity, maternal age, maternal diabetes, gestational age at birth (as a continuous variable), mode of delivery (vaginal vs Caesarean), and a low 5-minute Apgar score. Maternal RPL exhibited an independent and significant association with the long-term risk for epilepsy and developmental disorders in the offspring with adjusted HRs of 1.23 (95% CI 1.01–1.50) and 2.41 (95% CI 1.60–3.64) respectively. When maternal age was replaced with parity in the regression model, results did not change significantly (not shown). Results remained unchanged when including preterm births only, and when adjusting for gestational age at birth (HR 1.75 [95% CI 1.07–2.86] and HR 2.82 [95% CI 1.03–7.68] respectively). Results remained unchanged using the Cox multivariable analysis (instead of the Weibull model): adjusted HR 1.24 (95% CI 1.03–1.50) for epilepsy and adjusted HR 2.29 (95% CI 1.52–3.45) for developmental disorders.
  • In this large population-based cohort study, we suggest a significant association between maternal history of RPL and later childhood and adolescent neurological morbidity in the offspring. We found an increase of 23% in epilepsy rates and over a twofold increase in developmental disorder rates in the exposed group of offspring. The association remained significant while controlling for several potential confounders in the multivariable analysis, including gestational age and low Apgar scores.
    We suspect these findings are the result of several possible explanations: (1) abnormal fetal development due to the abnormal uterine microenvironment in females with RPL; and/or (2) abnormal and potentially hereditary tendency for RPL also involved in brain function and development.
    A hint for intrauterine processes, which influence embryonic and fetal development, may be found in the placenta. Inflammatory placental lesions, such as villitis of unknown aetiology, were reported to be associated with maternal immune intolerance for fetal structures resembling host versus graft rejection pathophysiology. Villitis of unknown aetiology was found to be associated with RPL, as well as pathological fetal brain development and cerebral palsy in newborn infants. In one study, infants born at term diagnosed with neonatal encephalopathy all had placental lesions associated with villitis of unknown aetiology. The authors suggested that villitis of unknown aetiology may cause a local inflammatory response or oxidative stress during the perinatal period, which may induce white matter injury.
    Autoimmunity, strongly associated with RPL, is another possible mechanism suggesting a hostile intrauterine microenvironment. Antiphospholipid antibody syndrome is the hallmark of this phenomenon, with a well-established autoimmune pathogenesis leading to RPLs. Other autoimmune disorders, such as systemic lupus erythematous, inflammatory bowel disease, autoimmune thyroiditis, coeliac disease, and even isolated elevated autoantibodies, were also found to be associated with higher RPL rates. Adequate management, sometimes involving systemic steroids, may control abnormal immune processes and prevent losses. However, maternal autoimmunity may also play a role in the neurological development of the offspring, as evident from studies focusing on maternal systemic autoimmune diseases and offspring neurological outcome. Maternal systemic lupus erythematous was shown to be associated with a spectrum of adverse developmental outcomes, including learning disabilities. In another study, focusing on children who were diagnosed with developmental delay, maternal autoimmune disorder was 46% more common than in controls. The authors suggested that under autoimmune flare-ups, fetal brain was subjected to an oxidative stress and to the direct effects of cytokines on neural development.
  • However, it may be that shared genetics or common autoimmune pathological pathways of mother and offspring are the explanation for both RPL in the mother and neurological morbidity in the child. Autoimmunity was recently reported to have a role in childhood seizures and epilepsy. Immune reactions may be involved in seizure aetiology via autoantibodies against various central nervous system targets (involved in neuronal activation) or when various central nervous system and peripheral immune responses are activated after seizures. Increased rates of maternal diabetes in the group with RPL were evident in our cohort, as expected. These exposures were all proven to independently impact on the child's future health, and increase the risk for abnormal neurological development. Thus, it may well be that this maternal background disorder leading to RPL also results in future offspring neurological morbidity, rather than an intrinsic aberrant uterine microenvironment or another explanation. Another potential bias is the higher rates of preterm delivery among patients with RPL. Rates of cerebral palsy and abnormal neurocognitive development are well known to be inversely related to gestational age. In order to reduce the possibility that maternal morbidity or pregnancy complications were responsible for the increased rate of neurological morbidity in the offspring, a multivariable regression model adjusted for these factors and others was created. The regression model showed that maternal RPL history was independently associated with a higher risk for future neurological morbidity in the offspring.
    Notably, higher rates of low 5-minute Apgar score, known to be associated with poorer long-term neurological outcome, were significantly more common in the comparison group, and thus cannot explain the association.
    The absolute risk for epilepsy and developmental disorders in the large cohort presented is small. This might be the result of a relatively small effect, as well as due to the lack of ambulatory data on offspring. However, this may be a first signal of a possible association and is worth further investigation.
    The main limitation of our study is its retrospective nature. Such studies may only suggest an association, rather than causation. Maternal RPL may serve only as a proxy to other maternal or pregnancy characteristics related to later neurological morbidity in the offspring and our findings, if real, may be caused by a number of different pathways.
  • We thus conclude that a history of maternal RPL appears to be associated with an increased long-term risk for features of developmental disorders and childhood epileptic disorders in the offspring. These morbidities, some of which require intensive interventions within critical periods of early infancy and childhood, may have a substantial impact on long-term personal well-being, lifespan, social function, associated morbidities, and lifetime health care expenditure.
    These are preliminary findings. Prospective studies are needed to substantiate these findings and consider other causative pathways and potentially beneficial interventions.

"Polycystic ovary syndrome and metformin in pregnancy" (2006)[edit]

Anna E Lilja, Elisabeth R Mathiesen; (2006). "Polycystic ovary syndrome and metformin in pregnancy". Acta Obstetricia et Gynecologica Scandinavica. 85 (7): 861–8. doi:10.1080/00016340600780441. PMID 16817087. S2CID 42002774.

  • Polycystic ovary syndrome patients are presumably more likely than healthy women to suffer from pregnancy-related problems like early pregnancy loss, gestational diabetes mellitus and hypertensive states in pregnancy. Recent data suggest sparing effects of continued metformin therapy throughout pregnancy on early pregnancy loss and gestational diabetes mellitus, but its impact on hypertensive complications to pregnancy appears less evident. Instead, metformin might even induce pre-eclampsia or exert no effect on blood pressure. Conclusion: So far, evidence for safety of continued therapy throughout gestation is insufficient, and existing papers are limited in design and might mask for fetal toxic outcomes due to metformin therapy. Prior to a recommendation of sustained metformin therapy throughout pregnancy, randomized placebo-controlled double-blinded clinical trials are awaited with interest, so that present assumptions on efficiency can be clarified, in order to assure efficient and safe management of pregnant polycystic ovary syndrome patients.
  • In addition to poor ovulation rates in PCOS, pregnancy among these patients has been associated with complications such as early pregnancy loss, gestational diabetes mellitus (GDM) and hypertensive states in pregnancy.
  • During recent times, speculations have been made on the possible protective effects of continued metformin therapy on complications to pregnancy in PCOS, including early pregnancy loss, GDM, and hypertensive states in pregnancy. However, existing research papers are limited in design, and the evaluation of possible severe complications in pregnancy is still restricted. The purpose of this review is to cover current concepts of continued metformin therapy throughout pregnancy in PCOS, while randomized controlled trials on this topic are awaited with interest. Reference material was primarily collected by extensive search and selection on http://www.pubmed.com (Search: PCOS; metformin; pregnancy).
  • Pregnancy in PCOS has been associated with an increased risk of early pregnancy loss, GDM, pregnancy-induced hypertension, and pre-eclampsia, but evidence for this association is still somewhat controversial. Several reports suggest a protective effect of metformin on such pregnancy-related conditions, but uncertainty remains about both beneficial as well as unfavorable outcomes of continued metformin therapy throughout gestation.
  • Regardless of plausibility and biomechanics, metformin might exert a sparing effect on early pregnancy loss in PCOS, even though appropriate dose and duration of therapy have not yet been established. In studies where a higher dose was administrated, the number of live births was correspondingly higher. This could indicate that there might be a “threshold”, with respect to therapy, of around 1.5 g metformin daily, in order to witness a noteworthy effect on abortion rates. The ovulation rate, on the contrary, was identical in all studies, regardless of metformin dose and early pregnancy loss observation.
  • PCOS patients are presumably more likely than healthy women to suffer from pregnancy-related problems such as early pregnancy loss, GDM and hypertensive states in pregnancy. Recent data suggest sparing effects of continued metformin therapy throughout pregnancy on early pregnancy loss and GDM, but its impact on hypertensive complications of pregnancy are less evident. Instead, metformin might even induce pre-eclampsia or exert no effect on blood pressure.

"Mycoplasma genitalium infection and female reproductive tract disease: a meta-analysis" (August 2015)[edit]

Rebecca Lis, Ali Rowhani-Rahbar, Lisa E. Manhart (August 2015). "Mycoplasma genitalium infection and female reproductive tract disease: a meta-analysis". Clinical Infectious Diseases. 61 (3): 418–26. doi:10.1093/cid/civ312. PMID 25900174.

  • Mycoplasma genitalium infection was significantly associated with increased risk of cervicitis (pooled odds ratio [OR], 1.66 [95% confidence interval {CI}, 1.35–2.04]), pelvic inflammatory disease (pooled OR, 2.14 [95% CI, 1.31–3.49]), preterm birth (pooled OR, 1.89 [95% CI, 1.25–2.85]), and spontaneous abortion (pooled OR, 1.82 [95% CI, 1.10–3.03]). Risk of infertility was similarly elevated (pooled OR, 2.43 [95% CI, .93–6.34]). In subanalyses accounting for coinfections, all associations were stronger and statistically significant. Testing of high-risk symptomatic women for M. genitalium may be warranted.
  • After excluding duplicate citations, there were 95 potentially eligible references, 82 of which were excluded after review of title, abstract, or publication language. Four additional studies were excluded following full text review. Although 10 studies met inclusion criteria, only 9 were included in the meta-analysis; 1 study assessing ectopic pregnancy was evaluated separately. Six studies presented information on preterm birth, 3 presented data on spontaneous abortion, and 2 presented data on the association between M. genitalium and stillbirth. All adverse pregnancy outcomes were defined clinically, and only 3 studies reported adjusted effect estimates. One study used TMA to detect M. genitalium, whereas all others used PCR. Eight studies were assigned “good” quality ratings, and 2 were designated “fair”.
  • In the meta-analysis of spontaneous abortion, M. genitalium infection was significantly associated with increased risk of spontaneous abortion, with a pooled OR of 1.82 (95% CI, 1.10–3.03). There was low between-study heterogeneity (I2 = 0.0% [95% CI, .0%–82.2%]) and no significant publication bias (Begg P = .60; Egger P = .26). Only 1 study adjusted for coinfections, precluding subanalysis.
  • These meta-analyses of the published literature on the association between M. genitalium and female reproductive tract disease produced remarkably consistent findings, demonstrating an approximately 2-fold increase in risk for cervicitis, PID, spontaneous abortion, preterm birth, and infertility. With the exception of analyses of infertility, these pooled estimates were all statistically significant. Subanalyses of studies that accounted for other known pathogens demonstrated greater pooled estimates for all 5 syndromes, all of which were statistically significant, providing strong evidence of an association.
  • Preterm delivery of an infant has numerous causes, and infectious agents contribute only a small proportion. Therefore, it was remarkable that we observed a 2-fold increase in risk for preterm birth and spontaneous abortion associated with M. genitalium infection, greater than the risk associated with T. vaginalis in a recent meta-analysis (pooled relative risk, 1.42 [95% CI, 1.15–1.75]). Nevertheless, the prevalence of this organism in low-risk populations is generally low (approximately 2.0%), suggesting that universal testing of pregnant women for M. genitalium is not warranted. Screening high-risk pregnant women (eg, women with multiple partners or previous STIs) may be warranted, but further studies to determine if treating M. genitalium reduces risk for preterm birth will be required prior to instituting recommendations.
  • These meta-analyses demonstrate an approximately 2-fold increased risk of cervicitis, preterm birth, spontaneous abortion, PID, and infertility in women infected with M. gentialium, providing strong evidence in support of a causal role. The severity and high costs associated with these conditions, as well as the limitations of syndromic therapies for M. genitalium infection, suggest that targeted testing of high-risk symptomatic women may be warranted. The increasing availability of diagnostic tests for M. genitalium will make this possible.

"Leisure time physical exercise during pregnancy and the risk of miscarriage: a study within the Danish National Birth Cohort” (2007)[edit]

M Madsen, T Jorgensen, ML Jensen, M Juhl,a J Olsen, PK Andersen, A-M Nybo Andersen; "Leisure time physical exercise during pregnancy and the risk of miscarriage: a study within the Danish National Birth Cohort”, BJOG. 2007 Nov 1; 114(11): 1419-1426, (2007 Sep 18).

  • In the existing body of literature, exercise during pregnancy has generally not been associated with miscarriage, and one case-control study has even reported a protective effect of exercise during pregnancy. In contrast, Hjollund et al. found an increased risk of early miscarriage among women who reported a high physical strain around the time of implantation of the embryo.
    Furthermore, lay people have tried to use excessive physical exercise as abortificant, and older literature mentions physical activity (e.g. jumping, running, and horseback riding) as a cause of miscarriage.
    Considering the relatively sparse literature and the somewhat inconsistent results, we wanted to examine the association between exercise during pregnancy and miscarriage in a large population-based cohort.
  • The main results based on the total data material showed that an increasing amount of time spent on exercise was associated with a greater risk of miscarriage compared with nonexercisers. Exercising 1-44 minutes/week was not associated with an increased risk of miscarriage.
  • In this study based on data from nearly 93 000 women, a dose-response relation was seen for the association between amount of weekly exercise and the risk of miscarriage early in pregnancy. Certain types of exercise, and particularly high impact types of exercise, were found to be associated with a higher risk of miscarriage. In the analyses based only on prospectively collected exposure data, the association did, however, attenuate, indicating a certain degree of recall bias. An alternative explanation to recall bias may be that exercise only in the early stages of pregnancy has an adverse effect on pregnancy outcome. In this case, the difference in the HRs between the analyses based on the total data material and the subcohort of only prospectively collected data is not as much a result of the mode of data collection as a reflection of the fact that the total data material encompasses the very early miscarriages. Even within the subperiods of gestational age the miscarriages occur earlier for the pregnancies with retrospectively collected exposure information than for pregnancies with a first pregnancy interview (Figure 2). In addition, we did see a positive trend in the association between exercise and the risk of miscarriages in the earliest period of pregnancy (gestational weeks 11-14) in the subcohort using prospectively collected data only.
  • It is difficult to investigate very early miscarriages using prospectively collected exposure information, since the time period, in which collection of exposure information must take place, that is the time from detection of pregnancy to the occurrence of an early miscarriage, is short.
  • Only few previous studies have investigated the association between exercise and miscarriage. The only study, which clearly supports our findings, is a cohort study, which concluded that self-reported physical strain around the time of implantation (days 6-9 after ovulation) was associated with an in-creased risk of miscarriage (HR 2.5, 95% CI = 1.3-4.6). In contrast, Latka et al found a reduced risk of miscarriage with no chromosome defect in women who exercised compared with those who did not (OR = 0.5, 95% CI = 0.3-1.0). The case-control design was, however, based on a hypothesis that exercise cannot lead to chromosome aberrations in the fetus, as the control group consisted of women with miscarriages with chromosome aberrations. This assumption may be questioned since mode of action is unknown. In a small prospective study, Clapp found no statistically significant difference in risk of miscarriage between recreational runners (n = 49), aerobic dancers (n = 39) and a control group of active women, who had stopped exercising before the time of conception (n = 29). The study population was in excellent condition and had been exercising for years prior to the pregnancy, and the results may not be representative of the population at large. Two other studies have only investigated late miscarriages.

“Miscarriage”, Mayo Clinic[edit]

  • Miscarriage is the spontaneous loss of a pregnancy before the 20th week. About 10 to 20 percent of known pregnancies end in miscarriage. But the actual number is likely higher because many miscarriages occur very early in pregnancy — before you might even know about a pregnancy.
    The term "miscarriage" might suggest that something went wrong in the carrying of the pregnancy. But this is rarely true. Most miscarriages occur because the fetus isn't developing as expected.
  • Most miscarriages occur before the 12th week of pregnancy.
    Signs and symptoms of a miscarriage might include:
    Vaginal spotting or bleeding
    Pain or cramping in your abdomen or lower back
    Fluid or tissue passing from your vagina
  • If you have passed fetal tissue from your vagina, place it in a clean container and bring it to your health care provider's office or the hospital for analysis.
    Most women who have vaginal spotting or bleeding in the first trimester go on to have successful pregnancies.
  • Most miscarriages occur because the fetus isn't developing as expected. About 50 percent of miscarriages are associated with extra or missing chromosomes. Most often, chromosome problems result from errors that occur by chance as the embryo divides and grows — not problems inherited from the parents.
  • In a few cases, a mother's health condition might lead to miscarriage. Examples include:
    Uncontrolled diabetes
    Hormonal problems
    Uterus or cervix problems
    Thyroid disease
  • Routine activities such as these don't provoke a miscarriage:
    Exercise, including high-intensity activities such as jogging and cycling.
    Sexual intercourse.
    Working, provided you're not exposed to harmful chemicals or radiation. Talk with your doctor if you are concerned about work-related risks.
  • Various factors increase the risk of miscarriage, including:
    Age. Women older than age 35 have a higher risk of miscarriage than do younger women. At age 35, you have about a 20 percent risk. At age 40, the risk is about 40 percent. And at age 45, it's about 80 percent.
    Previous miscarriages. Women who have had two or more consecutive miscarriages are at higher risk of miscarriage.
    Chronic conditions. Women who have a chronic condition, such as uncontrolled diabetes, have a higher risk of miscarriage.
    Uterine or cervical problems. Certain uterine conditions or weak cervical tissues (incompetent cervix) might increase the risk of miscarriage.
    Smoking, alcohol and illicit drugs. Women who smoke during pregnancy have a greater risk of miscarriage than do nonsmokers. Heavy alcohol use and illicit drug use also increase the risk of miscarriage.
    Weight. Being underweight or being overweight has been linked with an increased risk of miscarriage.
    Invasive prenatal tests. Some invasive prenatal genetic tests, such as chorionic villus sampling and amniocentesis, carry a slight risk of miscarriage.
  • Some women who miscarry develop an infection in the uterus. This is also called a septic miscarriage. Signs and symptoms of this infection include:
    Lower abdominal tenderness
    Foul-smelling vaginal discharge
  • Often, there's nothing you can do to prevent a miscarriage. Simply focus on taking good care of yourself and your baby:
    Seek regular prenatal care.
    Avoid known miscarriage risk factors — such as smoking, drinking alcohol and illicit drug use.
    Take a daily multivitamin.
    Limit your caffeine intake. A recent study found that drinking more than two caffeinated beverages a day appeared to be associated with a higher risk of miscarriage.

"Organophosphate flame-retardant metabolite concentrations and pregnancy loss among women conceiving with assisted reproductive technology" (November 1, 2018)[edit]

Messerlian, Carmen; Williams, Paige L.; Mínguez-Alarcón, Lidia; Carignan, Courtney C.; Ford, Jennifer B.; Butt, Craig M.; Meeker, John D.; Stapleton, Heather M.; Souter, Irene; Hauser, Russ (November 1, 2018). "Organophosphate flame-retardant metabolite concentrations and pregnancy loss among women conceiving with assisted reproductive technology". Fertility and Sterility. 110 (6): 1137–1144.e1. doi:10.1016/j.fertnstert.2018.06.045. ISSN 0015-0282. PMID 30396558.

  • Result(s)
    Of the 179 pregnancies, 31% ended in pregnancy loss (12% in biochemical loss). Among the three metabolites with high detection frequency [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), and isopropylphenyl phenyl phosphate (ip-PPP)], an increased risk of biochemical loss was observed for women with DPHP concentrations in the fourth vs. first quartile (RR 1.64; 95% CI 0.61–4.39). Also found was an elevated risk of biochemical pregnancy loss among women in the highest quartile of the molar sum of urinary PFR metabolites compared with the lowest (RR 1.89; 95% CI 0.64–5.58). Urinary concentrations of ip-PPP and BDCIPP were not associated with either outcome.
    Among subfertile women, urinary DPHP metabolite concentrations measured during the ART cycle of conception may be associated with early pregnancy loss.
  • Pregnancy loss is the most frequent unintended perinatal outcome, affecting 31% of all conceptions. The spontaneous loss of a biochemical or clinical pregnancy contributes to reduced fecundity—the cycle probability of live birth. Although some women may be able to achieve pregnancy, they may not be able to maintain that pregnancy throughout gestation and deliver a live-born infant. Thus, such women may be considered subfecund but not technically infertile. Among subfertile women undergoing assisted reproductive technology (ART), pregnancy loss is a costly and emotional outcome. Predictors of pregnancy loss occurrence are not well established; however, environmental causes are thought to play a role.
  • Recently, concentrations of some PFR metabolites have been associated with reduced fertilization, implantation, and clinical pregnancy and live birth rates among subfertile couples. In this study we aimed to prospectively examine whether urinary concentrations of PFRs are associated with biochemical and total pregnancy loss (<20 weeks’ gestation) among women conceiving with ART.
  • Of the 179 pregnancies, 31% ended in pregnancy loss (12% were a biochemical loss). Among the three metabolites with high detection frequency (BDCIPP, DPHP, and ip-PPP), we observed a possible increased risk of biochemical loss for women with DPHP concentrations in the fourth vs. first quartile (RR 1.64; 95% CI 0.61–4.39). Although also imprecise, we found an elevated risk of biochemical pregnancy loss for women in higher quartiles of the sum of PFR metabolite concentrations (ΣPFR) compared with those in the lowest quartile: Q2, 1.61 (95% CI 0.49–5.23); Q3, 1.05 (95% CI 0.30–3.84); Q4, 1.89 (95% CI 0.64–5.58). There was also a suggestive increased risk of pregnancy loss of up to 20 weeks’ gestation in relation to higher quartiles of the sum of PFR metabolite concentrations. The BDCIPP and ip-PPP concentrations were not associated with either biochemical or total pregnancy loss.
    In our age-stratified sensitivity analysis, we observed an elevated risk of both biochemical and total pregnancy loss among younger (<35 years) compared with older women (≥35 years) in the highest quartile of the sum of PFR metabolite concentrations. Evidence of statistically significant interaction was significant for biochemical pregnancy loss (P value for interaction by age = .16) but limited for total pregnancy loss (P value for interaction by age = .51).
  • In this study of subfertile women conceiving with ART, we found suggestive evidence of an association between cycle-specific urinary concentrations of the sum of PFR metabolites and biochemical pregnancy loss. Although imprecise and nonlinear, elevated risk of biochemical loss was most apparent in the highest quartile compared with the lowest. We also observed an elevated risk of biochemical pregnancy loss for DPHP metabolite concentrations among women in the highest exposure group. Total pregnancy loss was also elevated among women in higher quartiles of sum of the urinary PFR metabolite concentrations. Overall, associations seemed more pronounced among younger compared with older women. However, our limited sample size precluded us from making more firm conclusions, and results from this study should be interpreted cautiously.
    To the best of our knowledge, this is the first study to examine biochemical pregnancy loss within a subfertile cohort of women conceiving with ART in relation to PFR exposure. In a recent prior study from our cohort, we reported that the sum of urinary PFRs was associated with reduced probability of fertilization, implantation, clinical pregnancy, and live birth. The unique nature of our study design permitted us to further examine biochemical pregnancies that were detected very early after implantation, by measuring serum β-hCG on day 17 (range, 15–20) after ET and confirming the pregnancy with a second positive β-hCG serum measurement. The present study further adds to our earlier work, suggesting that associations with reduced clinical pregnancy and live births are partially due to impaired fertilization and implantation; however, a portion of the association is likely also due a higher risk of pregnancy loss, especially very early, biochemical losses. With approximately one-third of all pregnancies ending before viability and a limited understanding of environmental causes of human pregnancy loss, the fertility treatment setting in this study offered a glimpse into the so-called “black box” of events in the postimplantation period.
  • Our results suggest a potential association between PFRs and pregnancy loss, potentially involving early stages of implantation, decidualization, placentation, or embryogenesis and possibly through uterine–embryo hormonal signaling. Although not designed to elucidate mechanisms, our findings are consistent with animal studies suggesting that PFRs affect early reproductive endpoints through disruption of regulatory pathways mediated by the hypothalamus–pituitary–gonadal axis. Studies in zebrafish report decreased hatching and survival and increased plasma E2, T, and thyroid hormone levels. Similarly, studies in chicken embryos have shown delayed hatching and endocrine disruption, including reduced thyroxine and cholesterol.
    Our study provides preliminary evidence that flame-retardant exposure may adversely impact very early reproductive processes, resulting in pregnancy failure. Early pregnancy failure is a significant and costly outcome in the fertility clinical setting, and although our results are only suggestive they may have important clinical and public health implications on a population level.
  • [T]hese findings may not be generalizable to women from the general population without fertility concerns; co-exposures to other select chemicals, such as phthalates and phenols, were also not accounted for; and exposure to PFRs may be reflective of other unknown lifestyle or fertility factors that might be associated with pregnancy loss.
  • Furthermore, in the present study, we have not considered the effect of paternal PFR exposure on pregnancy loss outcomes via DNA methylation or other epigenetic modifications of imprinted genes in male gametes.
  • In conclusion, to our knowledge this is the first study to examine PFRs in relation to pregnancy loss. Among subfertile women, urinary PFR metabolite concentrations measured during ART may be associated with pregnancy loss. Although the study setting is uniquely designed to investigate early markers of pregnancy success and maintenance, our small sample size likely contributed to imprecision. As exposure to PFRs continues to grow, given their increasing use as replacement chemicals to traditional flame retardants, more studies will be needed to investigate their potential to impact pregnancy and reproduction.

"Thinking About Another Pregnancy" (2013)[edit]

"Thinking About Another Pregnancy" (PDF). Miscarriage Association. 2013. Archived

  • Miscarriage *can be a very unhappy and frightening experience. Even some time later you may still be coping with feelings of shock and great sadness. You may also be feeling

anxious about the future – especially about trying again.

  • Should we try again?
    You may feel quite confident about trying for another baby. But you may be very anxious about having another miscarriage. Or you may be worried about whether you will manage to conceive.
    * Reasons for and against
    You may want to try again because:
    * You simply want a baby – or another baby if you already have one. Even if you didn’t plan the last pregnancy, the miscarriage may have made you realise that’s what you want
    * It seems the best way to get over the ‘empty’ feeling that is common after miscarriage
    * You feel confident that the next pregnancy will go well
    * It’s important to your partner
    * You feel it’s your last chance – if you are an older mother, for example.
    • p.2
  • You may want to put off trying again because:
    * You fear the next pregnancy will end badly too
    * You don’t think you’ll be able to cope with another miscarriage
    * You think you’re unlikely to conceive – because of age, or fertility problems or relationship issues
    * You are worried about how your

anxiety will affect another pregnancy
* You are worried about how a stressful pregnancy, and maybe another miscarriage, will affect your partner and family.

    • p.3
  • Other things to consider
    Deciding whether to try again is not always easy. Other things that might influence you include:
    * Your partner’s feelings about another pregnancy
    * What your family and friends have to say
    * What your doctor says about the risk of another miscarriage
    * Any tests and treatment you might need
    * Work and career pressures
    * Money issues, especially if fertility treatment is involved.
    You may not be ready to decide either way. But if you are not sure, it may help to read our leaflet ‘When the Trying Stops’.
    • p.3
  • When’s the best time?
    There is no right answer to this.You may want to get pregnant again as soon as possible; or you may want to wait a while, particularly if the thought of another pregnancy makes you anxious.
    You may need time to recover physically. You and your partner may both need time to come to terms with your loss and to grieve for your

Women and their partners often have mixed feelings about the next pregnancy: hope mixed with fear and excitement mixed with worry.

    • p.4
  • Now or later?
    You may want to get pregnant as soon as possible if:
    * You think another pregnancy will help you to cope with your loss and move forward
    *You want to be pregnant by the time the baby you lost would have been due
    * You have no time to waste because of age or fertility problems
    * You can’t bear not being pregnant.
    • p.4
  • You may want to wait if:
    *You don’t feel well enough yet *You are too upset or anxious to even think about another baby
    * You are still being followed up after surgery or a molar or ectopic pregnancy
    * You are still waiting for medical tests or results
    * You want to wait until after the baby you lost would have been due, or some other important date
    * You are on a waiting list for fertility treatment
    * There are practical reasons, such as your partner being away from home.
    • p.4
  • How soon can we start?
    Doctors usually advise against having sex after miscarriage until all the bleeding has stopped.This is to avoid infection.
    They often advise having at least one period before trying for another baby. This is because the first menstrual cycle after miscarriage is often much longer or shorter than usual. If you get pregnant during that cycle, it may be difficult to work out when you conceived.
    So you may think you are eight weeks pregnant, say, when a scan shows a six- week pregnancy. If you’ve already had a miscarriage that involved confusion over dates, that kind of uncertainty can be very hard to deal with.
    If you do get pregnant in that first cycle, that’s not going to make you more likely to miscarry.There is even some evidence that conceiving in the first six months after a miscarriage actually lowers your risk of miscarriage next time.
    Usually you and your partner are the best judges of how soon to try again.
    But you may be advised to wait longer if:
    *you’ve had a molar or ectopic pregnancy
    * you’ve had a late miscarriage
    * you are having tests after recurrent miscarriage.
    It can be very frustrating to have the decision about when to try again taken out of your hands.
    • p.5
  • Will it happen again?
    No one can say for sure.What we do know is that you are much more likely to have a healthy pregnancy than another loss after:
    * one or two miscarriages
    * an ectopic pregnancy
    * a molar pregnancy.

The odds are still on your side after three or even four miscarriages. But age is a factor too; and the older you are, the higher your risk of miscarriage, particularly over 40.
The risk of having another ectopic pregnancy is lower than you might expect, though being older increases the risk. But the state of your tubes is more important: if one or both are blocked or damaged, your risk may be higher.You may want to talk more about this to one of the doctors who treated you in hospital.
After a molar pregnancy you will be advised not to get pregnant until you have finished follow-up.Then your risk of a second molar pregnancy is very low. You can see your risk of another loss in percentage terms in the box opposite.

  • Your percentage risk of another pregnancy loss
    1 miscarriage 20%
    2 miscarriages 28%
    3 miscarriages 43%
    Ectopic pregnancy
    1 ectopic pregnancy 2-10%
    2 ectopic pregnancies 16-20%
    Molar pregnancy
    1 molar pregnancy under 2%
    2 molar pregnancies 17%
  • What do those numbers mean for me?
    Lots of people want to know about their percentage risk of miscarriage. But even with the numbers in front of you, it can be hard to make sense of them.You may be able to see that your risk is very low (after one molar pregnancy) or fairly high (after three miscarriages). But that won’t tell you what you really want to know: will I be okay next time – or not?
  • p.6
  • Can I reduce my risk of another miscarriage?
    There may be things you can do and we’ll explain about some of these in the next sections. But it’s important to know that however hard you try, you can’t completely rule out the chance of another miscarriage.
    It’s helpful to know the difference between a risk and a cause.Take alcohol for example: we know that regular or heavy drinking in pregnancy raises the risk of miscarriage even if you drank a lot in your last pregnancy, that doesn’t mean it caused your miscarriage.
    Even so, you might decide to cut down or stop drinking altogether next time.
    So what can I do?
    You and your partner may be able to take steps to improve your general health, diet and lifestyle.This can make a difference to your chances of getting pregnant and having a healthy pregnancy.
    We don’t know why these improvements make a difference; or why they help some people more than others. As we said earlier, there are no guarantees. But you might find the information in the next pages helpful.
    • p.7
  • Eat a healthy diet
    A well-balanced diet, including food from the four main groups below, seems to reduce the risk of miscarriage:
    * Fruit and vegetables
    - fresh or frozen is best
    – 5 portions a day if you can
    – wash fresh fruit and salad thoroughly.
  • Meat, fish, eggs, lentils, soya, tofu
    - cook meat and eggs thoroughly
    - avoid pâté and foods made with raw eggs
    - don’t eat liver more than once a week.
    *Milk, cheese or vegan alternatives
    – avoid unpasteurised milk or cheese
    – avoid mould-ripened cheese like Brie, Camembert and blue cheeses
    – cream and cottage cheeses are fine.
  • Cereal, breads and grains, including:
    – rice and pasta
    – breakfast cereals, which often have added vitamins and minerals.
  • p.8
  • Think about vitamins and minerals
    A well balanced diet should give you all the vitamins and minerals you need. But there is some evidence that a multivitamin supplement specifically designed for pregnancy can reduce the risk of miscarriage 5 and of having a baby that is small for gestational age (SGA: a baby that is smaller than it should be at that stage).
    If you are trying to conceive, or you’re in the first 12 weeks of pregnancy, it’s good to take folic acid supplements. These reduce the risk of neural tube defects like spina bifida (where the baby’s spinal cord doesn’t develop normally). Once you are pregnant they are prescribed free of charge.
    • p.8
  • Aim for a reasonable weight
    You may be slender, curvy or somewhere in between. But whatever your shape it is best to avoid:
    * being very underweight.This means having a body mass index (BMI) of less than 18.5
    * being very overweight.This means having a BMI of more than 30. You may want to talk to your doctor if you are worried about your weight, diet or appetite, or if you don’t know how to measure your BMI.Your doctor might refer you to a dietician

for advice on how to lose or gain weight safely before you get pregnant.

  • p.8
  • Cut down on alcohol, smoking and caffeine
    Research shows that even moderate drinking, smoking or caffeine consumption can increase the risk of miscarriage.The guidance below might help you reduce your risk:
  • Alcohol
    The miscarriage risk is highest for women who drink every day and/or more than 14 units per week. Heavy drinking by your partner can reduce the quantity and quality of his sperm. An occasional drink is unlikely to be harmful. But the usual advice is to stick to just one or two units a week, or stop drinking altogether before you conceive and during pregnancy.
  • Smoking
    Researchers don’t all agree about how much smoking affects the risk of miscarriage; but it is probably safest to give up in pregnancy or cut down as much as you can.This will reduce your risk of miscarriage and of having a very small baby.
  • Caffeine
    Pregnant women are advised to limit caffeine to 200mg a day – equal to about two mugs of coffee. Be aware, though, that caffeine is also found in:
    * tea
    * ‘energy drinks’ and some soft drinks
    * some medicines, such as cold and ‘flu remedies
    * chocolate – there is about 6mg in a 30g bar of milk chocolate.
    Women often go off coffee and tea in early pregnancy, especially if they are feeling sick; so cutting down may not be a problem for you.
  • p.9
  • Take care with medicine and drugs
    The general advice is to avoid all medicines and drugs unless your doctor or pharmacist says they are safe when you are trying to conceive or pregnant.
    This applies to prescribed medicines as

well as those you can buy over the counter, including herbal remedies.
If you are already taking tablets or other forms of medication, the guidance below should help when trying to conceive:

  • Treatment after miscarriage,
    such as antibiotics for infection.Wait until you have finished the course and any infection has cleared up.
  • Treatment for ectopic pregnancy.
    The usual advice is to wait three months after methotrexate treatment.
  • Short-term treatment for another illness or infection.
    It may be best to wait until you have finished the course.
  • Treatment for chronic or long-term illness,
    such as epilepsy, diabetes or depression. Talk to your GP or consultant about safety when you are trying to conceive or pregnant.You also need to know about any risks to you – and possibly your baby – from stopping treatment or reducing the dose.
  • Treatment prescribed to reduce your risk of miscarriage.
    Talk to your GP or consultant before trying to conceive.
  • Treatment bought privately, eg over the internet.
    Paying for medicine that is prescribed privately should be fine. But you should not buy medicine from other sources because you’ve heard it might reduce your risk of miscarriage; there

are risks with medicines obtained through the internet or other unofficial sources. It is best to avoid using street drugs like cannabis, heroin, crack and cocaine before and during pregnancy.Your doctor should be able to advise you and refer you on for help and support if necessary.

  • p.10
  • Treating and avoiding infection
    Some infections can increase your risk

of miscarriage or harm your baby in pregnancy; so it is worth avoiding or treatment them before you get pregnant if you can.That’s not always possible because some infections have no signs or symptoms and you only know you are infected if you have a test.
Infections that can increase the risk of miscarriage include:

  • Chlamydia
    This is a sexually transmitted infection (STI) that often has no symptoms. If there is a chance that you or your partner is infected, it is a good idea for both of you to be tested.Then you can be treated, if necessary, before you get pregnant.
    You can arrange this through your GP or by visiting your local GUM (genito-urinary medicine) clinic.Your GUM clinic can also check you for signs of other STIs.
  • Chlamydia psittaci
    This is a rare form of Chlamydia that you can catch through contact with infected sheep or cattle during lambing or calving. If possible, avoid touching these animals if you are trying to conceive or pregnant.
  • Other infections of the vagina or uterus (womb)
    If you are worried that you might have an infection you could ask to be tested. Again, these infections don’t always have symptoms.
  • Listeria
    This is caused by consuming unpasteurised cheese or milk. See page 8 for a list of what to avoid.
  • Toxoplasmosis
    You can avoid this by cooking meat thoroughly and washing fresh fruit and salad. Cats can carry this infection in their guts; so it’s best to wear gloves when cleaning out litter trays and when gardening.
  • Parvovirus
    This is a viral infection, which is sometimes called ‘slap-cheek’. Although it can cause late miscarriage, most women who are infected have a normal pregnancy.
  • p.11
  • Exercising and relaxing
    Exercise in moderation won’t do you or the baby any harm. On the plus side, it can improve your mood.
    If you need help relaxing, yoga or meditation might help; or you could try a treatment like massage or reflexology. But always tell the teacher or therapist if you are trying to conceive or already pregnant.
  • Coping with stress and anxiety
    We all feel stressed or anxious at times. And this is particularly likely when you are facing pregnancy after miscarriage.
    We can’t say whether stress on its own actually causes miscarriage. But

we do know that women under a lot of stress are more likely to miscarry; and the more stressful events they have to cope with, the higher the risk.
Work that is demanding and very stressful may also increase the risk of miscarriage, especially if the stress goes on for a long time.
On the other hand, we know that good care and support after miscarriage can increase the chances of things going well next time.That may be because your stress is reduced. You may find it helps to do one or more of the things suggested here:

  • Talk to your partner about how you are both feeling.
    You may be able to find ways to support each other before and during the next pregnancy.
  • Talk to family and friends.
    They may be able to help in practical ways or just by listening.
  • Talk to your manager or colleagues about reducing stress at work.
    This might mean changing your hours or the way you work; or it could be about arranging time off for extra GP or hospital appointments before and during the next pregnancy. Remember

that you are protected by employment law when you are pregnant (see our leaflet ‘Miscarriage and the Workplace’).

  • Talk to other people who have been through miscarriage.
    You can do this by:
    * contacting our helpline (see page 15)
    *talking to one of our telephone contacts
    * going to a support group meeting
    *joining our online support forum.
  • p.12
  • Talk to your GP about any questions and worries you have about another pregnancy. Or you could try the local early pregnancy unit, or our helpline.
  • Ask about extra care, such as an early scan.
    This is especially important after an ectopic pregnancy, to check that the baby is growing in your uterus. But early scans – or extra scans at critical times – can be reassuring after any loss.This may not be true for you if the thought of a scan makes you more anxious rather than less.
  • Thinking about another pregnancy: a summary
    It is natural and normal to feel anxious about pregnancy after miscarriage.You may be worried about trying to conceive or about what will happen if you can’t.You may feel most anxious at

the stage when you miscarried before. Or you may worry more as your due date gets closer. We hope that that the information in this leaflet will help you to feel calmer and more confident about the next pregnancy. And we wish you well for the future.

  • p.13

"Grief Issues Special to Miscarriage – the broken bond" (April 22, 2015)[edit]

"Grief Issues Special to Miscarriage – the broken bond". www.miscarriagesupport.org.nz. April 22, 2015. Archived from the original on July 4, 2017. Retrieved September 9, 2017.

  • As women, we regard our foetus’ as part of ourselves. Miscarriage is a complex grief that leaves us particularly vulnerable. Grief Issues Special to Miscarriage involve a number of other potential significant losses and additional suffering which is not necessarily present with other types of bereavement, except a stillbirth which is a similar loss occurring after 20 weeks. Not only have we lost our baby, we are suffering from the effects of both a birth and a death.
    Grief issues special to miscarriage are unique (unless someone has disappeared) in that we have very little remains to bury. This is either because no baby has formed properly or it is unfortunately passed when using the toilet. When this happens, (or even with a later miscarriage and an identifiable little body), our loss can be minimised and invalidated by others. This can lead us to question our feelings of grief. However, unrecognised or not, it is the strength of the bond with our baby not the length of the pregnancy that determines the depth of our grief. This mothering bond can have begun to form as early as us playing with our dolls as little girls, so our grief is a normal reaction to a broken bond.
  • For recurrent miscarriers, grief will usually be compounded by their previous loss/es. For those women who require ‘reproductive technology’ (IVF) to conceive, researchers at the University of Hong Kong have found they are more likely to experience trauma. The emotionally draining toll from prolonged infertility and the physically invasive conception process stretches women’s coping skills. The associated psychological issues and the uncertainty of a successful pregnancy can result in anxiety and depression. This may remain longer than for others who conceive naturally. (We think that would also depend on each individual and their life experiences and the number of losses they had experienced.)
  • A funeral normally gives people their cue of how to behave appropriately with protocols to follow. When there isn’t one, others are often at a loss themselves and may not even realise we are grieving. This adds to our stress as we can feel we need to explain this. With a still-birth or loss of a child, everyone is aware of the devastation and expects us to grieve. People may not want to talk about what has happened perhaps because of their discomfort with the issue of death, and it’s the only thing we can think of. This leaves us open to well meaning platitudes or disbelief that we are grieving.
  • Living in a world where science has overcome many things, especially in the health area. Parents-to-be can be shocked and dismayed to find that there are no straight-forward answers to miscarriage from the health professionals.
  • A miscarriage can be seen as a minor medical occurrence by health professionals and the grief that it can generate is not always understood. We have found that women heal more quickly when they experience an understanding and empathetic attitude from their medical LMC.
  • Women are born with about 2 million eggs although only about 400 of these will be released in our lifetime. Something many women are not aware of is that, the perfection of these eggs decreases with a woman’s age beginning at approximately 27. From 35 years on, the rate of decline accelerates. This leads to a higher rate of pregnancy loss and can also create problems even if the baby is carried to full term. Women can feel pressured (by themselves or others) to try again quickly, often not taking the time to allow the grief from their miscarriage to pass (3 to 6 months is a guideline). This can have consequences such as partnership stress and/or post-natal depression later following a successful pregnancy.
    Women are always looking for answers to ‘why’. Although there are reasons, they do not usually find out what they are. So miscarriage grief is not so much about finding the answer they yearn for, as learning how to live without one.

"International comparisons of fetal and neonatal mortality rates in high-income countries: should exclusion thresholds be based on birth weight or gestational age?" (2013)[edit]

Ashna D. Mohangoo, Béatrice Blondel, Mika Gissler, Petr Velebil, Alison Macfarlane, Jennifer Zeitlin, and the Euro-Peristat Scientific Committee; Linda Wright, Editor (2013). "International comparisons of fetal and neonatal mortality rates in high-income countries: should exclusion thresholds be based on birth weight or gestational age?". PLOS ONE. 8 (5): e64869. Bibcode:2013PLoSO...864869M. doi:10.1371/journal.pone.0064869. PMC 3658983. PMID 23700489.

  • Background
    Fetal and neonatal mortality rates are essential indicators of population health, but variations in recording of births and deaths at the limits of viability compromises international comparisons. The World Health Organization recommends comparing rates after exclusion of births with a birth weight less than 1000 grams, but many analyses of perinatal outcomes are based on gestational age. We compared the effects of using a 1000-gram birth weight or a 28-week gestational age threshold on reported rates of fetal and neonatal mortality in Europe.
  • Principal Findings
    For fetal mortality, rates based on gestational age were significantly higher than those based on birth weight (p<0.001), although these differences varied between countries. The use of a 1000-gram threshold included 8823 fetal deaths compared with 9535 using a 28-week threshold (difference of 712). In contrast, the choice of a cut-off made little difference for comparisons of neonatal deaths (difference of 16). Neonatal mortality rates differed minimally, by under 0.1 per 1000 in most countries (p = 0.370). Country rankings were comparable with both thresholds.
    Neonatal mortality rates were not affected by the choice of a threshold. However, the use of a 1000-gram threshold underestimated the health burden of fetal deaths. This may in part reflect the exclusion of growth restricted fetuses. In high-income countries with a good measure of gestational age, using a 28-week threshold may provide additional valuable information about fetal deaths occurring in the third trimester.
  • There is an ongoing debate about the value of international comparisons of fetal and neonatal mortality rates, given differences between countries in recording of births and deaths at borderline viability. Fetal and neonatal mortality rates are highly sensitive to these inclusion criteria. Differences in recording criteria are most acute for fetal deaths. These deaths are recorded from as early as 16 completed weeks of gestation in Norway or 20 completed weeks in the United States to 26 completed weeks in Italy and Spain. Denmark and Sweden recorded fetal deaths beginning at 28 completed weeks until 2004 and 2008, respectively. While only a small proportion of births occur before 24 completed weeks of gestation (about 1 per 1000), survival is rare and most of them are either fetal deaths or live births followed by a neonatal death. These births have a substantial impact on perinatal mortality statistics. Valid analyses of fetal and neonatal mortality across countries thus require specifying common inclusion limits. These criteria are based either on gestational age, or on birth weight or on a combination of these.
    The World Health Organization (WHO) recommends the use of a 1000-gram threshold for international comparisons of perinatal mortality rates. This limit makes it possible to provide a measure of the health burden of third trimester perinatal deaths, since 1000 grams corresponds approximately to the birth weight at 28 completed weeks of gestation, the beginning of the third trimester. This measure provides only a partial view of overall mortality, since a large proportion of deaths in high-income countries (between 25–60%) occur to babies born in the second trimester, but using this threshold has the benefit of enabling greater comparability between countries. Participants in a recent international collaboration on stillbirths agreed that an analysis of third trimester deaths has public health relevance for international comparisons in high-income countries.
    The aim in international comparisons is to maximise both comparability and scientific and policy relevance. The primary aim of using a birth weight threshold for international comparisons is to ensure comparability because birth weight measures are considered to be less prone to error than calculations of gestational age. When the date of the last menstrual period (LMP) is used alone to calculate gestational age, the results can be inaccurate, especially if the woman has no antenatal care or if antenatal care starts late in pregnancy. However, most high-income countries use a clinical estimate of gestational age that incorporates information from dating ultrasounds and is therefore of better quality. Birth weight data also have limitations since babies who are stillborn or die before they can be transferred to a neonatal unit may not be systematically weighed.
    Gestational age is generally considered to be a more relevant variable than birth weight for studying perinatal outcomes. Recent European cohorts have analysed the outcome for very preterm rather than very low birth weight babies, as gestational age has a better prognostic value. Furthermore, when obstetricians are making decisions during pregnancy, they have reasonably precise information about gestational age but not about birth weight. Finally, birth weight distributions differ between and within populations and European comparisons have found that the birth weight at which mortality is lowest varies between European countries. Using birth weight cut-offs will exclude relatively more births and deaths in countries where average birth weights are lower and this may introduce bias.
    While the hypothesis underlying the current WHO recommendation is that the 1000-gram threshold provides a good approximation for the 28th week of gestation or the beginning of the third trimester, this hypothesis has not been tested. The aim of this analysis was therefore to compare the use of a 1000-gram birth weight threshold with a 28-week gestational age threshold in terms of their impact on reporting of fetal and neonatal mortality rates within European countries and on comparisons between European countries.
  • Most countries had fewer than 5% of data missing for fetal and neonatal deaths by birth weight and gestational age, as presented in Table S2. However, there were some exceptions. The percentages of fetal deaths with birth weights missing were 30.7% in Denmark, 25.0% in Italy, 22.7% in Brussels, 13.9% in Valencia, 6.4% in Portugal, 5.9% in Luxembourg, and 5.1% in France. Gestational age was missing for 17.0% of fetal deaths in Brussels, 11.7% in Valencia and 9.5% in Portugal. We excluded countries where the proportion of fetal deaths with missing birth weight was significantly different from the proportion with missing gestational age. These were Denmark (30.7% of birth weights vs. 4.2% of gestational ages) and Italy (25.0% of birth weights and 0% for gestational age). These divergent proportions of missing data would have biased our ability to compare rates.
    For neonatal deaths, fewer countries had high proportions of data missing. Over 5% of birth weights were missing for Denmark (14.8%), Luxembourg (9.1%), Sweden (7.1%), Scotland (6.8%), and Valencia (5.8%). Gestational ages were missing for over 5% in Luxembourg (9.1%), Denmark (7.0%), Portugal (6.8%), and Valencia (6.8%). As with fetal deaths, we excluded countries with highly divergent proportions of missing birth weights and gestational ages. We therefore excluded Denmark (14.8% of birth weights vs. 7.0% of gestational ages) and Sweden (7.1% of birth weights and 0% for gestational age). Live birth data were missing for less than 5% with the exception of Brussels and Valencia where 6.3% and 5.5% of gestational ages were missing respectively.
    For countries included in the analyses, we excluded missing data from our primary analyses as this would reflect the reality if these cut-offs were used, but we also did a second set of analyses with missing data distributed according to observed birth weight and gestational age distributions for live births, and fetal and neonatal deaths separately.
  • Except for the Czech Republic (0.16‰) and Estonia (0.21‰), where rates were 0.2 per 1000 higher with a birth weight cut-off, most countries had higher rates of fetal deaths when a gestational age cut-off was used, as illustrated in Figure 1. For seven out of 25 countries/regions, the two rates were very similar with minimal differences of 0.1 per 1000 or less. The widest differences were 0.8 per 1000 in Brussels (0.82‰) and France (0.76‰). At an individual country level, differences between fetal mortality rates based on gestational age and those based on birth weight were not significantly different from zero, except in the Netherlands where the difference was 0.50 per 1000 with 95% confidence interval 0.09–0.91 (p = 0.018) and England and Wales where the rate difference was 0.45 per 1000 with 95% confidence interval 0.23–0.66 (p<0.001). In contrast, differences between neonatal mortality rates were minimal, with 15 out of 21 countries/regions having differences between −0.1 and +0.1 per 1000. Rates calculated with a gestational age cut-off were not significantly higher or lower than those with a birth weight cut-off, although in Latvia (−0.35‰), Brussels (+0.27‰) and Malta (+0.25‰) differences were 0.25 per 1000 or more.
    Differences between countries in fetal mortality rates based on gestational age compared with those based on birth weight were significant (p<0.001 for Wilcoxon signed rank test). The corresponding neonatal mortality rates did not differ significantly between countries (p = 0.370), however twelve countries had a positive difference while eight had a negative and there was one tie. In total, 8823 fetal deaths were included when a 1000-gram threshold was used compared with 9535 with a 28-week threshold, a difference of 712 fetal deaths (7.5% of all fetal deaths). In contrast, the difference in neonatal deaths was minimal, 4710 using a 1000-gram threshold versus 4726 using a 28-week threshold (a difference of 16).
    Results did not change when the observed birth weight and gestational age distributions for fetal and neonatal deaths and live births were used to include births and deaths with missing birth weights and gestational ages in the analyses. Fetal mortality rates based on gestational age were still significantly higher than those based on birth weight (p = 0.002); while the choice of a cut-off made no difference for comparisons of neonatal mortality rates (p = 0.380).
    Fetal and neonatal mortality rates computed using a birth weight threshold were highly correlated with rates computed using a gestational age threshold, with Spearman rank correlations of ρ = 0.952 (p<0.001, n = 25) for fetal mortality and ρ = 0.963 (p<0.001, n = 21) for neonatal mortality. Country rankings were therefore similar with a few exceptions such as Brussels which ranked sixth for birth weight and thirteenth for gestational age. Even for the Netherlands and England and Wales, where differences in fetal mortality rates calculated using the two definitions were significantly different, their ranks only differed by two places (19 and 18 out of 25 for birth weight to 21 and 20 out of 25 for gestational age, respectively (data not shown in table).
  • Our analysis showed that fetal mortality rates in European countries were higher when based on a 28-week gestational age threshold compared with a 1000-gram birth weight threshold, whereas the choice of a threshold made little difference for neonatal mortality rates. These results suggest that a substantial proportion of fetal deaths occurring at or after 28 weeks of gestation have a birth weight under 1000-grams. Despite this difference, however, the selection of a cut-off did not change countries’ relative positions. The small differences between neonatal mortality rates calculated using birth weight and gestational age cut-offs and the similarity in rankings suggest that differences in average birth weight between populations do not create a bias when rates are computed using a birth weight cut-off.
  • Finally, while the Euro-Peristat project requests data based on the best obstetric estimate of gestational age in weeks from clinical records, it was not possible to evaluate differences in the ways in which participating countries actually measure gestational age. In most European countries, however, dating ultrasounds are a standard component of care during pregnancy and most women have their first antenatal visit in the first trimester.
    Using a birth weight cut-off of 1000 grams resulted in 712 fewer fetal deaths overall compared with using a cut-off of 28 completed weeks of gestation leading to systematically lower fetal death rates. A previous review also suggested that stillbirth rates were higher using gestational age limits based on Norwegian data showing that a 500 grams cut-off point excluded more stillbirths than a 22 week cut-off point; neonatal deaths were not included in this study. By comparing neonatal deaths with fetal deaths, our results show that this effect specifically relates to stillbirths and does not reflect the gestational age and birth weight distribution of all births.
    There are several possible explanations for this finding. First, using a birth weight cut-off may exclude growth restricted fetuses. As concluded by a recent review of stillbirths in high-income countries, small for gestational age is the pregnancy condition with the highest population attributable risk (measured at one out of four for stillbirths). Fetal growth restriction is a particularly important risk factor for antepartum deaths, which constitute over 80% of fetal deaths in high-income countries. Second, fetal weight loss after antepartum death may also contribute to lower birth weights, although the extent of this phenomenon is still unknown.
  • In the European countries included in our analysis, fetal mortality rates calculated using a threshold of 28 weeks of gestation were higher than those based on birth weight cut-offs of 1000 grams, probably due in part to the role of intra-uterine growth restriction in antepartum fetal deaths. Assessing the health burden of third trimester fetal deaths using a cut-off based on gestational age provides valuable additional information. Comparisons based on this cut-off are possible in countries where a clinical estimate of gestational age is recorded in routine data sources and where women have access to early antenatal care and dating ultrasound as is the case in European and other high-income countries.

“Can sex during pregnancy cause a miscarriage? A concise history of not knowing” (2012)[edit]

Andrew Moscrop, “Can sex during pregnancy cause a miscarriage? A concise history of not knowing”, Br J Gen Pract. 2012 Apr; 62(597): e308–e310.

  • What do we tell pregnant women who want to know whether sex could cause them to miscarry? How do we counsel women who wonder whether having sex might have caused their miscarriage?
    Sexual intercourse is acknowledged to be one (neither necessary nor sufficient) cause of pregnancy, but can coitus cause pregnancy loss? Our professional response has been prudish, paternalistic, and fearful of women's sexuality, but it has never provided a satisfactory answer.
  • In 1980, authors of the 13th edition of the seminal Gynaecology by Ten Teachers textbook were certain: ‘coitus’ was listed among the causes of early pregnancy loss (‘spontaneous abortion’ as it was then termed). In the management of ‘threatened abortion’, they asserted that ‘intercourse is forbidden’. Similarly for ‘habitual abortion’: ‘coitus is forbidden’. A decade later, in 1990, the 15th edition of that same text (its team of 10 contributing teachers slightly altered, but still exclusively male) demonstrated a partial retreat from its earlier hardline view on sex in pregnancy:
    ‘… coitus has no effect in a normal pregnancy, but it is unwise in the case of a woman with a history of abortion in a previous pregnancy’.
    The recommended management for threatened abortion reiterated previous advice regarding the forbiddance of intercourse. For ‘recurrent abortion’ it was professed that ‘in the absence of specific treatment, good results can be obtained by rest, avoidance of intercourse, and encouragement by the doctor’. Assertion of the physician's authority is a subtext. Today's 19th edition of the Ten Teachers textbook contains no mention of sex being ‘forbidden’ (or of the less obviously authoritarian ‘avoidance of intercourse’) in the context of early pregnancy loss. There is, indeed, no mention of sexual activity during pregnancy at all.
  • The retreating, then deleting, of medical judgements on the subject of sexual activity and pregnancy loss is evident in journal articles also. In 1991, the BMJ published a clinical review of ‘vaginal bleeding in early pregnancy’ which advised that ‘avoidance of sexual intercourse is probably sensible as it might act as a local stimulus’. The two review articles addressing this same subject published in the BMJ within the past decade make no reference to sexual activity.
  • ‘Will having sex during pregnancy harm my baby?’ asks the NHS Choices website. ‘You may be advised not to have sex at certain stages of pregnancy if you have a history of miscarriage.’ The website suggests ‘you should speak to your doctor or midwife …’.
  • Searching PubMed, the online database of biomedical literature, using combinations of terms used to describe early pregnancy loss (‘miscarriage’, ‘spontaneous abortion’) and sexual intercourse (‘coitus’, ‘sex’, ‘intercourse’, ‘sexual intercourse’, ‘sexual activity’) finds no studies of the effect of sexual intercourse on early pregnancy outcomes.
    In 2005, one author, discussing the absence of evidence relating to sexual intercourse and miscarriage, could still quote Sheila Kitzinger's Woman's Experience of Sex, published 20 years earlier in 1985: ‘Kitzinger states that “no studies have been done to show whether not having sexual intercourse in early pregnancy helps to avoid miscarriage …”.’In the two intervening decades there had been no new studies on the subject and no new knowledge.
    A 2007 review of ‘non-surgical interventions’ for the prevention of miscarriage confirmed the situation: ‘no study has been done on the effect of sexual intercourse on first trimester miscarriages specifically’. The authors state: ‘more data is required to determine whether sexual intercourse has a negative impact on first trimester miscarriages. Till then, most doctors recommend that women with bleeding in pregnancy to refrain from sexual activity while permitting those without pain or bleeding in pregnancy to continue with coitus’.
    In an article published in Pulse during 2009, the unevidenced advising described above is given an explicitly paternalistic rationale:
    ‘There is no evidence that sexual intercourse causes miscarriage. But it can be pragmatic to advise women with threatened miscarriage to avoid intercourse until after the bleeding has completely resolved so, if miscarriage does occur, the couple does not feel that they may have triggered or exacerbated events.’
  • A gross discrepancy is apparent between the dearth of useful evidence and the potential significance of evidence-based knowledge in this area. A Canadian study found almost half of its 141 pregnant participants worried that sexual intercourse might harm their pregnancy. A Malaysian study found that almost three-quarters of pregnant women avoided sex at least some of the time, and for most women this was due to concerns about harm to the baby or risk of pregnancy loss. A Nigerian study found a correlation between beliefs that intercourse could cause miscarriage, reduced frequency of intercourse, and increased likelihood of husbands having extra-marital sexual relations while their wife was pregnant; the authors reported:
    ‘Approximately one-third of husbands engage in extra-marital relationships as a way to satisfy their unmet sexual need during pregnancy.’
    ‘In the UK women with bleeding in early pregnancy are likely to consult their GPs before any other health professionals. For this reason research into threatened miscarriage is most appropriately conducted in general practice.’
    This statement, made in an article that examined general practice management of threatened miscarriage 25 years ago, remains true today. The authors found that ‘two-thirds of the practitioners advised [sexual] abstinence’ and concluded that among GPs there is ‘considerable collective uncertainty about the management of this common complication of pregnancy’. That 25 years later research should still be absent (research that could be ‘most appropriately conducted in general practice’) and doctors should still be unable to satisfactorily answer questions about sex and miscarriage on account of the absence of research is clearly problematic in the context of pre-emptive advising and, equally significantly, retrospective counselling of women and their partners. These important questions remain inadequately addressed by researchers and clinicians, despite being potentially answerable.
  • Past efforts and advice to prohibit sex during pregnancy were clearly not based on evidence, but on (mostly male) doctors' presumptions about female bodies and how they should behave. Persisting prejudice and prudishness may still be visible in the directions of recent research efforts that incline towards biological (anti-phospholipid syndrome, hypertension), or less provocative lifestyle (smoking, caffeine consumption) risk factors for pregnancy loss, rather than the effects of behaviours that include sexual activity.
  • The overall underrepresentation of early pregnancy loss in the research agenda appears distinctly at odds with, and indeed may suggest the hollowness of, concepts of the fetus' “right to life”: if such rights exist they might be better protected by increased knowledge of the causes and prevention of early pregnancy loss than by increased restrictions on pregnancy termination, for instance. However, the underrepresentation of early pregnancy loss in medical research is not at all at odds with, and indeed is wholly consistent with, an undervaluing of women's experiences and concerns within the medical world. This undervaluing becomes apparent in our consultations when we acknowledge that without any medical certainties to offer, advice delivered by doctors about preventing early pregnancy loss can be little more than superstition; and any counselling post-loss can be little more than supposition. In this context, our “professional opinions” and paternalistic endeavours to reassure, being base-less and backed by no superior knowledge, appear patronising and serve only to substantiate our professional authority while disempowering our patients.
    “Can sex during pregnancy cause a miscarriage?” Before answering this question we need first to confront our muddled and inhibited thinking about sexuality; to begin considering the patients' agendas and the issues that are important to them in the construction of an evidence base; and to reassess the undervaluing of women and women's health issues, specifically early pregnancy loss, in the research agenda.

"'Miscarriage or abortion?' Understanding the medical language of pregnancy loss in Britain; a historical perspective" (December 2013)[edit]

Moscrop A (December 1, 2013). [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841747/ "'Miscarriage or abortion?' Understanding the medical language of pregnancy loss in Britain; a historical perspective". Medical Humanities. 39 (2): 98–104. doi:10.1136/medhum-2012-010284. PMC 3841747. PMID 23429567.

  • Clinical language applied to early pregnancy loss changed in late twentieth century Britain when doctors consciously began using the term ‘miscarriage’ instead of ‘abortion’ to refer to this subject. Medical professionals at the time and since have claimed this change as an intuitive empathic response to women's experiences. However, a reading of medical journals and textbooks from the era reveals how the change in clinical language reflected legal, technological, professional and social developments. The shift in language is better understood in the context of these historical developments, rather than as the consequence of more empathic medical care for women who experience miscarriage.
  • ‘It is curious’, began a letter to the Lancet published in 1985, ‘that, in a language as descriptively rich as English, no clear distinction is made between a spontaneous and an induced expulsion of the contents of the uterus in early pregnancy.’ The communication, printed under the heading ‘Miscarriage or Abortion?’, came from a group at St Mary's Hospital London led by Richard Beard, then Professor of Obstetrics and Gynaecology. It continued: ‘Doctors use the word ‘abortion’ regardless of whether it was a spontaneous or induced event, yet our patients always speak of 'miscarriages’ unless they have had a termination of pregnancy. It seems likely that the words have been interchangeable for many centuries...’ Beard et al described the offence caused to those women who miscarry ‘by the use of the word abortion to describe their condition’. They appealed to doctors and all health professionals ‘to start using the word miscarriage rather than abortion for a spontaneous pregnancy loss before 28 weeks of pregnancy.’
    Seven years later psychologist Beverly Chalmers asserted that ‘publications in the British Journal of Obstetrics and Gynaecology have taken heed’. She observed ‘a change in terminology used before and after the editorial (sic) by Beard et al’. In a 1997 British Medical Journal (BMJ) editorial Emeritus Professor of Obstetrics Geoffrey Chamberlain also credited Richard Beard with moving clinicians towards a more empathetic practice.
  • If the terms ‘miscarriage’ and ‘abortion’ had, among doctors, been ‘interchangeable for many centuries’ as Beard and his colleagues suggested, why did they call for change in 1985? Did medical language change subsequently? If so, why? What factors, other than Beard's Lancet letter, might explain a change in the medical language of early pregnancy loss?
  • In 1992, Beverly Chalmers perceived the impact of Beard's ‘Miscarriage or Abortion?’ Lancet letter upon papers published in the British Journal of Obstetrics and Gynaecology. She had reviewed the titles of articles on the subject of early pregnancy loss at the beginning and end of the 1980s and found that ‘whereas almost all the papers at the start of the decade used the term ‘abortion’ in their titles, none of those published later did so.’
    This trend can be analysed in greater detail. The graph in figure 1 plots the annual incidence of articles published on the subject of early pregnancy loss in the British Journal of Obstetrics and Gynaecology from 1975 to 1999; it differentiates between those using ‘abortion’ and ‘miscarriage’ in their titles. Around 1986, a definitive flip occurred in the titles of articles referring to early pregnancy loss: from the exclusive use of ‘abortion’ to ‘miscarriage’ as the descriptor.
    Meanwhile, in the BMJ, use of ‘abortion’ or ‘spontaneous abortion’ in article titles referring to early pregnancy loss declined slowly between 1985 and 1995 (See figure 2): thereafter ‘miscarriage’ is always employed.
    In the Lancet a shift in the terminology of early pregnancy loss is less obvious, but a divergence between the incidences of ‘abortion’ and ‘miscarriage’ becomes apparent after 1985 (see figure 3).
    In the BMJ and Lancet, the gradual change in published article titles suggests a gradual shift in terminology used by contributors, rather than deliberate editorial policy on the part of the journals. Closer inspection of published articles supports this conclusion of variable and slow-changing use of terms among doctors. In 1987, a paper on management of threatened miscarriage published in the BMJ consistently uses the term ‘miscarriage’ throughout; yet while some correspondents responding to the article used only ‘miscarriage’ in their letters, others used the term ‘abortion’ exclusively. Similarly, in 1991 the BMJ published an editorial titled ‘Recurrent miscarriage’ to which two correspondents responded: one letter headed ‘Recurrent miscarriage’; the other, ‘Recurrent abortion’.
  • Medical journals in fact appear slow to have acknowledged the changing use of language by their readers: ‘Miscarriage’ appears for the first time in the index of the BMJ in 1978, and until 1999 readers looking under ‘M’ were advised ‘Miscarriage—see abortion’. In the indices of the Lancet, ‘miscarriage’ only appears after 1988 and readers were referred to ‘abortion’ until 1994.
    As late as 1995, the Ten Teachers (who by then numbered two women alongside eight male contributors), in the 16th edition of their Gynaecology text, continued, as in earlier editions, to refer to early pregnancy loss as ‘abortion’. They began the chapter on this subject by asserting ‘the terms abortion and miscarriage are synonymous’. They continued to use the terms interchangeably in their text, but conceded ‘generally miscarriage carries connotations of spontaneous loss and is best used when talking to women’.
  • Before the 1967 Abortion Act eased legal impediments to ending an unwanted pregnancy, the distinction between ‘spontaneous’ and ‘induced’ abortion alluded to in medical journals and textbooks of the time remained academic.
    Although many abortions were carried out illegally, women who developed problems afterwards would rarely disclose their procedure for fear of criminalising themselves. Instead, they might claim to have had a ‘spontaneous’ abortion (miscarriage). Meanwhile, clinicians would not normally have been able to distinguish between ‘spontaneous’ and ‘induced’ abortions, despite their recognition that many cases of early pregnancy bleeding (particularly instances of ‘septic abortion’, in which pregnancy loss was complicated by infection) were accounted for by ill-managed illegal abortion attempts.
  • In 1961 an article in the BMJ observed that:
    It is notoriously difficult to obtain reliable histories from patients suffering from septic abortion, and it is often suspected that criminal interference, which the patient will not acknowledge, has taken place. <r> A 1964 BMJ article on the subject of ‘bleeding in early pregnancy’ spoke of ‘criminal interference’ that ‘such interference is so often denied, even when it is obvious, that many doctors do not inquire about the possibility.’
    Textbooks of the era exhibit similar suspicions. In 1966, the year before the Abortion Act was passed, the 11th edition of Obstetrics by Ten Teachers advised doctors on how they might discern an induced abortion when, presumably, it was not admitted by the patient: ‘the presence of abrasions or lacerations in the genital tract... strongly suggests criminal interference.’ Nonetheless, ‘criminal abortion’ was listed alongside other presumptive, but apparently indeterminable, ‘causes of abortion’ that were ‘to a certain extent, theoretical and arbitrary’. These included: ‘reflex stimulation of the uterus by emotional disturbances’ and ‘coitus during the first 3 months of pregnancy’.
    Before 1967, statutes relating to pregnancy termination prevented doctors discerning abortions that were ‘induced’ from those that were ‘spontaneous’. Distinction between ‘abortion’ and ‘miscarriage’ was impossible in clinical practice and meaningless in clinical language.
  • The ‘clinical varieties of abortion’ had long been distinguished and systematised in medical textbooks. With the aid of illustrative line drawings and monochrome photographs of pathological specimens, consecutive editions of the Ten Teachers’ texts had elaborated an inventory of: threatened, inevitable, complete, incomplete, septic, missed and habitual abortions.
    Since they were first described, the difficulty of distinguishing these clinical varieties in practice had remained unchanged. Before ultrasound technologies permitted clinicians to look inside the wombs of women experiencing pain or bleeding in early pregnancy, it was impossible to discern the varieties of abortion and distinguish these from a potentially life threatening ‘tubal’ (ectopic) pregnancy. Often the only effective diagnostic method was hospital admission and a prolonged period of observation. The pathological specimens featured in textbooks of this era attested to an impasse: until the uterus expelled its content, or emergency surgery was carried out, or the mother died, it might be impossible to discern the cause of bleeding occurring in early pregnancy. Ultimate diagnostic knowledge was as likely to be obtained by the hospital pathologist as by the clinician.
  • Evidence produced in the mid-1970s had endorsed ‘the diagnosis of early pregnancy failure by sonar’ and demonstrated the benefits of this technique over the traditional methods of urinary hormone assays and clinical judgement. The early years of the 1980s saw elaboration of understanding of ultrasound's value in the specific context of early pregnancy problems along with growing acknowledgement of its routine potential in early pregnancy.
    Demonstrating the timely relevance of ultrasound to understanding of ‘spontaneous abortion’ and the speed of developments around this time, in 1984 a Canadian research group claimed ‘the second report on the frequency of spontaneous abortions in ultrasound-assessed intact pregnancies’ just 6 weeks after a Dutch group had claimed the ‘first report’ of this subject.
    In 1980, the 13th edition of Gynaecology by Ten Teachers gave ultrasound only a limited place in the assessment of early pregnancy bleeding (‘threatened abortion’). A single sentence alluded to the role of the unfamiliar-sounding technology: ‘After the 12th week the ultrasonarscope (e.g. Sonicaid) may be used to determine whether the fetus is alive.’ Five years later, in the 14th edition of that textbook, the single sentence on the use of ultrasound in threatened abortion had expanded to become a paragraph that sounded very much more enthused:
    As soon as the initial bleeding has stopped an ultrasonic scan is performed. This will reveal whether or not the pregnancy is intact...
    ...With a high resolution real time mechanical sector scanner cardiac activity can consistently be recognised at 8 weeks.
  • During the early 1980s, developments in relation to ultrasound technology and its application in the context of early pregnancy problems changed clinical practice. By the middle of the decade, a survey of general practitioners’ management of bleeding in early pregnancy found that ‘the patient was sent to hospital for ultrasound examination as an outpatient by 1045 (81%) respondents’. In 1990, the 15th edition of the Ten Teachers text reflected that:
    The management of patients with bleeding early pregnancy has been enormously simplified by ultrasound. Prior to ultrasound, patients with a missed abortion often spent many days in hospital until it became clinically clear that the pregnancy had ended.
  • Richard Beard's 1985 ‘miscarriage or abortion?’ Lancet letter attests to the potential impact of ultrasound technology upon medical terminology, and to the application of technologically determined medical language to women's experiences:
    ‘Intrauterine death at x weeks’ is really a more satisfactory way of accurately describing what has happened and is appropriate now that ultrasound can distinguish between the blighted ovum and a fetus that has developed but died.
    Accurate descriptions and conformity in language would become a feature of new technology-derived medical knowledge and physicians’ new diagnostic authority.
  • By the 1980s, thanks to legal and technical developments, early pregnancy loss could increasingly be diagnosed by doctors.
    However, it remained ambiguously designated: ‘abortion’ was often used in the medical literature without a clarifying prefix (‘spontaneous’ or ‘induced’) to describe spontaneous pregnancy loss, induced termination of pregnancy or (deliberately exploiting the dual meaning of the term) both.
    Early pregnancy loss also remained ambiguously positioned: it had not yet been claimed by a specialist group. Research on the subject frequently appeared in the general medical journals and was carried out by a wide range of contributors (including paediatricians, medical geneticists, psychiatrists, epidemiologists, general physicians and haematologists). In 1980, the chapter on ‘Abortion’ (miscarriage) appeared for the last time in the 13th edition of Obstetrics by Ten Teachers and materialised for the first time in the 13th edition of their Gynaecology text. Early pregnancy loss did not gain a home in a specialist niche until the growth of perinatology.
  • When the 2nd edition of Beard's Fetal Medicine textbook appeared it had expanded by over 50%: from 542 pages in 1976 to 823 pages in 1984. With regard to ‘spontaneous abortion’, the 1976 1st edition referred only to the possible causative role of immunological factors; in 1984, the 2nd edition text referred in seven separate entries to the potential significance of a variety of hormones, immunological and infective agents. The growing knowledge base of perinatology was addressing the problems of early pregnancy.
  • Richard Beard's acknowledgement of women's emotional reactions to miscarriage and of the distress caused by the medical terminology of ‘spontaneous abortion’ suggests the influence of contemporaneous non-medical developments. Although miscarriage and the upset that it could cause women might have posed difficulties to feminists on account of its resonance with antiabortionist argument, some notable advocates sought to encourage a more woman-centred approach among health professionals.
    The Miscarriage Association had been established in 1982 to offer information and support to women affected by pregnancy loss. Richard Beard acknowledged in his Lancet letter that ‘the Miscarriage Association found that 85% of women who have had a miscarriage felt strongly that the word abortion should be changed’.
  • In 1984, sociologists Ann Oakley and Helen Roberts along with general practitioner Ann McPherson had published Miscarriage: the ‘first British book of its kind on the subject’. Writing for ‘women having miscarriages and those providing care for them’, they sought to address ‘the surprising lack of information that there is, especially in the areas of women's emotional reactions to miscarriage, and with respect to what is considered appropriate treatment by the professionals’. Early in the book the point about terminology (‘miscarriage’ preferred to ‘abortion’) was made emphatically and emotively. Richard Beard in his Lancet letter makes no reference to Oakley, McPherson and Roberts, but their analysis of the issue is echoed distinctly in his.
  • The early 1980s were a dynamic period for feminist politics. The high-profile and widely-reported case of Wendy Savage in 1985 prompted consideration within the medical profession of the role of women as doctors and as pregnant patients. A comprehensive BMJ write-up of the Savage case in June 1985 described ‘a battle between the high tech, interventionist, hospital based school of obstetric practice and the community based, woman centred approach’ of Savage. It was a battle undoubtedly won by the woman-centred approach. Richard Beard would align with that approach a few months later when he acknowledged that ‘our patients always speak of 'miscarriages’ and called for ‘all health professionals, to start using the word miscarriage rather than abortion.’
  • The conscious distinction by doctors of ‘miscarriage’ from ‘abortion’ (‘induced’ and ‘spontaneous’) may be seen to have reflected certain legal, technical, professional and societal developments. The distinction in language may also be read as part of the process of assigning meaning to those women to whom the language was applied, a process by which women who experience miscarriage could be defined as distinct from women who experience an induced abortion. Future work should elaborate these meanings, but some initial impressions are offered below.
    Political implications of Beard's ‘Miscarriage or abortion?’ letter became apparent only a fortnight after its publication when the Lancet printed a response from Caroline Woodroffe, then General Secretary of the Brook Advisory Centres. Woodroffe highlighted a further benefit of Beard's suggested change in terminology: that ‘confusion in Parliament and public debate would also be reduced.’ Considerable public and parliamentary debate followed shortly when David Alton introduced the Abortion (Amendment) Bill to parliament in autumn 1987.
    Correspondence in the medical press around this time testifies to the strength of feeling among practitioners and the moral judgements of some doctors relating to abortion, both as an act (‘killing foetuses’) and as an implication about sexual behaviour. Beard refers tangentially to the moral stigma of abortion in his Lancet letter suggesting that: ‘Most women associate the word with what in the past was an illegal act and therefore socially unacceptable...’ For doctors (like Beard) dealing with women who had miscarried the distinction of ‘miscarriage’ from ‘abortion’ permitted the distinguishing of their patients (and themselves) from a subject that was heavily stigmatised and ‘socially unacceptable’.
  • In his letter to the Lancet, Beard portrays women who miscarry using the following words and phrases: ‘unmitigated misery’, ‘fortitude’, ‘deep disappointment’, ‘uncomplaining’ and ‘at their lowest ebb’, an image of suffering consolidated by his final appeal for change ‘on humanitarian grounds’. Meanwhile, he uses no adjectives or emotional descriptors in referring to women who experience abortion (potentially a very difficult life-event). Nor does Beard consider what significance the ‘socially unacceptable’ term ‘abortion’ might carry for women who seek a termination of pregnancy (a decision that might be made for a great variety of reasons by women in many different circumstances). Beard's letter demonstrates a selective empathy and represents a construction of the sensitivities of women who experience miscarriage as much as a response to those sensitivities. The distinction in language of ‘miscarriage’ from ‘abortion’ at this moment in history facilitated the splitting of two groups of women who could potentially be very differently constructed.
    After Beard in 1985 asked ‘doctors, indeed all health professionals, to start using the word miscarriage rather than abortion for a spontaneous pregnancy loss’, other medical authors subsequently wrote articles whose titles addressed ‘Terminology used in early pregnancy loss’ and advocated that ‘Terminology for early pregnancy loss must be changed’. In each of these instances use of the term ‘miscarriage’ rather than ‘abortion’ was advised. Whether or not we perceive that the term ‘miscarriage’ (as might be suggested) implies an inherent accusation in its literal allusion to a pregnancy miscarried by the mother's womb or that (as might be speculated) the phrase ‘spontaneous abortion’ ciphers ideas of hysteria and a typically irrational womb impulsively ejecting its content, it is quite apparent that neither of these two terms overtly acknowledges a pregnancy, or a loss. The fact that the phrase ‘pregnancy loss’ was repeatedly employed by medical authors writing on the subject for other doctors, but was apparently not considered suitable for use in front of, or by, women themselves, is notable. The reluctance of doctors to offer ‘pregnancy loss’ to women as a possible descriptor might suggest a professional denial of the experience or persisting professional efforts to maintain some sort of control.
  • Following Beard's appeal to doctors and the shift in medical language, there appears to have been less of a shift in the depth of actual woman-centredness likely to be found within the medical profession or in the degree of real empathy likely to be extended toward women who miscarried. Two clinical review papers on the subject of miscarriage published in the BMJ since the turn of the century contained no allusion to potential distress and emotional upset. Conversely, during the 1990s and 2000s, medical researchers advocating for improved care after miscarriage tended to emphasise the ‘psychiatric morbidity, including anxiety and depression’ among women and highlight ‘psychiatric cases’: arguably, by these and other means, miscarriage has tended to be pathologised, perhaps perceived as a potential precursor of psychiatric illness, rather than being acknowledged as a troubling event in its own right, one that lies within the breadth of human experience and that warrants greater physician empathy.
  • The clinical terminology applied to women's health experiences in Britain changed after the mid-1980s when doctors consciously began using the term ‘miscarriage’ instead of ‘abortion’ to refer to early pregnancy loss. In this essay I have sought to convey the meaning of this change in language: the factors behind it and its subsequent significance. Until now, Richard Beard's 1985 letter to the Lancet has tended to be perceived as an isolated stimulus to the shift in medical language and as a spontaneous response to women's feelings. However, evidence from medical journals and textbooks of the time reveals how Beard's letter and the change in medical language can be better understood in the context of certain historical developments that enabled and encouraged both the letter-writing and language shift.
    From the late 1960s onwards, the changes in Britain's legislation allowing women greater access to abortion services also enabled them to discuss these issues with doctors without fear of being criminalised. In turn, doctors could engage in conversations with women without concern that they were being deceived: specifically, they could be confident that women describing symptoms of spontaneous pregnancy loss were not concealing a deliberate (and previously illegal) termination. Doctors’ terminology for early pregnancy loss could now refer to something actually knowable. By the 1980s, developments in ultrasound technology enabled the content of a woman's uterus and any early pregnancy pathologies to be visualised in real time. Doctors were now able to apply their terminology diagnostically in the clinic.
  • For the first time in the medical history of early pregnancy loss, following the legal and technological developments described above, diagnostic language could be immediately coupled to a clinically knowable reality. For clinicians, this would have conferred greater significance upon the medical terminology and may have heightened consciousness of language in this context. Meanwhile, the need to define accurate and unambiguous terminology for describing diagnoses of fetal loss would have been given impetus by rapidly expanding medical knowledge of the fetus and the establishment of a new fetal-focused medical speciality. Consistent with this, the communication that sought to define the terminology came from a senior figure at the forefront of this burgeoning speciality.
    The emotional experiences of women who miscarry were the most proximal stimulus to Richard Beard's writing and the justification that he refers to in his letter. Most probably, given the temporality of other writing on this issue, these experiences were acknowledged after being channelled by women's associations and feminist commentators. The fact that the emotional experiences of women formed the basis for Beard's appeal to doctors suggests that these experiences, in theory at least, had some importance for clinicians, reflecting a growing value placed upon empathy and the patient's experience.
    Despite the prominence of empathy implied in the call for doctors to use the term ‘miscarriage’ instead of ‘abortion’ when referring to early pregnancy loss, it is doubtful whether the subsequent shift in language among clinicians was accompanied by any similar shift toward more genuinely empathic medical care for women who experienced miscarriage. Conceivably, the emphasis upon ‘empathic’ terminology made the real challenge (an empathetic response to the loss not only of a pregnancy, but of an expected child, motherhood and apparent certainties) appear amenable to a simple technical solution (the substituting of one word for another). This may have aided the language shift among doctors, and brought some small improvement to the experiences of women who miscarried, but it did not necessarily betoken a more empathic or women-centred approach.
  • In 1998, a BMJ editorial wondered whether using the term ‘miscarriage’ rather than ‘abortion’ was really the medical profession's most effective intervention in the context of pregnancy loss. It warned that changing medical language ‘while laudable in its intentions, may not be enough to alleviate mothers’ dissatisfaction with the care that they receive. The risk is that mere use of ‘correct’ terminology... could lead to professional complacency.’
    The importance of ensuring appropriate standards of care is underscored by the estimation that one in five pregnancies will miscarry, and most of these women will seek medical attention. Research findings have demonstrated repeatedly that mothers’ dissatisfaction with medical care in the context of early pregnancy loss has not yet been alleviated in Britain. In October 2011, the internet based charity ‘Mumsnet’ felt compelled to launch a campaign for ‘Better Miscarriage Care’. The first ever NHS guideline dealing specifically with the issue of miscarriage was published in December 2012; it placed considerable emphasis upon the need for support, information-giving and the offer of follow-up for women. This may represent a significant development, but the shift of medical language from ‘abortion’ to ‘miscarriage’ reminds us that it will take more than words to truly improve patients’ experiences.

“Maternal exposure to arsenic and mercury and associated risk of adverse birth outcomes in small-scale gold mining communities in Northern Tanzania” (April 2020)[edit]

Elias C. Nanza, Deborah Dewey, Mange Manyama, Honathan W. Martin, Henniffer Hatfield, Francois P. Bernier; “Maternal exposure to arsenic and mercury and associated risk of adverse birth outcomes in small-scale gold mining communities in Northern Tanzania”, Environment International, Volume 137, (April 2020)

  • Results: Statistically significant differences were found in median T-As (9.6 vs. 6.3 μg/L, Mann-Whitney U-tests, Z = −3.50, p < 0.001) and median T-Hg blood concentrations (1.2 vs. 0.70 μg/L, Z = −9.88, p-value < 0.001) between women living in ASGM and non-ASGM areas respectively. In ASGM areas, the adjusted relative risk (aRR) of a composite adverse birth outcome increased with increasing T-As (aRR 1.23, 95%CI: 1.14–1.33, p < 0.0001) and T-Hg (aRR 1.17, 95%CI: 1.1–1.25, p < 0.0001) exposure. Spontaneous abortion (aRR 1.53, 95%CI: 1.28–1.83), stillbirth (adjusted odds ratio (aOR) 1.97, 95%CI: 1.45–2.66) and preterm birth (1.17, 95%CI: 1.01–1.36) were significantly associated with elevated T-As, whereas elevated T-Hg was significantly associated with stillbirth (aOR 2.49, 95%CI: 1.88–3.29) and visible congenital anomalies (aOR 2.24, 95%CI: 1.3–3.87).
    Conclusion: Over half (54.7%) of women in ASGM areas of Northern Tanzania had adverse birth outcomes and the risk of adverse birth outcomes was significantly associated with increased prenatal exposure to arsenic and mercury.
    • p.1
  • Conflicting associations between prenatal arsenic and mercury exposure and adverse birth outcomes, and evidence of widespread environmental contamination of arsenic and mercury in ASGM areas (Nyanza et al., 2014) supports the need for further research in vulnerable communities. The current study directly addresses this knowledge gap by examining the association between direct measures of maternal exposure to arsenic and mercury and adverse birth outcomes in ASGM and non-ASGM communities in Northern Tanzania. We hypothesized that: (1) the risk of adverse birth outcomes would be higher in areas with ASGM activities compared to areas with no ASGM activities, and (2) that elevated maternal arsenic and mercury exposure would be associated with a higher incidence of adverse birth outcome (i.e., of spontaneous abortion, stillbirth, preterm birth, low birth weight and visible congenital anomalies), particularly in ASGM communities where exposure is likely to be higher.
    • p.2
  • The overall prevalence of the composite adverse birth outcome in both communities combined was 49.6% (477/961). When the women were examined by place of residence, the prevalence of the composite adverse birth outcome in ASGM areas (54.7%, n = 431/788) was significantly higher than in non-ASGM areas (26.6%, n = 46/173) areas ( χ 2 = 44.8, p < 0.001). The prevalence of each specific adverse birth outcome among women in areas with ASGM activities was 12.3% (n = 97/788) for spontaneous abortion, 11% (n = 87/ 788) for stillbirth, 24.4% (n = 192/788) for preterm birth, 19.8% (n = 120/605) for low birth weight, and 1.5% (n = 12/788) for visible congenital anomalies (3 hydrocephalus, 3 facial-cleft, 2 omphalocele, 5 neural tube defects). In non-ASGM areas, no visible congenital anomalies were reported in any infants; the prevalence of spontaneous abortion was 8.7% (n = 15/173), stillbirth 1.7% (n = 3/173), preterm birth 8.1% (n = 14/173), and low birth weight 12.3% (n = 19/155).
    • p.4
  • The relative risk of spontaneous abortion increased by 1.38 and the odds of stillbirth increased by 2.08 for every 10-fold increase in T-As. For every 10-fold increase in T-Hg, the relative risk of spontaneous abortion increased by 0.96 and the odds of stillbirth in- creased 2.71 times. Women in areas with non-ASGM activities had 0.78 reduced odds of stillbirth as compared to the women from ASGM areas. The risk of spontaneous abortion was 55% higher among women in the low SES group compared to those in the moderate SES group. Women with a history of previous preterm birth had an 84% higher risk of spontaneous abortion compared to those who had no history of preterm birth.
    • p.5
  • Exposure to toxic chemical elements such as arsenic and mercury, is a major health concern that could significantly effect maternal and child health outcomes. Our findings support the hypothesis that ASGM activities pose a significant risk to pregnant women and their offspring. The risk of an adverse birth outcome was twice as high (54% vs 27%) in areas with ASGM activities as compared to areas with no ASGM activities, and higher exposure to arsenic and mercury during pregnancy in Tanzanian women was associated with an increased prevalence of adverse birth outcomes including spontaneous abortion, stillbirth, preterm birth, low birth weight, and visible congenital anomalies. Our findings are consistent with previous research that has reported more adverse birth outcomes in areas with higher environmental pollution as compared to areas with lower pollution or minimal environmental exposures (Elghany et al., 1997; Ahmad et al., 2001; Thakur et al., 2010; Henn et al., 2016; Yorifuji et al., 2017). Indeed, Ahmad et al., (2001), reported a higher risk of adverse birth outcomes in areas with high arsenic exposure from contaminated drinking water in Bangladesh. Evidence from communities in the US, Japan, and Nigeria has revealed a higher risk of adverse birth outcomes among women exposed to mercury as compared to unexposed women (Elghany et al., 1997; Yorifuji et al., 2017; Otebhi and Osadolor, 2016)
    • p.8
  • This study builds on several previous studies in Bangladesh, Hungary, India and Chile that have reported links between arsenic concentrations in drinking water, and spontaneous abortion and still-birth (Hopenhayn-Rich et al., 2000; Ahmad et al., 2001; Milton et al., 2005; Chakraborti et al., 2004; Rahman et al., 2016). We found higher levels of T-As exposure were associated with significantly increased odds of spontaneous abortion and stillbirth in ASGM areas, which is consistent with the findings reported in ecological studies that used concentrations in drinking water as proxies for exposure (Ahmad et al., 2001; Hopenhayn et al., 2003; Milton et al., 2005). Further, a recent systematic review of chronic arsenic exposure and pregnancy outcomes revealed that higher arsenic exposure was associated with increased odds of for spontaneous abortion and stillbirth ranging from 1.2 to 2.9 and 1.7 to 6.07, respectively (Milton et al., 2017).
    In areas with ASGM activities, spontaneous abortion accounted for 22.5% of all of the adverse birth outcomes. The finding that the odds of a spontaneous abortion increased with lower SES cannot be over- emphasized. Studies by Weck et al. (2008) and Röllin et al. (2017) found that women with low SES had higher exposure to toxic chemicals as compared to women with moderate or high SES. Further, they were more likely to work in high risk jobs, such as mining, in order to secure their livelihood throughout their pregnancy period, which placed them at higher risk of exposure (Weck et al., 2008; Spiegel 2009; Röllin et al., 2017). Previously, we reported a strong association between lower maternal SES and higher maternal levels of arsenic and mercury among women in ASGM Areas (Nyanza et al., 2019a). The finding that a significant proportion of male partners (25.6% in ASGM areas) were involved in gold mining activities increases the potential of exposure to women in ASGM areas as most of the mining equipment and chemicals used are stored in their homes without adequate safety precaution. All these factors could contribute to an increased risk for adverse birth outcomes in ASGM areas. Future research is needed to clarify how these various factors interact to predict birth outcomes.
    • p.8
  • This study contributes to the growing literature supporting the association between maternal arsenic and mercury exposure and increased risk of adverse birth outcomes. A significant proportion of women in ASGM areas of Tanzania have adverse birth outcomes. Our study suggests that higher levels of arsenic and mercury exposure contribute significantly to this increased risk. Further research is needed to confirm these findings; however, the present study provides initial, compelling evidence that prenatal exposure to arsenic and mercury is a major public health issue in ASGM communities.
    • p.10

"Miscarriage – Causes" (December 7, 2017)[edit]

Choices, NHS (December 7, 2017 Page last reviewed: 09 March 2022). "Miscarriage – Causes". www.nhs.uk.

  • There are many reasons why a miscarriage may happen, although the cause is often not identified.
    If a miscarriage happens during the first trimester of pregnancy (the first 3 months), it's usually caused by problems with the unborn baby (foetus). About 3 in every 4 miscarriages happen during this period.
    If a miscarriage happens after the first trimester of pregnancy, it may be the result of things like an underlying health condition in the mother.
    These late miscarriages may also be caused by an infection around the baby, which leads to the bag of waters breaking before any pain or bleeding. Sometimes they can be caused by the neck of the womb opening too soon.
  • Sometimes something can go wrong at the point of conception and the foetus receives too many or not enough chromosomes. The reasons for this are often unclear, but it means the foetus will not be able to develop normally, resulting in a miscarriage.
    This is very unlikely to recur. It does not necessarily mean there's any problem with you or your partner.
  • If there's a problem with the development of the placenta, it can also lead to a miscarriage.
  • An early miscarriage may happen by chance. But there are several things known to increase your risk of problems happening.
    Your age can also have an influence:
    in women under 30, 1 in 10 pregnancies will end in miscarriage
    in women aged 35 to 39, up to 2 in 10 pregnancies will end in miscarriage
    in women over 45, more than 5 in 10 pregnancies will end in miscarriage
  • A pregnancy may also be more likely to end in miscarriage if you:
    are obese
    use drugs
    drink lots of caffeine
    drink alcohol
  • Several long-term (chronic) health conditions can increase your risk of having a miscarriage in the second trimester, especially if they're not treated or well controlled.
    These include:
    diabetes (if it's poorly controlled)
    severe high blood pressure
    kidney disease
    an overactive thyroid gland (hyperthyroidism)
    an underactive thyroid gland (hypothyroidism)
    antiphospholipid syndrome (APS)
  • The following infections may also increase your risk:
    rubella (german measles)
    cytomegalovirus (CMV)
    bacterial vaginosis
    HIV <br chlamydia
  • Food poisoning, caused by eating contaminated food, can also increase the risk of miscarriage. For example:
    listeriosis – most commonly found in unpasteurised dairy products, such as blue cheese
    toxoplasmosis – which can be caught by eating raw or undercooked infected meat
    salmonella – most often caused by eating raw or partly cooked eggs
  • Medicines that increase your risk include:
    misoprostol – used for stomach ulcers
    retinoids – used for eczema and acne
    methotrexate – used for conditions such as rheumatoid arthritis
    non-steroidal anti-inflammatory drugs (NSAIDs) – such as ibuprofen; these are used for pain and inflammation
  • Problems and abnormalities with your womb can also lead to second trimester miscarriages. Possible problems include:
    non-cancerous growths in the womb called fibroids
    an abnormally shaped womb
  • In some cases, the muscles of the cervix (neck of the womb) are weaker than usual. This is known as a weakened cervix or cervical incompetence.
    A weakened cervix may be caused by a previous injury to this area, usually after a surgical procedure. The muscle weakness can cause the cervix to open too early during pregnancy, leading to a miscarriage.
  • Polycystic ovary syndrome (PCOS) is a condition where the ovaries are larger than normal. It's caused by hormonal changes in the ovaries.
    PCOS is known to be a leading cause of infertility as it can prevent the release of an egg (ovulation). There's some evidence to suggest it may also be linked to an increased risk of miscarriage.
  • An increased risk of miscarriage is not linked to:
    your emotional state during pregnancy, such as being stressed or depressed
    having a shock or fright during pregnancy
    exercise during pregnancy – but discuss with your GP or midwife what type and amount of exercise is suitable for you during pregnancy
    lifting or straining during pregnancy
    working during pregnancy – or work that involves sitting or standing for long periods
    having sex during pregnancy
    travelling by air
    eating spicy food
  • About 1 in 100 women experience recurrent miscarriages (3 or more in a row) and many of these women go on to have a successful pregnancy.

"Miscarriage – Afterwards" (Page last reviewed: 21/05/2015)[edit]

Choices, NHS. "Miscarriage – Afterwards". www.nhs.uk. (Page last reviewed: 21/05/2015) Archived from the original on September 5, 2017. Retrieved September 5, 2017.

  • A miscarriage can have a profound emotional impact, not only on the woman herself, but also on her partner, friends and family.
  • It's usually possible to arrange a memorial and burial service if you want one. In some hospitals or clinics, it may be possible to arrange a burial within the grounds.
    You can also arrange to have a burial at home, although you'll need to consult your local authority before doing so.
    Cremation is an alternative to burial and can be performed at either the hospital or a local crematorium. However, not all crematoriums provide this service and there won't be any ashes for you to scatter afterwards.
    Unlike a stillbirth, you don't need to formally register a miscarriage. However, some hospitals can provide a certificate to mark what has happened if you want one.
  • Sometimes the emotional impact is felt immediately after the miscarriage, whereas in other cases it can take several weeks. Many people affected by a miscarriage go through a bereavement period.
    It's common to feel tired, lose your appetite and have difficulty sleeping after a miscarriage. You may also feel a sense of guilt, shock, sadness and anger – sometimes at a partner, or at friends or family members who have had successful pregnancies. <br. Different people grieve in different ways. Some people find it comforting to talk about their feelings, while others find the subject too painful to discuss.
    Some women come to terms with their grief after a few weeks of having a miscarriage and start planning for their next pregnancy. For other women, the thought of planning another pregnancy is too traumatic, at least in the short term.
    The father of the baby may also be affected by the loss. Men sometimes find it harder to express their feelings, particularly if they feel their main role is to support the mother and not the other way round. It may help to make sure you openly discuss how both of you are feeling.
    Miscarriage can also cause feelings of anxiety or depression, and can lead to relationship problems.
  • If you're worried that you or your partner are having problems coping with grief, you may need further treatment and counselling. There are support groups that can provide or arrange counselling for people who have been affected by miscarriage.
  • You should avoid having sex until all of your miscarriage symptoms have gone. Your periods should return within four to six weeks of your miscarriage, although it may take several months to settle into a regular cycle.
    If you don't want to get pregnant, you should use contraception immediately. If you do want to get pregnant again, you may want to discuss it with your GP or hospital care team. Make sure you are feeling physically and emotionally well before trying for another pregnancy.
  • It's important to remember that most miscarriages are a one-off and are followed by a healthy pregnancy.
    Although it's not usually possible to prevent a miscarriage, there are some ways you can reduce the risk. See preventing miscarriage for more information and advice.
  • It's natural to want to know why a miscarriage happened, but unfortunately this is not usually possible. Most miscarriages are thought to be caused by a one-off problem with the development of the foetus.

"How do health care providers diagnose pregnancy loss or miscarriage?" (July 15, 2013)[edit]

"How do health care providers diagnose pregnancy loss or miscarriage?". www.nichd.nih.gov/. July 15, 2013.

  • If a pregnant woman has any of the symptoms of pregnancy loss, such as abdominal cramps, back pain, light spotting, or bleeding, she should contact her health care provider immediately. Remember that vaginal bleeding during pregnancy does not definitely mean a pregnancy loss is occurring.
  • Depending on how far along the pregnancy is, health care providers may use different methods to determine whether a pregnancy loss has occurred:
    A blood test to check the level of human chorionic gonadotropin (hCG), the pregnancy hormone
    A pelvic exam to see whether the woman's cervix is dilated or thinned, which can be a sign of pregnancy loss
    An ultrasound test, which allows the provider to look at the pregnancy, uterus, and placenta
    If a woman has had more than one miscarriage, she may want to have a health care provider check her blood for chromosome problems, hormone problems, or immune system disorders that may be contributing to pregnancy loss.
  • Treatments for pregnancy loss focus on ensuring that the nonviable pregnancy leaves the woman's body safely and completely. Women going through pregnancy loss are at risk for bleeding, pain, and infection, especially if some of the pregnancy tissue remains behind in the uterus.
    The specific treatment used depends on how far along the pregnancy was, the woman's overall health, her age, and other factors.
    In many cases, pregnancy loss before 20 weeks may not require any special treatment. The bleeding that occurs with pregnancy loss empties the uterus without any further problems.
    Women who have heavy bleeding during pregnancy loss should contact a health care provider immediately. For reference, heavy bleeding refers to soaking at least two maxi pads an hour for at least 2 hours in a row.
    Some women may need a surgical procedure called a dilation and curettage (D&C) to remove any pregnancy tissue that is still in the uterus. A D&C is recommended if a woman is bleeding heavily or if an ultrasound shows pregnancy tissue is still in the uterus. D&C may also be used if a woman has any signs of infection, such as a fever, or if she has other health problems, such as cardiovascular disease or a bleeding disorder.
    Some women are treated with a medication called misoprostol, which helps the tissue pass out of the uterus and controls the resulting bleeding. Research shows that misoprostol is safe and effective in most cases.
    Women who lose a pregnancy may also need other treatments to control mild to moderate bleeding, prevent infection, relieve pain, and help with emotional support.
  • Although this is rare in the United States, some women who have a miscarriage may get an infection in the uterus, which can be life threatening. Women who have the following symptoms more than 24 hours after treatment should call 911:
    *A fever higher than 100.4 degrees Fahrenheit on more than two occasions
    *Severe pain in the lower abdomen
    *Bloody discharge from the vagina that includes pus or is foul smelling

"Depression and Anxiety Following Early Pregnancy Loss: Recommendations for Primary Care Providers” (2015)[edit]

Johnna Nynas, Puneet Narang, Murali K. Kolikonda, and Steven Lippmann; “Depression and Anxiety Following Early Pregnancy Loss: Recommendations for Primary Care Providers”, Prim Care Companion CNS Disord. 2015; 17(1): 10.4088/PCC.14r01721.

  • Early pregnancy loss is a shocking and traumatic event for women and their families. Miscarriage usually induces an intense period of emotional distress. This reaction tends to improve over the following several months, but some residual psychological concerns remain. It is important to screen for depression and anxiety in patients following a miscarriage. Most women in this circumstance do become pregnant again, yet mood disturbances can still coexist. When women are having difficulties at conception, worries may be magnified. Most women and physicians see post-miscarriage intervention as desired, and it is important to provide appropriate treatment. Management of depressive and anxiety symptoms after pregnancy loss can benefit future patient well-being.
  • Among the 6.5 million pregnancies in the United States in 2008, about 1.1 million ended in miscarriage. Approximately 10%–25% of all pregnancies end in miscarriage, making it a common early pregnancy complication. Pregnancy and birth are regarded as a joyful time, but early pregnancy loss is usually a shocking and traumatic event for women and their families. At the time of miscarriage, most women will experience a period of intense emotional distress. This reaction tends to improve by 6 weeks, with further resolution of symptoms after several months. During the initial weeks following a loss, symptoms of grief may be impossible to distinguish from depression, and some women may continue to experience depressive symptoms for months. Screening this population for depression and anxiety is difficult.
  • The psychological impact of miscarriage is sometimes overlooked because miscarriage is so common and its management is medically straightforward. Although 90% of women desired specific follow-up care from their physician, only 30% of them received such attention. Primary care providers, family physicians, obstetricians, and others may lack comfort and training in assessing patients at risk for mental health problems following miscarriage. Some women are inadequately screened for depression or anxiety following early pregnancy loss, leaving them unidentified, untreated, and at increased risk of mental health sequelae.
  • Women who experience the trauma of a miscarriage experience psychological distress, and the prevalence of clinically significant depressive symptoms is often underestimated. Subjects interviewed at 6 to 8 weeks following a miscarriage experienced substantially more depression than a matched cohort of nonpregnant women. Further, 20% of them were considered overtly symptomatic for affective illness. Six weeks after a miscarriage, approximately 11% of Chinese women suffered major depression and 1.4% were diagnosed with anxiety disorders; however, the incidence of major depression was lower than in studies conducted in Western cultures.At 6 months following miscarriage, women are at a significantly increased risk for minor depressive episodes, and the majority developed symptoms within the first month after miscarrying.
    The uncertainties that women experience after a pregnancy loss contribute to a high level of anxiety, which may represent a greater psychological burden than depression. Concerns include waiting for the return of menstrual cycles, desire to conceive, risk of recurrent miscarriage, and fears about their reproductive abilities. At 12 weeks after miscarriage, anxiety was more frequent and intense than depression. A 2007 investigation at 1, 6, and 13 months following miscarriage documented anxiety as more likely than depression at all 3 endpoints.
    Not only are anxiety and depression common following miscarriage, these symptoms tend to persist. While there is a gradual decrease in depression and anxiety over time, even at 30 months, some parents who experienced infant loss due to perinatal death or sudden infant death syndrome continued to show almost twice the level of psychological distress as controls. A longitudinal study of over 13,000 women in the United Kingdom who had experienced previous prenatal losses revealed that some of them experience persistent depressive and anxiety symptoms after 33 months. Depression following miscarriage persisted for up to 1 year.
  • Between 50% and 80% of women who experience miscarriage become pregnant again. A subsequent pregnancy represents a time of intense and often conflicting emotions; couples balance being hopeful, while also worrying about the risk of a repeat loss. After miscarriage, 68% of women were still upset 2 years after the event, and 64% reported that it affected decisions about subsequent pregnancies. Contrary to popular belief, becoming pregnant again is not a protective factor against depression or anxiety. Mood symptoms following a prenatal loss do not always resolve with the birth of a subsequent healthy child.
    A prior pregnancy loss is also a risk factor in developing depression and anxiety during future pregnancies. Research on over 20,000 pregnant Chinese women noted that those with a history of miscarriage had a greater risk of anxiety and depression during the first trimester than primigravid subjects. Even conception less than 6 months after their loss did not reduce anxiety during the first trimester regardless of maternal age, education, body mass index, income, and residence. Those with a history of miscarriage have higher levels of pregnancy-related fear during their first trimester, which correlates with complications including increased rates of vaginal bleeding, fatigue, hospitalization, and low APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) scores in the neonate. Although controversial, research suggests that the presence of anxiety or depression in a new pregnancy constitutes a risk factor for perinatal complications.
  • Managing prenatal care in women with a history of miscarriage is challenging. Not only are these women at increased risk for psychiatric problems, they also may struggle with maladaptive coping skills that further complicate their situation. In parents studied, mothers tend to diminish the significance of previous loss in order to remain hopeful for the current pregnancy, while fathers experience frequent thoughts about the previous loss.
  • Not everyone who experiences a miscarriage will develop clinically significant anxiety or depression, but several factors have been identified that can predict which women may experience greater emotional distress. These factors include loss of a planned pregnancy, history of infertility or long periods of trying to conceive, no warning signs of the loss, prior miscarriages, loss at a later gestational age, no living children, social isolation, relationship strain between partners, and prior history of poor coping skills. Miscarriage exerts a greater depressive effect on women who are younger, Hispanic, and of lower socioeconomic status, and the level of depression rises with increased number of miscarriages.
    Miscarriage management may also impact psychiatric symptoms. Surgical intervention after failed management exerts greater psychological distress. Even though symptoms diminish during the early months after miscarriage, 25% of women experience clinical depression at 1 year. Those who were depressed initially after miscarriage are more likely to remain depressed a year later.
  • There are discrepancies between patient needs and current medical practice. Women are responsible for seeking medical attention following miscarriage, and their perceptions of care following miscarriage indicate this approach is inadequate. Among health care providers, 74% believe that routine psychological support should be provided following miscarriage, but only 11% feel that the level of care was adequate.
    Studies of patient satisfaction indicate the need for improvement in follow-up. After a miscarriage, many women want information about why their miscarriage occurred, implications for future pregnancies, and support from health care professionals. Patient dissatisfaction often focuses on psychological issues. Even though a follow-up appointment was desired by most women following miscarriage, there were no significant differences in levels of anxiety, depression, or grief between subjects who attended follow-up appointments and those who did not. However, those not offered the opportunity to discuss their feelings during a follow-up visit reported more anxiety. Health care professionals should address the psychological needs of patients who miscarry and assure them that mental health care is available.
  • The timing of follow-up care plays a role in psychiatric symptoms. Because feelings of guilt experienced immediately following the loss can be particularly difficult, all women should be asked about self-blame. Since distress is most marked immediately after the loss, initial counseling should begin within 1 week of miscarriage. Immediate counseling right after the miscarriage is diagnosed while patients are distressed is less helpful; it is better to reinforce this information at a later time. Telephone interviews conducted at 2 weeks after miscarriage were associated with significant reduction in depressive symptoms at 6 weeks and 6 months. A 6-week post-miscarriage primary care office visit is the best time to screen patients. Unfortunately, follow-up visits after medically managed miscarriages are rarely offered.
  • Extensive training is not needed to identify patients experiencing clinically significant symptoms. The Patient Health Questionnaire-2 instrument is sensitive and specific for detecting postpartum depression. When significant distress or impaired functioning persists for more than 2 months after miscarriage, a formal mental health evaluation is indicated. Untreated anxiety is associated with an increased risk of developing depression. Primary care providers should counsel women with a history of miscarriage that they may experience an increase in emotional distress during a subsequent pregnancy. Clinicians should review the patient’s obstetric history for past traumatic experiences that could increase the risk of depression and anxiety during subsequent pregnancies. Providers should consistently be proactive in discussing previous losses, current emotional states, ongoing psychological distress, and plans for future pregnancies.
  • The World Health Organization recommends waiting 6 months following miscarriage before conceiving again to allow time for physical and mental recovery. However, for women who have a desire to have a child quickly, delaying efforts to conceive may be an additional strain. Infertility is recognized as a source of psychiatric morbidity regardless of miscarriage history. Clinicians should counsel women on the warning signs of developing anxiety or depression and screen them for symptoms during each prenatal visit.
    The American College of Obstetricians and Gynecologists recognizes the increased incidence of depression during pregnancy and postpartum, yet, they do not recommend universal screening despite acknowledging the benefits of the practice. Miscarriage is a significant source of psychiatric morbidity, and the lack of screening increases the risk of psychiatric sequelae. Primary care providers should maintain a high index of suspicion and a low threshold to screen women for developing depressive symptoms following miscarriage. This is especially important for those with a history of prior miscarriage, those who are younger or Hispanic, those who have a history of infertility or lower socioeconomic status, and those with a history of depression, anxiety, or poor coping skills. Distress following a miscarriage falls along a continuum of symptoms and follows a waxing and waning course, and frequent screening is indicated.

“Miscarriages”, Nemours Kids Health, (Date reviewed: October 2020)[edit]

  • A miscarriage is the loss of a pregnancy (the loss of an embryo or fetus before it's developed enough to survive). This sometimes happens even before a woman knows she is pregnant. Unfortunately, miscarriages are fairly common.
    A miscarriage usually happens in the first 3 months of pregnancy, before 12 weeks' gestation. A very small number of pregnancy losses are called stillbirths, and happen after 20 weeks’ gestation.
  • Often, a woman can have an extra heavy menstrual flow and not realize it’s a miscarriage because she hadn’t known she was pregnant.
    Some women who miscarry have cramping, spotting, heavier bleeding, abdominal pain, pelvic pain, weakness, or back pain. Spotting does not always mean a miscarriage. Many pregnant women have spotting early in the pregnancy and go on to have a healthy baby. But just to be safe, if you have spotting or any of these other symptoms anytime during your pregnancy, talk with your doctor.
  • The most common cause of pregnancy loss is a problem with the chromosomes that would make it impossible for the fetus to develop normally.
    Other things that could play a role include:
    low or high hormone levels in the mother, such as thyroid hormone
    uncontrolled diabetes in the mother
    exposure to environmental and workplace hazards, such as radiation or toxic agents
    some infections
    uterine abnormalities
    incompetent cervix, which is when the cervix begins to open (dilate) and thin (efface) before the pregnancy has reached term
    the mother taking some medicines, such as the acne drug Accutane
  • A miscarriage also can be more likely in pregnant women who:
    smoke, because nicotine and other chemicals in the mother’s bloodstream cause the fetus to get less oxygen
    drink alcohol and or use illegal drugs
  • If a woman miscarries, her doctor will do a pelvic exam and an ultrasound to confirm the miscarriage. If the uterus is clear of any fetal tissue, or it is very early in the pregnancy, many won’t need further treatment.
    Sometimes, the uterus still contains the fetus or other tissues from the pregnancy. A doctor will need to remove this. The doctor may give medicine to help pass the tissue or may dilate the cervix to do:
    a dilation and curettage (D&C), a scraping of the uterine lining
    a dilation and extraction (D&E), a suction of the uterus to remove fetal or placental tissue
    A woman may have bleeding or cramping after these procedures.
  • In most cases, a miscarriage cannot be prevented because it’s caused by a chromosomal abnormality or problem with the development of the fetus. Still, some things — such as smoking and drinking — put a woman at a higher risk for losing a pregnancy.
    Good prenatal care can help moms and their babies stay healthy throughout the pregnancy. If you’re pregnant:
    Eat a healthy diet with plenty of folic acid and calcium.
    Take prenatal vitamins daily.
    Exercise regularly after you've gotten your doctor's OK.
    Keep a healthy weight. Pregnant women who are overweight or too thin may be more likely to have miscarriages.
    Avoid drugs and alcohol.
    Avoid deli meats and unpasteurized soft cheeses such as feta and other foods that could carry listeriosis.
    Limit caffeine intake.
    If you smoke, quit.
    Talk to your doctor about all medicines you take. Unless your doctor tells you otherwise, many prescription and over-the-counter medicines should be avoided during pregnancy.
    Avoid activities that could cause you to get hit in the belly.
    Make sure you’re up to date on all recommended vaccines.
    Know your family medical and genetic history.
    Go to all of your scheduled prenatal visits and discuss any concerns with your doctor.
    Call your doctor right away if you have fever; feel ill; notice the baby moving less; or have bleeding, spotting, or cramping.
  • If you've had a miscarriage, take time to grieve. The loss of a baby during pregnancy is like the loss of any loved one. Give yourself time to heal emotionally and physically. Some health care providers recommend that women wait one menstrual cycle or more before trying to get pregnant again.
    Some other things that can help you get through this difficult time:
    Find a support group. Ask your doctor about local support groups for women who are trying again after a loss.
    Find success stories. Other women who have had a successful pregnancy after having a miscarriage can be a great source of encouragement. Your doctor might know someone to talk with.
  • During future pregnancies, it can help to:
    Be proactive. The more you know about the medical aspects of your pregnancy, the better you'll be able to discuss treatment options and outcomes with your doctor.
    Monitor the baby's movements. If you're far enough along to feel kicks and jabs — usually between 18 and 22 weeks — keep a log of the baby's activities each morning and night and report any changes or lack of movement to your doctor. If your baby isn't moving, eat or drink something sugary and lie down on your side. You should feel at least 10 movements in a 2-hour period. If you don't, call your doctor right away.
    Try not to compare. No two pregnancies are exactly alike, so try not to dwell on any similarities between this pregnancy and the one that ended in a loss.
    Stay positive. Envision a good end to help you stay positive.

“Cortisol levels and very early pregnancy loss in humans” (February 22, 2006)[edit]

Pablo A. Nepomnaschy, Kathleen B. Welch, Daniel S. McConnell, and Barry G. England; “Cortisol levels and very early pregnancy loss in humans”, PNAS, (February 22, 2006) 103 (10) 3938-3942

  • Maternal stress is commonly cited as an important risk factor for spontaneous abortion. For humans, however, there is little physiological evidence linking miscarriage to stress. This lack of evidence may be attributable to a paucity of research on maternal stress during the earliest gestational stages. Most human studies have focused on “clinical” pregnancy (>6 weeks after the last menstrual period). The majority of miscarriages, however, occur earlier, within the first 3 weeks after conception (≈5 weeks after the last menstrual period). Studies focused on clinical pregnancy thus miss the most critical period for pregnancy continuance. We examined the association between miscarriage and levels of maternal urinary cortisol during the first 3 weeks after conception. Pregnancies characterized by increased maternal cortisol during this period (within participant analyses) were more likely to result in spontaneous abortion (P < 0.05). This evidence links increased levels in this stress marker with a higher risk of early pregnancy loss in humans.
    • p.1
  • Spontaneous abortions can be triggered by maternal and fetalpathologies or immunological incompatibilities. However, pathologies and incompatibilities alone do not explainall miscarriages. Maternal stress is commonly cited as apotential cause for at least part of pregnancy losses that remain‘‘unexplained’’. Yet, for humans, little physiologicalevidence exists in support of this hypothesis.
    Empirical evidence indicates that most spontaneous abortions inhumans take place during the first 3 weeks after conception (or 5weeks after the last menstrual period), which, coincidentally, is the time required for the placenta’s structural and functional units to develop. During the ‘‘placentation’’ period, human embryos depend heavily on their mothers for survival. For example, until theplacenta is able to replace the corpus luteum as the main source of steroids, the fate of a pregnancy relies on adequate maternal production of estrogens and progestins. Thus, humanembryos might be especially vulnerable to maternal challenges until the placenta matures.
    Placentation is, therefore, a particularly relevant period forstudying the relationship between maternal stress and pregnancyfate in humans. Previous research on the topic, however, hasfocused mainly on clinical pregnancy ( 6 weeks after lastmenstrual period, equivalent to 4 weeks after conception).Furthermore, except for studies on women with known fertilityproblems, past studies have rarely included physiologicmeasures. Whereas some previous studies foundstress to be associated with spontaneous abortion,others did not. Thus, whether this relationship exists inhumans remains unclear.
    To fill this gap, we examine the association between a physiological marker of stress (cortisol) during the first 3 weeks afterconception and pregnancy fate in a nonclinical population of nominally fertile women. Cortisol is commonly used as a stressmarker because its production by the adrenal cortex tends toincrease as a result of energetic, immunological, and psychological challenges. To address concerns about the use ofcortisol as a stress marker, we account for the effects of awide variety of confounding factors as well as for baselinedifferences among individuals and possible correlations withinindividuals.
    • p.1
  • Fetal loss rates reported in humans range from 31% to 89% of all conceptions. This high rate of miscarriages hasled health scientists to describe human reproduction as in-efficient and, therefore, an evolutionary paradox. Evolutionary theorists, however, propose that aborting un-healthy, defective, or otherwise substandard embryos, or thosegestating under impoverished reproductive conditions, can be reproductively advantageous. Our results indicat-ing an association between high cortisol levels and increasedrisk of miscarriage should be considered within the lattercontext. Impoverished reproductive conditions refers toreductions in the quality of females’ environment and or health status, such as droughts, infections, or social conflicts. Miscarriage under such conditions could help minimize thecost of pregnancies with diminished chances of success, pre-serve valuable resources to be invested in future offspring withhigher fitness prospects, and free those resources to be used ona woman’s own survival and already existing offspring, whichcould be crucial during a crisis.
    Nonetheless, current adaptive abortion models propose thatvery early abortions would be better explained by problems with the embryo’s quality, rather than environmental challenges. They argue that to reduce the risk of terminating pregnancies thatcould otherwise be successful (should the reproductive contextimprove), gestation should be allowed to continue for as long aspossible. The contradiction between this prediction and ourresults may be explained by two factors. First, these models do not consider the different costs and benefits of interrupting reproduction for species with different reproductive schedules. Whereas forseasonal breeders, interrupting a pregnancy could imply losing anentire reproductive year, for continuous breeders such as humans, the opportunity costs of very early miscarriages are comparatively lower. Second, these models are primarily based on maternalcost–benefit analyses and ignore the potential constraints that fetaldevelopment imposes on maternal reproductive strategies. Thethreshold of conditions under which it would be beneficial for afetus to be born should be lower than that for the mother. Each genetically unique fetus has but one opportunity to be born. Thus, it is not surprising that within hours of fertilization conceptuses begin secreting a battery of metabolites that reduce the risk of miscarriage. The physiologic maturation of the fetus, however, is necessarily gradual; therefore, fetuses should be most vulnerable to stress-triggered abortive mechanisms during the first weeks of gestation.
    • pp.1-2
  • Our finding of an association between increased maternal cortisol and higher risk of miscarriage within the first 3 weeks of conception, together with the failure of previous research to find such an association later during gestation, suggests that pregnancy may be particularly sensitive to maternal stressduring the placentation period. Future longitudinal studieswith larger samples will be necessary to both replicate ourresults and further test this hypothesis by comparing cortisol levels and risk of miscarriage across the entire duration ofgestation. Further research will also be necessary to explorethe physiological pathways that might mediate the observed association.
    • p.3

“The links between pollution and miscarriage: “This is the stuff nightmares are made of” (28 Mar 2023)[edit]

Isabelle Oderberg, “The links between pollution and miscarriage: “This is the stuff nightmares are made of”, The Guardian, (28 Mar 2023)

  • As I watched thick bushfire smoke blanket Sydney at the end of 2019, into the early months of 2020, I was already working on researching what eventually became my book on early pregnancy loss and miscarriage, Hard to Bear: Investigating the science and silence of miscarriage. Knowing the effects of particulate matter on the body, I wondered if pollution, whether extreme or “normal levels”, might contribute to early pregnancy loss. It turns out that it does and that led to a story published in the Guardian and a podcast and later resulted in RANZCOG changing its guidelines for pregnancy in relation to pollution. But that’s not where this issue ended, at least, not for me.
  • “There’s no doubt you’ve seen plastic containers at the supermarket proudly bearing the label BPA-free. What that means is that they do not contain bisphenol A, a dangerous endocrine-disrupting chemical. Not only can it raise your risk profile in terms of miscarriage and early pregnancy loss, but it can have a wealth of other negative effects on physiology to humans, including those in utero. But what you don’t know is that it’s in lots of other places, including supermarket receipts. Despite us knowing about its ill-effects for more than 15 years, only late last year did the big chain supermarkets undertake to remove it from receipts that are being handled by their staff hundreds of times a day and by their customers too.
  • Every single expert I spoke to in the context of my research on miscarriage said that while we’re not tracking miscarriage numbers, they believe miscarriage rates are rising. These are not crackpots. These are world-renowned obstetricians and endocrinologists from Columbia University w:Yale:Yale, Imperial College in London and right here in Australia.

“Pesticide Risk and Recurrent Pregnancy Loss in Females of Subhumid Region of India” (Mar-Apr 2020)[edit]

Akancha Pandey, Shyam Pyari Jaiswar,Nasreen Ghazi Ansari, Sujata Deo, Pushplata Sankhwar, Shriya Pant, and Sushil Upadhyay; “Pesticide Risk and Recurrent Pregnancy Loss in Females of Subhumid Region of India” Niger Med J. 2020 Mar-Apr; 61(2): 55–59.

  • Based on the incidence of sporadic pregnancy loss, the incidence of recurrent pregnancy loss (RPL) should be approximately 1 in 300 pregnancies. Although the specific cause of RPL is not yet known, considerable evidence suggests that both genetics and the environment play an important role in the origin and evolution of this disease. Pesticides are the class of man-made environmental chemicals that can affect the body’s development, growth, and hormone balance. Pesticides are usually designed to target a particular pest, but due to its broad range of toxicity, it can also be directed to other nontarget species. In the majority of cases, however, human exposure is unintentional.
    Previous studies also examined the role of other factors such as infections, hormonal aberrations, menstrual irregularities, malnutrition, psychological conditions, stressful events, high alcohol, nicotine, and caffeine intake, but the results are inconsistent. In recent years, the high risk of miscarriages has been reported in smoking women. Settimi et al. also reported the positive association between pesticides exposure and increased risk of pregnancy loss. Pesticides exposure may also cause reproductive and developmental disorders. A definite cause of RPL can be identified only through intensive diagnostics.
    Environmental pollutants or xenobiotics have been suspected for their strong role in causing RPL and other reproductive aberrations, but pesticides such as organochlorine (OCP) and organophosphate (OPP) are suggested as the main culprits. Pesticides such as dichlorodiphenyltrichloroethane and hexachlorocyclohexane are officially banned in India. However, they are still in use to control the disease-carrying vectors.
    OCP and OPP both have a long half-life. These pesticides accumulate in the adipose tissue and thus enter into the food chain and circulate.8 On exposure through different means such as air, water, food, and soil, these may enter in blood circulation and can induce endocrinological disorders, immunological aberrations, oxidative damage, and eventually molecular damage. The roles of di chloro di phenyl tri chloro ethane (DDT) exposure in spontaneous pregnancy loss have previously been reported. However, more studies with diverse patient groups are required to establish the association of pesticides in the etiology of RPL. The present study was conducted to further investigate this claim. The levels of OCP and OPP were quantified and compared between the cases with repeated pregnancy loss and women having successful full-term delivery among the population of subhumid region of India.
    • pp.55-56
  • We observed an elevated level of pesticide quartile in case with respect to the control group. Table 1 shows OCPs and OPPs levels in case and control groups in terms of descriptive statistics. The Mann–Whitney U-test was used to calculate the significance difference between the groups. The result revealed that levels of pesticides, beta-hexachlorocyclohexane(β-HCH), γ-HCH, δ-HCH, chlorpyrifos, pp-DDD, and fenvalerate were statistically significantly higher in the patients of the case group as compared with the control group (all P < 0.05).
    The results for all the 14 pesticides (12°CP and 2 OPP) were analyzed through the Mann–Whitney test. We observed statistically significantly higher levels of β-HCH (P: 0.04), γ-HCH (P: 0.001), δ-HCH (P: 0.002), chlorpyrifos (P: 0.001), pp-DDD (P: 0.001), and fenvalerate (P: 0.001) in the patients of the case group in comparison to the patients of the control group. These pesticides were known to be endocrine disrupting and carcinogenic.
    • p.56
  • The RPL and their causative factors are well demonstrated in this study and are compared with earlier studies. The impact of environmental exposure and oxidative stress in the etiology of RPL was evaluated, and the findings were corroborated with Pathak et al. The identification of environmental factors that enhance the threat of PCa must therefore be a goal for disease prevention. As previously outlined, pesticides and its derivatives, especially OCP (DDT, dioxins, and polychlorinated biphenyls) and OPP (malathion and chlorpysifos) possess weak estrogenic and androgenic effects. Their availability in the body may interfere at several control points in the hormone-signaling pathways. As a result, the response cascade of natural hormones can either be inhibited or excessively enhanced, at the wrong time, in the wrong tissue.
    In this study, a statistically significant higher level of pesticides, namely β-HCH, γ-HCH, δ-HCH, chlorpysifos, pp-DDD, and fenvalerate (P < 0.005) is found in the case group compared to its control group. OCP pesticides exhibit hormonal activity in various tissues with mechanisms involving the steroidogenic pathway, receptor-mediated changes in protein synthesis, or anti-androgenic and estrogenic actions. Most of their endocrine effects are as a result of their ability to mimic 17-β-estradiol and may lead to miscarriage, but the evidence is inconclusive. It was established that the lipophilic nature of OCP pesticides disturbs the normal estrogen-progesterone balance, which is particularly important in the maintenance of pregnancy. Pathak et al. reported that high β-HCH levels in cord blood were associated with preterm labor and high γ-HCH levels were associated with a higher risk of recurrent miscarriage. In the earlier literatures, it was well established that cyfluthrin, a synthetic pyrethroid is a most frequently detected pesticide in the contaminants of breast milk in India. Thus, these synthetic chemicals play a key role as a health risk to nursing infants. The concentration of a potent pesticide, chlorpyrifos in umbilical cord blood was negatively associated with birth weight, size, and neurodevelopment among infants born to low-income minority mothers. This significance showed that the levels of pesticides are associated with an increased risk or excess incidence of pregnancy loss in the female population.
    • pp.56-57
  • The current study demonstrates the importance of environmental factors in the context of RPL. Significantly higher levels of pesticides with endocrine-disrupting potential in cases suggest the possible role of these compounds as one of the causes of RPL. Increased pesticide level appears to indicate the increased levels of oxidative damage that has been associated with possible cause of RPL, and it may reflect indirect evidence of toxicity rather than a direct cause. However, our study has several limitations such as a small sample size. Moreover, we are also unable to determine if the observed association between γ-HCH and repeated miscarriages was due to the exposure of the mother during pregnancy or early childhood of an individual that affected their subsequent reproductive development. Furthermore, we must emphasize that toxicity depends on numerous additional factors such as genetic predisposition, dietary habits, and contamination with other pollutants. Hence, there is a need for further epidemiological studies with a larger cross-sectional population to be carried out to clearly determine the relationships between OCPs exposures and recurrent miscarriages along with the assessment of endocrine disruption, genetic polymorphism, and genetic environmental interaction.
    • pp.57-58

"Use of antidepressants during pregnancy and the risk of spontaneous abortion" (July 2010)[edit]

Hamid Reza Nakhai-Pour, Perrine Broy, and Anick Bérard, (July 2010). "Use of antidepressants during pregnancy and the risk of spontaneous abortion". CMAJ. 182 (10): 1031–7. doi:10.1503/cmaj.091208. PMC 2900326. PMID 20513781.

  • Background
    The risk of relapse of depression or the diagnosis of some other psychiatric disorders during pregnancy necessitates the use of antidepressants despite possible adverse effects. Whether such use increases the risk of spontaneous abortion is still being debated. We evaluated the risk of spontaneous abortion in relation to the use of antidepressants during pregnancy.
    • p.1031
  • Results
    A total of 284 (5.5%) of the women who had a spontaneous abortion had at least one prescription for an antidepressant filled during the pregnancy, as compared with 1401 (2.7%) of the matched controls (odds ratio [OR] 2.09, 95% confidence interval [CI] 1.83–2.38). After adjustment for potential confounders, we found that the use of antidepressants during pregnancy was associated with an increased risk of spontaneous abortion (OR 1.68, 95%CI 1.38–2.06). Stratified analyses showed that use of selective serotonin reuptake inhibitors alone (OR 1.61, 95% CI 1.28–2.04), serotonin–norepinephrine reuptake inhibitors alone (OR 2.11, 95% CI 1.34–3.30) and combined use of antide-pressants from different classes (OR 3.51, 95% CI 2.20–5.61) were associated with an increased risk of spontaneous abortion. When we looked at antidepressant use by type versus no use, paroxetine use alone (OR 1.75, 95% CI 1.31–2.34) and venlafaxine use alone (OR 2.11, 95% CI 1.34–3.30) were associated with an increased risk of spontaneous abortion.
    The use of antidepressants, especially paroxetine, venlafaxine or the combined use of different classes of antidepressants, during pregnancy was associated with an increased risk of spontaneous abortion.
    • p.1031
  • Antidepressants are widely used during pregnancy for the treatment of depression, anxiety, bipolar disease and pain. Up to 3.7% of pregnant women will use antidepressants at some point during the first trimester. Discontinuation of the medication during pregnancy can result in relapse of depressive episodes, which put the mother and fetus at risk.
    One out of four pregnancies ends in a clinically apparent spontaneous abortion. The majority of previous studies of antidepressants did not look at spontaneous abortion as a primary outcome, had small samples and therefore lacked statistical power, or had inherent biases owing to unmeasured confounders. Furthermore, the risk of spontaneous abortion associated with specific antidepressant classes, types and doses has not been adequately studied. Two recent reviews of the association between exposure to antidepressants during early pregnancy and the risk of spontaneous abortion reported contradictory findings.
    We investigated the risk of spontaneous abortion associated with different classes, types and doses of antidepressants during pregnancy, adjusting for indication for use.
    • p.1031
  • We investigated a dose–response relationship between the use of paroxetine (mean daily dose of 1–20, 20–25 or > 25 mg) and venlafaxine (mean daily dose of < 150 mg or ≥ 150 mg) and the risk of spontaneous abortion. These dosage categories have clinical significance and have been used in previous studies: higher mean daily doses of paroxetine have been associated with the risk of major congenital malformations, and a mean daily dose of less than 150 mg of venlafaxine has ternal chronic conditions, medication use suspected to have an adverse effect on the risk of spontaneous abortions, pattern of antidepressant use in the year before pregnancy and use of health care services in the year before or during pregnancy. To take into account the severity of the psychiatric disorders, we included as covariates the number of days antidepressants were prescribed and the number of visits to a psychiatrist in the year before pregnancy. To evaluate the robustness of our results, we conducted sensitivity analyses in which exposure to anti-depressants was defined from 30 days before the first day of gestation to the index date.
    • p.1032
  • We identified 69 742 pregnant women who met the inclusion criteria, 5124 (7.3%) of whom had a clinically detected spontaneous abortion. The mean gestational age at the index date was 10.5 weeks (standard deviation 2.2). Compared with the 51 240 matched controls, the women who had a spontaneous abortion were more likely to be older, to live in an urban setting, to be recipients of social assistance, to have a diagnosis of depression or anxiety, to have visited a psychiatrist during the year before pregnancy and to have a longer duration of exposure to antidepressants during the year before pregnancy. They also used more health care services during the year before pregnancy and were more likely to have diabetes mellitus and asthma. The prevalence of cardiovascular disease and untreated thyroid disease did not differ significantly between the two groups of women.
    • pp.1032,1034
  • Overall, 284 (5.5%) of the women who had a spontaneous abortion had filled at least one prescription for an anti-depressant during the pregnancy, as compared with 1401 (2.7%) of the matched controls (OR 2.09, 95% CI 1.83–2.38). After adjustment for potential confounders, we found that exposure to anti-depressants (v. no exposure) during pregnancy (OR 1.68, 95% CI 1.38–2.06) and a history of depression (OR 1.19, 95% CI 1.03–1.38) were factors independently associated with an increased risk of spontaneous abortion.
    The use of selective serotonin reup-take inhibitors alone (OR 1.61, 95% CI 1.28–2.04), serotonin–norepinephrine reuptake inhibitors alone (OR 2.11, 95% CI 1.34–3.30) and the combined use of more than one class of antidepressants (OR 3.51, 95% CI 2.20–5.61) were independently associated with an increased risk of spontaneous abortion. The risk of spontaneous abortion associated with these three categories of anti-depressant use was significantly higher than with tricyclic antidepressants or other antidepressants alone, with the magnitude of the adjusted OR ranging from 1.27 to 1.53 (p < 0.05).
    • p.1034
  • When we grouped women according to the specific antidepressant they received and compared them with non-users, paroxetine use alone (OR 1.75, 95% CI 1.31–2.34) and venlafaxine use alone (OR 2.10, 95% CI 1.34–3.30) were independently associated with an increased risk of spontaneous abortion. We found no significant difference in the risk of spontaneous abortion between specific types of selective serotonin reup-take inhibitors (p > 0.05).
    A higher mean daily dose of paroxetine or venlafaxine was associated with an increased risk of spontaneous abortion (p < 0.05), consistent with a dose–response relationship (Table 4). Our sensitivity analyses resulted in similar findings (data not shown).
    • pp.1034,1035
  • We found that antidepressant use during pregnancy was associated with a 68% relative increase in the overall risk of spontaneous abortion. Specifically, we observed significant associations with the use of selective serotonin reuptake inhibitors, particularly paroxetine, as well as with venlafaxine. Use of more than one class of antidepressant doubled the risk of spontaneous abortion. Furthermore, we observed an association between a higher mean daily dose of paroxetine or venlafaxine during pregnancy and an increased risk of spontaneous abortion, which is consistent with a dose–response relationship.
    • p.1035
  • Previous studies have produced inconsistent findings. Pastuszak and colleagues reported a nonsignificant increase in the prevalence of spontaneous abortion among pregnant women receiving selective serotonin reuptake inhibitors (14.8%) or tricyclic antidepressants (12.2%) compared with those who did not receive such medications (7.8%). Similarly, Djulus and colleagues observed a higher rate of spontaneous abortion among women exposed to mirtazapine or to other antidepressants than among nonusers, but none of the differences was statistically significant. In another study, involving 136 women exposed to bupropion early in their pregnancy, Chun-Fai-Chan and colleagues reported more spontaneous abortions in the bupropion group than in the comparison groups.
    In contrast, Chambers and colleagues observed no statistically significant difference in the occurrence of spontaneous abortion between women taking fluoxetine during pregnancy and pregnant women not taking the medication. Similarly, Kulin and colleagues observed no significant association between the use of antidepressants during pregnancy and the risk of spontaneous abortion among 92 women who received fluvoxamine in combination with other antidepressants compared with 267 pregnant women not taking antidepressants. Three other studies, involving 434 women in total, found no significant association between paroxetine use during gestation and the risk of spontaneous abortion. Einarson and colleagues found no statistically significant association between venlafaxine use during pregnancy and the risk of spontaneous abortion among 150 women.
    Two recent reviews reported contradictory findings. Gentile did not find a consistent statistically significant association between the use of serotonergic antidepressants during gestation and the risk of spontaneous abortion. However, Broy and Bérard, who also included studies published in 2009, reported an increased risk of spontaneous abortion associated with the overall use of antidepressants, specifically paroxetine and venlafaxine.
    • p.1035
  • Much remains unclear with regard to the exact mechanism of action, although it has been suggested that the effect of selective serotonin reuptake inhibitors on spontaneous abortion is probably mediated by a serotonergic mechanism.
    • p.1036
  • Some evidence suggests that pregnant women with depression are at increased risk of spontaneous abortion, which is similar to our findings. Although we adjusted for history of depression, anxiety and use of psychiatric services, we cannot completely exclude the possibility of residual confounding by underlying disease in the risk estimates for venlafaxine or for combined use of more than one class or type of antidepressant, because venlafaxine and antidepressant combinations are most often prescribed in severe cases of psychiatric disorders and in cases of drug-resistant disorders. Moreover, given the number of comparisons made in our study, we can- not rule out the possibility of chance findings in 5% of our statistically significant associations.
    Finally, even with our large sample, our analyses of specific classes and types of antidepressants may have missed significant associations because of lack of statistical power. Although the risk of spontaneous abortion was higher with the use of selective serotonin reuptake inhibitors during pregnancy than with the use of other antidepressant classes, we did not observe significantly different risks between specific types of selective serotonin reuptake inhibitors. These results, which suggest an overall class effect of selective serotonin reuptake inhibitors, are highly robust given the large number of users studied. However, comparisons with other selective serotonin reuptake inhibitors or tricyclic antidepressants or other antidepressants alone are less robust because of smaller numbers of users.
    • p.1036
  • The use of antidepressants during pregnancy, especially paroxetine and venlafaxine, as well as the combined use of more than one class or type of antidepressant, was associated with an increased risk of clinically detected spontaneous abortion in our study population. In addition, we observed an association between a higher mean daily dose of paroxetine or venlafaxine during pregnancy and an increased risk of spontaneous abortion, which is consistent with a dose–response relationship. In light of our results, physicians who have patients of child-bearing age taking antidepressants or have pregnant patients who require antidepressant therapy early in pregnancy may wish to discuss the risks and benefits with them.
    • p.1037

"Standard terminology for reporting of reproductive health statistics in the United States" (1988)[edit]

"Standard terminology for reporting of reproductive health statistics in the United States". Public Health Reports. 103 (5): 464–71. 1988. PMC 1478116. PMID 3140271.

  • Fetal Mortality Measures. The population at risk for fetal mortality is the number of live births plus the number of fetal deaths in a year. Alternatively, the number of live births alone is sometimes used as the population at risk. Fetal death indices indicate the likelihood that pregnancies in a population group would result in fetal death. It is recognized that most States report fetal deaths based upon gestational age. However, birth weight can be more accurately measured than gestational age. Therefore, minimum reporting requirements of fetal deaths based upon and labeled as to specific birth weight rather than gestational age are recommended for adoption by States (see Fetal Death in "Reporting Requirements/Recommendations" page 469.). In addition, statistical tabulations of fetal deaths should include, at a minimum, fetal deaths of 500 grams or more.
    • p.467
  • It is recognized that States will not be able to translate data from gestational age to weight immediately, and, for comparative purposes, it may be desirable to know fetal death rates for varying gestational time periods. Therefore, the collection of both weight and gestational age is recommended to allow for these comparisons. When calculating fetal death rates based upon gestational age, the number of weeks or more of stated or presumed gestation can be substituted for weight in the above formulae.
    • p.467
  • Fetal Death. Reporting requirements for fetal deaths now vary from State to State. At present, most States require reporting of fetal deaths by gestational age. It is generally recognized that birth weight can be more accurately measured than gestational age.
    It must be emphasized that a specific birth weight criterion for reporting of fetal deaths does not imply a point of viability and should be chosen instead for its feasibility in collecting useful data.
    Current statistical tabulations of fetal deaths, include, at a minimum, fetal deaths of 500 grams or more. Furthermore, all but three States now require either reporting of all fetal deaths or reporting of some fetal deaths below 500 grams, for example, those which fall below 500 grams because of the variation in birth weights at a given required gestational age such as 20 weeks. Therefore, it is recommended that
    * Statistical tabulations for comparisons of perinatal mortality rates within the United States exclude fetal deaths of less than 500 g.
    * Each State adopt a specific birth weight criterion for reporting of fetal deaths which will result in continued collection of data on as close as possible to 100 percent of the population of fetal deaths currently reported in that State. When birth weight is unknown, an estimate of gestational age should be utilized to determine whether or not this event is required to be reported.
    * All State fetal death report forms include birth weight and gestational age.
    • p.470

“Evidence Based Management in recurrent Pregnancy Loss” (2018)[edit]

Rashmi “Evidence Based Management in recurrent Pregnancy Loss” Ch. 15, Sumita Mehta; Bindiya Gupta (2018). Recurrent Pregnancy Loss. Springer.

  • Recurrent pregnancy loss (RPL) is defined as three pregnancy losses before the 20th week of gestation and excludes ectopic, molar, and biochemical pregnancies. The American Society of Reproductive Medicine (ASRM) recommends clinical evaluation following two first-trimester pregnancy losses [1]. RPL has been associated with factors reated to genetics; age; anatomic, immunological, congenital, and acquired thrombophilias; errors or metabolism; hormonal imbalance; infections; sperm parameters; and lifestyle issues. But still despite a thorough evaluation, 50% of cases of RPL will remain unexplained (Fig 15.1).
    Evaluation and treatment are generally started after two consecutive miscarriages,more so if the couple have had infertility treatment or when the woman is older than 35 years of age. RPL evaluation includes a complete history and diagnostic evaluation for all possible causes enumerated in Table 15.1. There is paucity of level one evidence in literature regarding the investigations to establish etiology and therapeutic interventions. The evidence-based treatment available will be discussed in this chapter.
    • p.181
  • 15.1 Genetic Factors
    Miscarriages due to chromosomal abnormalities either structural or numerical are seen in 30-57% of cases, most common being aneuploidy.
    • p.181
  • Congenital and acquired uterine anomalies are found in 10-15% of women with RPL compared with 7% of all reproductive-aged women. Of these uterine anomalies, untrauterine adhesions and uterine fibroids or polyps are the commonest.
    15.2.1 Congenital Uterine Anomalies
    A review of several studies found that congenital anomalies are present in 4.3% of normal population (range 2.75-16.7&) and in 12.6% (range 1.5-37.6%) of patients with RPL. A high rate of miscarriage occurred in patients with septate (n = 5499, 44.3% loss), bicornuate (n = 5627, 36.0% loss), and arcuate (n =5241, 25.7% oss) uteri.
    • p.183
  • 15.2.2 Acquired Uterine Abnormalities
    surgical intervention in patients with RP with acquired uterine abnormalities, such as adhesions, polyps, retained products of conception, and fibroids, is debated. Only fibroids that distort the uterine cavity, such as the ones located in the cavity and intramural fibroids with an intracavitary component, result in infertility and recurrent miscarriage. The role of myomectomy in smaller leiomyomas is unclear.
    Excessive curettage of endometrium of genital tuberculosis leads to intrauterine adhesions (Asherman’s syndrome) thus impairing implantation. There are no randomized controlled trials showing that surgical intervention ecreases the subsequqent miscarriage rate; however, the consensus is that hysteroscopic correction of these defects is helful because of the potential impact on subsequent fertility, miscarriage, and pregnancy outcomes.
    • p.184
  • 15.2.3 Cervical incompetence
    Cervical incompetence commonly causes pregnancy loss in the second trimester. Uterine abnormalities suc as septate or bicornuate uterus are causative in causing incompetence of cervix. It may also be acquired following conization, loop electrosurgical excision procedures, obstetric injury, and over-dilation of the cervix during termination of pregnancy. There are no diagnostic tests to confirm cervical insufficiency. Cervical incompetence is treated with expectant management, cervical cerclage, and/or progestogen therapy.
    According to a meta-analysis of four trials, cerclage in women with a history of previous preterm birth anda short cervix helps in continuation of pregnancy (Evidence level 1). The American College of Obstetricians and Gynecologists (ACOG) and Royal College of Obstetricians and Gynecologissts (RCOG) recommend that cerclage should be offere to women if their cervical length is less than 2.5 cm on ultrasound before 24 weeks gestation. This is more pertinent if such women have a history of one or more spontaneous midtrimester losses or preterm births. Women with history of three or more previous preterm births and/or econd-trimester losses should also undergo cerclage.
    The CERVO trial showed no added benefit of cervicalocclusion to cerclage Evidence supports emergency cerclage as cocmpared to bed rest (Evidence level III). Shirodkar technique for ultrasound-indicated cerclage is better ccompared to the McDonald cerclage in singleton pregnancies (Evidence level III). However, vaginal progesterone and mechanical pessary are equally effective when short cervix is detected on midtrimester scan (Evidence level II). Cervical length is not very accurate predictor of preterm delivery.
    • p.184-185
  • 15.3 Endocrinologic Causes of RPL
    Endocrine factor may contribute to 8-12% of recurrent pregnancy loss and s an evaluation for endocrine disorders should form part of workup of women with RPL.
    • p.185
  • 15.3.2 Diabetes Mellitus
    Poorly controlled diabetes is associated with pregnancy loss, and blood sugar should be properly controlled with insulin and.or oral hypoglycemic drugs like metformin and glyburide. Increase in early pregnancy loss and congenital malformatios is well correlated to high-glycosylated hemoglobin (HbA1C) values (>8%). In women with well-controlled diabetes mellitus, there is no increased risk of miscarriage.
    • p.185
  • 15.3.3 Hyperprolactinemia
    Hyperprolactinemia causes changed in hypothalamic-pituitary-ovarian axis, thereby impairing follicile formation, abnormal maturation of oocyte, and short luteal phase. A randomized trial demonstrated improvement in pregnancy outcomes after prolactin levels fell down to normal following treatment with dopamine agonist.
    • p.185
  • 15.3.4 Luteal Phase Deficiency
    Luteal phase deficiency (LPD) is defined as endometrial development unsuitable for embryonic implantation due to decreased progesterone levels due to corpus luteum insufficiency. The use of histologic and/or biochemical testing for iagnosis is unrealiable and not reproducible (Evidence level III). Therefore assessment for luteal phase defect in women with RPL is not advocated.
    • p.186
  • 15.3.5 Empirical Progesterone Supplementation
    Progesterone supplementation is usually given empirically in cases of RPL for not only to correct any undiagnosed luteal phase defect but also due to immunomodulatory role of the progesterone.
    A chochrane review of four small trials showed that owmen who received progesterone had a significantly lower risk of miscarraiges that those who received placebo or no treatment. A more reent double-blind, pacebo-controlled, randomized trial of oral dydrogesterone also showed that progesterone was helpful in reducing subsequent miscarriage. Rates of live births were not assesse in any of these trials. According to a large, randomized, placebo-controlled trial (Progesterone in Recurrent Miscarriages [PROMISE]), progesterone therapy in the first trimester of pregnancy does not significantly increase live births among women wih a history of unexplained recurrent miscarriages. In this study progesterone treatment was initiated after pregnancy confirmation, and so it is difficult to say whether progesterone supplementation could be more effective if fiven before pregnancy is confirmed, i.e., in the luteal phase.
    The types of progesterone supplements vary; but in general, intramuscular injections and vaginal suppositories are the most iwdley used. Oral progesterone is ineffeti ay increasing uterine progesterone levels. Recommendations differ on the timing of empirical progesterone supplement. Traditionally, progesterone administration as given after ovulation in the luteal phase.
    Although evidence demonstrating benefit is not very clear, progesterone supplementation is advisable as there is no harm following treatment. With the PROMISE trial’s results, routine use of progesterone in early pregnancy in cases of RPL doesn’t seem beneficial (Evidence level II). Routine use of progesterone is not recommended and is entirely based on clinician’s discretion (Evidence level III).
    • p.186
  • 15.3.6 PCO, Elevated LH, and Insulin Resistance
    Mechanisms of RPL include hypersecretion of basal LH and insulin resistance. The role of metformin for treatment in RPL is not clear. Some studies have shown that metformin may reduce insulin levels, thus reducing the risk of miscarriage by restoring normal hemostasis. In women with RPL and associated PCOS, metformin treatment is not advocated (Evidence level III).
    • p.186
  • 15.3.7 Diminished Ovarian Reserve
    iscarriages are increased in women with an increased level of follicile-stimulating hormone (FSH), a low anti-Mullerian hormone (AMH), and a diminished antral follicile count. Although these conditions cannot be treated, their presence should be followed up with appropriate counseling.
    • p.187
  • 15.4 Immune Factors in RPL
    Immune factors implicated as cause of RPL can be either autoimmune or alloimmune.
    15.4.1 Autoimmune Factors: Antiphospholipid Antibody Syndrome (APA)
    The treatment of documented APS consists of lw-dose aspirin (usually 75 mg daily) preconceptionally and heparin (usually 5000 units by subcutaneous injection twice a day) beginning with a positive pregnancy tet, reducing miscarriage rates by 54%. Aspirin or low-molecular weight herapin alone has not been found much useful.
    Glucocorticoids can be used in secondary APS with underlying connective tissue disorder. Obstetric outcomes in APS have not shown to improve and may be associated with an increased risk of getational hypertension and gestational diabetes after addition of prednisone.
    Multiple large randomized trials examining the use of heparin and/or aspirin in women with RPL not meeting strict criteria for APS have shown no difference in cinical outomes. Therefore, the use of heparin and aspirin should be limited to only women who have met both the clinical and laboratory criteria for APS.
    • p.187
  • 15.4.2 Alloimmune Factors (Immunitherapy)
    Although immunological mechanisms have been implicated as an important cause of RPL, there is no evidence for routine testing for immunological causes of recurrent miscrriages, and testing for peripheral blood natural killer (NK) cells and ccyttokine tests is not done (Evidence lvel I)
    Treatments designed to develop immune tolerance, such as paternal white bloo cell immunization (also known as lymphocyte immunization therapy), donor leukocytes, and trophoblast membranes, have not been shown to be effective at decreasing the risk of miscarriage and also do not increase the live birth rat.e Rnadomized controlled trials using intravenous immunoglobulin (IvIG) have shown them to be ineffective. Further sub-analyses revealed increased in the rates of live brith in secondary recurrent miscarriage with IvIG. Complications with IvIG include immunological side effects and risk of transmiting infections ike cyromegalovirus. Investigations and treatment for immunolological causes should be only in research context (Evidence level II).
    • pp.187-188
  • 15.4.3 Hereditary Thrombohilias
    Screening for inherited thrombophilias may be justified in patients with either a personal histry of thrombosis or a first-degree relative who is ahigh risk for thrombophilia and recurrent miscarriage. Unlike APS, the role of low molecular weight heparin for treatment of thrombophilia-related RPL is not very cclear due to lack of good-quality studies, and treatment is only recommened to prevent thromboembolism (Evidence level I).
    • p.188
  • 15.4.4 Hyperhomocyteinemia and MTHFR Mutation
    Testing for MYHFR mutation is routinely recommended (Evidence level II). The use of high-dose folic acid (5 mg) and vitamin B 12 (0.5 mg once daily) for treatment of recurrent miscarriage is not recommended, although they help reduce levels o homocysteine (Evidence level III).
    • p.188
  • 15.7 Environmenal and Psychological Factors
    Association between stress, environmental toxins, and addictions has not been shown to be significant. RPL is estraordinarily impactful on a patient’s emotional well-being, and awareness of the psychological needs of these patients is important. The grief nad sense of loss for these couples can manifest itself in all aspects of personal and work life and may impact uccess with future pregnancies. Lifestyle modification by improements in diet, exercise, abstinence from drugs, and stress reduction improve pregnancy outcomes (Evidence level III).
    • p.189
  • Microbiologic Factors as a Cause of RPL
    routine screening for infectious agents in patients with RPL is not recommended. The use of empirical antibiotics in patietns with asymptomatic RPL is not supported by randomized prospective studies.
    There is no need to test for TORCH group of infections when investigating recurrent miscarriage (Evidence level II) except syphilis which needs to be reated before next pregnancy.
    Bacterial vaginosis (BV) is an important risk factor for preterm delivery and later misccarriages, and screening for BV is recommended in women at high risk for the same. Oral clindamycin early in the second trimester is recommended for treatment (Evidence II).
    • p.189
  • 15.6 Male Factor
    Association between sperm DNA defragmentation and recurrent miscarriage is not significant, and tests are not recommended in clinical practice outside research settings (Evidence level II).
    • p.189
  • 15.8 Unexplained Recurrent Miscarriage
    In the absence of any caue for repeated miscarriages, unproven therapies, especially if they are invasive and expensive, should not be undertaken. Reassurance and emotional support are the most effective in such cases.
    15.8.1 Tender Loving Care and Lifestyle Advice.
    The strategy of emotional support and reassurance works well in unexplained cases as even no treatment shows a good prognosis in 60-80% cases (Evidence level III). Some small prospective studies have showna positive influence in patients with RPL with the use of tender loving care (TLC) defined as psychological support with weekly medical and ultrasound.
    • p.189
  • 15.8.2 Drug Therapy
    There is no role of aspirin in unexplained RPL (Evidence level II). As mentioned earlier, after the PROMISE trial, there seems to be no role of progesterone in cses of RPL (Evidence level II) Further evidence is required whether progesterone started in luteal phase is helpful (Evidence level III). The role of LMWH is only established in APS, and its use in other clinical situations of preventing RPL is not recommended (Evidence level II). Evidence lso fails to support the use of hCG for preventing miscarriages (Evidence level II). The evidence to recommend the use of steroids, IV ummunoglobulins, or intralipid for unexplained recurrent miscarriage is weak (Evidence level III).
    • p.189
  • To conclude, treatment for recurrent miscarriage is still an obstetrician’s dilemma as there is lack of randomized studies and multicenter trials, and treatment strategies are still based on expert opinions.
    • p.190
  • Key points
    Couples with unexplained recurrent miscarriage have a high chance of a successful outcome with empathic care and support and no medical treatment.
    The role of surgical correction of uterine anomaly is not well established in imporiving pregnanc outcomes.
    Antiphospholipid syndrome is successfully treated with aspirin and heparin; however, the role in inherited thrombophilia is not well established.
    routine chromosomal analysis of produccts of conception is not recommende din resource poor settings although it may yield useful prognostic information.
    Balanced translocations are seen in 2-4% patients and is of limited clinical relevance.
    Role for immunotherapy is limited. Role of metformin, hCG, and progesterone therapy is also unclear.
    • p.190
  • Genetic counseling and screening
    All patients should undergo genetic counseling and karyotyping of products of conception
    Amniocentesis: all women of advanced maternal age
    Parental karyotyping: This is done when karyotyping of the abortus is abnormal or in men with family history of genetic abnormalities
  • ACAs (IgG and igM) and lupus anticoagulant
    Should be done in all women, before the enxt pregnancy. At least two readings 6-8 weeks apart should be undertaken
  • Mullerian anomalies
    Prelvic ultrasound and hysteroscopy should be done in all patients
    Treatment is according to the anomaly detected
    Universal screening for syphilis and bacterial vaginosis in women with risk of preterm delivery and late recurrent miscarriage

TSH, fasting glucose/HbA1c
Routine screening is recommended in all women with RPL

  • ACAs anticardiolipin antibodies, TSH thyroid-stimulating hormone, HbA1c glycosylated hemoglobin
  • Table 15.3 Evidence-base workup of couples with recurrent pregnancy loss, p.191

“Exposure to dirty air in the world’s most polluted region linked to pregnancy loss, study finds” (January 6, 2021)[edit]

Helen Regan, “Exposure to dirty air in the world’s most polluted region linked to pregnancy loss, study finds”, CNN, (January 6, 2021)

  • Pregnant women in South Asia who have been exposed to air pollution face an increased risk of pregnancy loss, miscarriage, and stillbirth, according to a new study.
    Researchers found that an estimated 349,681 pregnancy losses each year across India, Bangladesh and Pakistan were associated with bad air quality.
    Published in the Lancet Planetary Health journal on Wednesday, the study suggests that if these countries met India’s air quality standard, it could have prevented 7% of the annual pregnancy losses.
    Dirty air has previously been linked to increased miscarriages, premature births and low birth weights among infants, as a result of the effects of pollution on the mother. Other research has found that pollution can breach a mother’s placenta and potentially reach fetuses in the womb.
    But the study is believed to be the first of its kind to quantify the effect of ambient pollution on pregnancy loss in South Asia (one of the most polluted regions on Earth) and the authors say their findings are important for improving public and maternal health, particularly in low income countries.
  • “South Asia has the highest burden of pregnancy loss globally and is one of the most PM2.5 polluted regions in the world. Our findings suggest that poor air quality could be responsible for a considerable burden of pregnancy loss in the region, providing further justification for urgent action to tackle dangerous levels of pollution,” said lead author of the study, Dr. Tao Xue, who is assistant professor at Peking University, China.
    PM2.5 is tiny particulate pollution that can move deep into the lungs when inhaled and enter the bloodstream. The particles, made up of dust, dirt, soot or smoke, originate from construction sites, unpaved roads, fields, smokestacks or fires, and can contain different chemicals. But most particles are a mix of pollutants from power plant, industrial and vehicle emissions.
  • Researchers focused on these tiny pollution particles. They found between 2000 and 2016, 7.1% of pregnancy losses in South Asia were attributable to the mothers being exposed to air pollution that exceeded India’s current air quality standard of 40 micrograms per cubic meter of air.
    For air pollution above the World Health Organization’s air quality guidelines, which recommends the safer 10 micrograms per cubic meter of air, exposure may have contributed to 29% of pregnancy losses, the study found.
    Expectant mothers from rural areas or those who were older were at greater risk than young mothers from urban areas, the study found. And pregnancy loss associated with air pollution was more common in the Northern plains region in India and Pakistan.
  • The authors say worse air quality can increase the burden of pregnancy loss in low and middle-income countries, so improving pollution levels could reduce miscarriages and stillbirths and lead to knock-on improvements in gender equality.
    “We know losing a pregnancy can have knock-on mental, physical and economic effects on women, including increased risk of postnatal depressive disorders, infant mortality during subsequent pregnancy, and increase the costs related to pregnancy, such as loss of labour,” said co-author Dr. Tianjia Guan, from the Chinese Academy of Medical Sciences and Peking Union Medical College.
    The study cautions that more research is needed to establish causality between pollution and pregnancy loss as they said the survey data is subject to recall bias. The researchers were also not able to distinguish between natural pregnancy loss and abortions. They also note that there was under reporting of natural pregnancy losses because of stigma or ignoring very early miscarriages.

"REPUBLIC ACT No. 11210"[edit]

  • Maternity leave shall be granted to female workers in every instance of pregnancy, miscarriage or emergency termination of pregnancy, regardless of frequency: Provided, That for cases of miscarriage or emergency termination of pregnancy, sixty (60) days maternity leave with full pay shall be granted.
  • Maternity leave of sixty (60) days, with full pay, shall be granted for miscarriage or emergency termination of pregnancy.
  • Any pregnant female worker in the private sector shall be granted a maternity leave of one hundred five (105) days with full pay, regardless of whether she gave birth via caesarian section or natural delivery, while maternity leave of sixty (60) days with full pay shall be granted for miscarriage or emergency termination of pregnancy.
  • (5) That if a female worker should give birth or suffer a miscarriage or emergency termination of pregnancy without the required contributions having been remitted for her by her employer to the SSS, or without the latter having been previously notified by the employer of the time of the pregnancy, the employer shall pay to the SSS damages equivalent to the benefits which said female member would otherwise have been entitled to.
  • Maternity leave with full pay shall be granted even if the childbirth, miscarriage, or emergency termination of pregnancy occurs not more than fifteen (15) calendar days after the termination of an employee’s service, as her right thereto has already accrued: Provided, That such period is not applicable when the employment of the pregnant woman worker has been terminated without just cause, in which case the employer will pay her the full amount equivalent to her salary for one hundred five (105) days for childbirth and sixty (60) days for miscarriage or emergency termination of pregnancy based on her full pay, in addition to the other applicable daily cash maternity benefits that she should have received had her employment not been illegally terminated.
  • Whoever fails or refuses to comply with the provisions of this Act shall be punished by a fine of not less than Twenty thousand pesos (₱20,000.00) nor more than Two hundred thousand pesos (₱200,000.00), and imprisonment of not less than six (6) years and one (1) day nor more than twelve (12) years or both. If the act or omission penalized by this Act shall be committed by an association, partnership, corporation, or any other institution, its managing head, directors, or partners shall be liable to the penalties provided in this Act for the offense.
    Failure on the part of any association, partnership, corporation, or private enterprise to comply with the provisions of this Act shall be a ground for non-renewal of business permits.

“The high abortion cost of human reproduction” (July 18, 2018)[edit]

William R. Rice, “The high abortion cost of human reproduction”, (July 18, 2018)

  • Information from many large data bases and published studies was integrated to estimate the age-specific spontaneous abortion rate in an economically-developed human population. Accuracy was tested with published data from a diverse array of studies. Spontaneous abortion was found to be: i) the predominant outcome of fertilization and ii) a natural and inevitable part of human reproduction at all ages. The decision to reproduce is inextricably coupled with the production of spontaneous abortions with high probability, and the decision to have a large family leads to many spontaneous abortions with virtual certainty. The lifetime number of spontaneous abortions was estimated for a “canonical” woman (constrained to have average age at marriage, first birth, inter-birth intervals, and family size) in two populations: one with and the other without effective birth control (including free access to elective abortions). Birth control was found to reduce lifetime abortions more than 6-fold.
    • p.1
  • Abortion is one of the most socially contentious issues in the United States and many other parts of the world. This overarching social influence underscores the need to fully understand the intrinsic scope and role of abortion in human reproductive biology. To date there is only one statistically rigorous estimate of the age-specific rate of spontaneous abortion in humans (that includes both clinically detected and earlier, occult [unperceived] abortions), and this was based on women living in an economically-undeveloped country. The sample size was large for a single study (all or part of 329 pregnancies were assayed): nonetheless this level of sampling represents an average of only 11 pregnancies screened per yearly age class (spanning 30 reproductive years). The purpose of this paper is to integrate recent data from many disparate sources to assess the rate of spontaneous abortion in a near-contemporary, economically developed population. With this synthesis I will: i) estimate the age-specific rate of spontaneous abortion in a European population with an exceptionally large (nation-wide) data base of medical records, ii) test the accuracy of this estimate with data from independent studies, iii) quantify the age-specific cost–in the currency of number of spontaneous abortions– of producing a newborn, iv) evaluate the influence of modern birth control –including elective abortions– on the expected number of abortions per lifetime.
    • pp.1-2
  • Despite the women coming from different continents, time periods and socioeconomic and nutritional conditions, and the difference in units (probability of a newborn per year vs. probability of an abortion per pregnancy) there is a virtually perfect negative correlation between births and abortions. This strong pattern has motivated the hypothesis that spontaneous abortion plays a predominant role in shaping the age-specific pattern of human fertility (i.e., the Wood-Boklage-Holman hypothesis:). That it is an elevated abortion rate of conceptuses from older eggs of older women that causes fertility decline with advancing age in human females –rather than deterioration of other aspects of a woman’s reproductive anatomy and physiology– is supported by data from assisted reproductive technology clinics. The capacity to carry an embryo (from in vitro fertilization) to birth declines precipitously with age only when a woman uses her own eggs: not when she uses eggs from a young egg donor.
    • pp.2-3
  • After accounting for spontaneous abortions that do not result in hospitalization, the detected rate of abortion would nonetheless only be a metaphorical tip of a much larger iceberg if most abortions occurred before a pregnancy could be clinically detected (this time point was ~3 weeks post-conception during the time period covered in Figs. 1 and 3). In the 1980s, a succession of laboratory studies using highly sensitive assays for human chorionic gonadotropin (hCG, produced by the human conceptus starting at implantation, and rapidly increasing above non-pregnancy levels as the implanted embryo develops) were used to detect pregnancies and abortions earlier than the standard clinical detection point (at ~2 weeks post conception). The “gold standard” study with the best design and appropriate controls was that of Wilcox et al. in late 1980s which found that 31% of detected pregnancies aborted (62 abortions/198 pregnancies), with 9% after clinical pregnancy detection and 22% pre-clinical detection. To account for the preclinical abortions detected by studies like that of Wilcox et al., I have added 22 occult abortions per 9 clinically detected abortions (adjusted for a 20% lack of hospitalization) to the graph in Fig. 3 (curve 3). Studies like that of Wilcox et al. clearly demonstrate that most abortions are occult (occurring before a pregnancy is clinically detected) but could not measure preimplantation abortions nor those that occurred soon after implantation, so a substantial number of spontaneous abortions may have been undetected.
    • p.5
  • One way to further improve the estimate of the abortion rate is to account for at least some of the occult abortions that are not detected by high-sensitivity comes from studies comparing aneuploidy in very young embryos (cleavage stage and blastocysts) to conceptuses that spontaneously aborted after a pregnancy had been clinically detected. At the early embryo stages, monosomy (missing one homolog from one or more of the 23 pairs of homologous chromosomes) and trisomies (a extra chromosome at one or more of the 23 pairs of homologous chromosomes) were found to be equally common. But among conceptuses that survive to clinical detection, and then abort, essentially no autosomal monosomies were observed (<<1%). This repeated finding demonstrates that all autosomal monosomic conceptuses spontaneously abort before a pregnancy can be detected by elevated levels of hCG, i.e., prior to implantation. As a consequence, for every observed aborted conceptus that carried one or more trisomies after clinical detection, there must have been one occult aborted conceptus due to one or more monosomies. At least 50% of aborted fetuses are karyotypically abnormal and at least 60% of these carry one or more trisomies. There are therefore at least 0.5*0.6* = 0.3 occult abortions due to monosomy for every detected post-implantation abortion. In Fig. 3, I have added these additional occult abortions to the total.
    • pp.5-6
  • There have been many studies estimating the maximum probability of a clinically detected pregnancy per menstrual cycle that includes sexual intercourse, but I focused on this study because it reports age-specific values, rather than a single value that was pooled across all ages. The sample size is substantial: 647 women, 2,939 menstrual cycles, and 433 detected pregnancies. The highest pregnancy rate occurred when couples had sexual intercourse two days prior to the estimated day of ovulation (estimated by both shifts in core body temperature and patterns of vaginal mucus discharge), and in this case the estimated probability of producing a detectable pregnancy was 0.53, 0.42, 0.36, and 0.29 for age categories (in years) of 19-26, 27-29, 30-34, and 35-39, respectively. The complementary probability for each of these values can be used to estimate the upper limit for the age-specific occult abortion rate. It is an upper limit because this estimate implicitly assumes that fertilization was 100% successful during each menstrual cycle that had an optimal timing of sperm delivery, so that all “no pregnancy” events were due to occult abortions. An upper bound for the total abortion rate is 1- (maximum pregnancy rate) + ([maximum pregnancy rate] * [proportion of the detected pregnancies that result a clinically detected abortion]), this latter term is calculated using curve 2 in Fig. 3. Using the mid-range of each age category, I have used these values to calculate the estimated upper bounds for total abortion rate (clinical + occult) in Fig. 3. The true (unbiased) curve for abortion rate vs. age is expected to be somewhere between the estimated upper ceiling and estimated lower floor.
    • pp.6-7
  • Boklage’s estimate of this survival function was: Pt = 0.73 e -0.1557*t + 0.27 e -0.0004*t where Pt is the probability of a conceptus surviving to time t, and t is days since conception. The value 0.73 is the estimated proportion of high-risk conceptuses (presumed to have abnormal karyotypes) with a rapid decay in survival with age, and 0.27 the proportion of normal-risk conceptuses with much higher daily survival (presumed to have normal karyotypes). Using this equation, the average abortion rate is 0.757. I have denoted this estimate by the circle labeled “B” in Fig. 3, centered over the age of 29 (the average age of women in the study by Wilcox). This value is well above the maximum abortion rate predicted by the data from clinically detected pregnancy rates when sperm is delivered at the optimal time.
    • pp.7-8
  • An alternative way to make use of the Bokeman equation is to use it to estimate the ratio of occult to clinically detected pregnancies. Assuming clinical pregnancy detection at 21 days post conception, the ratio of occult to clinical pregnancies is 13.15 to one (using a later pregnancy detection time would increase the ratio).
    • p.8
  • [T]here is strong biological support for the two-category (high and low mortality) model of conceptus mortality because cytogenetic studies of aborted conceptuses consistently find a high proportion that are karyotypically abnormal, and nearly all conceptuses with one or more monosomies or trisomies abort.
    To obtain an unbiased and statistically rigorous estimate of the age- specific abortion rate, Darryl Holman and James Wood designed and implemented a study to directly estimate the age- specific abortion rate in a natural fertility population in Bangladesh. Their analysis allows for the existence of two biologically distinct categories of conceptuses, each with its own distinct survival curve: one type with an abnormal karyotype that causes a rapid, exponential decline in surviving embryos over time (nearly all of these conceptuses would be expected to abort within 6 weeks of age), and another type with a normal karyotype that has a much less steeply declining exponential decay function (due to all other causes of pre-term mortality).
    • p.8
  • To utilize the exceptionally high quality data from the Holman and Wood study, I next focused on their estimate of the proportion of total abortions that were occult vs. clinically detectable. If women in Bangladesh had higher abortions rates because less favorable environmental conditions produced higher abortion rates throughout pregnancy (irrespective of conceptus category –karyotypically normal or abnormal), then the ratio of occult to total abortions would be expected to be far more similar to that of the Danish population compared to total abortion rates. Using these estimates (Fig. 8.17 from Holman 1996), the estimated ratio of total abortions (i.e., clinical + occult) to clinically detected abortions (clinical) was 6.258, 8.318, 9.280, and 9.706 for age 18, 28, 38, and 48 respectively, assuming a clinical detection of pregnancy on day-21 post- conception in the Danish data set. Using a cubic-spline to interpolate intervening values, I have plotted Holman-Wood- adjusted abortion rates for the Danish data set in Fig. 3. I consider this curve to be a potentially unbiased estimate of the human age-specific abortion rate in Denmark.
    • p.9
  • The first data source is a one-of-a- kind study in which Labarta et al. collected 46 eggs from egg donors without chemical stimulation (that is routinely used in assisted reproductive technology [ART] clinics to induce multiple ovulated eggs per menstrual cycle). Egg donors are healthy, fertile women who donate eggs to be used by other couples who are experiencing fertility problems. This study therefore eliminates any elevation in chromosomal abnormality rate that may be an artifact of: i) women using ART clinics not being a random sample of the population as a whole, and ii) chemical stimulation of the mother to ovulate multiple follicles during a single menstrual cycle. To guarantee fertilization, each egg was fertilized via intracytoplasmic sperm injection (ICSI), and then a cell from a 3-day old embryo was screened via FISH (fluorescence in situ hybridization) for ploidy level for nine chromosomes (13, 16, 18, 21, 22, 15, 17, X, and Y). Sampling a single cell from an embryo may produce an inaccurate estimate of the proportion of karyotypically abnormal embryos due to mosaicism, but in this study the researchers reanalyzed samples of embryos scored as karyotypically abnormal on day-3 (based on a single cell) again on day-5 (scoring every cell in the embryo) and found 92% concordance (i.e, 92% of all day-3 embryos scored as abnormal –by assay of a single cell–were also scored the same two days later when all cells were measured), so this potential problem was not substantial. The proportion of embryos displaying abnormal karyotypes was 34.8% (16 of 46). Munne et al. used a combination of 12 chromosome FISH as well as comparative genomic hybridization (CGH, which measures ploidy at all chromosomes simultaneously with 98.1% accuracy) to show that the 9 chromosome FISH protocol used by Labarta et al. would be expected to detect 72.65% of all karyotypically abnormal embryos: so the true karyotypic abnormality rate in the unstimulated sample is estimated to be 100*(.348 / .7265) = 47.9%. The mean age of the oocyte donors (± SD) was 25.4 ± 4.0 years old, so in Fig. 3 I have denoted this estimate for the spontaneous abortion rate (weakly downwardly biased, since it would not include karyotpically normal aborted conceptuses) by a green circle above age 25.4. There is a close match between the estimated proportion of karyotypically abnormal embryos and the HW-adjusted curve for abortion rate.
    • p.10
  • In a parallel treatment of the same egg donors with a “moderate” dose of gonadotropins for ovarian stimulation (150 IU FSH and 75 IU human menopausal gonadotropin), the number of eggs analyzed was increased to 303 and the estimated percent of karyotpically abnormal embryos (after adjustment for screening only 9 chromosomes) was 52.6% (which did not differ statistically from the unstimulated sample of 46 eggs, P = 0.64). I have denoted this larger-N estimate of the spontaneous abortion rate (also weakly downwardly biased, since it would not include karyotpically normal aborted conceptuses) by a black circle at age 25.4. Again, there is close agreement with the WH-adjusted abortion rate.
    • pp.10-11
  • There is empirical evidence that ovarian stimulation (used to generate eggs for in vitro fertilization) increases aneuploidy rate, although other studies found no effect, so the estimates for embryonic aneuploidy used to check the accuracy of the WH-adjusted abortion curve may be biased upward.
    • pp.11-12
  • It is reasonable to assume that –in women with normal fertility– the fate of each conceptus is independent of the fate of previous conceptions because its fate depends predominantly on its karyotype –which is determined by a new draw from the pool of dormant oocytes and and a new draw from the sperm donor. In this case, the number of failures (abortions) that occur before the first success (newborn) will follow a negative binomial distribution (NB[r,p]) with parameters r = 1 = one live birth, and p = the probability of a newborn, i.e. number abortions per newborn ~ NB(1,prob newborn). The mean of a NB(1,p) distribution is its odds ratio = (1-p)/p and its variance = (1-p)/p2 . For example, at age 32, the HWadj -curve predicts a 60% probability of a conception ending in an abortion, so the average number of abortions per newborn is 0.6/0.4 = 1.5 and the variance 0.6/0.42 = 3.75 and the standard deviation = √3.75 = 1.94.
    • p.13
  • One of the most extensive data sets for women following a natural fertility mode comes from the detailed records kept by frontier Mormons during their population expansion in the Western United States. From these records the distribution of family sizes and inter-birth intervals for these families has been tabulated by Anderton & Bean. Using the average marriage age of a woman, average birth intervals and family size during a period when the population remained under natural fertility conditions (the 1840s) reported in and, the abortions per lifetime can be calculated for a “canonical” frontier Mormon woman. This value is the sum of eight NB(1,pi) values, where pi is one minus the expected abortion rate taken from the HWadj -curve in Fig. 3. This sum is 16.8 abortions per lifetime. It is reasonable to apply the HWadj -curve from Fig. 3 to frontier Mormons because this population was composed primarily of people with western European ancestry (including many Danes and other Scandinavians) and because this population was well nourished.
    If I had included variation in marriage age and birth intervals, the average of 16.8 abortions per lifetime would be increased because the curve of abortions per newborn has a positive second derivative, causing random variation to earlier times to have a smaller reducing effect on lifetime abortions than the increasing effect of random variation to later times. This is especially relevant for the last few children produced because of the steep rise in abortions per newborn after age 35. By constraining the “canonical” woman to have the average birth interval between each of eight newborns, a woman’s last conception occurs at age 39. If a last child were produced during the early forties, or sexual intercourse continued into this time period after a last child was produced in her late thirties, the high ratio of abortions per newborn at these elevated ages would cause a substantial increase in her abortions per lifetime. So, the value 16.8 abortions/lifetime reported here for a “canonical” frontier Mormon woman is conservative –probably to a high degree.
    • pp.14-15
  • To estimate the variation about the mean value of 16.8 abortions per lifetime for a canonical woman, I have generated 100,000 random samples of eight NB(1,pi) values (with pi determined from Fig. 3 using the average ages at marriage and birth of each of 8 children and then tallied their sum in Fig. 4, red histogram. This distribution of abortions per lifetime for a canonical frontier Mormon woman (constrained to have average age at marriage, family size and birth intervals) shows that it would not be uncommon (i.e., >20% of the time) for a woman following a natural fertility birth pattern to have more than 23 abortions per lifetime.
    For comparison, I calculated the abortions per lifetime for a canonical Danish woman –who would have had free access to modern birth control and elective abortions up through week 12 of gestation– during the time frame when the abortion data reported in Figs. 1 and 3 were measured. These woman had an average family size of 1.7 children with an average of 0.37 elective abortions per newborn. The distribution in Fig. 5-blue (including 0.37 elective abortions per newborn added as a binomial random variable) has a mean of 2.51 abortions per life time, and the 95% upper bound of the distribution (6.3 abortions per lifetime) is far less than the average for the frontier Mormon women, i.e. the frontier Mormons had 570% more lifetime abortions. So modern birth control, even when elective abortions of early-stage conceptuses are legally and freely available, leads to markedly fewer abortions per lifetime compared to natural fertility.
    • p.15
  • One of the striking features of the calculations displayed in Figs. 3-5, and a conclusion reached in earlier studies is that the predominant outcome of fertilization in a human female adhering to a natural fertility program is abortion: in my canonical analysis of frontier Mormons, on average, abortions outnumbered newborns by more than a factor of two.
    • p.15
  • Abortion, in the form of a miscarriage during a clinically detected pregnancy, is the exception rather than the norm, when one excludes older women or those with a predisposing medical condition. This observation leads to the intuitive conclusion that spontaneous abortion is a fairly uncommon reproductive anomaly in humans. However, studies in the 1980s using highly sensitive assays for cGH clearly demonstrated that most spontaneous abortions are occult and go completely unnoticed by women. Subsequent studies estimating total abortion rate made a strong case that spontaneous abortions are common in humans, even at young ages. The most comprehensive data, including maximum likelihood estimates of all relevant parameters, came from a natural fertility population in Bangladesh. The data that I surveyed in this study expands the previous work by integrating many very large data sets to estimate the age-specific abortion rate (and test the estimate’s accuracy) in a near-contemporary population from an economically developed country. This analysis corroborates the previous studies and thereby empirically reaffirms the conclusion that spontaneous abortion is a common and fundamental component of human reproduction at all ages.
    • p.16
  • [T]here is no a priori reason to expect spontaneous abortion rates to be identical between populations experiencing markedly different nutrition, socio-economic conditions, and access to modern medicine –and as would be expected, the spontaneous abortion rate is estimated to be higher in the population experiencing less optimal conditions.
    • p.16
  • The estimated curve for age-specific abortion rate can be used to estimate the cost, in the currency of spontaneous abortions, of producing a newborn. The curve shows why, in humans, a choice to produce one or more newborns must come at a considerable abortion cost. Abortion is nearly as common as live-birth for conceptions that occur in a woman’s early-twenties, but after the mid-twenties, abortions are the norm rather than the exception.
    • p.17
  • A synthesis of many large-scale studies from the last 15 years unambiguously confirms the Wood-Boklage-Holman hypothesis that abortion is an intrinsic and overarching component of human reproduction. It is the most common outcome of conception across a woman’s lifetime and the predominant factor controlling age-specific variation in human female fertility. To reproduce, a human female cannot forgo a high risk of abortion, and to have a large family it is virtually impossible to avoid multiple abortions. Modern birth control with access to elective abortions, markedly reduces –rather than increases– the lifetime number of abortions a woman produces.
    • p.17

"Pregnancy loss" (January 2014)[edit]

Robinson GE (January 2014). "Pregnancy loss". Best Practice & Research. Clinical Obstetrics & Gynaecology. 28 (1): 169–78. doi:10.1016/j.bpobgyn.2013.08.012. PMID 24047642. S2CID 32998899.

  • Women who lose desired pregnancies by miscarriage, stillbirth, or genetic termination are at risk of suffering from grief, anxiety, guilt and self-blame that may even present in subsequent pregnancies. It is important to find effective means of helping women deal with these losses. The approach to stillbirth has shifted from immediately removing the child from the mother to encouraging the parents to view and hold the baby. This approach has been questioned as possibly causing persistent anxiety and post-traumatic stress disorder. Women who miscarry are currently encouraged to find ways to memorialise the lost fetus. Couples who decide to terminate a pregnancy after discovering a defect may deal not only with sadness but also guilt. Immediate crisis intervention and follow-up care should be available, recognising that individual women may experience different reactions and their specific post-loss needs must be assessed.
  • The loss of a desired pregnancy by miscarriage, stillbirth or termination for genetic indications can result in grief, guilt, self-doubt, anxiety and post-traumatic stress disorder (PTSD). These losses may result in immediate and long-term psychological consequences. Caregivers need to identify the best practices for managing women and their partners who have experienced such losses. Recent research has raised questions about the efficacy of practices that have become the standard of care in many settings.
  • Miscarriage or spontaneous abortion is defined as an unintended termination of pregnancy resulting in fetal death before 20 weeks of gestation. The overall incidence is 15–20%; 27% in women between aged between 25 and 29 years and 75% in women aged over 45 years [1]. About three-quarters of losses occur before week 12. Although the causes of these losses are numerous, in the case of a first or second miscarriage, causes are seldom investigated and often remain unknown.
  • Unwanted pregnancy loss may be associated with a great deal of pain and grief. Each type of loss has similarities and differences. All may be associated with grief, anxiety, fear of future infertility, and difficulties in seeing the pregnancies or babies of others. Whether unanticipated, such as miscarriage or stillbirth, or chosen, such as genetic terminations, the losses tend to be associated with guilt and self-blame. The effect of these losses is not associated with the length of gestation.

"Miscarriage misconceptions boost feelings of guilt and shame, study says" (2015)[edit]

Haroon Sadique, "Miscarriage misconceptions boost feelings of guilt and shame, study says", The Guardian, (11 May 2015)

  • A significant number of the respondents were under misapprehensions as to what caused the loss of the pregnancy. Three-quarters believed that a stressful event could bring about a miscarriage, 64% thought that lifting a heavy object could be a cause, and a fifth that previous use of oral contraceptives could induce pregnancy loss.
  • Of those who took part 15% said they or their partner had suffered a miscarriage, but the majority of respondents (55%) believed that miscarriages are uncommon (defined as less than 6% of all pregnancies). The truth is that miscarriages end one in four pregnancies and are by far the most common pregnancy complication, the paper says.
    A fifth of people incorrectly believed that lifestyle choices during pregnancy, such as smoking or using drugs or alcohol, were the single most common cause of miscarriage, more common than genetic or medical causes. In reality, 60% of miscarriages are caused by a genetic problem.
  • The authors concluded: “Patients who have experienced miscarriage may benefit from further counseling by healthcare providers, identification of the cause, and revelations from friends and celebrities. Healthcare providers have an important role in assessing and educating all pregnant patients about known prenatal risk factors, diminishing concerns about unsubstantiated but prevalent myths and, among those who experience a miscarriage, acknowledging and dissuading feelings of guilt and shame.”

"The investigation and treatment of couples with recurrent miscarriage" (May 2003)[edit]

Royal College of Obstetricians and Gynaecologists (May 2003). "The investigation and treatment of couples with recurrent miscarriage". Green-top Guideline No. 17.

  • 1. Purpose and scope
    Recurrent miscarriage is defined as the loss of three or more pregnancies. Recurrent miscarriage is a heterogeneous condition that has many possible causes; more than one contributory factor may underlie the recurrent pregnancy losses.
    The purpose of this guideline is to review the literature and provide guidance on the investigation and treatment of couples with recurrent miscarriage.
    • p.1
  • 3. Introduction and background
    Recurrent miscarriage is a distressing problem that affects 1% of all women. This incidence is greater than that expected by chance alone, since 10–15% of all clinically recognised pregnancies end in a miscarriage 2 and the theoretical risk of three consecutive pregnancy losses is 0.34%. Hence, only a proportion of women presenting with recurrent miscarriage will have a persistent underlying cause for their pregnancy losses. Maternal age and previous number of miscarriages are two independent risk factors for a further miscarriage. Advanced maternal age adversely affects ovarian function, giving rise to a decline in the number of good quality oocytes, resulting in chromosomally abnormal conceptions that rarely develop further.
    • p.1
  • 4. Investigations and treatments
    4.1 Genetic factors
    All couples with a history of recurrent miscarriage should have peripheral blood karyotyping performed. The finding of an abnormal parental karyotype should prompt referral to a clinical geneticist.
    In approximately 3–5% of couples with recurrent miscarriage, one of the partners carries a balanced structural chromosomal anomaly. The most common types of parental chromosomal abnormality are balanced reciprocal or Robertsonian translocations. The identification of an abnormal parental karyotype warrants prompt referral to a clinical geneticist. Genetic counselling offers the couple a prognosis for future pregnancy, familial chromosomal studies, counselling and appropriate prenatal diagnosis in future pregnancies where there is a 5–10% chance of a pregnancy with an unbalanced translocation. Recently, preimplantation genetic diagnosis has been explored as a treatment option for translocation carriers. However, this is a technically demanding procedure and experience is still limited. Since the technique necessitates that the couple undergo in vitro fertilisation (IVF) to produce embryos, couples with proven fertility need to be aware of the low implantation and live birth rates per cycle following IVF. Further, they should be informed that they have a 40–50% chance of a healthy live birth in future untreated pregnancies following natural conception.
    In all couples with a history of recurrent miscarriage cytogenetic analysis of the products of conception should be performed if the next pregnancy fails.
    Recurrent pregnancy loss may be due to an abnormal embryo, which is incompatible with life, e.g. chromosomal abnormalities or structural malformations. As the number of miscarriages increases, the prevalence of chromosomal abnormality decreases and the chance of recurring maternal cause increases. If the karyotype of the miscarried pregnancy is abnormal, there is a better prognosis in the next pregnancy. Cytogenetic testing is an expensive tool and may be reserved for patients who have undergone treatment in the index pregnancy or have been participants in a research trial; for them, karyotyping the products of conception provides useful information for counselling and future management.
    • p.2
  • 4.2 Anatomical factors
    It is difficult to assess the exact contribution that congenital uterine anomalies make to recurrent pregnancy loss. The prevalence and reproductive implications of uterine anomalies in the general population have not been clearly established. The reported prevalence of uterine anomalies in recurrent miscarriage populations range between 1.8% and 37.6%. This variability reflects the differences in the criteria and techniques used for diagnosis and the fact that available studies have included women with two, three or more miscarriages at both early and late stages of pregnancy. The prevalence of uterine malformations appears to be higher in women with late miscarriages compared with women who suffer early miscarriages but this may be related to the cervical weakness that is frequently associated with uterine malformation. A recent retrospective review of reproductive performance in patients with untreated uterine anomalies has suggested that these women experience high rates of miscarriage and preterm delivery and a term delivery rate of only 50%. Open uterine surgery is associated with postoperative infertility and carries a significant risk of uterine scar rupture during pregnancy. These complications are less likely to occur after hysteroscopic surgery but no randomised trial assessing the benefits of surgical correction of uterine abnormalities on pregnancy outcome has been performed.
    The routine use of hysterosalpingography as a screening test for uterine anomalies in women with recurrent miscarriage is questionable. It is associated with patient discomfort, carries a risk of pelvic infection and radiation exposure and is no more sensitive than the non-invasive two-dimensional pelvic ultrasound assessment of the uterine cavity with (or without) Sonohysterography, when performed by skilled and experienced personnel.
    The diagnostic value of three-dimensional ultrasound has been explored and appears promising. Since three-dimensional ultrasound offer both diagnosis and classification of uterine malformation its use may obviate the need for diagnostic hysteroscopy and laparoscopy.
    All women with recurrent miscarriage should have a pelvic ultrasound to assess uterine anatomy and morphology.
    • pp.2-3
  • 4.3 cervical weakness
    Cervical cerclage is associated with potential hazards related to the surgery and the risk of stimulating uterine contractions and hence should only be considered in women who are likely to benefit.
    Cervical weakness is often over-diagnosed as a cause of mid-trimester miscarriage. There is currently no satisfactory objective test that can identify women with cervical weakness in the non-pregnant state. The diagnosis is usually based on a

history of late miscarriage, preceded by spontaneous rupture of membranes or painless cervical dilatation. Transvaginal ultrasound assessment of the cervix during pregnancy may be useful in predicting preterm birth in some cases of suspected cervical weakness. However, two randomised controlled trials failed to demonstrate any resulting significant improvement in perinatal survival from ultrasound-indicated cervical cerclage. The MRC/RCOG trial of elective cervical cerclage reported a small decrease in preterm birth and delivery of very-low-birthweight babies, but the benefit was most marked in women with three or more second-trimester miscarriages or preterm births. However, there was no significant improvement in perinatal survival.
Transabdominal cerclage has been advocated as a treatment for second-trimester miscarriage and the prevention of early preterm labour in selected women with previous failed transvaginal cerclage and/or a very short and scarred cervix. In the absence of any control groups, the reported improvement in pregnancy outcome is difficult to assess. A recent systematic review compared abdominal versus vaginal cerclage in women with failed vaginal cerclage in a previous pregnancy. This review concluded that abdominal cerclage may be associated with a lower risk of perinatal death or delivery before 24 weeks of gestation, but it may be associated with a higher risk of serious operative complications.

    • p.3
  • 4.4 Endocrine factors
    Routine screening for occult diabetes and thyroid disease with oral glucose tolerance and thyroid function tests in asymptomatic women presenting with recurrent miscarriage is uninformative.
    Systemic maternal endocrine disorders such as diabetes mellitus and thyroid disease have been associated with miscarriage. Women with diabetes who have high haemoglobin A1c levels in the first trimester are at risk of miscarriage and fetal malformation. However, well-controlleddiabetes mellitus is not a risk factor for recurrent miscarriage, nor is treated thyroid dysfunction. The prevalence of diabetes mellitus and thyroid dysfunction in women who suffer recurrent miscarriage is similar to that expected in the general population.
    There is insufficient evidence to evaluate the effect of progesterone supplementation in pregnancy to prevent a miscarriage.
    A review of pregnancy rates following hormonal treatments for luteal phase deficiency concluded that the benefits are uncertain. The only meta-analysis to assess progesterone support for pregnancy in recurrent miscarriage found progesterone to have a beneficial effect. However, this meta-analysis was based on three small controlled studies alone, none of which detected significant improvement

in pregnancy outcome. Furthermore, the low progesterone levels that have been reported in early pregnancy loss may reflect a pregnancy that has already failed. Exogenous progesterone supplementation should only be used in the context of randomised controlled trials.
There is insufficient evidence to evaluate the effect of human chorionic gonadotrophin (hCG) in pregnancy to prevent miscarriage.
A multi-centre placebo controlled study of early pregnancy hCG supplementation failed to show any benefit in pregnancy outcome. However, another small placebo controlled study cited that the benefit of hCG is confined to a small subgroup (n = 23) of patients with recurrent miscarriage and oligomenorrhoea. HCG supplementation in early pregnancy should only be used in the context of randomised controlled trials.
Prepregnancy suppression of high luteinising hormone (LH) concentration among ovulatory women with recurrent miscarriage and polycystic ovaries who hypersecrete LH does not improve the live birth rate.
Polycystic ovarian syndrome (PCOS) has been linked to miscarriage. LH hypersecretion, a frequent feature of PCOS, has been reported as a risk factor for early pregnancy loss. A randomised controlled trial 37 has shown that prepregnancy pituitary suppression of LH among ovulatory women with recurrent miscarriage and polycystic ovaries who hypersecrete LH does not improve the live birth rate. Furthermore, the outcome of pregnancy without pituitary suppression is similar to that of patients without raised LH.
Polycystic ovary morphology itself does not predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously.
Polycystic ovary morphology is a classical feature of PCOS. The prevalence of polycystic ovaries, identified using pelvic ultrasound criteria, is significantly higher among women with recurrent miscarriage (41%) when compared with the general population (22%). However, despite this high prevalence, polycystic ovary morphology itself does not predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously. Future research should be directed at identifying alternative endocrine features that are predictive of miscarriage in women with PCOS.
A history of subfertility (conception delay greater than 12 months) is present in 25–30% of women with recurrent miscarriage. It is most frequently due to ovulatory disorders and confers a poor prognosis for future pregnancy outcome. 6 Persistently raised follicle-stimulating hormone levels are found in a small percentage of these women and this should prompt further investigation and counselling for the implications of premature ovarian failure.
There is insufficient evidence to assess the effect of hyperprolactinaemia as a risk factor for recurrent miscarriage.
The role of hyperprolactinaemia as a risk factor for recurrent miscarriage is debatable and the evidence is conflicting. A randomised controlled trial involving 64 women with a history of two or more miscarriages and hyperprolactinaemia not associated with any ovarian or endocrine abnormality has reported that the percentage of successful pregnancies was significantly higher in the bromocriptine-treated group (85.7%) compared with those receiving no treatment (52.4%). However, this study is open to criticism due to the definitions used for hyperprolactinaemia and recurrent miscarriage.

    • pp.3-5
  • 4.5. Immune factors
    4.5.1.Antithyroid antibodies
    Routine screening for thyroid antibodies in women with recurrent miscarriage is not recommended.
    A case–control study has shown that women with recurrent miscarriages are no

more likely than fertile controls to have circulating thyroid antibodies. A prospective study has shown that the presence of thyroid antibodies in euthyroid women with a history of recurrent miscarriage does not affect future pregnancy outcome.

    • p.5
  • 4.5.2.Antiphospholipid syndrome
    Primary antiphospholipid syndrome (APS) refers to the association between antiphospholipid antibodies (aPL) and adverse pregnancy outcome or vascular thrombosis. Adverse pregnancy outcomes include (a) three or more consecutive miscarriages before ten weeks of gestation, (b) one or more morphologically normal fetal deaths after the tenth week of gestation and (c) one or more preterm births before the 34 th week of gestation due to severe pre-eclampsia, eclampsia or placental insufficiency. Where APS exists in chronic inflammatory disorders, such as systemic lupus erythematosus, it is referred as secondary APS.
    The mechanisms by which aPL causes pregnancy morbidity include inhibition of trophoblastic function and differentiation and, in later pregnancy, thrombosis of the uteroplacental vasculature.
    To diagnose APS it is mandatory that the patient should have two positive tests at least six weeks apart for either lupus anticoagulant or anticardiolipin (aCL) antibodies of IgG and/or IgM class present in medium or high titre.
    In detection of lupus anticoagulant, the dilute Russell’s viper venom time (dRVVT) test is more sensitive and specific than either the activated partial thromboplastin time (aPTT) or the kaolin clotting time (KCL) tests. Anticardiolipin antibodies are detected using a standardised enzyme-linked immunosorbent assay (ELISA). The detection of aPL is subject to considerable inter-laboratory variation. This is due to temporal fluctuation of aPL titres in individual patients, transient positivity secondary to infections, suboptimal sample collection and preparation and lack of standardisation of laboratory tests for their detection.
    Antiphospholipid antibodies are present in 15% of women with recurrent miscarriage. By comparison, the prevalence of aPL in women with a low risk obstetric history is less than 2%. In women with recurrent miscarriage associated with aPL, the live birth rate in pregnancies with no pharmacological intervention may be as low as 10%.
    Currently there is no reliable evidence to show that steroids improve the live birth rate of women with recurrent miscarriage associated with aPL when compared with other treatment modalities; their use may provoke significant maternal and fetal morbidity.
    Two small randomised controlled trials have reported that treat