First-trimester Exposure Research Articles

Exposure to multiple air pollutant mixtures and the subtypes of hypertensive disorders in pregnancy: A multicenter study

BackgroundHypertensive disorders in pregnancy (HDP) have heterogeneous etiologies. Previous studies have linked individual air pollutants to overall HDP with inconsistent results. Moreover, it has not been explored how exposure to a mixture of multiple air pollutants may affect the risks of the subtypes of the disorders. ObjectivesTo investigate the associations of exposure to air pollutant mixture in the 1st and 2nd trimesters of pregnancy with the risks of HDP and its subtypes. MethodsPregnancy data were obtained from the China Labor and Delivery Survey, a nationwide cross-sectional survey in 2015 and 2016. Levels of air pollutants [including fine particulate matter (PM2.5), carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), and sulfur dioxide (SO2)] in the 1st and 2nd trimesters were estimated based on the model developed by the Institution of Atmospheric Physics, Chinese Academy of Science. Generalized linear mixed models were built to assess the single-exposure effects of air pollutants in early gestation on HDP. The restricted cubic spline function was further applied to assess the potential non-linearity. The weighted quantile sum (WQS) regression was used to investigate the effects of co-exposure to multiple air pollutants. ResultsA total of 67,512 pregnancies were included, and 2,834 were HDP cases. The single-effect analysis showed that CO, PM2.5, and SO2 exposure in the 2nd trimester was positively associated with the risks of gestational hypertension (GH), with adjusted odds ratios (aORs) and 95% confidence intervals (CI) of 1.16 (1.04, 1.28), 1.19 (1.04, 1.37), and 1.13 (1.04, 1.22), respectively. The first-trimester O3 exposure was also associated with an increased preeclampsia/eclampsia (PE) risk (aOR = 1.17; 95%CI: 1.02, 1.33). WQS regression confirmed positive associations of air pollutant mixture with HDP subtypes, with PM2.5 as the main contributing pollutant to GH, and CO and O3 as the main pollutants to PE. ConclusionsExposure to multiple air pollutant mixtures in early pregnancy was associated with increased risks of hypertensive disorders in pregnancy.

Pregnancy Outcomes in Patients Exposed to OnabotulinumtoxinA Treatment: A Cumulative 29-Year Safety Update.

A previous publication of pregnancy outcomes in onabotulinumtoxinA-exposed mothers demonstrated that the prevalence of major fetal defects (0.9%, 1/110) was comparable with background rates in the general population. There is continued interest to better understand the safety of onabotulinumtoxinA during pregnancy. This analysis evaluated pregnancy outcomes after onabotulinumtoxinA exposure to provide a cumulative 29-year update. The Allergan Global Safety Database was searched from January 1, 1990, to December 31, 2018. Data from women (younger than 65 years or unknown) during pregnancy or ≤3 months before conception treated with onabotulinumtoxinA were assessed to estimate birth defect prevalence rates of live births only from prospective pregnancies. Of 913 pregnancies, 397 (43.5%) were eligible with known outcomes. Maternal age was known in 215 pregnancies: 45.6% were 35 years or older. Indication was known in 340 pregnancies: most frequent were aesthetic (35.3%) and migraine/headache (30.3%). The timing of exposure was known in 318 pregnancies: 94.6% were before conception or during the first trimester. OnabotulinumtoxinA dose information was known in 242 pregnancies; most (83.5%) were exposed to <200 U. Of 195 prospective pregnancies with 197 fetuses, there were 152 (77.2%) live births and 45 (22.8%) fetal losses (32 spontaneous, 13 elective). Of 152 live births, 148 (97.4%) had normal outcomes and 4 had abnormal outcomes. Among the 4 abnormal outcomes, there were 1 major birth defect, 2 minor fetal defects, and 1 birth complication. The prevalence rate for overall fetal defects was 2.6% (4/152, 95% CI 1.0%-6.6%) and 0.7% (1/152, 95% CI 0.1%-3.6%) for major fetal defects (3%-6% in the general population). Among cases of live births and known determinable exposure times, there was 1 birth defect with preconception exposure and 2 with first-trimester exposure. Although subject to reporting bias due to the nature of the postmarketing database review, this 29-year retrospective analysis of safety data in pregnant women exposed to onabotulinumtoxinA demonstrates that the prevalence rate of major fetal defects among live births is consistent with the rates reported in the general population. Although there are limited data available for second-trimester and third-trimester exposure, this updated and expanded safety analysis provides important real-world evidence to health care providers and their patients. This analysis provides Class III data that demonstrate that the prevalence rate of major fetal defects among live births subsequent to in utero onabotulinumtoxinA exposure is comparable with the reported background rates.

The Association between Maternal Urinary Phthalate Concentrations and Blood Pressure in Pregnancy: A Systematic Review and Meta-Analysis.

Phthalates are commonly found in a wide range of environments and have been linked to several negative health outcomes. While earlier research indicated a potential connection between phthalate exposure and blood pressure (BP) during pregnancy, the results of these studies remain inconclusive. The objective of this meta-analysis was to elucidate the relationship between phthalate exposure and BP in pregnancy. A comprehensive literature search was carried out with PubMed, EMBASE, and Web of Science, and pertinent studies published up until 5 March 2023 were reviewed. Random-effects models were utilized to consolidate the findings of continuous outcomes, such as diastolic and systolic BP, as well as the binary outcomes of hypertensive disorders of pregnancy (HDP). The present study included a total of 10 studies. First-trimester MBP exposure exhibited a positive association with mean systolic and diastolic BP during both the second and third trimesters (β = 1.05, 95% CI: 0.27, 1.83, I2 = 93%; β = 0.40, 95% CI: 0.05, 0.74, I2 = 71%, respectively). Second-trimester monobenzyl phthalate (MBzP) exposure was positively associated with systolic and diastolic BP in the third trimester (β = 0.57, 95% CI: 0.01, 1.13, I2 = 0; β = 0.70, 95% CI: 0.27, 1.13, I2 = 0, respectively). Conversely, first-trimester mono-2-ethylhexyl phthalate (MEHP) exposure demonstrated a negative association with mean systolic and diastolic BP during the second and third trimesters (β = -0.32, 95% CI: -0.60, -0.05, I2 = 0; β = -0.32, 95% CI: -0.60, -0.05, I2 = 0, respectively). Additionally, monoethyl phthalate (MEP) exposure was found to be associated with an increased risk of HDP (OR = 1.12, 95% CI: 1.02, 1.23, I2 = 26%). Our study found that several phthalate metabolites were associated with increased systolic and diastolic BP, as well as the risk of HDP across pregnancies. Nevertheless, given the limited number of studies analyzed, additional research is essential to corroborate these findings and elucidate the molecular mechanisms linking phthalates to BP changes during pregnancy.

Congenital malformations and preeclampsia associated with integrase inhibitor use in pregnancy: A single-center analysis.

Antiretroviral therapy (ART) decreases perinatal HIV transmission, but concerns exist regarding maternal and infant safety. We compared the incidence of congenital malformations and other adverse outcomes in pregnancies exposed to integrase inhibitor (INSTI) versus non-INSTI ART. Single-site review of all pregnancies among women living with HIV between 2008 and 2018. We used binomial family generalized estimating equations to model the relationship of congenital anomalies and pregnancy outcomes with exposure to INSTI or dolutegravir (DTG) versus non-INSTI ART. Among 257 pregnancies, 77 women received ≥1 INSTI (54 DTG, 14 elvitegravir, 15 raltegravir), 167 received non-INSTI, and 3 had missing data. Fifty congenital anomalies were identified in 36 infants. Infants with first-trimester DTG or any first-trimester INSTI exposure had higher odds of congenital anomalies than infants with first-trimester non-INSTI exposure (OR = 2.55; 95%CI = 1.07-6.10; OR = 2.61; 95%CI = 1.15-5.94, respectively). Infants with INSTI exposure after the second trimester had no increased odds of anomalies. Women with INSTI exposure had higher odds of preeclampsia (OR = 4.73; 95%CI = 1.70-13.19). Among women who received INSTI, grade ≥3 laboratory abnormalities were noted in 2.6% while receiving the INSTI and 3.9% while not receiving the INSTI, versus 16.2% in women who received non-INSTI. There was no association between INSTI exposure and other pregnancy outcomes. In our cohort, first-trimester INSTI exposure was associated with increased rates of congenital anomalies and use of INSTI during pregnancy was associated with preeclampsia. These findings underscore the need for continued monitoring of the safety of INSTI in pregnancy.

Risk of Major Malformations in Infants After First-Trimester Exposure to Stimulants: Results From the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications.

The prevalence of attention-deficit/hyperactivity disorder in adult females is 3% to 4%. Attention-deficit/hyperactivity disorder is highly comorbid with other psychiatric disorders such as mood, anxiety, and substance use disorders. For reproductive-aged women, the treatment of attention-deficit/hyperactivity disorder with stimulant medications may be considered during pregnancy or breastfeeding, although historically, data are lacking to inform these decisions. The aim of this investigation was to determine the risk of major malformations in infants after first-trimester prescription stimulant exposure in a small but rigorously characterized sample. The Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications systematically ascertains information from pregnant females including demographic information, medical and psychiatric history, use of prescription medications, and other information relevant to fetal outcomes. Participants provide verbal informed consent and are interviewed twice during gestation and again at approximately 3 months postpartum. The primary outcome of interest is the presence of a major malformation identified within 6 months after birth. Redacted cases of major malformations are reviewed by a dysmorphologist blinded to medication exposure. A total of N = 1988 women were eligible for this analysis, including the following exposures: n = 173 to mixed amphetamine salts; n = 40 to lisdexamfetamine; n = 45 to methylphenidate; n = 3 to dexmethylphenidate; and n = 1755 controls. The odds ratio of a major malformation among infants after first-trimester exposure to any stimulant was 0.39 (95% confidence interval, 0.09-1.61) compared with controls. There were no major malformations observed in infants exposed to lisdexamfetamine, methylphenidate, or dexmethylphenidate. Although preliminary, this analysis from an ongoing pregnancy registry provides reassurance that these stimulants do not appear to have major teratogenic effects. ClinicalTrials.gov identifier: NCT01246765 .

Prevention of mania in a primigravida at ultra-high risk of postpartum recurrence.

Prevention of mania in a primigravida at ultra-high risk of postpartum recurrence.

Maternal antipsychotic use during pregnancy and congenital malformations

Existing data may underestimate the potential teratogenic effects of prenatal antipsychotic exposure because of lacking data on miscarriages and induced abortions. This study aimed to present a comprehensive analysis based on information on pregnancies ending in termination, miscarriage, stillbirth, and live birth. We conducted a population-based cohort study in Denmark of clinically recognized singleton pregnancies with the first-trimester scan performed from 2008 to 2017. We compared the risk of major malformations between pregnancies exposed to antipsychotics in the first trimester and unexposed pregnancies. In secondary analyses, the comparison was made with pregnancies of women who used antipsychotics before but not during pregnancy (discontinuers). We used weighted log-binomial regression to estimate adjusted prevalence ratios and propensity score fine stratifications for confounding control. We performed 4 sensitivity analyses, including a sibling-controlled analysis. Of the 503,158 pregnancies, 1252 (0.2%) were of women who filled an antipsychotic prescription in the first trimester. Major malformations were present in 7.3% of antipsychotic-exposed pregnancies, 5.1% of unexposed pregnancies, and 6.0% of discontinuers' pregnancies. The adjusted prevalence ratio was 1.23 (95% confidence interval, 1.01-1.50) among exposed pregnancies compared with unexposed pregnancies. The prevalence ratio was attenuated to 1.14 (95% confidence interval, 0.88-1.48) compared with discontinuers and 1.08 (95% confidence interval, 0.47-2.49) in the sibling analysis. Similar findings were observed with cardiac malformations. Results were consistent for classes and individual antipsychotics, and remained robust across the 4 sensitivity analyses. Our findings suggest limited or no overall teratogenic effect of first-trimester antipsychotic exposure. For individual antipsychotics, with estimations based on very few cases, further studies with sufficient sample sizes are warranted.

Risk of major congenital malformations associated with first-trimester antihypertensives, including amlodipine and methyldopa: A large claims database study 2010-2019.

To evaluate the major congenital malformation (MCM) risk of first-trimester antihypertensive exposure, specifically of amlodipine and methyldopa. A large administrative claims database was used. The prevalence of antihypertensive prescriptions during pregnancy was described in 91,390 women giving birth between 2010 and 2019. The MCM risk of first-trimester antihypertensives was evaluated in 1,185 women diagnosed with hypertensive disorders in the first trimester. The MCM risk of first-trimester amlodipine and methyldopa was evaluated in 178 women who were prescribed antihypertensives in the first trimester. Antihypertensives were prescribed to 278 (0.30%) women during their first trimester. The prescription prevalence in the first trimester was highest for methyldopa (115, 0.13%), followed by amlodipine (55, 0.06%). Antihypertensives were prescribed to 2,955 (3.23%) women during pregnancy. Nifedipine (903, 0.99%) and nicardipine (758, 0.83%) were the most frequently prescribed oral and injectable antihypertensives during pregnancy, both with a significant increase in annual prevalence. Of the 1,185 women diagnosed with hypertensive disorders in the first trimester, antihypertensives were prescribed to 178 women. The adjusted odds ratio (aOR) of MCMs in the first-trimester prescription of any antihypertensive medication was 1.124 (95% confidence interval [CI], 0.618-2.045). Amlodipine and methyldopa were prescribed to 44 and 93 of the 178 women, respectively. The aORs of MCMs in the first-trimester prescription of amlodipine and methyldopa were 1.219 (95% CI, 0.400-3.721) and 0.921 (0.331-2.564), respectively. The MCM risk of first-trimester exposure to antihypertensives, including amlodipine and methyldopa, was not suggested.

Risk of Major Malformations Following First-Trimester Exposure to Olanzapine

Since its US Food and Drug Administration approval in 1996, olanzapine has been one of the most commonly prescribed atypical antipsychotics, making a better understanding of its reproductive safety profile critical. The goal of the current analysis was to determine the risk of major malformations among infants exposed to olanzapine during pregnancy compared with a group of nonexposed infants. The National Pregnancy Registry for Psychiatric Medications is a prospective pharmacovigilance program in which pregnant women are enrolled and interviewed during pregnancy and the postpartum period. Labor and delivery and pediatric medical records were screened for evidence of major malformations followed by adjudication by a dysmorphologist blinded to medication exposure. Infants with first-trimester exposure to olanzapine were compared with controls without second-generation antipsychotic exposure. As of April 18, 2022, 2619 women have enrolled in the study. At the time of data extraction, 49 olanzapine-exposed infants and 1156 infants in the comparison group were eligible for these analyses. There were no major malformations associated with olanzapine exposure in the first trimester. The absolute risk for major malformations in the exposure group was 0.00% (95% confidence interval, 0.00-7.25) for olanzapine compared with 1.64% (95% confidence interval, 0.99-2.55) in the control group. In this prospective cohort, no major malformations were associated with olanzapine exposure during the first trimester. Although these data are preliminary and cannot rule out more modest effects, they are nonetheless important, adding to the growing reproductive safety data for olanzapine.

PS-P07-1: TERATOGENIC RISK OF FIRST TRIMESTER EXPOSURE TO ANTIHYPERTENSIVES, INCLUDING AMLODIPINE AND METHYLDOPA: AN ANALYSIS OF AN ADMINISTRATIVE DATABASE 2010–2019

Objective: No firm conclusions on the teratogenic risk of antihypertensives have been drawn, although methyldopa and amlodipine are relatively frequently prescribed in the first trimester (FT) in Japan [1]. The primary objective was to evaluate the teratogenic risk of FT exposure to antihypertensives, including amlodipine and methyldopa. Design and method: This study used a large claims database from JMDC Inc. The dates of pregnancy onset and delivery were estimated using published algorithms [2] and infant birth months. The prevalence of antihypertensive prescriptions during pregnancy was described in 91,390 women who gave birth between 2010 and 2019. The time trends of antihypertensive prescription were evaluated using a multivariate logistic regression model adjusted for maternal age. The teratogenic risk of FT antihypertensive exposure was evaluated in 1,185 women diagnosed with hypertensive disorders in the FT. The teratogenic risk of FT exposure to amlodipine and methyldopa was evaluated in 178 women who were prescribed antihypertensives in the FT. Logistic regression analysis was used to estimate the odds ratios (ORs) for overall major congenital malformations (MCMs). The results were presented for analyses adjusted for multiple confounding factors. The MCMs in claims were validated and the overall positive predictive value was 91.5% [3]. Results: Antihypertensives were prescribed to 278 (0.30%) women during their FT. The prescription prevalence in the FT was highest for methyldopa (0.13%), followed by amlodipine (0.06%), oral hydralazine (0.03%), and nifedipine (0.02%). Antihypertensives were prescribed to 2,955 (3.23%) pregnant women. Nifedipine (0.99%) was the most frequently prescribed oral antihypertensive medication, with a significant increase in annual prevalence (P &lt; 0.0001), followed by methyldopa (0.78%), hydralazine (0.34%), and furosemide (0.14%) during pregnancy. Nicardipine (0.83%) was the most frequently prescribed injectable antihypertensive agent, with a significant increase in annual prevalence (P &lt; 0.0001), followed by furosemide (0.42%), nitroglycerin (0.26%), and hydralazine (0.20%) during pregnancy. The adjusted OR (aOR) of MCMs in the FT prescription of any antihypertensive medication was 1.096 (95% confidence interval [CI], 0.612–1.964). The aORs of MCMs in the FT prescription of amlodipine and methyldopa were 1.161 (95% CI, 0.347–3.882) and 0.937 (0.313–2.809), respectively. Conclusions: FT exposure to antihypertensive drugs, including amlodipine and methyldopa, was not associated with MCM risk in infants. REFERENCE 1. Pharmacoepidemiol Drug Saf 2018; 27:1325–1334.2. Pharmacoepidemiol Drug Saf 2018; 27:751–762.3. Pharmacoepidemiol Drug Saf 2021; 30:975–978.

Assessing medical product safety during pregnancy using parameterizable tools in the sentinel distributed database.

The US Food and Drug Administration established the Sentinel System to monitor the safety of medical products. A component of this system includes parameterizable analytic tools to identify mother-infant pairs and evaluate infant outcomes to enable the routine monitoring of the utilization and safety of drugs used in pregnancy. We assessed the feasibility of using the data and tools in the Sentinel System by assessing a known association between topiramate use during pregnancy and oral clefts in the infant. We identified mother-infant pairs using the mother-infant linkage table from six data partners contributing to the Sentinel Distributed Database from January 1, 2000, to September 30, 2015. We compared mother-infant pairs with first-trimester exposure to topiramate to mother-infant pairs that were topiramate-unexposed or lamotrigine-exposed and used a validated algorithm to identify oral clefts in the infant. We estimated adjusted risk ratios through propensity score stratification. There were 2007 topiramate-exposed and 1 066 086 unexposed mother-infant pairs in the main comparison. In the active-comparator analysis, there were 1996 topiramate-exposed and 2859 lamotrigine-exposed mother-infant pairs. After propensity score stratification, the odds ratio for oral clefts was 2.92 (95% CI: 1.43, 5.93) comparing the topiramate-exposed to unexposed groups and 2.72 (95% CI: 0.75, 9.93) comparing the topiramate-exposed to lamotrigine-exposed groups. We found an increased risk of oral clefts after topiramate exposure in the first trimester in the Sentinel database. These results are similar to prior published observational study results and demonstrate the ability of Sentinel's data and analytic tools to assess medical product safety in cohorts of mother-infant pairs in a timely manner.

Association of In Utero Antipsychotic Medication Exposure With Risk of Congenital Malformations in Nordic Countries and the US

Psychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps. To evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes. This cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022. One or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs. Any major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization. A total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions. In this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.

Probing prenatal bisphenol exposures and tissue-specific DNA methylation responses in cord blood, cord tissue, and placenta

The early-gestational fetal epigenome establishes the landscape for fetal development and is susceptible to disruption via environmental stressors including chemical exposures. Research has explored how cell- and tissue-type-specific epigenomic signatures contribute to human disease, but how the epigenome in each tissue comparatively responds to environmental exposures is largely unknown. This pilot study compared DNA methylation in four previously identified genes across matched cord blood (CB), cord tissue (CT), and placental (PL) samples from 28 mother-infant pairs in tthe Michigan Mother Infant Pairs study; evaluated association between prenatal exposure to bisphenols (BPA, BPF, and BPS) and DNA methylation (DNAm) by tissue type; compared epigenome-wide DNAm of CB and PL; and explored associations between prenatal bisphenol exposures and epigenome-wide DNAm in PL. Bisphenol concentrations were quantified in first-trimester maternal urine. DNAm was assessed at four genes via pyrosequencing in three tissues; epigenome-wide DNAm analysis via Infinium MethylationEPIC array was completed on CB and PL. Candidate gene analysis revealed tissue-specific differences across all genes. In adjusted linear regression, BPA and BPF were associated with DNAm across candidate genes in PL but not CB and CT. Epigenome-wide comparison of matched CB and PL DNAm revealed tissue-specific differences at most CpG sites and modest associations between maternal first-trimester bisphenol exposures and PL but not CB DNAm. These data endorse inclusion of a variety of tissues in prenatal exposure studies. Overlapping and divergent responses in CB, CT, and PL demonstrate their utility in combination to capture a fuller picture of the epigenetic effect of developmental exposures.

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis

Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

Maternal urine phthalate metabolite exposure and miscarriage risk: a nested case-control study of the Zunyi Birth Cohort.

Phthalates (PAEs) are widespread persistent organic pollutants and endocrine disruptors. However, the associations between PAE exposure and the risk of miscarriage in humans are unclear, and an insufficient number of studies have evaluated the possible threshold or dose-dependent effects of first trimester PAE exposure on miscarriage risk. Our research measured the levels of mono-methyl phthalate (MMP), mono-ethyl phthalate, mono-isobutyl phthalate, MiBP mono-butyl phthalate (MBP), mono-octyl phthalate, mono-benzyl phthalate, mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) in maternal urine collected in early gestation between 150 pregnancies ending in miscarriage and 150 pregnancies with live birth. We also estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for miscarriage and each PAE as a continuous variable or quartile. A restrictive cubic splines was used to assess dose-dependent effects after controlling for maternal characteristics (e.g., age, educational level). we identified monotonically increasing dose-dependent effects of MEHHP and MMP on the risk of miscarriage. The largest effect estimates were approximately threefold higher for the highest MBP (OR = 2.57; 95% CI = 1.32-5.01) or MMP quartile (OR = 3.57; 95% CI = 1.82-7.00) and two-fold higher for the highest MEHHP quartile (OR = 2.12; 95% CI = 1.10-4.11). Our research preliminarily obtained possible thresholds of MBP, MEHHP, and MMP which were 18.07, 2.38, and 0.80µg/g Cr for the risk of miscarriage, respectively. First-trimester exposure to MBP, MEHHP, and MMP exceeding certain thresholds increases the risk of miscarriage.

Neuropsychiatric outcomes in offspring after fetal exposure to maternal influenza infection during pregnancy: A systematic review

Increasing evidence suggests that influenza infection in pregnancy may disrupt fetal neurodevelopment. The impact of maternal influenza infection on offspring neuropsychiatric health has not been comprehensively reviewed. We systematically reviewed comparative studies evaluating associations between maternal influenza infection and neuropsychiatric health outcomes in offspring. We searched MEDLINE, EMBASE, CINAHL, and Web of Science for articles published until January 7, 2022. Included were English studies evaluating neuropsychiatric outcomes in offspring aged > 6 months born to women with and without influenza during pregnancy, defined as clinical or laboratory-confirmed influenza illness, or being pregnant during pandemics/epidemics. Of 12,010 records screened, 42 studies were included. Heterogeneity in study design, exposures, and outcome definitions precluded meta-analyses. Four of 14 studies assessing schizophrenia reported adjusted ratio estimates from 0.5 to 8.2; most 95% CIs contained the null value; study quality was high in three of four. Two studies reported an increased risk of schizophrenia with influenza exposure any time during pregnancy (adjusted incidence rate ratio 8.2, 95% CI: 1.4–48.8; adjusted odds ratio 1.3, 95% CI: 1.2–1.5); another reported a reduced risk with first-trimester exposure (adjusted risk ratio 0.5, 95% CI: 0.3–0.9). Seven studies of autism spectrum disorder reported adjusted ratio estimates from 0.9 to 4.0; all 95% CIs included the null value; study quality was high in four. No conclusions could be drawn about the association between exposure to maternal influenza and neuropsychiatric outcomes due to the limited quantity and quality of available research. Large observational studies with long-term follow-up are required to investigate these associations.

Risk of major malformations in infants after first-trimester exposure to benzodiazepines: Results from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications.

Perinatal anxiety affects 20% of women, and untreated maternal mental illness can cause deleterious effects for women and their children. Benzodiazepines are commonly used to treat anxiety disorders. The reported risk of congenital malformations after in utero benzodiazepine exposure has been inconsistent. The Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications prospectively enrolls pregnant women with psychiatric illness who take one or more psychiatric medications. Participants are interviewed twice during pregnancy and at 12 weeks postpartum. Women taking any benzodiazepine during the first trimester of pregnancy were compared with a group of women taking psychiatric medication(s) other than benzodiazepines during pregnancy. A total of 1053 women were eligible for this analysis; N = 151 women who had taken a benzodiazepine during the first trimester, and the comparison group was N = 902 women. There were 5 (3.21%) major malformations in the exposure group and 32 (3.46%) in the comparison group (odds ratio 0.92; 95% confidence interval 0.35-2.41). This ongoing pregnancy registry offers reassurance that benzodiazepines do not appear to have major teratogenic effects. The precision of relative risk estimate will improve as the number of participants increases. This and other pregnancy registries will better inform the reproductive safety of benzodiazepines.

Pregnancy outcomes after first-trimester exposure to buspirone: prospective longitudinal outcomes from the MGH National Pregnancy Registry for Psychiatric Medications.

Buspirone is commonly used to treat anxiety disorders among reproductive-aged women. To date, the reproductive safety of buspirone in humans has been particularly sparse. We sought to provide preliminary data from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications (NPRPM) on the risk of major malformations after first-trimester buspirone exposure. The NPRPM enrolls pregnant women with psychiatric disorders to prospectively assess for major congenital malformations after in utero exposure to psychotropics. Women are interviewed twice during pregnancy and once at 12weeks postpartum. Data regarding women who took buspirone during the first trimester were extracted from the NPRPM database. Data were assessed as a rigorously ascertained case series to determine the incidence of major malformations among those exposed to buspirone. The primary outcome was obtained by maternal postpartum interview and medical record review. As of January 6, 2022, N = 97 women enrolled in the registry took buspirone during their first trimester. Of these women, 68 were evaluable and eligible for this analysis. Four women had twins, resulting in 72 infants. Among this sample, there were no malformations present. These preliminary data represent the only prospectively ascertained sample of pregnancy outcomes after first-trimester buspirone exposure. Albeit asmallsample, no major malformations were observed in this cohort. The rigorous prospective ascertainment of outcomes is a strength of this study. Future analyses are planned that will include larger numbers of women with exposures to buspirone and comparison with control groups matched for demographic and diagnostic variables.

Higher free thyroxine associated with PFAS exposure in first trimester. The Odense Child Cohort.

BackgroundPerfluoroalkyl substances (PFAS) are endocrine disrupting chemicals with elimination half-lives ranging from four to eight years. Experimental studies found PFAS able to interfere with thyroid hormone-binding proteins. During the first 20 weeks of gestation (GW), the fetus is reliant on placental transfer of maternal thyroid hormones, mainly free thyroxine (FT4). However, previous studies investigating associations between exposure to PFAS and thyroid hormone status mainly focused on blood samples from late pregnancy or umbilical cord with mixed findings. ObjectivesTo investigate associations between serum-PFAS concentrations and thyroid hormone status in early pregnancy as reflected by FT4 and thyroid-stimulating hormone (TSH). MethodsIn the Odense Child Cohort, a single-center study, we measured maternal pregnancy serum concentrations of five PFAS: perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA); and FT4 and TSH in 1048 pregnant women at median GW 12 (25th, 75th percentile: 10, 15). Multivariate linear regression models were performed to estimate associations between PFAS exposure and thyroid hormone status. ResultsA doubling in PFOS, PFOA, and PFNA concentrations was associated with an increment in FT4 concentration by 1.85% (95% CI: 0.66%, 3.05%), 1.29% (95% CI: 0.21%, 2.39%), and 1.70% (95% CI: 0.48%, 2.94%), respectively, in adjusted analyses. A statistically significant dose-response relationship was observed across exposure quartiles for PFOS, PFOA, and PFNA in the association with FT4. No association was found between concentrations of PFAS and TSH in adjusted analyses. ConclusionExposure to PFOS, PFOA, and PFNA was associated with higher FT4 concentrations in women during early pregnancy. The potential clinical implications of these findings remain to be clarified.

Higher free thyroxine associated with pfas exposure in first trimester. The odense child cohort

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)