Exposure to golimumab during pregnancy: Results from the Company's global safety database.

Data on the use of golimumab (GLM) during pregnancy are limited. This study evaluated pregnancy outcomes in women treated with GLM during pregnancy. Cumulative data on GLM-exposed pregnancies from the Company's global safety database (GSD) are summarized. Cases were medically confirmed maternal exposures to GLM during pregnancy or within 3 months prior to conception with a reported pregnancy outcome. Pregnancy outcomes (e.g., live births) and congenital anomalies in prospectively reported cases (i.e., pregnancy outcome not known when first reported to the company) are presented in a descriptive manner. As of May 31, 2022, 261 prospectively reported pregnancies exposed to GLM were reported in the GSD: 214 (82.0%) live births (including six sets of twins), 31 (11.9%) spontaneous abortions (including one set of twins), 13 (5.0%) induced/elective abortions, 2 (0.8%) reported intrauterine death/still birth, and 1 (0.4%) fetal adverse event in an ongoing pregnancy. The majority of pregnancies had exposure to GLM at least in the first trimester of pregnancy. In total, seven congenital anomalies (7/261; 2.7%) were reported. Of these seven congenital anomalies, five were considered major according to EUROCAT classification version 1.4. Among the five prospectively reported congenital anomalies noted in live births (5/214; 2.3%), four were classified as major (4/214; 1.8%). The rates of adverse pregnancy outcomes and major congenital anomalies in prospectively reported pregnancy cases with exposure to GLM in the Company's GSD were consistent with published background rates for the general population.

The maternal drug exposure birth cohort (DEBC) in China.

Drug exposure during pregnancy lacks global fetal safety data. The maternal drug exposure birth cohort (DEBC) study, a prospective longitudinal investigation, aims to explore the correlation of maternal drug exposure during pregnancy with pregnancy outcomes, and establish a human biospecimen biobank. Here we describe the process of establishing DEBC and show that the drug exposure rate in the first trimester of pregnant women in DEBC (n = 112,986) is 30.70%. Among the drugs used, dydrogesterone and progesterone have the highest exposure rates, which are 11.97% and 10.82%, respectively. The overall incidence of adverse pregnancy outcomes is 13.49%. Dydrogesterone exposure during the first trimester is correlated with higher incidences of stillbirth, preterm birth, low birth weight, and birth defects, along with a lower incidence of miscarriage/abortion. Due to the limitations of this cohort study, causative conclusions cannot be drawn. Further follow-up and in-depth data analysis are planned for future studies.

First-trimester use of antiseizure medications and the risk of miscarriage: a population-based cohort study.

BACKGROUND: Antiseizure medications (ASMs) during the first trimester of pregnancy have been associated with an increased risk of miscarriage. METHODS: We carried out a population-based cohort study using routinely collected healthcare data from the UK, 1995-2018. Pregnancies were identified in the Clinical Practice Research Datalink and we estimated the HR of miscarriage associated with prescriptions of ASMs during the first trimester of pregnancy, using Cox regression, adjusting for potential confounders, including ASM indications. RESULTS: ASMs were prescribed during the first trimester in 7832 (0.8%) of 1 023 787 included pregnancies. 14.5% of pregnancies with first-trimester exposure to ASMs ended in miscarriage, while 12.2% without ASM exposure in the first trimester ended in miscarriage; after adjustment, there was a 1.06-fold relative hazard of miscarriage (95% CI 1.00 to 1.13) in women with first-trimester ASM use. After restricting to women with specific ASM indications, this association was not evident in women with epilepsy (adjusted HR 0.98, 95% CI 0.89 to 1.08), but was observed in women with bipolar or other psychiatric conditions (1.08, 95% CI 1.00 to 1.16) although CIs overlapped. Compared with discontinuation of ASMs prior to pregnancy, there was no evidence of increased risk of miscarriage for first-trimester ASM use in women with bipolar or other psychiatric conditions (1.02, 95% CI 0.87 to 1.20). CONCLUSION: We found no clear evidence to suggest that first-trimester ASM use increased the risk of miscarriage. Taken together, our analyses suggest that apparent associations between first-trimester ASM use and miscarriage may be the result of confounding by the presence of a bipolar disorder or associated unmeasured variables.

Does the use of bisphosphonates during pregnancy affect fetal outcomes? A systematic review.

PURPOSE: This systematic review aimed to determine the effects of maternal exposure to bisphosphonates (BPs) during pregnancy on neonatal outcomes. It aimed to disclosfe the impact of BPs on neonates and identify aspects that require further investigation. METHODS: A comprehensive search of PubMed, Science Direct, LILACS, EMBASE, and Web of Science was conducted until August 2022, with no time restrictions. The selection criteria included studies published in English that evaluated pregnant women who were exposed to BPs. RESULTS: From an initial pool of 2169 studies, 13 met the inclusion criteria for this systematic review. These studies collectively included 106 women (108 pregnancies) who were exposed to BPs either before orduring pregnancy. A summary of the key characteristics of the selected studies and the risk of bias assessment are provided. Exposure to BPs occurs at various stages of pregnancy, with different indications for BP treatment. The most frequently reported neonatal outcomes were spontaneous abortion, congenital malformations, hypocalcemia, preterm birth, and low birth weight. CONCLUSION: Although previous reports have linked BPs before or during pregnancy with adverse neonatal outcomes, these associations should be interpreted with caution. Given the complexity of these findings, further research is necessary to provide more definitive insights to guide clinical decisions regarding the use of BPs in pregnant women.

Environmental BaP/BPDE suppressed trophoblast cell invasion/migration and induced miscarriage by down-regulating lnc-HZ01/MEST/VIM axis.

Environmental benzo(a)pyrene (BaP) and itsmetabolite benzo(a)pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE), classic endocrine disrupting chemical and persistent organic pollutant, could cause miscarriage. However, the detailed mechanisms are still largely unclear and should be further explored. In this study, we discovered that exposure of trophoblast cells with BPDE could suppressed cell invasion/migration by inhibiting MEST/VIM (Vimentin) pathway. Moreover, BPDE exposure also increased lnc-HZ01 expression level, which further inhibited MEST/VIM pathway and then suppressed invasion/migration. Knockdown of lnc-HZ01 or overexpression of MEST could efficiently rescue invasion/migration of BPDE-exposed Swan 71 cells. Furthermore, lnc-HZ01 was highly expressed and MEST/VIM were lowly expressed in recurrent miscarriage (RM) villous tissues compared with healthy control (HC) group. Finally, we also found that BaP exposure inhibited murine Mest/Vim pathway in placental tissues and induced miscarriage in BaP-exposed mice. Therefore, the regulatory mechanisms were similar in BPDE-exposed human trophoblast cells, RM villous tissues, and placental tissues of BaP-exposed mice with miscarriage, building a bridge to connect BaP/BPDE exposure, invasion/migration, and miscarriage. This study provided novel insights in the toxicological effects and molecular mechanisms of BaP/BPDE-induced miscarriage, which is helpful for better elucidating the toxicological risks of BaP/BPDE on female reproduction.

Association of acetaminophen use with perinatal outcomes among pregnant women: a retrospective cohort study with propensity score matching.

BACKGROUND: Although acetaminophen is widely used in women during pregnancy, its safety has not been clearly stated. The study aimed to investigate the association between acetaminophen use and adverse pregnancy outcomes in pregnant women in China. METHODS: We conducted a retrospective cohort study by collecting data on pregnant women who delivered in the Beijing Obstetrics and Gynecology Hospital from January 2018 to September 2023. An acetaminophen use group and a control group were formed based on prenatal exposure to acetaminophen. The pregnancy outcomes that we focused on were stillbirth, miscarriage, preterm birth, APGAR score, birth weight, and congenital disabilities. Pregnant women exposed to acetaminophen were matched to unexposed in a 1:1 ratio with propensity score matching, using the greedy matching macro. SPSS software was used for statistical analysis. Multivariable logistics regression was used to assess the association between acetaminophen use during pregnancy and adverse pregnancy outcomes. RESULTS: A total of 41,440 pregnant women were included, of whom 501 were exposed to acetaminophen during pregnancy, and 40,939 were not exposed. After the propensity score matching, the acetaminophen use and control groups consisted of 501 pregnant women each. The primary analysis showed that acetaminophen exposure during pregnancy was associated with an increased risk of stillbirth (adjusted OR (aOR) = 2.29, 95% CI, 1.19-4.43), APGAR score < 7 at 1 min (aOR = 3.28, 95% CI, 1.73-6.21), APGAR score < 7 at 5 min (aOR = 3.54, 95% CI, 1.74-7.20), APGAR score < 7 at 10 min (aOR = 3.18, 95% CI, 1.58-6.41), and high birth weight (HBW) (aOR = 1.75, 95% CI, 1.05-2.92). Drug exposure during the first and second trimesters increased the odds of stillbirth, miscarriage, APGAR < 7, and the occurrence of at least one adverse pregnancy outcome. In addition, the frequency of drug use more than two times was associated with a higher risk of preterm birth and APGAR score < 7. CONCLUSIONS: Exposure to acetaminophen during pregnancy was significantly associated with the occurrence of adverse pregnancy outcomes, particularly exposure in the first and second trimesters and frequency of use more than twice. It is suggested that acetaminophen should be prescribed with caution in pregnant women.

Pregnancy and fetal outcomes following paternal exposure to glatiramer acetate.

OBJECTIVES: This study aimed to examine pregnancy and fetal outcomes following paternal exposure to glatiramer acetate (GA). METHODS: Pregnancy reports of paternal GA-exposure at time of conception from 2001 to 2022 were extracted from Teva Global Pharmacovigilance database. Pregnancy reports obtained prior to (prospective) or after (retrospective) knowledge of the pregnancy outcome were included. The primary endpoint was major congenital malformation (MCM) in the offspring according to the US Metropolitan Atlanta Congenital Defects Program (MACDP) and European Surveillance of Congenital Anomalies and Twins (EUROCAT) classification. Other pregnancy and fetal outcomes, including spontaneous abortion, pregnancy termination, fetal death, preterm birth, and low birth weight, were assessed. RESULTS: A total of 466 paternal GA-exposed pregnancies were retrieved, 232 prospective cases and 234 retrospective cases. Of 349 (74.9%) pregnancies with known outcomes, 316 (90.5%) were live births, 28 (8.0%) were spontaneous abortions, 3 (0.9%) were elective pregnancy terminations, and 2 (0.6%) were stillbirths. In prospective live birth cases, there were 7/111 (6.3%) preterm births and 5/115 (4.3%) neonates with a low birth weight. The prevalence of total MCM among prospective cases was 1.7% (2 cases of 116 live births and fetal death/stillbirth), which is slightly lower than the background rates from MACDP (3%) and EUROCAT (2.1%). CONCLUSIONS: This study did not indicate an increase in the rate of adverse pregnancy and fetal outcomes after paternal exposure to GA. These results provide additional information regarding pregnancy outcomes following paternal exposure to GA for healthcare professionals, male patients and their female partners who are considering pregnancy while their male partner is using GA.

This research aimed to look at how pregnancies and babies were affected when fathers with multiple sclerosis have been prescribed and taken the medication, glatiramer acetate (GA). Researchers looked at reports of pregnancies where the father had taken GA around the time of conception, from 2001 to 2022. They got this information from the Teva Global Pharmacovigilance database. They included reports where the pregnancy was known about either before (prospective) or after (retrospective) the outcome was known. They looked at outcomes like major birth defects, miscarriages, pregnancy terminations, fetal deaths, premature births, and low birth weight. The study found a total of 466 pregnancies where the father had taken GA. Of these pregnancies, the final outcome of pregnancy was found for 349 pregnancies. Most of these pregnancies (90.5%) resulted in live births, 8.0% ended in miscarriage, 0.9% in termination, and 0.6% in stillbirth. Among prospective live births, 6.3% were premature, and 4.3% had low birth weight. The amount of major birth defects was 1.7%, which was slightly lower than usual. The study did not suggest that exposure of the father to GA negatively affects the pregnancy or the baby. These findings can help healthcare providers, male patients taking GA, and their partners who are thinking about pregnancy while the male partner is taking GA.

Exposure to high dose of polystyrene nanoplastics causes trophoblast cell apoptosis and induces miscarriage.

BACKGROUND: With rapid increase in the global use of various plastics, microplastics (MPs) and nanoplastics (NPs) pollution and their adverse health effects have attracted global attention. MPs have been detected out in human body and both MPs and NPs showed female reproductive toxicological effects in animal models. Miscarriage (abnormal early embryo loss), accounting for 15-25% pregnant women worldwide, greatly harms human reproduction. However, the adverse effects of NPs on miscarriage have never been explored. RESULTS: In this study, we identified that polystyrene (PS) plastics particles were present in women villous tissues. Their levels were higher in villous tissues of unexplained recurrent miscarriage (RM) patients vs. healthy control (HC) group. Furthermore, mouse assays further confirmed that exposure to polystyrene nanoplastics (PS-NPs, 50 nm in diameter, 50 or 100 mg/kg) indeed induced miscarriage. In mechanism, PS-NPs exposure (50, 100, 150, or 200 µg/mL) increased oxidative stress, decreased mitochondrial membrane potential, and increased apoptosis in human trophoblast cells by activating Bcl-2/Cleaved-caspase-2/Cleaved-caspase-3 signaling through mitochondrial pathway. The alteration in this signaling was consistent in placental tissues of PS-NPs-exposed mouse model and in villous tissues of unexplained RM patients. Supplement with Bcl-2 could efficiently suppress apoptosis in PS-NPs-exposed trophoblast cells and reduce apoptosis and alleviate miscarriage in PS-NPs-exposed pregnant mouse model. CONCLUSIONS: Exposure to PS-NPs activated Bcl-2/Cleaved-caspase-2/Cleaved-caspase-3, leading to excessive apoptosis in human trophoblast cells and in mice placental tissues, further inducing miscarriage.

A preliminary understanding of the relationship between synthetic phenolic antioxidants and early pregnancy loss: Uncovering the potential molecular mechanisms.

Mounting evidence suggests that environmental pollutants may affect reproductive health, potentially leading to adverse outcomes like pregnancy loss. However, it remains unclear whether exposure to synthetic phenolic antioxidants (SPAs) correlates with early pregnancy loss (EPL). This study explores SPA exposure's link to EPL and its potential molecular mechanisms. From 2021 to 2022, 265 early pregnant women (136 serum and 129 villus samples) with and without EPL were enrolled. We quantified 17 SPAs in serum and chorionic villus, with AO1010, AO3114, BHT, AO2246, and BHT-Q frequently being detected, suggesting their ability to cross the placental barrier. AO1135 showed a positive relationship with EPL in sera, indicating a significant monotonic dose-response relationship (p-trend <0.001). BHT-Q exhibited a similar relationship with EPL in villi. Inhibitory effects of BHT-Q on estradiol (E2) were observed. Molecular docking revealed SPA-protein interactions involved in E2 synthesis. SPA-induced EPL might occur with specific serum levels of AO1135 and certain villus levels of AO1010, BHT-Q, and AO2246. BHT-Q emerges as a potential biomarker for assessing EPL risk. This study provides insights into understanding of the exposure to SPAs and potential adverse outcomes in pregnant women.

Environmental copper exposure, placental cuproptosis, and miscarriage.

Copper pollution has become global environmental concern. Widespread Cu pollution results in excessive Cu exposure in human. Epidemiological studies and animal experiments revealed that Cu exposure might have reproductive toxicity. Cuproptosis is a newly reported Cu-dependent and programmed cell death formTsvetkov et al., 2022. However, whether copper exposure at real environmental exposure dose might cause placental cuproptosis and induce miscarriage was completely unexplored. In this study, we found that Cu exposure during pregnancy induced miscarriage or complete pregnancy loss by inducing placenta cuproptosis in CuCl2-exposed pregnant mice. Notably, Cu exposure at 1.3 mg/kg/d (a real environmental exposure dose) was enough to cause placenta cuproptosis. CuCl2 exposure disrupts the TCA cycle, causes proteotoxic stress, increases Cu2+ ion import/decreases Cu2+ export, and results in the loss of Fe-S cluster proteins in mouse placenta, which induces placenta cuproptosis. Moreover, we also identified that Cu exposure down-regulates the expression levels of mmu-miR-3473b, which interacts with Dlst or Rtel1 mRNA and simultaneously positively regulates Dlst or Rtel1 expression, thereby disrupting the TCA cycle and resulting in the loss of Fe-S cluster proteins, and thus epigenetically regulates placental cuproptosis. Treatment with TTM (a cuproptosis inhibitor) suppressed placental cuproptosis and alleviated miscarriage in CuCl2-exposed mice. This work provides novel reproductive toxicity of Cu exposure in miscarriage or complete pregnancy loss by causing placental cuproptosis. This study also provides new ways for further studies on other toxicological effects of Cu and proposes a new approach for protection against Cu-induced reproductive diseases.

Pregnancy outcomes and birth defects in offspring following Non-steroidal anti-inflammatory drugs exposure during pregnancy: A systematic review and meta-analysis.

There is a high global prevalence of NSAIDs during pregnancy. However, current evidence is largely conflicting regarding the safety of gestational NSAIDs use both for the pregnancy and offspring health. The aim of this study is to systematically review the relationship between NSAIDs use during pregnancy and the risk of adverse pregnancy outcomes and congenital abnormalities. Cohort studies and case control studies on congenital malformations, miscarriage and preterm birth in infants born to mothers who were exposed to NSAIDs during pregnancy were identified via PubMed, Medline, Embase, the Cochrane Library databases and the Reprotox® database from inception to 26 March 2021, and updated on 6 April 2023. On the whole, compared with the unexposed group, infants exposed to NSAIDs during early pregnancy showed a 28% increased risk of overall congenital anomalies (OR 1.28, 95%CI 1.16-1.40), and 19% for major birth defects (OR 1.19, 95%CI 1.08-1.30). Contrary to previous beliefs, there appeared to be a trend towards a higher risk of miscarriage among women who were exposed to NSAIDs during pregnancy, but the association was not statistically significant (OR 1.20, 95%CI 0.93-1.55). According to our study findings, the use of NSAIDs by pregnant women has been linked to a higher risk of congenital anomalies and a negative impact on preterm birth. Therefore, we advise pregnant women to carefully consider the potential benefits and risks before using NSAIDs during pregnancy.

Association between urinary polycyclic aromatic hydrocarbons and unexplained recurrent spontaneous abortion from a case-control study.

Polycyclic aromatic hydrocarbons (PAHs) have been reported to be associated with adverse pregnancy outcomes. However, there is limited knowledge regarding the effects of single or mixed PAHs exposure on unexplained recurrent spontaneous abortion (URSA). This study aimed to investigate the association between monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) and URSA in a case-control study. The results showed that 1-NAP, 2-NAP, 9-FLU, and 1-PYR were detected in 100% of the subjects among measured all sixteen OH-PAHs. Compared with those in the lowest quartiles, participants in the highest quartiles of 3-BAA were associated with a higher risk of URSA (OR (95%CI) = 3.56(1.28-9.85)). With each one-unit increase of ln-transformed 3-BAA, the odds of URSA increased by 41% (OR (95%CI) = 1.41(1.05-1.89)). Other OH-PAHs showed negative or non-significant associations with URSA. Weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and quantile-based g-computation (qgcomp) analyses consistently identified 3-BAA as the major contributor to the mixture effect of OH-PAHs on URSA. Our findings suggest that exposure to 3-BAA may be a potential risk factor for URSA. However, further prospective studies are needed to validate our findings in the future.

Potential pathological mechanisms and pharmacological interventions for cadmium-induced miscarriage.

The prevalence of cadmium (Cd) contamination has emerged as a significant global concern. Exposure to Cd during pregnancy is associated with adverse pregnancy outcomes, including miscarriage. However, there is currently a lack of comprehensive summaries on Cd-induced miscarriage. Therefore, it is imperative to further strengthen research into in vivo studies, clinical status, pathological mechanisms, and pharmacological interventions for Cd-induced miscarriage. This study systematically presents the current knowledge on animal models and clinical trials investigating Cd exposure-induced miscarriage. The underlying mechanisms involving oxidative stress, inflammation, endocrine disruption, and placental dysfunction caused by Cd-induced miscarriage are also extensively discussed. Additionally, potential drug interventions such as melatonin, vitamin C, and vitamin E are highlighted for their pharmacological role in mitigating adverse pregnancy outcomes induced by Cd.

The impact of air pollutants on spontaneous abortion: a case-control study in Tongchuan City.

OBJECTIVES: Studies related to air pollutants and spontaneous abortion in urban northwestern China are scarce, and the main exposure windows of pollutants acting on pregnant women are unclear. STUDY DESIGN: Case-control study. METHODS: Data were collected from pregnant women in Tongchuan City from 2018 to 2019. A total of 289 cases of spontaneous abortion and 1156 cases of full-term labor were included and analyzed using a case-control study. Logistic regression models were developed to explore the relationship between air pollutants and spontaneous abortion after Chi square analysis and Air pollutant description. RESULTS: O3 (odds ratio [OR] = 1.028) is a risk factor for spontaneous abortion throughout pregnancy. PM2.5 (OR = 1.015), PM10 (OR = 1.010), SO2 (OR = 1.026), and NO2 (OR = 1.028) are risk factors for spontaneous abortion in the 30 days before the last menstrual period. PM2.5 (OR = 1.015), PM10 (OR = 1.013), SO2 (OR = 1.036), and NO2 (OR = 1.033) are risk factors for spontaneous abortion in the 30-60 days before the last menstrual period. PM2.5 (OR = 1.028), PM10 (OR = 1.013), SO2 (OR = 1.035), and NO2 (OR = 1.059) are risk factors for spontaneous abortion in the 60-90 days before the last menstrual period. CONCLUSION: Exposure to high levels of air pollutants may be a cause of increased risk of spontaneous abortion, especially in the first trimester of the last menstrual period.

Final analysis of 379 pregnancy outcomes after exposure to dimethyl fumarate in a prospective international registry.

BACKGROUND: Dimethyl fumarate (DMF) has a favorable benefit-risk profile treating people with multiple sclerosis and should be used in pregnant women only if the potential benefits outweigh potential risks to the fetus. OBJECTIVE: Assess pregnancy outcomes in a completed international registry (TecGistry) of women with MS exposed to DMF. METHODS: TecGistry included pregnant women with MS exposed to DMF, with data collected at enrollment, 6-7 months gestation, 4 weeks after estimated due date, and at postpartum weeks 4, 12, and 52. Outcomes included live births, gestational size, pregnancy loss, ectopic/molar pregnancies, birth defects, and infant/maternal death. RESULTS: Of 397 enrolled, median (range) age was 32 years (19-43). Median (range) gestational week at enrollment was 10 (0-39) and at first DMF exposure was 1 (0-13). Median (range) duration of gestational DMF exposure was 5 weeks (0-40). Fifteen (3.8%) spontaneous abortions occurred. Of 360 (89.1%) live births, 323 were full term and 37 were premature. One neonatal death and no maternal deaths occurred. Adjudicator-confirmed EUROCAT birth defects were found in 2.2%. CONCLUSION: DMF exposure during pregnancy did not adversely affect pregnancy outcomes; birth defects, preterm birth, and spontaneous abortion were in line with rates from the general population.

Association between antidepressant use during pregnancy and miscarriage: a systematic review and meta-analysis.

BACKGROUND: Literature surrounding the association between antidepressant use during pregnancy and miscarriage is conflicting. We aimed to conduct a systematic review and meta-analysis of studies among pregnant women regarding the association between exposure to antidepressants during pregnancy and the risk of miscarriage, compared with pregnant women not exposed to antidepressants. DESIGN: We conducted a systematic review and meta-analysis of non-randomised studies. DATA SOURCES: We searched Medline, Embase and PsychINFO up to 6 August 2023. ELIGIBILITY CRITERIA AND OUTCOMES: Case-control, cohort and cross-sectional study designs were selected if they compared individuals exposed to any antidepressant class during pregnancy to comparator groups of either no antidepressant use or an alternate antidepressant. DATA EXTRACTION AND SYNTHESIS: Effect estimates were extracted from selected studies and pooled using a random-effects meta-analysis. Risk of bias (RoB) was assessed using the Risk of Bias in Non-Randomised Studies of Interventions (ROBINS-I) tool, and heterogeneity assessed using the I2 statistic. Subgroup analyses were used to explore antidepressant classes and the impact of confounding by indication. RESULTS: 1800 records were identified from the search, of which 29 were included in the systematic review and meta-analysis. The total sample included 5 671 135 individuals. Antidepressant users initially appeared to have a higher risk of miscarriage compared with unexposed individuals from the general population (summary effect estimate: 1.24, 95% CI 1.18 to 1.31, I2=69.2%; number of studies (n)=29). However, the summary estimate decreased when comparing against unexposed individuals with maternal depression (1.16, 1.04 to 1.31; I2=58.6%; n=6), suggesting confounding by indication may be driving the association. 22 studies suffered from serious RoB, and only two of the 29 studies were deemed at moderate RoB. CONCLUSIONS: After accounting for maternal depression, there is little evidence of any association between antidepressant use during pregnancy and miscarriage. Instead, the results indicate the biasing impact of confounding by indication.

Impact of maternal first trimester treatment regimen on the outcome of valproate exposed pregnancies: an observational Embryotox cohort study.

Effects of valproate (VPA) dose and treatment discontinuation during the first trimester of pregnancy on the risks of spontaneous abortions (SAB) and major birth defects were analyzed. Pregnancies with first trimester VPA exposure (n = 484) prospectively recorded by the German Embryotox center in 1997-2016 were compared with a randomly selected, non-exposed cohort (n = 1446). The SAB risk was not significantly increased in the VPA cohort [HRadj 1.31 (95% CI 0.85-2.02)] but major birth defects were significantly more frequent [8.7% vs. 3.4%; ORadj 2.61 (95% CI 1.51-4.50)]. Risk was even higher in pregnancies with no VPA discontinuation in first trimester [ORadj 3.66 (95% CI 2.04-6.54)]. Significant ORs were found for nervous system defects in general [ORadj 5.69 (95% CI 1.73-18.78)], severe microcephaly [ORadj 6.65 (95% CI 1.17-37.68)], hypospadias [ORadj 19.49 (95% CI 1.80-211)] and urinary system defects [ORadj 6.51 (95% CI 1.48-28.67)]. VPA dose had a stronger effect than antiepileptic poly- versus monotherapy; for VPA dose ≥ 1500 mg/day the ORadj was 5.41 (95% CI 2.32-12.66)]. A daily dose increase of 100 mg was calculated to raise the risk for major birth defects by 15% [OR 1.15 (95% CI 1.08-1.23)]. Overall, maternal first trimester treatment regimen had a relevant impact on birth defect risk.

Prenatal Exposure to Air Pollution and Respiratory Distress in Term Newborns: Results from the MIREC Prospective Pregnancy Cohort.

BACKGROUND: Respiratory distress is the leading cause of neonatal morbidity and mortality worldwide, and prenatal exposure to air pollution is associated with adverse long-term respiratory outcomes; however, the impact of prenatal air pollution exposure on neonatal respiratory distress has not been well studied. OBJECTIVES: We examined associations between prenatal exposures to fine particular matter (PM2.5) and nitrogen dioxide (NO2) with respiratory distress and related neonatal outcomes. METHODS: We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a prospective pregnancy cohort (n=2,001) recruited in the first trimester from 10 Canadian cities. Prenatal exposures to PM2.5 (n=1,321) and NO2 (n=1,064) were estimated using land-use regression and satellite-derived models coupled with ground-level monitoring and linked to participants based on residential location at birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between air pollution and physician-diagnosed respiratory distress in term neonates in hierarchical logistic regression models adjusting for detailed maternal and infant covariates. RESULTS: Approximately 7% of newborns experienced respiratory distress. Neonates received clinical interventions including oxygen therapy (6%), assisted ventilation (2%), and systemic antibiotics (3%). Two percent received multiple interventions and 4% were admitted to the neonatal intensive care unit (NICU). Median PM2.5 and NO2 concentrations during pregnancy were 8.81 µg/m3 and 18.02 ppb, respectively. Prenatal exposures to air pollution were not associated with physician-diagnosed respiratory distress, oxygen therapy, or NICU admissions. However, PM2.5 exposures were strongly associated with assisted ventilation (OR per 1-µg/m3 increase in PM2.5=1.17; 95% CI: 1.02, 1.35), multiple clinical interventions (OR per 1-µg/m3 increase in PM2.5=1.16; 95% CI: 1.07, 1.26), and systemic antibiotics, (OR per 1-µg/m3 increase in PM2.5=1.12; 95% CI: 1.04, 1.21). These associations were consistent across exposure periods-that is, during prepregnancy, individual trimesters, and total pregnancy-and robust to model specification. NO2 exposure was associated with administration of systemic antibiotics (OR per 1-ppb increase in NO2=1.03; 95% CI: 1.00, 1.06). DISCUSSION: Prenatal exposures to PM2.5 increased the risk of severe respiratory distress among term newborns. These findings support the development and prioritization of public health and prenatal care strategies to increase awareness and minimize prenatal exposures to air pollution. https://doi.org/10.1289/EHP12880.

How to account for early overly small risk sets in the analysis of pregnancy outcome data?-Comparison of different methods for stabilizing the Aalen-Johansen estimator.

PURPOSE: In analyzing pregnancy data concerning drug exposure in the first trimester, the risk of spontaneous abortions is of primary interest. For estimating the cumulative incidence function, the Aalen-Johansen estimator is typically used, and competing risks such as induced abortion and livebirth are considered. However, the delayed study entry can lead to overly small risk sets for the first events. This results in large jumps in the estimated cumulative incidence function of spontaneous abortions or induced abortions using the Aalen-Johansen estimator, and consequently in an overestimation of the probability. METHODS: Several approaches account for early overly small risk sets. The first approach is conditioning on the event time being greater than the event time causing the large jump. Second, the events can be ignored by censoring them. Third, the events can be postponed until a large enough number is at risk. These three approaches are compared. RESULTS: All approaches are applied using data of 54 lacosamide-exposed pregnancies. The Aalen-Johansen estimate of the probability of spontaneous abortion is 22.64%, which is relatively large for only three spontaneous abortions in the dataset. The conditional approach and the ignore approach have an estimated probability of 7.17%. In contrast, the estimate of the postpone approach is 16.45%. In this small sample, bootstrapped confidence intervals seem more accurate. CONCLUSIONS: In the analyses of pregnancy data with rare events, the postpone approach is favorable as no events are excluded. However, the approach that ignores early events has the narrowest confidence interval.

Antiepileptic treatment with levetiracetam during the first trimester and pregnancy outcome: An observational study.

OBJECTIVE: Levetiracetam is increasingly used in pregnant women with epilepsy. Although teratogenic effects have not been observed so far, data on the risks of spontaneous abortion and major birth defects are still limited, especially for the frequently used dual therapy of levetiracetam and lamotrigine. Our primary aim was to analyze rates of major birth defects and spontaneous abortion after maternal levetiracetam treatment. METHODS: This was a cohort study based on pregnancies recorded by the Embryotox Center from 2000 to 2017. Outcomes of prospectively ascertained pregnancies with first trimester levetiracetam monotherapy (n = 221) were compared to pregnancies with lamotrigine monotherapy for epilepsy (n = 469). In addition, all pregnancies with levetiracetam (n = 364) exposure during the first trimester were analyzed in comparison to a nonexposed cohort (n = 729). Pregnancies with the most frequently used combination therapy comprising levetiracetam and lamotrigine (n = 80) were evaluated separately. RESULTS: There was no significantly increased risk of major birth defects or of spontaneous abortions after first trimester exposure to levetiracetam. Birth weight of male neonates was significantly lower after levetiracetam monotherapy compared to lamotrigine monotherapy. Dual therapy with levetiracetam and lamotrigine resulted in a significantly increased risk of spontaneous abortion (adjusted hazard ratio = 3.01, 95% confidence interval [CI] = 1.43-6.33) and a nonsignificant effect estimate for major birth defects (7.7%, n = 5/65, adjusted odds ratio = 1.47, 95% CI = .48-4.47) compared to a nonexposed cohort. SIGNIFICANCE: Our study confirms the use of levetiracetam as a suitable antiepileptic drug in pregnancy. The lower birth weight of male neonates after maternal levetiracetam monotherapy and the unexpectedly high risk of spontaneous abortion and birth defects after dual therapy with levetiracetam and lamotrigine require further investigation.