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Objective: To determine the prevalence of maternal morbidity and death from pregnancy loss before 28 weeks in referral-level hospitals in Nigeria., Design: Secondary analysis of a nationwide cross-sectional study., Setting: Fifty-four referral-level hospitals., Population: Women admitted for complications arising from pregnancy loss before 28 weeks between 1 September 2019 to 31 August 2020., Methods: Frequency and type of pregnancy loss were calculated using the extracted data. Multilevel logistic regression was used to determine sociodemographic and clinical factors associated with early pregnancy loss. Factors contributing to death were also analysed., Main Outcome Measures: Prevalence and outcome of pregnancy loss at <28 weeks; sociodemographic and clinical predictors of morbidity after early pregnancy loss; contributory factors to death., Results: Of the 4798 women who had pregnancy loss at <28 weeks of pregnancy, spontaneous abortion accounted for 49.2%, followed by missed abortion (26.9%) and ectopic pregnancy (15%). Seven hundred women (14.6%) had a complication following pregnancy loss and 99 women died (2.1%). Most complications (26%) and deaths (7%) occurred after induced abortion. Haemorrhage was the most frequent complication in all types of pregnancy loss with 11.5% in molar pregnancy and 6.9% following induced abortion. Predictors of complication or death were low maternal education, husband who was not gainfully employed, grand-multipara, pre-existing chronic medical condition and referral from another facility or informal setting., Conclusion: Pregnancy loss before 28 weeks is a significant contributor to high maternal morbidity and mortality in Nigeria. Socio-economic factors and delays in referral to higher levels of care contribute significantly to poor outcomes for women., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To evaluate the risk of miscarriage following SARS-CoV-2 vaccination, while accounting for the competing risk of induced abortion., Design: Population-based cohort study., Setting: Ontario, Canada., Participants: Women aged 15-50 years with a confirmed pregnancy at ≤19 completed weeks' gestation., Methods: Exposure to first SARS-CoV-2 vaccination, handled in a time-varying manner, was defined as (i) unvaccinated, (ii) remotely vaccinated >28 days before the estimated conception date or (iii) recently vaccinated ≤28 days before conception and up to 120 days after conception., Main Outcome Measures: The outcome was miscarriage, occurring between the estimated date of conception and up to 19 completed weeks of pregnancy. Fine-Grey hazard models, accounting for the competing risk of induced abortion, generated hazard ratios (aHR), adjusted for socio-demographic factors, comorbidities, and biweekly periods., Results: Included were 246 259 pregnant women, of whom 34% received a first SARS-CoV-2 vaccination. Miscarriage occurred at a rate of 3.6 per 10 000 person-days among remotely vaccinated women and 3.2 per 10 000 person-days among those recently vaccinated, in contrast to a rate of 1.9 per 10 000 person-days among unvaccinated women, with corresponding aHR of 0.98 (95% confidence interval [CI] 0.91-1.07) and 1.00 (95% CI 0.93-1.08)., Conclusions: SARS-CoV-2 vaccination was not associated with miscarriage while accounting for the competing risk of induced abortion. This study reiterates the importance of including pregnant women in new vaccine clinical trials and registries, and the rapid dissemination of vaccine safety data., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: This study explores the possible pathogenesis of recurrent spontaneous abortion (RSA) caused by vitamin D (VD), provides evidence-based bases for prevention and treatment of RSA, improves female reproductive health., Methods: This study randomly selected 305 patients without spontaneous abortion (SA0), 216 patients with a spontaneous abortion (SA1) and 200 patients with RSA from 1421 women of childbearing age who visited the RSA specialty clinic of Hangzhou First People's Hospital from January 2021 to June 2023 to conduct a prospective clinical study. Then, we collected the data of clinical diagnosis and treatment, conducted intervention and follow-up, and finally executed statistical analysis., Results: (1) RSA patients were significantly older than the other two groups. (2) The rates of VD deficiency in SA1 and RSA patients were significantly higher than those in SA0. (3) When BMI < 20  or > 24 kg/m 2 , there were abnormal increase in VD and increased number of spontaneous abortions. (4) The bilateral S/D of the VD-sufficient, VD-insufficient and VD-deficient groups gradually increased with statistical significance (p ≤ .018). (5) Among the 65 cases undergoing embryo chromosome examinations, chromosomal abnormalities accounted for 55.38% and 69.05% in RSA patients. (6) Among 186 patients with abnormal ACA, there was a certain negative correlation between ACA and VD, which was stronger among RSA patients. Moreover, ACA significantly decreased (p < .001) after effectively supplementing VD, and the miscarriage rate of re-pregnancy also decreased., Conclusion: The rate of VD deficiency is higher in RSA patients. VD deficiency may be related to the age of women of childbearing age and too low or high BMI, and may cause abnormal plasma antiphospholipid antibodies, increased uterine artery resistance and abnormal chromosomal division during fertilization, leading to spontaneous abortion and even RSA. The improvement of VD deficiency may reduce the risk of RSA occurrence., (© 2024 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

Objective: To investigate the association between vaginal bleeding (VB) in pregnancy and women's mortality, using VB-unaffected pregnancies, terminations and miscarriages as comparators., Design: Observational cohort study., Setting: Nationwide registries of Denmark linked at an individual level., Population or Sample: 1 354 181 women and their 3 162 317 pregnancies (1979-2017), including 70 835 VB-affected pregnancies and comparators: 2 236 359 VB-unaffected pregnancies ending in childbirth; 589 697 terminations; and 265 426 miscarriages., Methods: We followed pregnancies until the earliest date of woman's death, emigration or end of data., Main Outcome Measures: All-cause and cause-specific mortality rates per 10 000 person-years (PY) and hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted using Cox proportional hazards regression for age, calendar year, pre-existing chronic conditions and socio-economic factors., Results: There were 2320 deaths from any cause among women following VB-affected pregnancy (mortality rate 15.2, 95% CI 14.6-15.9 per 10 000 PY); 55 030 deaths following VB-unaffected pregnancy (mortality rate 12.7, 95% CI 12.6-12.8); 27 500 deaths following a termination (mortality rate 21.9, 95% CI 21.6-22.1), and 10 865 deaths following a miscarriage (mortality rate 19.2, 95% CI 18.8-19.6). For comparison of VB-affected versus VB-unaffected pregnancies, associations with all-cause (HR 1.14, 95% CI 1.09-1.19), natural causes (HR 1.15, 95% CI 1.09-1.22) and non-natural causes (HR 1.27, 95% CI 1.08-1.48) mortality were attenuated in a sensitivity analysis of pregnancies recorded in 1994-2017 (HR 1.00, 95% CI 0.90-1.12, HR 0.98, 95% CI 0.85-1.14 and HR 1.04, 95% CI 0.72-1.51, respectively). Contrasts with remaining comparators did not suggest increased risks of all-cause, natural or non-natural mortality causes., Conclusion: We found no evidence of an increased risk of women's mortality following VB-affected versus VB-unaffected pregnancy, termination or miscarriage., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To investigate whether Day 3 (D3) embryo status matter to reproductive outcomes of blastocyst transfer cycles., Design: Retrospective cohort study., Setting: Assisted Reproduction Department of Shanghai Ninth People's Hospital, Shanghai, China., Population: A total of 6906 vitrified-thawed single blastocyst transfer cycles in 6502 women were included., Methods: Generalised estimated equation regression models were used to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the associations between embryo status and pregnancy outcomes., Main Outcome Measures: Biochemical pregnancy, miscarriage, live birth., Results: High-quality blastocysts derived from poor-grade D3 embryos had comparable pregnancy outcomes to those derived from high-grade D3 embryos (40.0% versus 43.2%, aOR 1.00, 95% CI 0.85-1.17 for live birth rate; 8.3% versus 9.5%, aOR 0.82, 95% CI 0.63-1.07 for miscarriage rate). Cycles with low D3 cell number (five cells or fewer) had significantly higher miscarriage rate (9.2% versus 7.6%, aOR 1.33, 95% CI 1.02-1.75) compared with cycles with eight cells on D3., Conclusions: Poor-quality cleavage embryos should be cultivated to the blastocyst stage because high-quality blastocysts derived from poor-grade D3 embryos had acceptable pregnancy outcomes. When the blastocyst grade is identical, choosing embryos with higher D3 cell number (eight or more cells) for transfer could reduce the risk of early miscarriage., (© 2023 John Wiley & Sons Ltd.)

Biologicals have transformed the management of severe disease phenotypes in psoriasis and are often prescribed in women of childbearing age. However, information on safety of biologicals in pregnancy are lacking. We conducted a systematic review and meta-analysis aimed to describe the characteristics and pregnancy outcomes in women with psoriasis exposed to biologics within 3 months before or during pregnancy, and to estimate the pooled prevalence of spontaneous, elective and total abortions, and congenital malformations in their newborns. Bibliographic searches were performed in the PubMed, Embase, Scopus and Web of Science databases up to 14 April 2022. No restrictions on sample size or publication date were applied. Review performance complied with PRISMA guidelines, and two reviewers assessed randomized controlled trials and nonrandomized studies reporting pregnancy outcomes in women exposed to biologics indicated for psoriasis during the pre-gestational and/or gestational period. Studies focusing on rheumatologic or gastroenterological immune-mediated inflammatory diseases were excluded. Regardless of data heterogeneity, a random-effects model was used to pool prevalence estimates. We included 51 observational studies, involving 739 pregnancies exposed to approved biologics for psoriasis. Administration was mostly (70.4%) limited to the first trimester, and the most common drug was ustekinumab (36.0%). The estimated prevalence of miscarriage was 15.3% (95% confidence interval [CI] 12.7-18.0) and elective abortions, 10.8% (95% CI 7.7-14.3). Congenital malformations occurred in about 3.0% (95% CI 1.6-4.8) of live births exposed to biologics during pregnancy. Altogether, exposure to biologics for psoriasis during pregnancy and/or conception does not seem to be associated with an increased risk of miscarriage/abortion or congenital malformations, showing similar rates to the general population. These results suggest that biologic drugs are safe and pose an acceptable risk to the foetuses/neonates., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Aim: Adult women experience several changes in physiological status, such as pregnancy and childbirth, during their life cycle. This study analyses the association between birth-related factors (the number of childbirths, abortions and miscarriages) and periodontitis using data from the Korea National Health and Nutrition Examination Survey, which represents Korean adults., Materials and Methods: The study used data from Korea National Health and Nutrition Examination Survey VI and VII (2013-2018) and included 10,072 women 19 years or older, with no missing data on the variables assessed. Periodontitis was defined according to the Community Periodontal Index (CPI) criteria. Multiple logistic regression analysis, adjusting for age, household income, education, alcohol consumption, smoking, stress, body mass index, waist circumference, hypertension, diabetes mellitus, an oral examination within 1 year, daily tooth brushing frequency, hygiene products and self-perceived oral health as identified via logistic regression analyses, was performed to determine the association between birth-related variables and periodontitis., Results: In the crude model, the odds ratio (OR) showed a significantly increased risk of periodontitis (CPI ≥ 3) and severe periodontitis (CPI = 4) based on the number of childbirths, abortions and miscarriages (p < .05). After covariate adjustment, periodontitis (CPI ≥ 3) was associated with the number of childbirths (1: OR = 1.92; 95% confidence interval [CI]: 1.47-2.50; 2: OR = 2.03; 95% CI: 1.57-2.61; ≥3: OR = 2.11; 95% CI: 1.60-2.78). Furthermore, severe periodontitis (CPI = 4) was also associated with the number of childbirths (1: OR = 2.33; 95% CI: 1.24-4.38; 2: OR = 2.99; 95% CI: 1.62-5.52; ≥3: OR = 3.34; 95% CI: 1.79-6.21)., Conclusions: The findings of this large-scale, nationally representative study suggest that the number of childbirths is associated with the severity of periodontitis. However, the relationship between the number of abortions and miscarriages and periodontitis (CPI ≥ 3) or severe periodontitis (CPI = 4) is not significant., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background Pregnancy loss has been associated with myocardial infarction, stroke, and all-cause mortality in women through unknown mechanisms. The aim of this study was to examine these associations in women and their male partners. Methods and Results In this register-based cohort study, all people born between 1957 and 1997, residing in Denmark between 1977 and 2017, and with a registered partner of the opposite sex were eligible for inclusion. Male partners through cohabitation, marriage, or paternity constituted the male cohort. Exposure to pregnancy loss was categorized as follows: 0, 1, 2, or ≥3 pregnancy losses. The outcomes of interest were myocardial infarction, stroke, and all-cause mortality. The Cox proportional hazards model estimated hazard ratios (HRs), adjusted for age, calendar year, parity, and parental history of myocardial infarction or stroke. During follow-up, 1 112 507 women experienced 4463 events of myocardial infarction compared with 13 838 events among 1 120 029 male partners. With the no pregnancy loss group as reference, the adjusted HRs of myocardial infarction in the female cohort after 1, 2, and ≥3 pregnancy losses were as follows: 1.1 (95% CI, 1.0-1.2), 1.3 (95% CI, 1.1-1.5), and 1.4 (95% CI, 1.1-1.8), respectively. In the male partner cohort, the corresponding estimates were 1.0 (95% CI, 1.0-1.1), 1.1 (95% CI, 1.0-1.2), and 1.0 (95% CI, 0.8-1.2), respectively. The outcome of stroke showed similar results. Pregnancy loss was not significantly associated with increased mortality in either sex. Conclusions Pregnancy loss or stillbirth was significantly associated with myocardial infarction and stroke in women but not their male partners. Pregnancy loss or stillbirth was not significantly associated with all-cause mortality in women or male partners.

Background: Higher-order multiple (HOM) pregnancies are associated with significant maternal and neonatal morbidity, especially consequent to preterm birth. Multi-fetal pregnancy reduction (MFPR) may be provided, though its benefits in prolonging gestation and improving neonatal outcomes must be weighed against its risks., Aims: The aim was to compare outcomes of HOM pregnancies where expectant management was chosen (EM) with those where MFPR was provided., Methods: The method involved a retrospective study of HOM pregnancies referred to a single quaternary hospital between 2007 and 2016. The primary outcome was gestational age. Secondary outcomes included miscarriage, nursery admission, hospital stay, Apgar scores, early fetal loss, stillbirth, neonatal death and composite fetal loss., Results: Fifty-seven pregnancies were eligible for inclusion. Median gestation at birth (weeks) was significantly higher for MFPR (35.3 vs 33.1, P < 0.01). Pregnancies after MFPR were less likely to lead to preterm birth (63.2 vs 100.0%, P < 0.001), half as likely to birth before 34 weeks (31.6 vs 60.0%, P = 0.09) but similarly likely to extremely preterm birth (<28 weeks, 8.6 vs 10.5%, P = 0.58). Miscarriage was more likely after MFPR (13.6 vs 0%, P = 0.05). EM neonates were more likely to be admitted to the nursery (P < 0.01) and have longer hospital stay (29.6 vs 20.2 days, P = 0.05); however, they had similar Apgar scores., Conclusion: Our study demonstrates that MFPR is associated with an increase in gestational age, with a reduction by almost half of births before 34 weeks, but no difference in extremely preterm births; the latter represents the highest risk group. This should be used to guide management counselling for HOM pregnancies., (© 2022 Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background and Aims: Alcohol use during pregnancy remains an important risk factor for adverse birth outcomes, but little is known regarding how alcohol prices affect pregnancy outcomes on the population level. We assess the associations between decreased alcohol prices with birth outcomes and abortions., Design: Using national registers, we used interrupted time-series modelling to compare outcomes of pregnancies conceived before and after a tax cut, resulting in 33% mean decrease of off-premise alcohol prices on 1 March 2004. We also addressed possible heterogeneity of the associations by maternal age and household income., Setting: Finland., Participants: All registered pregnancies starting 2 years before and 1 year after the alcohol price cut (analysis sample consisted of 169 735 live births and 32 441 abortions)., Measurements: The outcomes were birth weight, gestational age, the probability of low birth weight (< 2500 g at birth), preterm birth (< 37 weeks of gestation), any congenital malformations and share of registered abortions of pregnancies., Findings: On the population level, lowered alcohol prices were associated with an increase in abortions immediately after the price cut [+0.84 percentage points; 95% confidence interval (CI) = 0.2, 1.4]. For birth outcomes, negative associations were observed among women in the lowest income quintile; for example, increased probabilities of low birth weight (+1.5 percentage points; 95% CI = 0.4, 2.6) and preterm birth (+1.98 percentage points; 95% CI = 0.8, 3.2). All changes were strongest immediately after the price cut and attenuated during the course of the following year., Conclusions: Lowered alcohol prices in Finland were associated with a short-term increase in adverse birth outcomes among low-income mothers and an overall increase in abortions., (© 2023 Society for the Study of Addiction.)

Objective: To investigate whether intervening miscarriages and induced abortions impact the associations between interpregnancy interval after a live birth and adverse pregnancy outcomes., Design: Population-based cohort study., Setting: Norway., Participants: A total of 165 617 births to 143 916 women between 2008 and 2016., Main Outcome Measures: We estimated adjusted relative risks for adverse pregnancy outcomes using log-binomial regression, first ignoring miscarriages and induced abortions in the interpregnancy interval estimation (conventional interpregnancy interval estimates) and subsequently accounting for intervening miscarriages or induced abortions (correct interpregnancy interval estimates). We then calculated the ratio of the two relative risks (ratio of ratios, RoR) as a measure of the difference., Results: The proportion of short interpregnancy interval (<6 months) was 4.0% in the conventional interpregnancy interval estimate and slightly increased to 4.6% in the correct interpregnancy interval estimate. For interpregnancy interval <6 months, compared with 18-23 months, the RoR was 0.97 for preterm birth (PTB) (95% confidence interval [CI] 0.83-1.13), 0.97 for spontaneous PTB ( 95% CI 0.80-1.19), 1.00 for small-for-gestational age ( 95% CI 0.86-1.14), 1.00 for large-for-gestational age (95% CI 0.90-1.10) and 0.99 for pre-eclampsia (95% CI 0.71-1.37). Similarly, conventional and correct interpregnancy intervals yielded associations of similar magnitude between long interpregnancy interval (≥60 months) and the pregnancy outcomes evaluated., Conclusion: Not considering intervening pregnancy loss due to miscarriages or induced abortions, results in negligible difference in the associations between short and long interpregnancy intervals and adverse pregnancy outcomes., Tweetable Abstract: Not considering pregnancy loss in interpregnancy interval estimation resulted no meaningful differences in observed risks of adverse pregnancy outcomes., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Problem: Previous studies had shown that there might be an association between serum vitamin D concentrations and the occurrence of recurrent spontaneous abortion (RSA). However, the conclusions remained controversial. The objective of this study was to systematically review the evidence for an epidemiological association between vitamin D and RSA., Method of Study: The literature search was performed in the following databases: PubMed, Web of Science, Embase and Chinese databases. The I 2 statistic was used to evaluate heterogeneity. Effect sizes were calculated using fixed or random effects models, including standardized mean difference (SMD), odds ratios (OR) and their 95% confidence intervals (95% CI). Then, we performed subgroup analysis, sensitivity analysis and publication bias analysis., Results: Fourteen studies from five countries were included. Based on the results, patients with RSA had lower vitamin D levels than controls (SMD = -1.48, 95% CI: -2.01, -.94, P < .001), and pregnant women with vitamin D deficiency (VDD) had a higher risk of developing RSA (OR = 4.02, 95% CI: 2.23, 7.25, P < .001). There was remarkable heterogeneity between studies (I 2 SMD  = 97.3%, P < .001; I 2 OR  = 82.2%, P < .001). The results of the subgroup analysis suggested that heterogeneity may be caused by the assay method, age and region. Sensitivity analysis showed the analysis results were robust., Conclusion: Patients with RSA had lower serum vitamin D levels than normal pregnant women, and pregnant women with VDD might be at higher risk for RSA., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: The objective of this meta-analysis was to determine whether maternal exposure to statins is associated with increased rates of major congenital malformations and other adverse pregnancy outcomes., Methods: PubMed/Medline, Web of Science and Reprotox® databases were searched. Cohort and case control studies with prenatal exposure to statins were included., Results: Analysis of five cohort studies and one case-control study showed no significant increase in rate of major congenital malformations when the exposed group was compared with the control ([OR 1.27; 95% CI 0.80-2.04], [aOR 1.05; 95% CI 0.84-1.31]). A significant increase in heart defect risk was detected in the statin-exposed group when unadjusted ORs were combined (OR 2.47; 95% CI 1.36-4.49). Further analysis of the same outcome by using adjusted ORs showed no significant increase in heart defect risk in the statin-exposed group compared with the controls (aOR 1.24; 95% CI 0.93-1.66). A significantly lower live birth rate (OR 0.60, 95% CI 0.49-0.75) and a higher spontaneous abortion rate (OR 1.36; 95% Cl 1.06-1.75) were detected in the statin-exposed group., Conclusions: Gestational statin exposure was not associated with a significant increase in risk of major congenital malformations, heart defects and other adverse pregnancy outcomes, except spontaneous abortion and live birth rate, which may be associated with maternal comorbidity and other unadjusted risk factors. Further research focusing on particular statins is needed to draw more definitive conclusions., (© 2022 British Pharmacological Society.)

Background: Ustekinumab, a human immunoglobulin G1 monoclonal antibody that binds to and inhibits interleukin (IL)-12/IL-23, is indicated for multiple immune-mediated diseases. Ustekinumab is actively transported across the placenta and theoretically could impact pregnancy outcomes. Limited data on pregnancy outcomes with ustekinumab exposure are available., Aim: To assess pregnancy outcomes in patients exposed to ustekinumab during pregnancy METHODS: Cumulative data on medically confirmed ustekinumab-exposed pregnancies from the manufacturer's Global Safety Database were summarised. Descriptive data for pregnancy outcomes were presented overall and by patient subgroups., Results: As of 31 August 2020, 408 medically confirmed, prospective, maternal ustekinumab-exposed pregnancies with reported outcomes were identified. The mean maternal age was 31 years. Of the 420 pregnancy outcomes (including 4 sets of twins), a , b 340 (81%) were live births, 51 (12.1%) spontaneous abortions, 25 (6%) elective/induced abortions, 3 (0.7%) stillbirths and 1 (0.2%) ongoing pregnancy with foetal congenital anomaly (CA). Among 340 live births, 33 (9.7%) were born pre-term. The rate of major CAs was similar by indication (Crohn's disease vs psoriasis), ustekinumab dose (45 mg vs 90 mg) and timing and duration of maternal exposure to ustekinumab. Prospective outcomes of pregnancies with paternal periconceptional ustekinumab exposure (n = 87) included 92% live births (1.2% major CA), 5.7% spontaneous abortions and 2.3% elective/induced abortions., Conclusions: Rates of adverse pregnancy outcomes or CAs with ustekinumab exposure were consistent with rates reported for the US general population and do not suggest a higher risk associated with maternal or paternal exposure to ustekinumab., (© 2022 Janssen Pharmaceuticals. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Objective: To examine the association between maternal exposure to ciprofloxacin and the risk of miscarriage and major malformations., Design: A nationwide register-based cohort study., Setting: Data were obtained from the Medical Birth Registry, the National Hospital Registry, the Danish National Prescription Registry and Statistics Denmark., Population: Data were collected in the period between 1997 and 2016 and included all registered pregnancies that ended in an elective termination, miscarriage, stillbirth or a live birth. Exposure was defined as redeeming one or more prescriptions of ciprofloxacin., Methods: Miscarriage was defined as a diagnosis given before 22 weeks without any medical intervention. Major malformations were classified according to EUROCAT 1.4. We matched ciprofloxacin-exposed pregnancies to unexposed pregnancies on the propensity score in a ratio 1:4. To estimate the hazard ratio (HR) of miscarriage a Cox proportional hazard regression model was used. A log binomial model was used to estimate the relative risk ratio (RR) of major malformations., Main Outcome Measures: HR of miscarriage and the RR of major malformations., Results: A total of 1 650 649 pregnancies were identified. Of these, 10 250 (2050 ciprofloxacin-exposed) and 6100 (1220 ciprofloxacin-exposed) were included in the miscarriage and major malformation analysis, respectively. The HR of miscarriage was 0.99 (95% confidence interval [CI] 0.84-1.17). For major malformation, the RR was 1.01 (95% CI 0.72-1.40). For the organ-specific major malformations and the sensitivity analyses, no significant increased risks were identified., Conclusion: We demonstrated no association between miscarriage and maternal ciprofloxacin exposure within the first 22 weeks of pregnancy, or between major malformations and maternal exposure during the first trimester., Tweetable Abstract: No association between maternal ciprofloxacin exposure and adverse pregnancy outcomes., (© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Genetically isolated populations that arise due to recent bottleneck events have reduced genetic variation reflecting the common set of founders. Increased genetic relatedness among members of isolated populations puts them at increased risk for some recessive disorders that are rare in outbred populations. To assess the burden on reproductive health, we compared frequencies of adverse reproductive outcomes between Amish couples who were both heterozygous carriers of a highly penetrant pathogenic or likely pathogenic variant and noncarrier couples from the same Amish community. In addition, we evaluated whether overall genetic relatedness of parents was associated with reproductive outcomes. Of the 1824 couples included in our study, 11.1% were at risk of producing a child with an autosomal recessive disorder. Carrier couples reported a lower number of miscarriages compared to noncarrier couples (p = 0.02), although the number of stillbirths (p = 0.3), live births (p = 0.9), and number of pregnancies (p = 0.9) did not differ significantly between groups. In contrast, higher overall relatedness between spouses was positively correlated with number of live births (p < 0.0001), pregnancies (p < 0.0001), and stillbirths (p = 0.03), although not with the number of miscarriages (p = 0.4). These results highlight a complex association between relatedness of parents and reproductive health outcomes in this community., (© 2022 Wiley Periodicals LLC.)

While neurologic complications are frequently reported among patients with COVID-19 in the general population, they are unknown in pregnant women. This paper summarizes the case reports of pregnant women with confirmed SARS-CoV-2 infection plus a specified neurologic diagnosis. Until November 2021, 18 case reports were found. Both the central and peripheral nervous systems were equally affected: delirium (n = 1), posterior reversible encephalopathy syndrome (n = 4), cerebrovascular disease (n = 2), acute cerebral demyelinating disease (n = 1), acute necrotizing encephalopathy (n = 1), Guillain-Barré syndrome (n = 5), including one patient who also had vestibular neuritis, Bell's palsy (n = 3), and rhabdomyolysis (n = 1). The median maternal age was 32.5 (25-35) years, the median gestational age was 34 (30-36.5) weeks, and 38.9% presented previous medical conditions. Respiratory symptoms were reported in 76.5%, and 76.5% received immunotherapies to treat the COVID-19 or the neurologic complications. Half the women required admission to ICU and, more often, were those with central nervous system involvement (77.8% vs. 22.2%; Chi-square test, p = .018). For 64.7% of women, the most common method of delivery was surgical, although just one case was due to the neurologic complication. There were reports of one spontaneous abortion, two fetal deaths, and no maternal deaths. Only one case presented a poor neurologic outcome. It is possible that our findings are underestimated, considering that there are thousands of reports regarding neurologic complications in the general population with COVID-19., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the association between mirtazapine exposure in pregnancy and risk of specific adverse pregnancy outcomes., Methods: A register-based nationwide cohort study was conducted including all registered pregnancies in Denmark from 1997 to 2016. Mirtazapine-exposed pregnancies were compared with mirtazapine unexposed pregnancies in a 1:4 ratio matched according to propensity scores. Outcomes were major congenital malformations analyzed using log binomial models, and spontaneous abortion, stillbirth and neonatal death analyzed using Cox proportional hazard regression., Results: From a source population of 1,650,649 pregnancies, the propensity score-matched cohort included 4475 pregnancies (895 mirtazapine exposed) in the analysis of major congenital malformations. The analyses of spontaneous abortion included 9 500 pregnancies (1900 mirtazapine exposed), and for the analyses of stillbirths and neonatal deaths 9725 (1 945 mirtazapine-exposed) and 4485 pregnancies (897 mirtazapine-exposed) were included, respectively. Thirty-one (3.5%) children were diagnosed with major congenital malformation among the mirtazapine exposed compared with 152 (4.3%) among the unexposed pregnancies (OR=0.81, 95% CI 0.55-1.20). Spontaneous abortion occurred in 237 (12.5%) of the mirtazapine exposed compared with 931 (12.3%) of the unexposed pregnancies (HR = 1.04%, 95% CI 0.91-1.20). The analyses revealed no increased risk of stillbirth (HR = 0.88%, 95% CI 0.34-2.29) or neonatal death (HR = 0.60%, 95% CI 0.18-2.02)., Conclusions: In this nationwide Danish register study, mirtazapine exposure in pregnancy was not associated with major congenital malformations, spontaneous abortion, stillbirth, or neonatal death. Clinicians and patients can be reassured that mirtazapine is safe in pregnancy., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Hydroxyurea reduces pain crises, acute chest syndrome, and blood transfusions in sickle cell disease (SCD), but potential detrimental effects on fertility and birth outcomes impede its use. Data on the effects of hydroxyurea taken for SCD during conception and pregnancy are scarce. The Sickle Cell Disease Implementation Consortium collected self-reported pregnancy history, corresponding hydroxyurea use, and pregnancy outcomes in women with SCD in the clinical setting. Among 1285 women 18-45 years of age, 737 (57.4%) reported 1788 pregnancies (1079 live births, 394 miscarriages, 40 stillbirths, 207 abortions, 48 current pregnancies, and 20 missing outcomes) of which 241 (15.9%) live births, miscarriages or stillbirths were conceived while on hydroxyurea. In univariate analyses, pregnancy number more than three, severe sickle genotype, history of stillbirth or miscarriage, and chronic kidney disease at enrollment were covariates significantly associated with a pregnancy ending in miscarriage or stillbirth. After adjustment for covariates and additional SCD severity markers in multivariate analyses, hydroxyurea use during conception and pregnancy, but not during conception only, was associated with an increase in the odds ratio (OR) of miscarriage or stillbirth (OR 2.21, 95% confidence interval [CI] 1.40-3.47). In analyses of live birth outcomes, hydroxyurea use during conception and pregnancy was associated with birth weight < 5.5 pounds in full-term infants (OR 2.98, 95% CI 1.09-7.38) but not with prematurity or serious medical problems at birth. These findings suggest that hydroxyurea use may be safe up to the time of conception, but that clinicians should continue to advise caution regarding use during pregnancy., (© 2022 Wiley Periodicals LLC.)

The Wisconsin Stillbirth Service Program (WiSSP) provided expert review by a dysmorphologist for community-acquired data on 3137 fetal deaths between 1983 and 2017. Intrinsic fetal causes were consistently identified in about 25% while placental and maternal causes were recognized with increasing frequency as attention was shifted from a primarily fetal to a multifocal approach. Identification of causes increased from 40% to 78% and in about half of cases results of the review altered recurrence risk and/or future pregnancy management. Banked data from WiSSP formed the basis of 24 publications, more than half of which have a genetic counselor and/or summer premedical student intern as an author. The earlier publications emphasized validation of the concept of community-based evaluation with central review, the utility of various parts of the WiSSP protocol, the similarity of second-trimester miscarriages <20 weeks to later stillbirths with respect to causes identified and recurrence risks, and the potential for results of etiologic evaluation to influence future prenatal care. The most important recurrent theme, however, was the interaction of intrinsic fetal, placental, and maternal factors in contributing to fetal demise. This implies that, at least in developed nations with available obstetric care, reduction in stillbirth will require careful attention to the myriad of factors contributing to fetal, placental, and maternal well-being., (© 2021 Wiley Periodicals LLC.)

Objective: To examine early and late pregnancy loss in women with and without polycystic ovary syndrome (PCOS) undergoing IVF/ICSI transfers., Design: Retrospective cohort study., Setting: Reproductive medicine centre at a tertiary hospital., Population: We studied women with a positive β-human chorionic gonadotropin (β-hCG) after in vitro fertilisation/intra-cytoplasmic sperm injection (IVF/ICSI) treatment from May 2014 to April 2019., Methods: Odds ratios (OR) for early (≤13 weeks) and late (>13 weeks) pregnancy loss were calculated among women with and without PCOS for plurality of the pregnancy with adjustment for confounding factors., Main Outcome Measures: Early pregnancy loss (EPL) and late pregnancy loss (LPL)., Results: From 21 820 women identified with a positive β-hCG, 2357 (10.8%) women had PCOS, and 19 463 (89.2%) women did not. EPL occurred in 16.6% (391) of women with PCOS versus 18.3% (3565) in women with non-PCOS (OR 0.89, 95% CI 0.79-0.99, P = 0.04). After adjustment for age and other confounders, the rate of EPL was not statistically significantly associated with PCOS status (adjusted OR [aOR] 0.91, 95% CI 0.80-1.05). Women with PCOS demonstrated a higher rate of LPL (6.4% in PCOS versus 3.6% in non-PCOS, OR 1.81, 95% CI 1.48-2.21, P < 0.001). In multivariable analysis, the potential impact of PCOS was less strong (aOR 1.38, 95% CI 0.96-1.98), with BMI and maternal comorbidities also associated with LPL (aOR 1.08, 95% CI 1.04-1.1 and aOR 2.07, 95% CI 1.43-3.00, respectively)., Conclusions: Polycystic ovary syndrome was not independently associated with EPL. There was an increased risk of LPL but this difference was not statistically significant., Tweetable Abstract: Polycystic ovary syndrome women are at increased risk of late pregnancy loss, partly driven by elevated BMI and maternal comorbidities., (© 2020 John Wiley & Sons Ltd.)

Single nucleotide polymorphism (SNP) array and karyotype analyses were conducted on 441 spontaneous miscarriage placental villous tissues collected from women from southern China. Subsequently, the results from these two analyses were compared to evaluate the best diagnostic strategy for subsequent pre-pregnancy planning. Here, the success rate of genetic testing using karyotyping and SNP array analysis was 78.46% (346/441) and 100.0% (441/441), respectively. The abnormality rate estimated by both methods was 54.9% (242/441). Three hundred and forty-six cases were successfully detected via both SNP array and karyotype analyses; the rate of consistent detection was 96.24% (333/346), whereas 13 cases were not consistent. There was no substantial positive correlation between age and genetic abnormalities such as Turner syndrome, structural variation or euploidy state in the different age groups studied. However, the aneuploidy rate was significantly different in each age group. Thus, although SNP array has higher success rate and resolution in genetic abnormality detection, supplementary karyotype analysis is needed for a more accurate revelation of the genetic aetiology of miscarriages. Therefore, this study indicates that simultaneous karyotype and SNP array analyses should be performed for spontaneous miscarriages. Furthermore, miscarriages irrespective of maternal age must be genetically analysed., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objective: To evaluate the effect of polycystic ovary syndrome (PCOS) without hyperandrogenism on pregnancy-related outcomes., Design: A retrospective cohort study., Setting: Reproductive Medicine Centre of Tongji Hospital., Population: Women without hyperandrogenism undergoing their first single blastocyst transfers in frozen-thawed cycles were divided into a PCOS group and a non-PCOS group according to the Rotterdam criteria., Methods: The pregnancy-related outcomes of women with and without PCOS were compared. Propensity score matching and multiple logistic regression models were used to eliminate essential impacts on pregnancy-related outcomes., Main Outcome Measures: Pregnancy-related outcomes included pregnancy loss and abnormal perinatal outcomes., Results: A total of 4083 women without hyperandrogenism met the study criteria, among whom 557 met the diagnostic criteria for PCOS. Women with PCOS had higher rates of clinical pregnancy (P = 0.035) and cumulative live births (P = 0.023). However, there were no significant differences in the rates of biochemical pregnancy, twins and pregnancy loss between the two groups. Among women with singleton pregnancies, the incidences of preterm birth, hypertensive disorders of pregnancy, gestational diabetes, placenta praevia, fetal malformation, macrosomia and low birthweight did not differ significantly between the two groups. The results remained unchanged even after adjustments were made for propensity score matching and multiple logistic regression analyses., Conclusion: Women with PCOS without hyperandrogenism may achieve higher rates of clinical pregnancy and cumulative live birth than those without PCOS, without increases in their rates of biochemical pregnancy, pregnancy loss or other abnormal perinatal outcomes., Tweetable Abstract: PCOS without hyperandrogenism was not associated with abnormal pregnancy-related outcomes., (© 2021 John Wiley & Sons Ltd.)

Pregnancy in the context of myeloproliferative neoplasms (MPN) poses unique fetal and maternal challenges. Current literature in this regard mostly involves essential thrombocythemia (ET) and less so polycythemia vera (PV) or myelofibrosis. In ET, live birth rate is estimated at 70% with first trimester fetal loss (˜ 30%) as the major complication. Risk of pregnancy-associated complications is higher in PV, thus mandating a more aggressive treatment approach. Herein, we appraise the relevant literature, share our own experience and propose management recommendations. Aspirin therapy may offer protection against fetal loss; however the additive benefit of systemic anticoagulation or cytoreductive therapy, in the absence of high risk disease, is unclear. We recommend cytoreductive therapy in the form of interferon alpha in all high risk and select low-risk ET and PV patients with history of recurrent fetal loss, prominent splenomegaly or suboptimal hematocrit control with phlebotomy. In addition, all women with PV should maintain strict hematocrit control <45% with the aid of phlebotomy. Systemic anticoagulation with low molecular weight heparin is advised in patients with history of venous thrombosis. Further clarification awaits prospective clinical trials that implement risk adapted therapeutic interventions., (© 2020 Wiley Periodicals LLC.)

Problem: Chronic endometritis (CE) influences the clinical outcomes of assisted reproductive technology. However, the effect of CE on the pregnancy outcome is still unknown., Method of Study: A retrospective case-control study was conducted in a single university. Subjects who conceived by in vitro fertilization within a year after a histological diagnosis of CE under 40 years of age from September 2013 to December 2017 were extracted. The rates of miscarriage, preterm birth, term birth, and live birth per pregnancy according to the presence or absence of CE were analyzed. A logistic regression analysis was performed for miscarriage, preterm birth, term birth, and live birth for eight explanatory variables of seven infertility factors and CE., Results: A total of 39 pregnancies in 38 subjects with non-CE and 35 pregnancies in 32 subjects with CE were ultimately analyzed. The rates of miscarriage, preterm birth, term birth, and live birth per pregnancy were 12.8% and 40.0% (P < .03), 2.6% and 14.3% (P = .1), 84.6% and 45.7% (P < .001) and 84.6% and 57.1% (P < .03) in the Non-CE and CE groups, respectively, although only the analysis for tem birth rate had sufficient power to exclude Type II error. In logistic analysis, CE was a factor affecting the objective variables of miscarriage, term birth, and live birth., Conclusions: The term birth rate among pregnancies decreased mainly due to an increase in miscarriages when CE was detected before pregnancy in patients treated with in vitro fertilization. A histopathological diagnosis of CE adversely affected the term birth rate per pregnancy., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Since its emergence in December 2019, COVID-19 has spread to over 210 countries, with an estimated mortality rate of 3-4%. Little is understood about its effects during pregnancy., Aims: To describe the current understanding of COVID-19 illness in pregnant women, to describe obstetric outcomes and to identify gaps in the existing knowledge., Methods: Medline Ovid, EMBASE, World Health Organization COVID-19 research database and Cochrane COVID-19 in pregnancy spreadsheet were accessed on 18/4, 18/5 and 23/5 2020. Articles were screened via Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The following were excluded: reviews, opinion pieces, guidelines, articles pertaining solely to other viruses, single case reports., Results: Sixty articles were included in this review. Some pregnant participants may have been included in multiple publications, as admission dates overlap for reports from the same hospital. However, a total of 1287 confirmed SARS-CoV-2 positive pregnant cases are reported. Where universal testing was undertaken, asymptomatic infection occurred in 43.5-92% of cases. In the cohort studies, severe and critical COVID-19 illness rates approximated those of the non-pregnant population. Eight maternal deaths, six neonatal deaths, seven stillbirths and five miscarriages were reported. Nineteen neonates were SARS-CoV-2 positive, confirmed by reverse transcription polymerase chain reaction of nasopharyngeal swabs. [Correction added on 2 September 2020, after first online publication: the number of neonates indicated in the preceding sentence has been corrected from 'Thirteen' to 'Nineteen'.] CONCLUSIONS: Where universal screening was conducted, SARS-CoV-2 infection in pregnancy was often asymptomatic. Severe and critical disease rates approximate those in the general population. Vertical transmission is possible; however, it is unclear whether SARS-CoV-2 positive neonates were infected in utero, intrapartum or postpartum. Future work should assess risks of congenital syndromes and adverse perinatal outcomes where infection occurs in early and mid-pregnancy., (© 2020 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Pregnancy has been linked to various microangiopathies, including primary atypical haemolytic uraemic syndrome (aHUS). Complement dysregulation, often linked to rare variants in complement genes, is key for primary aHUS to manifest and may play a role in pregnancy complications of the mother and fetus. The burden of such complications is unknown, making counselling of women with primary aHUS and asymptomatic relatives difficult. We analyzed the maternal and fetal outcomes of 39 pregnancies from 17 women with primary aHUS and two asymptomatic relatives. Seven out of 39 pregnancies were complicated by pregnancy-associated aHUS. Five out of 32 pregnancies not linked to pregnancy-associated aHUS were complicated by pre-eclampsia or HELLP. Rare genetic variants were identified in 10 women (asymptomatic relatives, n = 2) who had a total of 14 pregnancies, including 10 uncomplicated pregnancies. Thirty-five out of 39 pregnancies resulted in live birth. Eight out of 19 women had progressed to end-stage kidney disease, with an incidence of 2·95 (95% confidence interval, 1·37-5·61) per 100 person-years after the first pregnancy. Thus, we emphasized the frequency of successful pregnancies in women with primary aHUS and asymptomatic relatives. Pregnancies should be monitored closely. Rare genetic variants cannot predict the risk of a given pregnancy., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Objective: To investigate the association between a history of placental bed disorders and later dementia., Design: Retrospective population-based cohort study., Setting: Sweden., Sample: All women giving birth in Sweden between 1973 and 1993 (1 128 709)., Methods: Women with and without placental bed disorders (hypertensive disorders of pregnancy including pre-eclampsia, fetal growth restriction, spontaneous preterm labour and birth, preterm premature rupture of membranes, abruptio placenta, late miscarriages) and other pregnancy complications were identified by means of the Swedish Medical Birth Register. International classification of disease was used. Data were linked to other National Registers. Participants were followed up until 2013. The Cox proportional hazards model was used to calculate hazard ratios for women with and without pregnancy complications and were adjusted for possible confounders., Main Outcome Measures: Diagnosis of vascular dementia and non-vascular dementia., Results: Adjusted for cardiovascular disease and socio-demographic factors, an increased risk of vascular dementia was shown in women with previous pregnancy-induced hypertension (Hazard ratio [HR] 1.88, 95% CI 1.32-2.69), pre-eclampsia (HR 1.63, 95% CI 1.23-2.16), spontaneous preterm labour and birth (HR 1.65, 95% CI 1.12-2.42) or preterm premature rupture of membranes (HR 1.60, 95% CI 1.08-2.37). No statistically significant increased risk was seen for other pregnancy complications or non-vascular dementia even though many of the point estimates indicated increased risks., Conclusions: Women with placental bed disorders have a higher risk for vascular disease. Mechanisms behind the abnormal placentation remain elusive, although maternal constitutional factors, abnormal implantation as well as impaired angiogenesis have been suggested., Tweetable Abstract: Placental bed syndromes associated with vascular dementia even after adjusting for cardiovascular disease., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Background: Cholera has harmful effects on the fetus but safety data on the oral cholera vaccine in pregnant women are controversial., Objectives: We conducted the first meta-analysis of studies in pregnant women comparing the effect of oral cholera vaccination on pregnancy outcomes with unvaccinated women. Outcomes of interest were adverse pregnancy outcome, miscarriage, stillbirth, preterm delivery, low birthweight, abortion and malformation., Search Strategy: The search was run in MEDLINE/PubMed, SCOPUS and Embase databases from inception up to December 2019., Selection Criteria: Inclusion criteria were: (1) studies that investigated the association between oral cholera vaccines and adverse pregnancy outcomes; (2) studies that reported outcomes with appropriate estimates; and (3) studies that contained an unvaccinated control group., Data Collection and Analysis: A random-effects model (DerSimonian and Laird) was run to evaluate the overall treatment effect (relative risk, RR). The PRISMA statement was followed in reporting this meta-analysis., Main Results: Five studies included in meta-analysis with 5584 women (2920 exposed and 2664 not exposed). No significant increase in adverse pregnancy outcome (RR 1.03, 95% CI 0.79-1.34), miscarriage (RR 1.15, 95% CI 0.84-1.57) or stillbirth (RR 1.11, 95% CI 0.69-1.80) following cholera vaccine administration was found compared with control group. There was also no association with an increased risk of preterm delivery (RR 0.61, 95% CI 0.35-1.06) low birthweight (RR 0.84, 95% CI 0.56- 1.26), accidental abortion (RR 1.02, 95% CI 0.77-1.35) or malformation (RR 0.70, 95% CI 0.22-2.25)., Conclusions: This study shows no evidence of an association between oral cholera vaccination and adverse pregnancy outcomes. The findings do not rigorously exclude the possibility that the vaccine protocol may result in some degree of harm., Tweetable Abstract: There is no evidence of an association between oral cholera vaccination and adverse pregnancy outcomes. The findings do not rigorously exclude the possibility that the vaccine protocol may result in some degree of harm., (© 2020 Royal College of Obstetricians and Gynaecologists.)

Background: In women with prolactinoma medical treatment with dopamine agonists (DA) can restore fertility. A number of studies have established the safety of DA during pregnancy and the impact of pregnancy and lactation on remission of prolactinoma. However, the total number of reported cases remains modest and further evidence is needed., Aims: To evaluate the safety of DA during pregnancy and remission of prolactinoma after pregnancy and lactation., Materials and Methods: Retrospective cohort study (2002-2014) of 57 pregnancies in 47 women with prolactinoma who received DA. Neonatal and pregnancy complications were recorded. Prolactin levels and treatment data were collected at the time of diagnosis, pre-conception, during pregnancy and lactation, and post-partum (up to 114 months)., Results: DA treatment was stopped a median of 4.5 weeks after conception in 49 pregnancies (86%). There were 49 live births (86% of pregnancies) and six miscarriages. Six pregnancies had an adverse neonatal outcome including two with congenital malformations. Following 26% of pregnancies women achieved remission after birth or lactation, and 25% of women were in remission at last follow-up. Remission was associated with older maternal age (P = 0.036), a lower prolactin level at diagnosis (P = 0.037), and a smaller adenoma at diagnosis (P = 0.045)., Conclusions: Successful pregnancy and lactation is common after DA treatment for prolactinoma. Fetal exposure in the first four weeks of pregnancy appears to be generally safe. Encouragingly, post-partum and after lactation a quarter of women had a normal prolactin level without medical treatment., (© 2019 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: Data relating to the association between inflammatory bowel disease (IBD) and pregnancy outcomes are lacking in Korea., Aims: To determine the incidence rates of pregnancy outcomes in women with IBD., Methods: A nationwide population study was performed using the Korean National Health Insurance claims database. A total of 2058 women with IBD consisting of ulcerative colitis (UC, n = 1469) and Crohn's disease (CD, n = 589) were pregnant between 2007 and 2016. We compared their incidence of pregnancy outcomes with 20 580 age-matched controls without IBD. We also stratified the patients into those with quiescent to mild and moderate to severe IBD and compared the outcomes between them., Results: The pregnancy rate of women with IBD was lower than that of women without (25.7% vs 32.3%, P < 0.001). Caesarean section (46.5% vs 38.8%, odds ratio [OR] 1.43, 95% confidence interval [CI]: 1.17-1.75), and intrauterine growth retardation (IUGR) (3.0% vs 1.0%, OR 2.89, 95% CI: 1.59-5.26) were increased in CD patients than the controls. In regards to disease severity, there were no significant differences in pregnancy outcomes between patients with quiescent to mild IBD and the controls. However, the live birth rate of patients with moderate to severe IBD was lower than that of the controls (65.0% vs 69.9%, OR 0.79, 95%CI: 0.66-0.94). In addition, moderate to severe IBD was significantly associated with spontaneous abortion (14.9% vs 11.9%, OR 1.33, 95% CI: 1.04-1.68), caesarean section (46.4% vs 38.8%, OR 1.41, 95% CI: 1.14-1.74) and IUGR (3.4% vs 1.0%, OR 3.20, 95% CI: 1.75-5.84)., Conclusions: With the exception of moderate to severe disease, the incidences of adverse pregnancy outcomes in women with IBD are similar to that of the general population., (© 2020 John Wiley & Sons Ltd.)

Background: Physical, psychological and sexual intimate partner violence (IPV) has been described in the literature as different types of IPV experienced by women during pregnancy all over the world., Objectives: To review and summarise systematically the empirical evidence on the links between IPV during pregnancy and the perinatal health of mothers and fetuses/neonates., Search Strategy: MEDLINE (Ovid), CINAHL, Embase, Nursing@ovid (Ovid) and LILACS were searched (2008-2018)., Selection Criteria: Observational studies that examined perinatal health outcomes (i.e. pre-term birth, low birthweight, miscarriage, perinatal death and premature rupture of membranes) in pregnant women exposed to IPV., Data Collection and Analysis: Information on study characteristics, type of IPV measured, study design, methodological quality and outcome variable extracted., Results: Fifty studies were included. Twenty-nine analysed undifferentiated IPV (n = 25 489), 34 included physical IPV (n = 7333), 22 analysed psychological IPV (n = 7833) and 18 examined sexual IPV (n = 2388). Fifteen studies were from Asia, 12 from North America and Oceania, and 12 from Central and South America. The studies examined the association between IPV and 39 different perinatal health outcomes. The most frequent outcomes reported were pre-term birth (50%), low birthweight (46%), miscarriage (30%), perinatal death (20%) and premature rupture of membranes (20%). A significant association with perinatal health outcomes was reported by 12 of the studies analysing undifferentiated IPV, 18 physical IPV, six psychological IPV and two sexual IPV., Conclusions: The relation between IPV and perinatal health outcomes can be seen in different epidemiological designs and countries. In all, 39 different outcomes were identified and 29 were associated with IPV., Tweetable Abstract: A variety of poor perinatal health outcomes are associated with psychological, physical and sexual IPV., (© 2020 Royal College of Obstetricians and Gynaecologists.)

An abnormal fetoplacental (F/P) ratio is a risk factor for poor pregnancy outcomes including fetal death, but studies of F/P ratio among stillbirths are limited. In the Wisconsin Stillbirth Service Program cohort of second and third trimester fetal deaths, 1,022 were at ≥24 weeks with data on fetal and placental weight. Comparison with data for viable infants of the same gestational ages (GAs) showed that the F/P ratio increases more rapidly with GA for stillbirths than for viable infants. While placentas of stillborn infants are small at all GA, weights of deceased fetuses are lowest early in the second trimester, becoming nearly normal by term. Excess high F/P ratios are noted at all GAs, increasing toward term, while low ratios are frequent at early gestation but rare near term. Analysis by cause of death shows that F/P ratios are markedly elevated for placental and maternal causes (about 50% above the 90th centile), somewhat elevated for cord accidents, non-hydropic fetal, and unknown causes (about 1/3 above the 90th centile), and variable with 40% below the 10th centile for hydropic stillbirths. Across all causes and GAs, placental weights are more abnormal than fetal weights, suggesting that diminished placental function may contribute to fetal demise even when non-placental causes (e.g., premature membrane rupture, cord accidents, and chromosomal disorders) are identified. About half of all stillbirths have abnormal F/P ratios, suggesting that improvements in prenatal assessment of placental size and function might aid in identifying pregnancies at risk for demise; unfortunately, therapeutic options for ongoing pregnancies with diminished placental function remain limited., (© 2019 Wiley Periodicals, Inc.)

Objective: The present study aimed to analyse the Korean National Health Insurance Service (NHIS) cohort data to examine the safety of acupuncture therapy during pregnancy., Design: Retrospective cohort., Setting: Korea., Population or Sample: Women with confirmed pregnancy between 2003 and 2012 from the 2002-13 NHIS sample cohort (n = 20 799)., Methods: Women with confirmed pregnancy were identified and divided into acupuncture or control group for comparison of their outcomes. Differences in other factors such as age, and rate of high-risk pregnancy and multiple pregnancy were examined. In the acupuncture group, the most frequent acupuncture diagnosis codes and the timing of treatment were also investigated., Main Outcome Measures: Incidence of full-term delivery, preterm delivery and stillbirth by pregnancy duration and among the high-risk and multiple pregnancy groups., Results: Of 20 799 pregnant women analysed, 1030 (4.95%) and 19 749 were in the acupuncture and control groups, respectively. Both overall (odds ratio [OR] 1.23; 95% CI 0.98-1.54), and in the stratified analysis of high-risk pregnancies (OR 1.09; 95% CI 0.73-1.64), there was no significant difference between acupuncture and control groups in preterm deliveries. No stillbirths occurred in the acupuncture group and 0.035% of pregnancies resulted in stillbirths in the control group., Conclusion: No significant difference in delivery outcomes (preterm delivery and stillbirth) was observed between confirmed pregnancies in the acupuncture and control groups. Therefore, in pregnancy, acupuncture therapy may be a safe therapeutic modality for relieving discomfort without an adverse delivery outcome., Tweetable Abstract: In pregnancy, acupuncture therapy may be a safe therapeutic modality for relieving discomfort without an adverse outcome., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Objective: To explore the relation between famine exposure in early life and subsequent pregnancy loss, including stillbirth, and spontaneous abortion in adulthood., Design: A population-based, partly ecological study., Setting and Population: Individual data of 58 601 females born around the time of the Great Chinese Famine in 1959-1961., Methods: Associations between the famine exposure in early life and pregnancy loss (stillbirth and spontaneous abortion) in adulthood were analysed using negative binomial regression, with the non-exposure group as reference, adjusting for region, highest education, monthly income, alcohol consumption, tobacco use, body mass index in 25-year-olds and metabolic equivalent. Further analyses were stratified by rural versus urban region., Main Outcome Measures: Continuous variables of times of stillbirths and spontaneous abortions were used according to the individual self-reported reproductive history., Results: No association was found between famine exposure and spontaneous abortion. In contrast, females experiencing the famine during their prenatal period (incidence rate ratio = 1.15, 95% CI 1.00-1.33) or infant period (incidence rate ratio = 1.27, 95% CI 1.12-1.44) were more likely to report stillbirth in later adult life. Such an association appeared stronger in women living in rural regions., Conclusions: Early life exposure of famine was associated with an increased risk of stillbirth but not spontaneous abortion in adulthood. The strength of such an association appeared stronger in rural areas. Given the high potential for unmeasured confounding, these associations must be interpreted with caution. Regarding the potential implication that undernutrition in the fetal period is related to reproductive outcome in adulthood, fetal nutritional supply may play an important role in human reproduction., Tweetable Abstract: Exposure to famine in early life was associated with increased pregnancy loss in adulthood., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Hydrops fetalis was diagnosed in 277 (9%) of 3,137 fetuses referred to the Wisconsin Stillbirth Service Program (WiSSP) for etiologic evaluation of stillbirth or second trimester miscarriage. Hydrops was clinically recognized at delivery in only about half the cases, while the remainder were diagnosed at autopsy or during evaluation of records, photographs, and radiographs. The peak incidence of hydrops was at 20-28 weeks. Hydropic fetuses were also frequent before 20 weeks but became increasingly rare toward term. The most frequent identifiable underlying cause was chromosomal (29%), followed by other syndromes (14%), and more distantly by cardiac (6%) and other single system disorders. While the overall prevalence of hydrops and chromosomal causes was comparable to other autopsy series, the frequency of nonchromosomal syndromes was higher, reflecting increased attention to syndrome identification. Lethal multiple pterygium syndrome (LMPS) was identified retrospectively in 17 cases, accounting for 6% of all hydrops; 3/17 had a previous affected sib, emphasizing the importance of accurate diagnosis and counseling. Depending on the underlying cause, hydropic fetuses may be either small (if the cause is chromosomal or LMPS) or large (in cases with other syndromes or cardiac causes) for gestational age. The relatively large number in the "idiopathic" group in WiSSP (104/277; 38%) is probably due to variability of autopsies at local hospitals and limited laboratory data. Improved recognition of hydrops and testing directed at diagnosis of specific underlying causes can lead to improved counseling for families., (© 2019 Wiley Periodicals, Inc.)

To systematically review and critically evaluate studies reporting alcohol exposure during pregnancy and miscarriage. We searched PubMed, EMBASE, PsycINFO, and ProQuest Theses for publications from January 1970 to January 2019. We identified studies about alcohol exposure during pregnancy and miscarriage. Information about study population, alcohol exposure assessment, outcome definition, covariates, and measures of association was collected. We assessed study quality using an adapted Newcastle-Ottawa Scale. Data were abstracted by 2 investigators independently. We conducted a random-effects meta-analysis to calculate the association between alcohol exposure and miscarriage risk and performed subgroup analyses to determine robustness of results to study differences. For studies reporting dose-specific effects, a pooled dose-response association was estimated using generalized least squares regression with and without restricted cubic spline terms for number of drinks consumed per week. Of 2,164 articles identified, 24 were eligible for inclusion. Meta-analysis of data from 231,808 pregnant women finds those exposed to alcohol during pregnancy have a greater risk of miscarriage compared to those who abstained (odds ratio [OR] 1.19, 95% confidence intervals [CI] 1.12, 1.28). Estimates did not vary by study design, study country, or method of alcohol ascertainment. For alcohol use of 5 or fewer drinks per week, each additional drink per week was associated with a 6% increase in miscarriage risk (OR 1.06, 95% CI 1.01, 1.10). Common study limitations reflect challenges inherent to this research, including difficulty recruiting participants early enough in pregnancy to observe miscarriage and collecting and quantifying information about alcohol consumption during pregnancy that accurately reflects use. This review provides evidence that alcohol consumption during pregnancy is associated with a dose-mediated increase in miscarriage risk. Future studies evaluating change in alcohol use in pregnancy are needed to provide insight into how alcohol consumption prior to pregnancy recognition impacts risk., (© 2019 by the Research Society on Alcoholism.)

Twins, particularly monochorionic (MC) pairs, are at increased risk for fetal death. Whereas previous work has sought to understand the mechanisms for this increased mortality, most studies analyze viable twin pregnancies or liveborn twin cohorts. In the Wisconsin Stillbirth Service Program cohort of 3,137 stillbirths and second trimester miscarriages, we identified 175 twin pregnancies for a twinning rate of 56/1,000, which is approximately double the general population. The excess of twins among miscarriages and stillbirths was attributable to MC pairs as the incidence of dizygotic (DZ) twinning was not increased compared to livebirth data. The leading causes of fetal demise among twins were twin-twin transfusion, acardia, and twin-twin disruption. Maternal causes of death, primarily premature rupture of membranes, were moderately increased in both MC and DZ twins relative to singletons. Although deceased twins were smaller than expected for viable twins at comparable gestational ages, placenta weights of deceased MC pairs were large compared to combined fetal weight, which indicates placental inefficiency likely due to vascular shunting. Co-twin survival was much lower for MC than for DZ pairs. Therefore, earlier diagnosis and treatment of MC twinning complications may decrease prenatal mortality., (© 2019 Wiley Periodicals, Inc.)

Objective: To ascertain whether stress biomarkers and psychological indices of stress may predict both conception and miscarriage rates in women undergoing in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI)., Design: Prospective observational study., Setting: A university-affiliated tertiary hospital., Population: Infertile women who were undergoing fresh or frozen IVF/ICSI cycles., Methods: Women were recruited to (1) complete validated psychological questionnaires (visual analogue scale of stress, state-trait anxiety inventory, perceived stress scale, fertility problem inventory, Beck depression inventory, and general health questionnaire), at the time of embryo transfer (ET) and pregnancy testing (PT), and (2) provide saliva samples for α-amylase (sAA) measurement before and after ET and at PT., Main Outcome Measures: Women were grouped according to subsequent reproductive outcome; scores/levels of all tests were then compared between groups at each time-point., Results: In all, 197 women completed the study, of which 92 conceived and 28 miscarried. The level of psychological stress, as measured by questionnaires, was highest at the time of PT, whereas the level of biological stress as measured by sAA level (IU/l) post-ET (1.8 × 10 5  ± 1.5 × 10 5 ) was significantly (P < 0.001) higher than pre-ET (1.2 × 10 5  ± 1.0 × 10 5 ) and at PT (1.0 × 10 5  ± 1.1 × 10 5 ). However, there was no difference in psychological scoring and in sAA levels between women who did or did not conceive and who had miscarried or had an ongoing pregnancy., Conclusions: The level of sAA is highest following ET, whereas psychological stress is highest at PT. However, neither stress level appeared to be of prognostic value in predicting conception or miscarriage., Tweetable Abstract: Stress level fluctuated at different time-points, but it did not predict conception or miscarriage., (© 2018 Royal College of Obstetricians and Gynaecologists.)

Objective: To assess the association between the outcome of a woman's first pregnancy and risk of clinical cardiovascular disease risk factors., Design: Prospective cohort study., Setting and Population: Nurses' Health Study II., Methods: Multivariable-adjusted Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between first pregnancy outcome and hypertension, type 2 diabetes, and hypercholesterolemia., Main Outcome Measures: Hypertension, type 2 diabetes, and hypercholesterolemia., Results: Compared to women who reported a singleton live first birth, women with early spontaneous abortion (<12 weeks) had a greater rate of type 2 diabetes (HR: 1.20; 95% CI: 1.07-1.34) and hypercholesterolemia (HR: 1.06; 95% CI: 1.02-1.10), and a marginally increased rate of hypertension (HR: 1.05, 95% CI: 1.00-1.11). Late spontaneous abortion (12-19 weeks) was associated with an increased rate of type 2 diabetes (HR: 1.38; 95% CI: 1.14-1.65), hypercholesterolemia (HR: 1.11; 95% CI: 1.03-1.19), and hypertension (HR: 1.15; 95% CI: 1.05-1.25). The rates of type 2 diabetes (HR: 1.45; 95% CI: 1.13-1.87) and hypertension (HR: 1.15; 95% CI: 1.01-1.30) were higher in women who delivered stillbirth. In contrast, women whose first pregnancy ended in an induced abortion had lower rates of hypertension (HR: 0.87; 95% CI: 0.84-0.91) and type 2 diabetes (HR: 0.89; 95% CI: 0.79-0.99) than women with a singleton live birth., Conclusions: Several types of pregnancy loss were associated with an increased rate of hypertension, type 2 diabetes, and hypercholesterolemia, which may provide novel insight into the pathways through which pregnancy outcomes and CVD are linked., Tweetable Abstract: Pregnancy loss is associated with later maternal risk of hypertension, type 2 diabetes, and hypercholesterolemia., (© 2018 Royal College of Obstetricians and Gynaecologists.)

Aims: To analyse prescribing patterns during pregnancy for antipsychotics (APs), antidepressants (ADs) and mood-stabilizing antiepileptics (AEDs) in Denmark from 2000 to 2016., Methods: Data were obtained from the Danish Medical Birth Register, the Register for Legally Induced Abortions, the Danish National Patient Register and the Register of Medicinal Product Statistics. Data were linked through a unique personal identifier by Statistics Denmark., Results: The use of APs increased 2.5-fold from a prevalence of 1.5 per 1000 pregnancies to 3.8 for pregnancies ending in a delivery. Use of mood-stabilizing AEDs increased from a prevalence of 0.1 to 2.1 during the study period. The prevalence for APs and mood-stabilizing AEDs was nearly twice as high for pregnancies ending in miscarriage or termination compared to pregnancies ending in delivery. A marked increase in the prevalence of ADs use during pregnancy was seen from 2000-2011 (from 6 to 41 per 1000 pregnancies ending in a delivery) but appears slightly in decline. Age, smoking, obesity and social status were generally associated with increased use of psychotropic drugs., Conclusions: The use of APs, ADs and mood-stabilizing AEDs during pregnancy has increased substantially in Denmark from 2000-2016. The use of ADs appears to be slightly in decline since 2011., (© 2018 The British Pharmacological Society.)

Recurrent pregnancy loss (RPL) affects approximately 1%-2% of reproductive women. Auto- and cellular immune responses seem to be associated with RPL. Vitamin D (VD) has been shown to play a role in the modulation of the immune system. Effects of VD deficiency (VDD) in pregnancy have been associated with preeclampsia, gestational diabetes, fetal growth restriction, preterm labor, and sporadic spontaneous abortion (SA). We systematically reviewed articles that studied women with 2 or more SA and its association with VD. Eleven studies were included. Studies reported a high prevalence of VD insufficiency (VDI) or VDD in women with RPL and suggested that this could be associated with immunological dysregulation and consequently with RPL. Immunological benefits were reported in the peripheral blood of women with RPL after VD exposure. Thus, it is possible to speculate a beneficial role for VD supplementation in RPL. It seems that there are not differences in the vitamin D receptor (VDR) and CYP27B1 expression in endometrium of women with RPL but, in villous and decidual tissues, RPL women seem to have a decreased expression of VDR and, perhaps, a decreased expression of CYP27B1. Further randomized controlled studies are required to investigate the association between VDD or VDI and RPL., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Many patients with autoimmune hepatitis are women of fertile age. Some concerns of these patients are related to pregnancy., Aim: To conduct a nationwide study on risk of miscarriage, birth rate, and birth outcomes in women with autoimmune hepatitis., Methods: From Danish healthcare registries, 1994-2015, we identified 179 births in 103 women with autoimmune hepatitis, 70 of which were first-time singleton births, and 1623 births in 1051 age-matched women (population controls), 662 of which were first-time singleton births. We calculated the risk of miscarriage and the birth rate after autoimmune hepatitis diagnosis in women with autoimmune hepatitis and controls. We used logistic regression to compare the odds of adverse birth outcomes (preterm birth, small for gestational age, congenital malformations and stillbirth) between women with autoimmune hepatitis and controls, adjusting for maternal age and smoking habits., Results: The risk of miscarriage was similar in women with autoimmune hepatitis and controls: risk ratio 1.17 (95% confidence interval 0.81-1.68). The first-time birth rate, including singleton and multiple births, per 1000 person-years in women with autoimmune hepatitis was 37 (95% confidence interval 29-46), in controls 32 (95% confidence interval 30-35). Age at first-births was similar in women with autoimmune hepatitis and controls. Women with autoimmune hepatitis had an increased risk of preterm birth (adjusted odds ratio 3.19, 95% confidence interval 1.53-6.64) and small for gestational age babies (adjusted odds ratio = 3.20, 95% confidence interval 0.33-31.29), but not of congenital malformations (adjusted odds ratio = 1.27, 95% confidence interval 0.48-3.34) or stillbirth. Birth outcomes did not differ in autoimmune hepatitis patients on or off immunosuppression, and with or without cirrhosis., Conclusions: In Danish women with autoimmune hepatitis, fertility was unaffected. They had an increased risk of preterm birth and small for gestational age children, but not of congenital malformations or stillbirth., (© 2018 John Wiley & Sons Ltd.)

Background: Quinolones were contraindicated during pregnancy because of concerns regarding fetal malformations and carcinogenesis in animals. The literature is conflicting regarding their safety in humans., Objectives: To conduct a meta-analysis evaluating the risk for fetal malformations and pregnancy complications following exposure to quinolones during pregnancy., Search Strategy: We searched Embase, PubMed, Medline, the Cochrane database, clinicaltrials.gov, and Dart Databases. We added articles found through the references of included articles., Selection Criteria: Relevant English citations using the terms quinolone/s, fluoroquinolone/s, and pregnancy in humans. Exclusion criteria were case reports, reviews, and articles without data regarding the study outcomes., Data Collection and Analysis: Two authors performed the database search, assessment of eligibility, and abstraction of data from included studies. Disagreement was settled by consensus among all authors. The pooled odds ratios (with 95% CIs) were estimated. The Cochrane's Q-test of heterogeneity and I² were used for the measurement of heterogeneity. A total of 256 papers were retrieved, 13 of which met the inclusion criteria and were then analysed., Main Results: No association was found between quinolones and fetal malformations (pooled odds ratio, OR 1.08; 95% CI 0.96-1.21), preterm delivery (pooled OR 0.97; 95% CI 0.75-1.24), stillbirth (pooled OR 1.11; 95% CI 0.34-3.6), or miscarriage (pooled OR 1.78; 95% CI 0.93-3.38)., Conclusions: Quinolones are not associated with unfavourable pregnancy outcomes; however, larger studies are needed before safety is established. Until then, it is suggested that quinolones should not be used as a first-line therapy during the first trimester., Tweetable Abstract: Quinolones were associated with favourable pregnancy outcomes; caution should be taken in the first trimester., (© 2018 Royal College of Obstetricians and Gynaecologists.)

Background and Aims: Opioid maintenance treatment (OMT) is recommended to opioid-dependent females during pregnancy. However, it is not clear which medication should be preferred. We aimed to compare neonatal outcomes after prenatal exposure to methadone (M) and buprenorphine (B) in two European countries., Design: Nation-wide register-based cohort study using personalized IDs assigned to all citizens for data linkage., Setting: The Czech Republic (2000-14) and Norway (2004-13). [Correction added after online publication on 26 April 2018: The Czech Republic (2000-04) corrected to (2000-14).] PARTICIPANTS: Opioid-dependent pregnant Czech (n = 333) and Norwegian (n = 235) women in OMT who received either B or M during pregnancy and their newborns., Measurements: We linked data from health registries to identify the neonatal outcomes: gestational age, preterm birth, birth weight, length and head circumference, small for gestational age, miscarriages and stillbirth, neonatal abstinence syndrome (NAS) and Apgar score. We performed multivariate linear regression and binary logistic regression to explore the associations between M and B exposure and outcomes. Regression coefficient (β) and odds ratio (OR) were computed., Findings: Most neonatal outcomes were more favourable after exposure to B compared with M, but none of the differences was statistically significant. For instance, in the multivariate analysis, birth weight was β = 111.6 g [95% confidence interval (CI) = -10.5 to 233.6 and β = 83.1 g, 95% CI = -100.8 to 267.0] higher after B exposure in the Czech Republic and Norway, respectively. Adjusted OR of NAS for B compared with M was 0.94 (95% CI = 0.46-1.92) in the Norwegian cohort., Conclusions: Two national cohorts of women receiving opioid maintenance treatment during pregnancy showed small but not statistically significant differences in neonatal outcomes in favour of buprenorphine compared with methadone., (© 2018 Society for the Study of Addiction.)

Aims: To evaluate the association between use of non-insulin antidiabetics in early pregnancy and the risk of miscarriages, stillbirths and major structural malformations., Materials and Methods: A cohort of 1511 pregnant women with pre-gestational diabetes linked to live births was identified using electronic medical records from The Health Improvement Network (THIN) for the period 1995 to 2012. Information on prescriptions, foetal outcomes and potential confounders was ascertained from both codes and free text in the THIN database. Odds ratios (OR) and 95% confidence intervals (CI) of adverse foetal outcomes in women treated with non-insulin antidiabetics during the first trimester compared to those on insulin were estimated using logistic regression to adjust for type of diabetes, glycaemic control and other maternal characteristics., Results: Among 311 pregnant women on non-insulin antidiabetics, 21.9% had a miscarriage and 1.6% a stillbirth; 1.9% of live births had major malformations. The corresponding frequencies for the 883 women on insulin were 13.3%, 1.7% and 9.6%. Insulin users more often had type 1 diabetes and poor glycaemic control. Compared to women with type 1 diabetes, those with type 2 diabetes had a higher risk of miscarriages (20.5% vs 12.8%) but a lower prevalence of malformations (4.0% vs 9.2%). Compared to women with HbA1c ≤7%, those with HbA1c >7% had a higher prevalence of malformations (12.6% vs 2.7%). After adjustment for diabetes type and glycaemic control, compared to insulin, non-insulin antidiabetic patients were associated with an OR for miscarriage of 1.19 (95% CI, 0.75-1.89), for stillbirths of 0.65 (95% CI, 0.16-2.58), and for major malformations of 0.25 (95% CI, 0.08-0.84)., Conclusion: Among women with diabetes, use of non-insulin antidiabetics early in pregnancy was not associated with greater risks of foetal losses or major malformations than was insulin., (© 2018 John Wiley & Sons Ltd.)

Aims: Metformin is used to treat type 2 diabetes, polycystic ovary syndrome associated infertility, and gestational diabetes. This study aims to evaluate the safety of metformin in early pregnancy., Method: We evaluated the risk of major birth defects and pregnancy losses in a cohort of pregnant women exposed to metformin during the first trimester for different indications relative to a matched unexposed reference group., Results: The risk of major birth defects was 5.1% (20/392) in pregnancies exposed to metformin during the first trimester and 2.1% (9/431) in the reference group [adjusted odds ratio (OR) 1.70; 95% CI 0.70-4.38]. Among metformin users, this risk was 7.8% (17/219) in patients with pre-gestational diabetes and 1.7% (3/173) in those without this diagnosis. Compared to the unexposed reference, the OR for metformin user with diabetes was 3.95 (95% CI 1.77-9.41) and for metformin with other indications it was 0.83 (95% CI 0.18-2.81). The risk of pregnancy losses (spontaneous abortions and stillbirths) was 20.8% in women on metformin during the first trimester and 10.8% in the reference group [adjusted hazard ratio (HR) 1.57; 95% CI 0.90-2.74]. The risks for women on metformin with and without pre-gestational diabetes were 24.0% and 16.8% respectively, with adjusted HR of 2.51 (95% CI 1.44-4.36) and 1.38 (95% CI 0.74-2.59) when compared to the reference., Conclusion: Pregnant women with pre-gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population. This appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks., (© 2017 The British Pharmacological Society.)

Background: Cardiovascular disease in women often develops without conventional risk factors. Prenatal loss is a common pregnancy outcome that may result in physiological changes can increase the potential future risk of cardiovascular disease. Insufficient information exists regarding the impact of pregnancy loss on early markers of cardiovascular disease risk., Methods and Results: Cross-sectional analysis of 1767 disease-free women from the MTC (Mexican Teachers' Cohort) who had been pregnant was used to evaluate the relationship between pregnancy loss and carotid intima-media thickness (IMT). Participants responded to a questionnaire regarding their reproductive history, risk factors, and medical conditions. We defined pregnancy loss as history of miscarriage and/or stillbirth. Trained neurologists measured IMT using ultrasound. We log-transformed IMT and defined subclinical carotid atherosclerosis (SCA) as IMT ≥0.8 mm and/or plaque. We used multivariable linear and logistic regression models to assess the relation of pregnancy loss, IMT, and SCA. The mean age of participants was 49.8±5.1 years. The prevalence of pregnancy loss was 22%, and we observed SCA in 23% of participants. Comparing participants who reported a pregnancy loss and those who did not, the multivariable-adjusted odds ratio for SCA was 1.52 (95% confidence interval, 1.12-2.06). Women who experienced a stillbirth had 2.32 higher odds (95% confidence interval, 1.03-5.21) of SCA than those who did not. Mean IMT appeared to be higher in women who reported a pregnancy loss relative to those who did not; nevertheless, this was not statistically significant., Conclusions: Pregnancy loss could be linked to cardiovascular disease later in life. The key findings of our study await confirmation and further investigation of the potential underlying mechanisms for this association is required., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)