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Although results from studies of first-trimester influenza vaccination and congenital heart defects (CHDs) have been reassuring, data are limited for specific CHDs.We assessed associations between reported maternal influenza vaccination, 1 month before pregnancy (B1) through end of third pregnancy month (P3), and specific CHDs using data from a multisite, population-based case-control study. Analysis included 2,982 case children diagnosed with a simple CHD (no other cardiac involvement with or without extracardiac defects) and 4,937 control children without a birth defect with estimated delivery dates during 2006-2011. For defects with ≥5 exposed case children, we used logistic regression to estimate propensity score-adjusted odds ratios (aORs) and 95% confidence intervals (CIs), adjusting for estimated delivery year and season; plurality; and maternal age at delivery, race/ethnicity, low folate intake, and smoking and alcohol use during B1P3.Overall, 124 (4.2%) simple CHD case mothers and 197 (4.0%) control mothers reported influenza vaccination from 1 month before through the third pregnancy month. The aOR for any simple CHD was 0.97 (95% CI: 0.76-1.23). Adjusted ORs for specific simple CHDs ranged from 0.62 for hypoplastic left heart syndrome to 2.34 for total anomalous pulmonary venous return (TAPVR). All adjusted CIs included the null except for TAPVR.Although we cannot fully exclude that exposure misclassification may have masked risks for some CHDs, findings add to existing evidence supporting the safety of inactivated influenza vaccination during pregnancy. The TAPVR result may be due to chance, but it may help inform future studies.

ObjectiveTo estimate COVID-19 diagnosis prevalence and trends among pregnant and postpartum individuals in Maine by rurality and common pregnancy conditions.MethodsWe used the Maine Health Data Organization’s All Payer Claims Data to identify deliveries during 2020-2021. We identified COVID-19 during pregnancy (Apr 2020 to Dec 2021 deliveries) and during the first 6 months postpartum (Apr 2020 to Jun 2021 deliveries) using the ICD-10 diagnosis code U071 on medical claims. We used Joinpoint regression software to model trends. We stratified the analysis by rurality of residence (based on ZIP code) and by common pregnancy conditions: gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), and prenatal depression.ResultsWe included 13,457 deliveries in our pregnancy and 9,143 deliveries in our postpartum analysis. COVID-19 diagnosis prevalence among pregnant individuals increased from 0.5% in Apr 2020 to 10.5% in Dec 2021 (Oct 2020 was the start of slope [0.43 per month], pConclusionCOVID-19 diagnosis among pregnant and postpartum individuals in Maine showed distinct patterns by rurality of residence and select pregnancy conditions. This information can be used for assessing the impact of the COVID-19 pandemic on maternal and infant health.

To assess associations between influenza vaccination during etiologically-relevant windows and selected major structural non-cardiac birth defects.We analyzed data from the National Birth Defects Prevention Study, a multisite, population-based case-control study, for 8233 case children diagnosed with a birth defect and 4937 control children without a birth defect with delivery dates during 2006-2011. For all analyses except for neural tube defects (NTDs), we classified mothers who reported influenza vaccination 1 month before through the third pregnancy month as exposed; the exposure window for NTDs was 1 month before through the first pregnancy month. For defects with five or more exposed case children, we used logistic regression to estimate propensity score-adjusted odds ratios (aORs) and 95% confidence intervals (CIs), adjusting for estimated delivery year and season; plurality; maternal age, race/ethnicity, smoking and alcohol use, low folate intake; and, for NTDs, folate antagonist medications.There were 334 (4.1%) case and 197 (4.0%) control mothers who reported influenza vaccination from 1 month before through the third pregnancy month. Adjusted ORs ranged from 0.53 for omphalocele to 1.74 for duodenal atresia/stenosis. Most aORs (11 of 19) were ≤1 and all adjusted CIs included the null. The unadjusted CIs for two defects, hypospadias and craniosynostosis, excluded the null. These estimates were attenuated upon covariate adjustment (hypospadias aOR: 1.25 (95% CI 0.89, 1.76); craniosynostosis aOR: 1.23 (95% CI: 0.88, 1.74)).Results for several non-cardiac major birth defects add to the existing evidence supporting the safety of inactivated influenza vaccination during pregnancy. Under-reporting of vaccination may have biased estimates downward.

BACKGROUND: Trends in the prevalence of hepatitis C virus (HCV) infection among women delivering live births may differ in rural vs. urban areas of the United States, but estimation of trends based on observed counts may lead to unstable estimates in rural counties due to small numbers. OBJECTIVES: The objective of the study was to use small area estimation methods to provide updated county-level prevalence estimates and, for the first time, trends in maternal HCV infection among live births by county-level rurality. METHODS: Cross-sectional natality data from 2016 to 2020 were used to estimate maternal hepatitis C prevalence using hierarchical Bayesian models with spatiotemporal random effects to produce annual county-level estimates of maternal HCV infection and trends over time. Models included a 6-Ievel rural–urban county classification, year, maternal characteristics and county-specific covariates. Data were analysed in 2022. RESULTS: There were 90,764/18,905,314 live births (4.8 per 1000) with HCV infection reported on the birth certificate. Hepatitis C prevalence was higher among rural counties as compared to urban counties. Rural counties had the largest annual increases in maternal hepatitis C prevalence (per 1000 births) from 2016 to 2020 (micropolitan: 0.39; noncore: 0.40), with smaller increases among less densely populated urban counties (medium metro: 0.28; small metro: 0.28) and urban counties (large central metro:0.11; large fringe metro: 0.14). CONCLUSIONS: The prevalence of maternal HCV infection was the highest in rural counties, and rural counties saw the greatest average prevalence increase during 2016–2020. County-level data can help in monitoring rural–urban trends in maternal HCV infection to reduce geographic disparities.

Introduction The prevalence of hepatitis C virus infection among women delivering live births in the U.S. may be higher in rural areas where county-level estimates may be unreliable. The aim of this study is to model county-level maternal hepatitis C virus infection among deliveries in the U.S. Methods In 2020, U.S. natality files (2010–2018) with county-level maternal residence information were used from states that had adopted the 2003 revised U.S. birth certificate, which included a field for hepatitis C virus infection present during pregnancy. Hierarchical Bayesian spatial models with spatiotemporal random effects were applied to produce stable annual county-level estimates of maternal hepatitis C virus infection for years when all states had adopted the revised birth certificate (2016–2018). Models included a 6-Level Urban–Rural County Classification Scheme along with the birth year and county-specific covariates to improve posterior predictions. Results Among approximately 32 million live births, the overall prevalence of maternal hepatitis C virus infection was 3.5 per 1,000 births (increased from 2.0 in 2010 to 5.0 in 2018). During 2016–2018, posterior predicted median county-level maternal hepatitis C virus infection rates showed that nonurban counties had 3.5–3.8 times higher rates of hepatitis C virus than large central metropolitan counties. The counties in the top 10th percentile for maternal hepatitis C virus rates in 2018 were generally located in Appalachia, in Northern New England, along the northern border in the Upper Midwest, and in New Mexico. Conclusions Further implementation of community-level interventions that are effective in reducing maternal hepatitis C virus infection and its subsequent morbidity may help to reduce geographic and rural disparities.

In many perinatal pharmacoepidemiologic studies, exposure to a medication is classified as “ever exposed” versus “never exposed” within each trimester or even over the entire pregnancy. This approach is often far from real-world exposure patterns, may lead to exposure misclassification, and does not to incorporate important aspects such as dosage, timing of exposure, and treatment duration. Alternative exposure modeling methods can better summarize complex, individual-level medication use trajectories or time-varying exposures from information on medication dosage, gestational timing of use, and frequency of use. We provide an overview of commonly used methods for more refined definitions of real-world exposure to medication use during pregnancy, focusing on the major strengths and limitations of the techniques, including the potential for method-specific biases. Unsupervised clustering methods, including k-means clustering, group-based trajectory models, and hierarchical cluster analysis, are of interest because they enable visual examination of medication use trajectories over time in pregnancy and complex individual-level exposures, as well as providing insight into comedication and drug-switching patterns. Analytical techniques for time-varying exposure methods, such as extended Cox models and Robins’ generalized methods, are useful tools when medication exposure is not static during pregnancy. We propose that where appropriate, combining unsupervised clustering techniques with causal modeling approaches may be a powerful approach to understanding medication safety in pregnancy, and this framework can also be applied in other areas of epidemiology.

Objective: Preliminary findings from selected health systems revealed interruptions in reproductive health care services due to the COVID-19 pandemic. We estimated changes in postpartum contraceptive provision associated with the start of the COVID-19 pandemic in Maine. Methods: We used the Maine Health Data Organization’s All Payer Claims Database for deliveries from October 2015 through March 2021 (n = 45 916). Using an interrupted time-series analysis design, we estimated changes in provision rates of long-acting reversible contraception (LARC), permanent contraception, and moderately effective contraception within 3 and 60 days of delivery after the start of the COVID-19 pandemic. We performed 6- and 12-month analyses (April 2020–September 2020, April 2020–March 2021) as compared with the reference period (October 2015–March 2020). We used Poisson regression models to calculate level-change rate ratios (RRs) and 95% CIs. Results: The 6-month analysis found that provision of LARC (RR = 1.89; 95% CI, 1.76-2.02) and moderately effective contraception (RR = 1.51; 95% CI, 1.33-1.72) within 3 days of delivery increased at the start of the COVID-19 pandemic, while provision of LARC (RR = 0.95; 95% CI, 0.93-0.97) and moderately effective contraception (RR = 1.08; 95% CI, 1.05-1.11) within 60 days of delivery was stable. Rates of provision of permanent contraception within 3 days (RR = 0.70; 95% CI, 0.63-0.78) and 60 days (RR = 0.71; 95% CI, 0.63-0.80) decreased. RRs from the 12-month analysis were generally attenuated. Conclusion: Disruptions in postpartum provision of permanent contraception occurred at the beginning of the COVID-19 pandemic in Maine. Public health policies should include guidance for contraceptive provision during public health emergencies and consider designating permanent contraception as a nonelective procedure.

PURPOSE: There is unmet need for decision support regarding medication use during pregnancy. We aimed to inform the development of a decision aid on oral corticosteroid (OCS) use during pregnancy through focus groups. METHODS: We invited patients from one health system who had a recent live birth and a condition for which OCSs may be prescribed (i.e., asthma or other autoimmune disease) to participate in focus groups. We conducted conventional qualitative content analysis of verbatim transcripts of the focus groups using inductive coding. RESULTS: There were 30 participants across five focus groups from May-June 2019. Women endorsed the need for patient-provider discussions about OCS use during pregnancy in which the provider shares risks and benefits and the patient makes her decision. Furthermore, women generally expressed support for patient-centered handouts about OCS use during pregnancy that the provider discusses with the patient. When considering whether to take OCSs in pregnancy, women had concerns about: the medication’s impact on their baby (e.g., miscarriage, birth defects, long-term effects), themselves (e.g., effects on mood, sleep, weight gain), pregnancy complications (e.g., preterm birth, increased blood pressure), and lactation. Women wanted information on OCSs (e.g., indications, length of treatment, and cost), alternative treatments, and risks of not taking OCSs. CONCLUSIONS: We established patient need for a decision aid on OCS use during pregnancy that providers can discuss with patients. To address patient concerns, the aid should at a minimum describe the medication’s impact on baby, including long-term effects, maternal health, pregnancy complications, and lactation.

BACKGROUND: Antidepressant use later in pregnancy has been associated with preeclampsia and postpartum hemorrhage (PPH) in some studies. OBJECTIVE: To evaluate the association between patterns of prenatal antidepressant dose across gestation and risk of precclampsia and PPH. METHODS: We utilized OptumLabs® Data Warehouse (2012–2016) administrative health care claims, identifying 226,932 singleton live-born deliveries for this retrospective cohort study. Antidepressant dispensing doses were converted to fluoxetine equivalents. Using k-means longitudinal, we identified women with similar patterns of antidepressant exposure, i.e., trajectory groups, during the first 20 and 35 gestational weeks. We estimated risk ratios (RR) and 95% confidence intervals (CI) for the association between trajectory groups and preeclampisa (20-week groups) and PPH (35-week groups), adjusting for demographics, comorbidities, and other psychotropic medications. Linear trend tests assessing increasing risk of the outcomes across groups were performed. RESULTS: Among 15,041 (6.6%) pregnancies exposed to an antidepressant, the following trajectory groups were identified: A-low exposure, starting pregnancy at ~10mg/day, with 1(st) trimester reduction/discontinuation, B-low sustained exposure of ~20 mg/day, C-moderate exposure (~40mg/day) with 1(st) trimester reduction/discontinuation, D-moderate sustained exposure of ~40 mg/day, and E-high sustained exposure of ~75mg/day. In the low exposure with reduction/discontinuation trajectory, risks were 8.2% for preeclampsia and 2.7% for PPH. Compared with this group, low, moderate, and high sustained trajectories were associated with preeclampsia [adjusted (a)RR: 1.17 (95% CI: 1.01, 1.34), aRR: 1.31 (95% CI: 1.12, 1.54), aRR: 1.41 (95% CI: 1.05, 1.90), respectively] and PPH [aRR: 1.32 (1.05, 1.66), aRR: 1.35 (95% CI: 1.03,1.78), aRR: 2.51 (95% CI: 1.69, 3.71), respectively]; p

To investigate causes of discrepancies in the association between early pregnancy oral glucocorticoid (OGC) use and preterm birth risk among women with rheumatoid arthritis (RA) in health care utilization data from California Medicaid (Medi-Cal) and the prospective cohort MotherToBaby Pregnancy Studies.Separately, we estimated risk ratios (RRs) between OGC exposure before gestational day 140 and preterm birth risk in data from Medi-Cal (2007-2013; n = 844) and MotherToBaby (2003-2014; n = 528). We explored differences in socioeconomic status, OGC dose distribution, exposure misclassification, and confounding by RA severity across the data sources.Preterm birth risk in women without OGC was 17.3% in Medi-Cal and was 9.7% in MotherToBaby. There was no association between OGC and preterm birth in Medi-Cal (adjusted RR 1.00 [95% confidence interval (95% CI) 0.71, 1.42]), and a 1.85-fold (95% CI 1.20, 2.84) increased preterm birth risk in MotherToBaby. When restricting each sample to women with a high-school diploma or less, preterm birth risk following no OGC exposure was 15.9% in Medi-Cal and 16.7% in MotherToBaby; adjusted RRs were 1.16 (95% CI 0.74, 1.80) in Medi-Cal and 0.81 (95% CI 0.25, 2.64) in MotherToBaby. Cumulative OGC dose was higher in MotherToBaby (median 684 mg) than in Medi-Cal (median 300 mg). An OGC dose of ≤300 mg was not associated with increased preterm birth risk. Exposure misclassification and confounding by RA severity were unlikely explanations of differences.Higher baseline preterm birth risk and lower OGC dose distribution in Medi-Cal may explain the discrepancies. Studies are needed to understand the effects of autoimmune disease severity and undertreatment on preterm birth risk in low-income populations.

Nhung TH Trinh,1 Hedvig ME Nordeng,1,2 Gretchen Bandoli,3,4 Kristin Palmsten,5 Malin Eberhard-Gran,6,7 Angela Lupattelli1 1PharmacoEpidemiology and Drug Safety Research Group, Department of Pharmacy, PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway; 2Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway; 3Department of Pediatrics, University of California San Diego, La Jolla, CA, USA; 4Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA; 5HealthPartners Institute, Minneapolis, MN, USA; 6Norwegian Research Centre for Women’s Health, Women’s and Children’s Division, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 7Institute for Clinical Medicine, University of Oslo, Oslo, NorwayCorrespondence: Nhung TH Trinh, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Post box 1068 Blindern, Oslo, 0316, Norway, Email nhung.trinh@farmasi.uio.noBackground: Few studies investigated longitudinal antidepressant exposure during pregnancy and included dosage in the assessment.Methods: We conducted a nationwide, registry-linkage study in Norway using data on antidepressant prescription fills in pregnancies lasting ≥ 32 weeks in women with a delivery between 2009 and 2018 who had a depression/anxiety diagnosis and antidepressant fills prior to pregnancy. Information on antidepressant exposure by week (measured by filled prescriptions) and prescribed average daily dose was used in longitudinal k-means trajectory modelling for a 108-week time window from six months prior to pregnancy to one year after delivery. Factors associated with trajectory group membership were examined using multinomial logistic regression models.Results: We included 8,460 pregnancies in 8,092 women. Four antidepressant fill trajectories were identified based on filled antidepressant prescriptions: two distinct discontinuing patterns, one at around the start of pregnancy (30.4%) and one around the end of pregnancy (33.8%); one continuing pattern (20.6%); and one interrupting pattern (15.2%). Using average usual daily dose, we identified low dose discontinuing (60.3%), medium dose reducing (20.6%) and high dose continuing (15.2%) patterns. The multinomial logistic regressions showed that the fill trajectory group membership was strongly associated with: antidepressant type and dose prior to pregnancy and co-medication prior to pregnancy, maternal age, marital status, parity, previous pregnancy loss, and pregnancy planning.Conclusion: Longitudinal trajectory modelling revealed distinct antidepressant fill and dosage patterns in the period around pregnancy. Knowledge about factors associated with utilization trajectories might be useful for health-care personnel counselling women about antidepressant use in pregnancy.Keywords: longitudinal k-means trajectory modelling, antidepressant fill trajectories, depression, anxiety, pregnancy, drug utilization

Purpose To evaluate the use of data from population-based surveys such as the National Health and Nutrition Examination Survey (NHANES) for external adjustment for confounders imperfectly measured in health care databases in the United States. Methods Our example study used Medicaid Analytic eXtract (MAX) data to estimate the relative risk (RR) for prenatal serotonin-norepinephrine reuptake inhibitors (SNRIs) exposure and cardiac defects. Smoking and obesity are known confounders poorly captured in databases. NHANES collects information on lifestyle factors, depression, and prescription medications. External adjustment requires information on the prevalence of confounders and their association with SNRI use; which was obtained from the NHANES. It also requires estimates of their association with the outcome, which were based on the literature and allowed us to correct the RR using sensitivity analyses. Results In MAX, the RR for the association between prenatal SNRI exposure and cardiac defects was 1.51 unadjusted and 1.20 adjusted for measured confounders and restricted to women with depression. In NHANES, among women of childbearing age with depression, the prevalence of smoking was 60.2% (95% Confidence Interval 43.2, 74.3) for SNRI users and 44.1% (39.6, 48.8) for nonusers of antidepressants. The corresponding estimates for obesity were 59.2% (43.2, 74.3) and 40.5% (35.9, 45.0), respectively. If the associations between smoking and obesity with cardiac defects are independent from each other and from other measured confounders, additional adjustment for smoking and obesity would move the RR from 1.20 to around 1.10. Conclusion National surveys like NHANES are readily available sources of information on potential confounders and they can be used to assess and improve the validity of RR estimates from observational studies missing data on known risk factors.

Objective To evaluate the associations between oral corticosteroid (OCS) dose early and late in pregnancy and preterm birth (PTB) among women with RA. Methods Pregnant women in the MotherToBaby Pregnancy Studies (2003–2014) with RA (n = 528) were included in the primary analysis. Information was collected by phone interview and from medical records. We estimated risk ratios (RR) for OCS dose trajectories and other disease-related medications before gestational day 140 and hazard ratios (HR) for time-varying exposures after gestational day 139. Results PTB risk was 15.5% overall. Compared with no OCS, PTB risk was increased in high (adjusted (a)RR: 4.77 (95% CI: 2.76, 8.26)) and medium (aRR: 1.81 (95% CI: 1.10, 2.97)) cumulative OCS dose trajectories during the first 139 gestational days. The low cumulative trajectory group was associated with an increased risk of PTB that was not statistically significant (aRR: 1.38 (95% CI: 0.79, 2.38)), and DMARDs were not associated with PTB (biologic DMARDs aHR: 1.08 (95% CI: 0.70, 1.66); non-biologic DMARDs aHR: 0.87 (95% CI: 0.55, 1.38)). OCS exposure to ⩾10 mg of prednisone equivalent daily dose after gestational day 139 vs none was associated with increased PTB rate (aHR: 2.45 (95% CI: 1.32, 4.56)), whereas Conclusion Higher OCS doses vs no OCS use, both earlier and later in pregnancy, were associated with an increase in PTB among women with RA.

PURPOSE: The state-assigned Case ID number in the Medicaid Analytic eXtract (MAX) allows for potential linkage of mothers to infants. No validation of respective linkage algorithms is available. We established and validated an algorithm within MAX that links mothers to infants and to identify factors influencing successful mother-infant linkage. METHODS: We identified all mother-infant pairs in FL and TX birth certificates records (BCR) that could be linked individually to MAX records (1999–2005 for FL and 1999–2010 for TX) based on Social Security Number (gold standard pairs). Case ID linkage performance was evaluated as the proportion of gold standard mother-infant pairs that were identified by the algorithm (sensitivity) and the proportion of algorithm defined mother-infant pairs that were correctly linked. Generalized estimating equations were used to calculate the probability for successful Case ID algorithm linkage versus non-linkage using maternal and infant characteristics. RESULTS: We identified 323,160 gold standard pairs in FL BCR and MAX and 1,025,350 in TX BCR and MAX. Depending on Medicaid enrollment the algorithm sensitivity ranged from 85.51% to 87.96% in FL and 19.60% to 35.75% in TX. In both states, positive predictive value exceeded 99%, regardless of enrollment periods. Determinants for successful linkage varied across states, but suggested better results for younger mothers, minority women, and those with lower educational achievement. CONCLUSIONS: Our algorithm can correctly link liveborn infants to their mothers. The algorithm’s sensitivity in identifying pairs varied across states, but PPV was consistently high. Linkage performance was associated with certain characteristics that may affect representativeness of successfully linked pairs.

OBJECTIVE: To provide updated prevalence estimates of asthma and asthma medication use for women of childbearing age in the United States. METHODS: Using data from 11,383 women aged 18–44, including a subset of 1,245 pregnant women, enrolled in the National Health and Nutrition Examination Survey (2001–2016), we assessed the age-adjusted prevalence of self-reported diagnosed asthma. For women aged 18–44, we stratified by year, demographics, and other characteristics. Furthermore, we assessed asthma medication use among women aged 18–44 with asthma. RESULTS: After age-adjustment, 9.9% (95% confidence interval (CI) 9.2%, 10.7%) of women aged 18–44 and 10.9% (95% CI 7.2%, 14.6%) of pregnant women reported having asthma. Asthma prevalence was highest in 2015–2016 (12.0% 95% CI 9.8%, 14.3%) and lowest in 2003–2004 (8.6% 95% CI 6.4%, 10.8%). Women aged 18–44 with Medicaid or State Children’s Health Insurance Program insurance coverage (16.8% 95% CI 14.5%, 19.2%), obesity (14.4% 95% CI 12.9%, 15.8%), diabetes (18.7% 95% CI 12.1%, 25.2%), hypertension (16.6% 95% CI 14.2%, 19.0%), and current smokers (12.8% 95% CI 11.4%, 14.2%) had the highest asthma prevalence. Of women with asthma, 38.3% (95% CI 34.5%, 42.1%) reported using asthma medications in the past 30 days. CONCLUSIONS: Among women of childbearing ages, asthma burden varies across demographic and clinical characteristics and has increased in recent years.

Background Early-onset preeclampsia, traditionally defined as presenting before 34 gestational weeks, is associated with even higher risks of perinatal death, placental abruption, and stroke, than late-onset preeclampsia. Objective We estimated the degree of misclassification in a high-risk population of lupus pregnancies and a general population comparator when gestational age at delivery defined preeclampsia phenotype compared to first preeclampsia diagnosis. Methods Patients with lupus and general population comparators from Sweden with ≥1 singleton pregnancy in the Medical Birth Register with a documented ICD code for preeclampsia were included (2002-2016). We used gestational age at delivery (

Background There is limited information regarding the impact of dose and gestational timing of oral corticosteroid (OCS) use on preterm birth (PTB), especially among women with asthma. Objectives To evaluate OCS dose and timing on PTB for asthma and, as a comparison, systemic lupus erythematosus (SLE). Methods We used health care data from California Medicaid enrollees linked to birth certificates (2007-2013), identifying women with asthma (n = 22,084) and SLE (n = 1174). We estimated risk ratios (RR) for OCS cumulative dose trajectories and other disease-related medications before gestational day 140 and hazard ratios (HR) for time-varying exposures after day 139. Results For asthma, PTB risk was 14.0% for no OCS exposure and 14.3%, 16.8%, 20.5%, and 32.7% in low, medium, medium-high, and high cumulative dose trajectory groups, respectively, during the first 139 days. The high-dose group remained associated with PTB after adjustment (adjusted RR [aRR]: 1.46; 95% confidence interval [CI]: 1.00, 2.15). OCS dose after day 139 was not clearly associated with PTB, nor were controller medications. For SLE, PTB risk for no OCS exposure was 24.9%, and it was 39.1% in low- and 61.2% in high-dose trajectory groups. aRR were 1.80 (95% CI: 1.34, 2.40) for high and 1.24 (95% CI: 0.97, 1.58) for low groups. Only prednisone equivalent dose >20 mg/day after day 139 was associated with increased PTB (adjusted HR: 2.54; 95% CI: 1.60, 4.03). Conclusions For asthma, higher OCS doses early in pregnancy, but not later, were associated with increased PTB. For SLE, higher doses early and later in pregnancy were associated with PTB.

BackgroundPrevious studies of prenatal acetaminophen use have not addressed what indications and maternal co-factors describe acetaminophen use.ObjectiveThe objective of this study was to describe these parameters in a well-characterised, prospective birth cohort.MethodsData were drawn from the MotherToBaby study of pregnant women enrolled from 2004 to 2018. Daily acetaminophen diaries were calculated for all exposed women with complete dose and duration information. Descriptive statistics were used to assess maternal characteristics associated with acetaminophen use. Prevalence by 2-year interval was described, and linear regression was used to test for trend. Indication of use and dose per indication were summarised.ResultsOf 2441 subjects, 1515 (62%) reported use of acetaminophen. Over the 15-year period, there was a decline in use of 2.5% for each 2-year period (test for trend=0.001) with 58% reporting acetaminophen use in 2017-2018. Among women with acetaminophen use in pregnancy (n=1515), 58% reported

OBJECTIVES: To estimate the risk of neonatal outcomes from patterns of prenatal antidepressant use. METHODS: From the OptumLabs Data Warehouse, 226 932 singleton deliveries were identified. Antidepressant claims with coverage between the last menstrual period and 35 weeks’ gestation were converted to fluoxetine equivalents, and a longitudinal cluster analysis was performed. Outcomes included major cardiac malformations (11.7 of 1000 births), preterm birth (75.7 of 1000 births), and newborn respiratory distress (54.2 of 1000 births). The lowest trajectory was the primary reference group, and depression and anxiety with no antidepressant claims served as secondary reference groups. RESULTS: From 15 041 (6.6%) pregnancies exposed to an antidepressant, use patterns were best described as (1) low use (∼10 mg/day) with first-trimester reduction, (2) low sustained use (∼20 mg/day), (3) moderate use (∼40 mg/day) with first-trimester reduction, (4) moderate sustained use (∼40 mg/day), and (5) high sustained use (∼75 mg/day). Moderate sustained use increased the risk of major cardiac malformations, although results included the null when compared with depression or anxiety reference groups. Moderate sustained (adjusted risk ratio [RR] 1.31; 95% confidence interval [CI] 1.16–1.49) and high sustained (adjusted RR 1.78; 95% CI 1.48–2.14) trajectories were associated with an increased risk of preterm birth. All 4 trajectories increased the risk of neonatal respiratory distress in a dose-response fashion (adjusted RRs 1.36 [95% CI 1.20–1.50] to 2.23 [95% CI 1.83–2.77]). CONCLUSIONS: Although findings support continuation of the lowest effective dose to treat depression or anxiety, which benefits the mother, they also highlight an increased risk for newborn respiratory distress in all groups and preterm birth at moderate to high sustained doses.

PurposeTo characterize prednisone use in pregnant women with rheumatoid arthritis using individual-level heat-maps and clustering individual trajectories of prednisone dose, and to evaluate the association between prednisone dose trajectory groups and gestational length.MethodsThis study included pregnant women with rheumatoid arthritis who enrolled in the MotherToBaby Autoimmune Diseases in Pregnancy Study (2003-2014) before gestational week 20 and reported prednisone use without another oral glucocorticoid during pregnancy (n=254). Information on medication use and pregnancy outcomes was collected by telephone interview plus by medical record review. Prednisone daily dose and cumulative dose were plotted by gestational day using a heat map for each individual. K-means clustering was used to cluster individual trajectories of prednisone dose into groups. The associations between trajectory group and demographics, disease severity measured by the Health Assessment Questionnaire at enrollment, and gestational length were evaluated.ResultsWomen used prednisone 3 to 292days during pregnancy, with daily doses ranging from

Background There are limited data regarding the comparability of medication exposure information during pregnancy from maternal report and medical records, including for rheumatoid arthritis and asthma-related medications. Methods This study included pregnant women with rheumatoid arthritis (n = 216) and asthma (n = 172) enrolled in the MothertoBaby Pregnancy Studies (2009-2014). Women reported types and dates of medications used through semi-structured telephone interviews up to three times during pregnancy and once after delivery, and medical records were obtained. We calculated Cohen's kappa coefficients and 95% confidence intervals (CIs) and per cent agreement for agreement between report and records. Results For rheumatoid arthritis, prednisone was reported most frequently (53%). During pregnancy, kappa coefficients for rheumatoid arthritis medications ranged from 0.32 (95% CI 0.15, 0.50) for ibuprofen, with 84.3% agreement, to 0.90 (95% CI 0.84, 0.96) for etanercept with 95.4% agreement, and was 0.44 (95% CI 0.33, 0.55) for prednisone, with 71.3% agreement. For asthma, albuterol was reported most frequently (77.9%). During pregnancy, kappa coefficients for asthma medications ranged from 0.21 (95% CI 0.08, 0.35), with 64.5% agreement for albuterol to 0.84 (95% CI 0.71, 0.96) for budesonide/formoterol, with 96.5% agreement. Where kappas for any use during pregnancy were less than excellent (i.e. ≤0.80), medication use was more frequently captured by report than record. Conclusions Agreement was higher for medications typically used continuously than sporadically. Information on medication use from medical records alone may not be adequate when studying the impact of intermittently used medications during pregnancy on perinatal outcomes.

BACKGROUND: Pre-existing conditions are imperfectly recorded in healthcare databases. We assessed whether pre-existing neurologic conditions (epilepsy, multiple sclerosis [MS]) were differentially recorded in the presence of major obstetric outcomes (Caesarean delivery, preterm delivery, preeclampsia) in delivery records. We also evaluated the impact of differential recording on measures of frequency and association between the conditions and outcomes. METHODS: The 2011-2014 Truven Health MarketScan® Commercial Claims Dataset was used to identify deliveries. We calculated the relative recording of epilepsy and MS at delivery compared with a 270-day pre-delivery interval, both overall and by the presence of major obstetric outcomes. We estimated risk ratios of the association between epilepsy and MS with the outcomes for each ascertainment window. RESULTS: We identified 909,065 deliveries in women continuously enrolled from 270-days before the delivery date. Of women with epilepsy identified in the pre-delivery interval, 73% had the condition coded at delivery. For MS, the proportion was 60%. MS recording at delivery did not vary by obstetric outcomes, however delivery-coded epilepsy was less likely confirmed in the pre-delivery interval in the presence of preeclampsia. Generally, the period of ascertainment did not meaningfully impact risk ratios, however the risk ratio for preeclampsia associated with epilepsy was 1.67 [95% CI: 1.47, 1.90] when epilepsy was ascertained at delivery and 1.26 [95% CI: 1.07, 1.48] when epilepsy was ascertained in the pre-delivery interval (heterogeneity, p=0.007). CONCLUSIONS: Ascertainment of epilepsy and MS in delivery records underestimated prevalence. However the window of recording generally did not impact associations with obstetric outcomes.

OBJECTIVE: To assess maternal and fetal outcomes associated with subclinical (pre-systemic lupus erythematosus [SLE] and SLE presenting up to 5 years postpartum) and prevalent maternal SLE during pregnancy compared with the general population. METHODS: This prospective cohort study used population-based Swedish registers to identify 13,598 women with first singleton pregnancies registered in the Medical Birth Register (551 prevalent SLE, 65 pre-SLE within 0-2 years, 133 pre-SLE within 2-5 years, and 12,847 general population). SLE was defined as ≥2 SLE-coded discharge diagnoses in the patient register with ≥1 diagnosis from a specialist. Unadjusted risks of adverse pregnancy or birth outcomes were calculated by SLE status, and Cochran-Armitage tests evaluated trend across exposure groups. RESULTS: Maternal outcomes such as preeclampsia, hypothyroidism, stroke, and infection were more common among women with SLE. Sixteen percent of prevalent-SLE pregnancies were diagnosed with preeclampsia compared with 5% of those from the general population. Among the pre-SLE women, preeclampsia was found in 26% of those with SLE within 2 years postpartum and 13% in those with SLE within 2-5 years postpartum. Similarly, infant outcomes, such as preterm birth, infection, and mortality, were worse among those born to mothers with prevalent SLE and pre-SLE during pregnancy. The test for trend was significant for most outcomes. CONCLUSION: Our data demonstrate that adverse maternal and fetal outcomes are more common in SLE pregnancies. Furthermore, these unfavorable outcomes are observed in pregnancies occurring prior to the diagnosis of SLE. Thus, the underlying immunologic profile of SLE and alterations preceding clinical SLE may contribute to these pregnancy complications. Funding agencies: Strategic Research Program in Epidemiology at Karolinska Institute; County Council of Ostergotland; Swedish Society for Medical Research; Swedish Rheumatism Association; Swedish Society of Medicine; Professor Nanna Svartz Foundation; King Gustaf V 80-Year

Background A "Table Fallacy," as coined by Westreich and Greenland, reports multiple adjusted effect estimates from a single model. This practice, which remains common in published literature, can be problematic when different types of effect estimates are presented together in a single table. The purpose of this paper is to quantitatively illustrate this potential for misinterpretation with an example estimating the effects of preeclampsia on preterm birth. Methods We analysed a retrospective population-based cohort of 2 963 888 singleton births in California between 2007 and 2012. We performed a modified Poisson regression to calculate the total effect of preeclampsia on the risk of PTB, adjusting for previous preterm birth. pregnancy alcohol abuse, maternal education, and maternal socio-demographic factors (Model 1). In subsequent models, we report the total effects of previous preterm birth, alcohol abuse, and education on the risk of PTB, comparing and contrasting the controlled direct effects, total effects, and confounded effect estimates, resulting from Model 1. Results The effect estimate for previous preterm birth (a controlled direct effect in Model 1) increased 10% when estimated as a total effect. The risk ratio for alcohol abuse, biased due to an uncontrolled confounder in Model 1, was reduced by 23% when adjusted for drug abuse. The risk ratio for maternal education, solely a predictor of the outcome, was essentially unchanged. Conclusions Reporting multiple effect estimates from a single model may lead to misinterpretation and lack of reproducibility. This example highlights the need for careful consideration of the types of effects estimated in statistical models.

Objective To evaluate the association between subclinical and clinical chorioamnionitis and risk of preterm birth (PTB). Methods Demographic and clinical characteristics were abstracted from medical records and placental examinations performed (N = 1371 pregnancies including spontaneous and medically-indicated PTBs). Pregnancies were classified as having clinical chorioamnionitis (with or without histologic chorioamnionitis), subclinical chorioamnionitis (histologic, but not clinical, chorioamnionitis), or no chorioamnionitis; pregnancies with histologic chorioamnionitis were further evaluated for fetal vasculitis. Relative risks for PTB, early and late PTB, and PTB ± premature rupture of membranes (PROM) were adjusted for maternal characteristics. Results Clinical (4.3%) and subclinical (24.5%) chorioamnionitis were not associated with PTB overall. In pregnancies without clinical or subclinical chorioamnionitis, the risk of PTB with PROM and early PTB was 2.2% and 8.6%, respectively. In comparison, clinical chorioamnionitis was associated with an increased risk of PTB with PROM (aRR: 3.42 (95%CI: 1.07, 10.98), whereas subclinical chorioamnionitis was associated with increased risk of PTB with PROM (aRR: 3.92 (95% CI: 2.15, 7.12)) and early PTB (aRR: 1.77 (95% CI: 1.18, 2.64)). Histologic chorioamnionitis with fetal vasculitis was associated with increased risk of PTB with PROM (aRR: 7.44 (95% CI: 3.68, 15.05)) and early PTB (aRR: 2.94 (95% CI: 1.78, 4.87)), whereas histologic chorioamnionitis without fetal vasculitis was associated with increased risk of PTB with PROM only (aRR: 2.64, 95% CI: 1.27, 5.50). Conclusions Subclinical chorioamnionitis and histologic chorioamnionitis with fetal vasculitis were associated with early PTB and PTB with PROM but not with PTB overall, likely due to inclusion of indicated PTBs.

PURPOSE: Studies of antidepressant safety in pregnancy typically do not address complex patterns of use throughout pregnancy. We performed longitudinal trajectory modeling to describe patterns of antidepressant use in the first 32 weeks of pregnancy, and test whether these trajectories are associated with a reduction in birth weight or gestational age at delivery. METHODS: Our study included 166 pregnant women with deliveries between 2011–2015 who were prescribed an antidepressant between 91 days prior to last menstrual period and 32 weeks of gestation. From electronic medical records, we estimated average daily dose and cumulative dose per week for the first 32 weeks of gestation and for the first 13 weeks postnatal. We clustered women with similar utilization patterns using k-means longitudinal modeling and assessed the associations between trajectory group and birth weight and gestational age at delivery. RESULTS: We identified four cumulative dose trajectory groups and three average daily dose trajectory groups in each period. Relative to the lowest trajectory group, the highest trajectory group during pregnancy was associated with reduced birth weight in multivariable analysis (average daily highest trajectory vs. lowest trajectory β −314.1g, 95% CI −613.7, −15.5) adjusted for depression severity score, maternal age, race, and pregnancy smoking. Trajectory groups were not associated with gestational age at delivery. CONCLUSIONS: The highest trajectory group of antidepressant use in pregnancy was associated with a modest reduction in birth weight but not with gestational age at delivery. Longitudinal trajectories allow for a dynamic visualization and quantification of medication use among pregnant women.

Purpose The decision whether to continue antidepressant use for depression during pregnancy requires weighing maternal and child risks and benefits. Little is known about the effectiveness of antidepressant therapy during pregnancy. The goal of this study is to evaluate whether standard administrative claims data can be used to evaluate the effectiveness of antidepressants. Methods Using prescription and healthcare visit Medicaid claims (2000–2007), we identified 28 493 women with a depression diagnosis and antidepressant fill in the 90 days before their last menstrual period. Antidepressant continuation was defined based on prescription fills during the first trimester. Depression hospitalizations and deliberate self-harm served as measures of the effectiveness of treatment continuation during pregnancy. Propensity score and instrumental variable analyses were used to attempt to account for confounding. Results Relative to women who discontinued antidepressant therapy, women who continued were more likely to have a depression inpatient stay (odds ratio [OR] = 2.2, 95% confidence interval [95%CI]: 2.0–2.4) and deliberate self-harm code (OR = 1.4, 95%CI: 0.7–2.7). Accounting for measured covariates in the propensity score analysis, including age, race, comorbidities, comedications, features of the depression diagnosis, and antidepressant class, led to slightly attenuated estimates (OR = 2.0, 95%CI: 1.8–2.2; OR = 1.1, 95%CI: 0.5–2.4). Similar associations were estimated in subgroups with different levels of baseline depression severity. Proposed preference-time, calendar-time-based, and geography-based instruments were unlikely to meet the required conditions for a valid analysis. Conclusions Our findings suggest that either antidepressant medications do not reduce the risk of depression relapse in pregnant women, or that administrative data alone could not be used to validly estimate the effectiveness of psychotropic medications during pregnancy. Copyright © 2015 John Wiley & Sons, Ltd.

Purpose To describe methods reported in the literature to estimate the beginning or duration of pregnancy in automated health care data, and to present results of validation exercises where available. Methods Papers reporting methods for determining the beginning or duration of pregnancy were identified based on Pubmed searches, by consulting investigators with expertise in the field and by reviewing conference abstracts and reference lists of relevant papers. From each paper or abstract, we extracted information to characterize the study population, data sources, and estimation algorithm. We then grouped these studies into categories reflecting their general methodological approach. Results Methods were classified into 5 categories: (i) methods that assign a uniform duration for all pregnancies, (ii) methods that assign pregnancy duration based on preterm-delivery or health care related codes, or codes for other pregnancy outcomes, (iii) methods based on the timing of prenatal care, (iv) methods based on birth weight, and (v) methods that combine elements from 2 and 3. Validation studies evaluating these methods used varied approaches, with results generally reporting on the mistiming of the start of pregnancy, incorrect estimation of the duration of pregnancy, or misclassification of drug exposure during pregnancy or early pregnancy. Conclusions In the absence of accurate information on the beginning or duration of pregnancy, several methods of varying complexity are available to estimate them. Validation studies have been performed for many of them and can serve as a guide for method selection for a particular study. Copyright © 2015 John Wiley & Sons, Ltd.

Hypospadias is one of the most common birth defects among males. Although the birth prevalence of hypospadias has been reported as increasing in some geographic regions, inconsistencies in ascertainment of mild cases and variability in reporting standards are likely contributing to these apparent trends. While hypospadias is highly heritable, there is limited knowledge about the specific genetic and epigenetic factors that play a role in its etiology. Risk factors for hypospadias include family history, older maternal age, nulliparity, high maternal prepregnancy body mass index, hypertension or preeclampsia, multiple gestations, reduced birth weight, and small for gestational age. Of the various prenatal exposures to medications that have been studied, the strongest evidence supports valproic acid as a contributor to hypospadias. Studies evaluating the impact of assisted reproductive technologies (ART) on hypospadias are inconclusive because of potential confounding by subfertility. Many causes of hypospadias may act through a few shared pathways, such as placental dysfunction.

The evidence to date regarding corticosteroid exposure in pregnancy and select pregnancy and birth outcomes is limited and inconsistent. Here we provide a narrative review of published literature summarizing the findings for oral clefts, preterm birth, birth weight, preeclampsia and gestational diabetes mellitus. Whenever possible, the results are limited to oral or systemic administration with a further focus on use in autoimmune disease. Although previous studies of corticosteroid exposure in pregnancy reported an increased risk of oral clefts in the offspring, more recent studies have not replicated these findings. Further, most of the literature lacks robust statistical analysis accounting for underlying disease or disease activity. The evidence to date suggests that first trimester corticosteroid use may confer a small increase in the odds of cleft lip with or without cleft palate, although data are conflicting and it is unknown to what extent the underlying maternal disease may contribute. There is little support that systemic corticosteroid use in pregnancy independently causes increases in risks of preterm birth, low birth weight, or preeclampsia. There is not sufficient evidence to determine whether corticosteroids could contribute to gestational diabetes mellitus.

BACKGROUND Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects. METHODS We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders. A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41). CONCLUSIONS The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.)

Purpose The aim of this study is to assess the validity of preeclampsia, congenital cardiac malformations, and persistent pulmonary hypertension of the newborn (PPHN) diagnoses in the US Medicaid Analytic eXtract (MAX), a nationwide healthcare utilization database that may be useful for perinatal research.

Importance The association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of persistent pulmonary hypertension of the newborn (PPHN) has been controversial since the US Food and Drug Administration issued a public health advisory in 2006. Objective To examine the risk of PPHN associated with exposure to different antidepressant medication classes late in pregnancy. Design and Setting Cohort study nested in the 2000-2010 Medicaid Analytic eXtract for 46 US states and Washington, DC. Last follow-up date was December 31, 2010. Participants A total of 3 789 330 pregnant women enrolled in Medicaid from 2 months or fewer after the date of last menstrual period through at least 1 month after delivery. The source cohort was restricted to women with a depression diagnosis and logistic regression analysis with propensity score adjustment applied to control for potential confounders. Exposures for Observational Studies SSRI and non-SSRI monotherapy use during the 90 days before delivery vs no use. Main Outcomes and Measures Recorded diagnosis of PPHN during the first 30 days after delivery. Results A total of 128 950 women (3.4%) filled at least 1 prescription for antidepressants late in pregnancy: 102 179 (2.7%) used an SSRI and 26 771 (0.7%) a non-SSRI. Overall, 7630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95% CI, 20.4-21.3 per 10 000 births) compared with 322 infants exposed to SSRIs (31.5; 95% CI, 28.3-35.2 per 10 000 births), and 78 infants exposed to non-SSRIs (29.1; 95% CI, 23.3-36.4 per 10 000 births). Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment. For SSRIs, odds ratios were 1.51 (95% CI, 1.35-1.69) unadjusted and 1.10 (95% CI, 0.94-1.29) after restricting to women with depression and adjusting for the high-dimensional propensity score. For non-SSRIs, the odds ratios were 1.40 (95% CI, 1.12-1.75) and 1.02 (95% CI, 0.77-1.35), respectively. Upon restriction of the outcome to primary PPHN, the adjusted odds ratio for SSRIs was 1.28 (95% CI, 1.01-1.64) and for non-SSRIs 1.14 (95% CI, 0.74-1.74). Conclusions and Relevance Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However, the absolute risk was small, and the risk increase appears more modest than suggested in previous studies.

Objective To determine whether outpatient exposure to calcium-channel blockers (CCBs) at the time of delivery is associated with an increased risk for postpartum haemorrhage (PPH). Design Cohort study. Setting United States of America. Population or sample Medicaid beneficiaries. Methods We identified a cohort of 9750 patients with outpatient prescriptions for CCBs, methyldopa, or labetalol for pre-existing or gestational hypertension whose days of supply overlapped with delivery; 1226 were exposed to CCBs. The risk of PPH was compared in those exposed to CCBs to those exposed to methyldopa or labetalol. Propensity score matching and stratification were used to address potential confounding. Main outcome measures The occurrence of PPH during the delivery hospitalisation. Results There were 27 patients exposed to CCBs (2.2%) and 232 patients exposed to methyldopa or labetalol (2.7%) who experienced PPH. After accounting for confounders, there was no meaningful association between CCB exposure and PPH in the propensity score matched (odds ratio 0.77, 95% CI 0.50–1.18) or stratified (odds ratio 0.79, 95% CI 0.53–1.19) analyses. Similar results were obtained across multiple sensitivity analyses. Conclusions The outpatient use of CCBs in late pregnancy for the treatment of hypertension does not increase the risk of PPH.

The risk of depression in women is greatest at childbearing age. We sought to examine and explain national trends in antidepressant use in pregnant women.This was a cohort study including pregnant women aged 12-55 who were enrolled in Medicaid during 2000-2007. We examined the proportion of women taking antidepressants during pregnancy by patient characteristics (descriptive), by region (mixed-effects model) and over time (interrupted time series).We identified 1,106,757 pregnancies in 47 states; mean age was 23 years, and 60% were nonwhite. Nearly 1 in 12 used an antidepressant during pregnancy. Use was higher for older (11.2% for age ≥30 vs. 7.6% for30) and white (14.4% vs. 4.0% for nonwhite) women. There was a four- to fivefold difference in rate of antidepressant use among states. Of the 5.3% of women taking antidepressants at conception, 33% and 17% were still on treatment 90 and 180 days, respectively, into pregnancy; an additional 4% began use during pregnancy. Labeled pregnancy-related health advisories did not appear to affect antidepressant use.Antidepressant use during pregnancy remains high in this population; treatment patterns vary substantially by patient characteristics and region. Comparative safety and effectiveness data to help inform treatment choices are needed in this setting.

Background Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that occurs during childbearing years and has been associated with preeclampsia. However, little is known about preeclampsia of early onset, which is associated with severe adverse maternal and perinatal outcomes. Methods Using national population-based Swedish registers we identified women with SLE (≥2 visits with corresponding ICD codes) and a sample without SLE who gave birth to singleton infants 2001–12. Risk ratios (RR) and 95% confidence intervals (CI) for early-onset preeclampsia (defined by ICD codes corresponding to preeclampsia registered at

Background Covariate selection to reduce bias in observational data analysis has primarily relied upon statistical criteria to guide researchers. This approach may lead researchers to condition on variables that ultimately increase bias in the effect estimates. The use of directed acyclic graphs (DAGs) aids researchers in constructing thoughtful models based on hypothesised biologic mechanisms to produce the least biased effect estimates possible. Methods After providing an overview of different relations in DAGs and the prevailing mechanisms by which conditioning on variables increases or reduces bias in a model, we illustrate examples of DAGs for maternal antidepressants in pregnancy and four separate perinatal outcomes. Results By comparing and contrasting the diagrams for maternal antidepressant use in pregnancy and spontaneous abortion, major malformations, preterm birth, and postnatal growth, we illustrate the different conditioning sets required for each model. Moreover, we illustrate why it is not appropriate to condition on the same set of covariates for the same exposure and different perinatal outcomes. We further discuss potential selection biases, overadjustment of mediators on the causal path, and sufficient sets of conditioning variables. Conclusion In our efforts to construct parsimonious models that minimise confounding and selection biases, we must rely upon our scientific knowledge of the causal mechanism. By structuring data collection and analysis around hypothesised DAGs, we ultimately aim to validly estimate the causal effect of interest.

Hypertensive disorders occur in approximately 6% to 8% of all pregnancies and are a significant source of maternal and fetal morbidity. Little is known about the range of agents routinely used in practice. We used Medicaid claims from 2000 to 2007 to identify completed pregnancies. We included women who were Medicaid beneficiaries from at least 3 months prior to last menstrual period to 1 month postdelivery, and were successfully linked to infant records. Maternal exposure to antihypertensive medications was derived from Medicaid pharmacy claim files, and duration of exposure was assigned based on the days’ supply dispensed. We identified 1 106 757 Medicaid patients in our cohort, of whom 48 453 (4.4%) were exposed to antihypertensive medications during pregnancy. The prevalence of antihypertensive use increased from 3.5% to 4.9% during the study period. Antihypertensive medication users were older than nonusers, more likely to be white or black, and more likely to have comorbid diabetes mellitus and renal disease. Overall, 1.9% of pregnant women were exposed during the first trimester, 1.7% during the second trimester, and 3.2% during the third trimester. The range of antihypertensive medications to which patients were exposed was highly heterogeneous and frequently included agents other than methyldopa or labetalol. Angiotensin-converting enzyme inhibitor exposure, which is contraindicated in late pregnancy, occurred in 928 (4.9%) antihypertensive medication users in the second trimester and 383 (1.1%) in the third trimester. Antihypertensive use during pregnancy is relatively common and increasing. The wide range of agents used during pregnancy includes medications considered contraindicated during pregnancy.

A previous study suggested an increased risk of preeclampsia among women treated with selective serotonin reuptake inhibitors (SSRIs). Using population-based health-care utilization databases from British Columbia (1997–2006), the authors conducted a study of 69,448 pregnancies in women with depression. They compared risk of preeclampsia in women using SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) between gestational weeks 10 and 20 with risk in depressed women not using antidepressants. Among prepregnancy antidepressant users, the authors compared the risk in women who continued antidepressants between gestational weeks 10 and 24 with the risk in those who discontinued. Relative risks and 95% confidence intervals were estimated. The risk of preeclampsia in depressed women not treated with antidepressants (2.4%) was similar to that in women without depression (2.3%). Compared with women with untreated depression, women treated with SSRI, SNRI, and TCA monotherapy had adjusted relative risks of 1.22 (95% confidence interval (CI): 0.97, 1.54), 1.95 (95% CI: 1.25, 3.03), and 3.23 (95% CI: 1.87, 5.59), respectively. Within prepregnancy antidepressant users, the relative risk for preeclampsia among continuers compared with discontinuers was 1.32 (95% CI: 0.95, 1.84) for SSRI, 3.43 (95% CI: 1.77, 6.65) for SNRI, and 3.26 (95% CI: 1.04, 10.24) for TCA monotherapy. Study results suggest that women who use antidepressants during pregnancy, especially SNRIs and TCAs, have an elevated risk of preeclampsia. These associations may reflect drug effects or more severe depression.