Patterns of paternal medication dispensation around the time of conception.

BACKGROUND: Past research on the safety of prenatal exposure to medications has focused on maternal use during gestation, with limited research into the potential effects of paternal use during the spermatogenic period preceding conception. Knowing the most common medications used by fathers around the time of conception can inform research priorities in this field. OBJECTIVES: To identify the most common medications dispensed to fathers in the preconception period. METHODS: Within the MarketScan research database of commercially insured individuals in the United States from 2011 to 2020, we identified pregnancies, estimated the date of conception, linked each pregnancy to the father using family enrolment information and required minimum enrolment period and prescription benefits. Then, we described the use of prescription medications by the father during the 90 days before conception based on pharmacy dispensation claims. RESULTS: Of 4,437,550 pregnancies, 51.6% were linked with a father. Among the 1,413,762 pregnancies connected with a father that also met the inclusion criteria, the most common classes of medications dispensed were psychotropics (8.66%), antibiotics (7.21%), and analgesics (6.82%). The most frequently dispensed medications were amoxicillin (3.75%), azithromycin (3.15%), fluticasone (2.70%) and acetaminophen/hydrocodone (2.70%). Some fathers filled prescriptions for medications associated with foetal embryopathy when used by the mother, including mycophenolate (0.04%), methotrexate (0.03%) and isotretinoin (0.02%). CONCLUSIONS: More than a third of fathers filled at least one prescription medication in the preconception period, and several of them are known to be embryotoxic, emphasizing the necessity for further investigation into the potential teratogenicity of paternal exposure.

Removing the FDA's Boxed Hepatotoxicity Warning and Liver Function Testing Requirement for Ambrisentan.

Importance: Endothelin receptor antagonists are first-line therapy for pulmonary arterial hypertension (PAH). The first 2 agents approved in the class, bosentan and ambrisentan, initially carried boxed warnings for hepatotoxicity and required monthly liver function tests (LFTs) as part of a risk evaluation and mitigation strategy (REMS); however, in 2011, as further safety data emerged on ambrisentan, the boxed hepatotoxicity warning and LFT requirements were removed. Objective: To analyze changes in the use of and LFT monitoring for ambrisentan and bosentan after changes to the ambrisentan labeling and REMS. Design, Setting, and Participants: This serial cross-sectional study used data from 3 longitudinal health care insurance claims databases-Medicaid, Optum's deidentified Clinformatics Data Mart, and Merative Marketscan-to perform an interrupted time series analysis of prescription fills and LFTs for patients taking ambrisentan and bosentan. Participants were patients filling prescriptions for ambrisentan and bosentan from July 1, 2007, to December 31, 2018. Data analysis was performed from April 2021 to August 2023. Exposure: Removal of the boxed warning for hepatotoxicity and the REMS LFT monitoring requirements on ambrisentan in March 2011. Main Outcomes and Measures: The primary outcomes were use of ambrisentan (ie, individuals with at least 1 dispensing per 1 000 000 individuals enrolled in the 3 datasets) vs bosentan and LFT monitoring (ie, proportion of initiators with at least 1 ordered test) before initiation and before the first refill. Results: A total of 10 261 patients received a prescription for ambrisentan during the study period (7442 women [72.5%]; mean [SD] age, 52.6 [17.6] years), and 11 159 patients received a prescription for bosentan (7931 women [71.1%]; mean [SD] age, 47.7 [23.7] years). Removal of the ambrisentan boxed hepatotoxicity warning and LFT monitoring requirement was associated with an immediate increase in the use of ambrisentan (1.50 patients per million enrollees; 95% CI, 1.08 to 1.92 patients per million enrollees) but no significant change in the use of bosentan. There were reductions in recorded LFTs before drug initiation (13.1% absolute decrease; 95% CI, -18.2% to -8.0%) and before the first refill (26.4% absolute decrease; 95% CI, -34.4% to -18.5%) of ambrisentan but not bosentan. Conclusions and Relevance: In this serial cross-sectional study of ambrisentan, labeling changes and removal of the REMS-related LFT requirement were associated with shifts in prescribing and testing behavior for ambrisentan but not bosentan. Further clinician education may be needed to maximize the benefits of REMS programs and labeling warnings designed to ensure the safe administration of high-risk medications.

Use of Real-World Data and Machine Learning to Screen for Maternal and Paternal Characteristics Associated with Cardiac Malformations.

Effective prevention of cardiac malformations, a leading cause of infant morbidity, is constrained by limited understanding of etiology. The study objective was to screen for associations between maternal and paternal characteristics and cardiac malformations. We selected 720,381 pregnancies linked to live-born infants (n=9,076 cardiac malformations) in 2011-2021 MarketScan US insurance claims data. Odds ratios were estimated with clinical diagnostic and medication codes using logistic regression. Screening of 2,000 associations selected 81 associated codes at the 5% false discovery rate. Grouping of selected codes, using latent semantic analysis and the Apriori-SD algorithm, identified elevated risk with known risk factors, including maternal diabetes and chronic hypertension. Less recognized potential signals included maternal fingolimod or azathioprine use. Signals identified might be explained by confounding, measurement error, and selection bias and warrant further investigation. The screening methods employed identified known risk factors, suggesting potential utility for identifying novel risk factors for other pregnancy outcomes.

Perinatal Outcomes Associated With Metformin Use During Pregnancy in Women With Pregestational Type 2 Diabetes Mellitus.

OBJECTIVE: We emulated a modified randomized trial (Metformin in Women With Type 2 Diabetes in Pregnancy [MiTy]) to compare the perinatal outcomes in women continuing versus discontinuing metformin during pregnancy among those with type 2 diabetes treated with metformin plus insulin before pregnancy. RESEARCH DESIGN AND METHODS: This study used two health care claims databases (United States, 2000-2020). Pregnant women age 18-45 years with type 2 diabetes who were treated with metformin plus insulin at conception were eligible. The primary outcome was a composite of preterm birth, birth injury, neonatal respiratory distress, neonatal hypoglycemia, and neonatal intensive care unit admission. Secondary outcomes included the components of the primary composite outcome, gestational hypertension, preeclampsia, maternal hypoglycemia, cesarean delivery, infants large for gestational age, infants small for gestational age (SGA), sepsis, and hyperbilirubinemia. We adjusted for potential baseline confounders, including demographic characteristics, comorbidities, and proxies for diabetes progression. RESULTS: Of 2,983 eligible patients, 72% discontinued use of metformin during pregnancy. The average age at conception was 32 years, and the prevalence of several comorbidities was higher among continuers. The risk of the composite outcome was 46% for continuers and 48% for discontinuers. The adjusted risk ratio was 0.92 (95% CI 0.81, 1.03). Risks were similar between treatments and consistent between databases for most secondary outcomes, except for SGA, which was elevated in continuers only in the commercially insured population. CONCLUSIONS: Our findings were consistent with those reported in the MiTy randomized trial. Continuing metformin during pregnancy was not associated with increased risk of a neonatal composite adverse outcome. However, a possible metformin-associated risk of SGA warrants further consideration.

Chronic Hypertension During Pregnancy: Prevalence and Treatment in the United States, 2008-2021.

BACKGROUND: Treatment of chronic hypertension during pregnancy has been shown to reduce the risk of adverse perinatal outcomes. In this study, we examined the prevalence and treatment of chronic hypertension during pregnancy and assessed changes in these outcomes following the release of the updated 2017 hypertension guidelines of the American College of Cardiology and American Heart Association. METHODS: We analyzed the MerativeTM Marketscan® Research Database of United States commercial insurance claims from 2007 to 2021. We assessed the prevalence of chronic hypertension during pregnancy and oral antihypertensive medication use over time. We then performed interrupted time series analyses to evaluate changes in these outcomes. RESULTS: The prevalence of chronic hypertension steadily increased from 1.8% to 3.7% among 1 900 196 pregnancies between 2008 and 2021. Antihypertensive medication use among pregnant individuals with chronic hypertension was relatively stable (57%-60%) over the study period. The proportion of pregnant individuals with chronic hypertension treated with methyldopa or hydrochlorothiazide decreased (from 29% to 2% and from 11% to 5%, respectively), while the proportion treated with labetalol or nifedipine increased (from 19% to 42% and from 9% to 17%, respectively). The prevalence or treatment of chronic hypertension during pregnancy did not change following the 2017 American College of Cardiology and American Heart Association hypertension guidelines. CONCLUSIONS: The prevalence of chronic hypertension during pregnancy doubled between 2008 and 2021 in a nationwide cohort of individuals with commercial insurance. Labetalol replaced methyldopa as the most commonly used antihypertensive during pregnancy. However, only about 60% of individuals with chronic hypertension in pregnancy were treated with antihypertensive medications.

Paternal Use of Metformin During the Sperm Development Period Preceding Conception and Risk for Major Congenital Malformations in Newborns.

BACKGROUND: Metformin is the most used oral antidiabetic medication. Despite its established safety profile, it has known antiandrogenic and epigenetic modifying effects. This raised concerns about possible adverse developmental effects caused by genomic alterations related to paternal use of metformin during the spermatogenesis period preceding conception. OBJECTIVE: To assess the potential adverse intergenerational effect of metformin by examining the association between paternal metformin use during spermatogenesis and major congenital malformations (MCMs) in newborns. DESIGN: Nationally representative cohort study. SETTING: A large Israeli health fund. PARTICIPANTS: 383 851 live births linked to fathers and mothers that occurred in 1999 to 2020. MEASUREMENTS: MCMs and parental cardiometabolic conditions were ascertained using clinical diagnoses, medication dispensing information, and laboratory test results. The effect of metformin use on MCMs was estimated using general estimating equations, accounting for concurrent use of other antidiabetic medications and parental cardiometabolic morbidity. RESULTS: Compared with unexposed fathers, the prevalence of cardiometabolic morbidity was substantially higher among fathers who used metformin during spermatogenesis, and their spouses. Whereas the crude odds ratio (OR) for paternal metformin exposure in all formulations and MCMs was 1.28 (95% CI, 1.01 to 1.64), the adjusted OR was 1.00 (CI, 0.76 to 1.31). Within specific treatment regimens, the adjusted OR was 0.86 (CI, 0.60 to 1.23) for metformin in monotherapy and 1.36 (CI, 1.00 to 1.85) for metformin in polytherapy, a treatment that was more common in patients with more poorly controlled diabetes. LIMITATION: Laboratory test results for hemoglobin A1c to assess underlying diabetes severity were available only for a subset of the cohort. CONCLUSION: Paternal use of metformin in monotherapy does not increase the risk for MCMs. Association for metformin in polytherapy could potentially be explained by worse underlying parental cardiometabolic risk profile. PRIMARY FUNDING SOURCE: None.

Metformin Use in the First Trimester of Pregnancy and Risk for Nonlive Birth and Congenital Malformations: Emulating a Target Trial Using Real-World Data.

BACKGROUND: Metformin is a first-line pharmacotherapy for type 2 diabetes, but there is limited evidence about its safety in early pregnancy. OBJECTIVE: To evaluate the teratogenicity of metformin use in the first trimester of pregnancy. DESIGN: In an observational cohort of pregnant women with pregestational type 2 diabetes receiving metformin monotherapy before the last menstrual period (LMP), a target trial with 2 treatment strategies was emulated: insulin monotherapy (discontinue metformin treatment and initiate insulin within 90 days of LMP) or insulin plus metformin (continue metformin and initiate insulin within 90 days of LMP). SETTING: U.S. Medicaid health care administration database (2000 to 2018). PARTICIPANTS: 12 489 pregnant women who met the eligibility criteria. MEASUREMENTS: The risk and risk ratio of nonlive births, live births with congenital malformations, and congenital malformations among live births were estimated using standardization to adjust for covariates. RESULTS: A total of 850 women were in the insulin monotherapy group and 1557 in the insulin plus metformin group. The estimated risk for nonlive birth was 32.7% under insulin monotherapy (reference) and 34.3% under insulin plus metformin (risk ratio, 1.02 [95% CI, 1.01 to 1.04]). The estimated risk for live birth with congenital malformations was 8.0% (CI, 5.7% to 10.2%) under insulin monotherapy and 5.7% (CI, 4.5% to 7.3%) under insulin plus metformin (risk ratio, 0.72 [CI, 0.51 to 1.09]). LIMITATION: Possible residual confounding by glycemic control and body mass index. CONCLUSION: Compared with switching to insulin monotherapy, continuing metformin and adding insulin in early pregnancy resulted in little to no increased risk for nonlive birth among women receiving metformin before pregnancy. Under conventional statistical criteria, anything between a 49% decrease and a 9% increase in risk for congenital malformations was highly compatible with our data. PRIMARY FUNDING SOURCE: National Institutes of Health.

Tramadol use in U.S. Adults With Commercial Health Insurance, 2005-2021.

INTRODUCTION: Tramadol has been associated with chronic opioid use and emergency room (ER) visits. However, little is known about trends in prescription tramadol use in the U.S. METHODS: Optum's de-identified Clinformatics® Data Mart Database was used to assess trends in monthly incident and prevalent tramadol use from 2005 to 2021, stratified by sex and age (18-64 vs. ≥65 years). State-specific trends following scheduling of tramadol as Class IV controlled substance in August 2014 were analyzed with random effects regression models. Demographics, comorbidities, initiation setting, dose, and co-dispensing with other opioids and central nervous system (CNS) agents were assessed in people initiating tramadol, stratified by age and initiation year (2005-2010, 2011-2015, 2016-2021). Analyses were performed in 2023 and 2024. RESULTS: During 2005-2021, the mean percentage using tramadol in a given month was 0.88% of younger females, 0.55% of younger males, 1.97% of older females, and 1.14% of older males; 5,729,652 initiations were identified. Since 2014, estimated relative yearly decrease was 4% (95% CI 3%; 5%) in use and 5% (95% CI 4%; 5%) in initiation, with variation across states. Primary care percentage of tramadol initiations declined from 49.2% in 2005-2010 to 37.2% in 2016-2021. During 2016-2021, co-dispensing with other CNS agents occurred in 37.8% of younger and 32.1% of older adults initiating tramadol. CONCLUSIONS: Tramadol use was higher in females and older adults, exhibited heterogeneous trends across states, and shifted from primary care to ER and specialist settings over time. Co-dispensing with other CNS agents was common and warrants further monitoring.

Association between gender-affirming hormone therapy and measures of glucose metabolism: A longitudinal study.

CONTEXT: The long-term effect of gender-affirming hormone therapy (GAHT) on glucose metabolism is an area of priority in transgender health research. OBJECTIVES: To evaluate the relation between GAHT and changes in fasting blood glucose (FG) and glycosylated hemoglobin (HbA1c) in transmasculine (TM) and transfeminine (TF) persons relative to the corresponding temporal changes in presumably cisgender persons (i.e. without any evidence of TGD status). DESIGN: Retrospective cohort study. SETTING: Three large integrated health systems. PARTICIPANTS: 2,425 TF and 2,127 TM persons compared with 33,995 cisgender males (CM) and 38,913 cisgender females (CF) enrolled in the same health plans. OUTCOMES/MEASURES: Temporal changes in FG and HbA1c levels examined using linear mixed models with main results expressed as ratios-of-ratios. RESULTS: The pre- versus post-GAHT ratios-of-ratio (95% confidence interval) estimates adjusted for age, race/ethnicity, study site, and body mass index in the model comparing TF and CM groups were 1.05 (1.01, 1.09) for FG and 1.03 (0.99, 1.06) for HbA1c. By contrast, the corresponding results in the models contrasting TM and cisgender cohort members were in the 0.99-1.00 range. The ratio-of-ratios comparing post-GAHT changes among transgender and cisgender persons were close to the null and without a discernable pattern. CONCLUSION: Though the within-transgender cohort data suggest an increase in the levels of FG and HbA1c following feminizing GAHT initiation, these changes were no longer evident when compared with the corresponding changes in cisgender referents. Based on these results, clinically important effects of GAHT on routine laboratory markers of glucose metabolism appear unlikely.

The association of short-term increases in ambient PM2.5 and temperature exposures with stillbirth: racial/ethnic disparities among Medicaid recipients.

Racial/ethnic disparities in the association between short-term (e.g. days, weeks) ambient fine particulate matter (PM2.5) and temperature exposures and stillbirth in the US have been understudied. A time-stratified, case-crossover design using a distributed lag non-linear model (0 to 6-day lag) estimated stillbirth odds due to short-term increases in average daily PM2.5 and temperature exposures among 118,632 Medicaid recipients from 2000-2014. Disparities by maternal race/ethnicity (Black, White, Hispanic, Asian, American Indian) and zip-code level socioeconomic status (SES) were assessed. In the temperature-adjusted model, a 10 µg/m3 increase in PM2.5 concentration was marginally associated with increased stillbirth odds at lag 1 (0.68% 95%CI:[-0.04,1.40]) and lag 2 (0.52% 95%CI:[-0.03,1.06]), but not lag 0-6 (2.80% 95%CI:[-0.81,6.45]). An association between daily PM2.5 concentrations and stillbirth odds was found among Black individuals at the cumulative lag (0-6 days: 9.26% 95%CI:[3.12,15.77]), but not among other races/ethnicities. A stronger association between PM2.5 concentrations and stillbirth odds existed among Black individuals living in zip codes with the lowest median household income (lag0-6:14.13% 95%CI:[4.64,25.79]). Short-term temperature increases were not associated with stillbirth risk among any race/ethnicity. Black Medicaid enrollees, and especially those living in lower SES areas, may be more vulnerable to stillbirth due to short-term increases in PM2.5 exposure.

TNF-α inhibitor use during pregnancy and the risk of preeclampsia: population-based cohort study.

BACKGROUND: Although the clinical importance of preeclampsia is widely recognized, few treatment options are available for prevention. TNF-α inhibitors have been hypothesized to potentially prevent the disease. We aimed to examine whether exposure to TNF-α inhibitors during pregnancy reduces the risk of preeclampsia. METHODS: We conducted a population-based pregnancy cohort study using nationwide samples of publicly (Medicaid data, 2000-2018) and commercially (MarketScan Research Database, 2003-2020) insured pregnant women linked to their liveborn infants. Exposure was ascertained based on a filled prescription or administration code for TNF-α inhibitors during the first and second trimester of pregnancy. The outcomes included early-onset preeclampsia, late-onset preeclampsia, and small-for-gestational age. For baseline confounding adjustment, we leveraged propensity score overlap weights to estimate risk ratios (RR). RESULTS: Among 4 315 658 pregnancies in the Medicaid and the MarketScan cohort, 2736 (0.063%) were exposed to TNF-α inhibitors during the first trimester and 1712 (0.040%) during the second trimester. After adjustment, the risk of early-onset preeclampsia was not decreased among mothers exposed during the first trimester compared with unexposed women with treatment indications [RRpooled: 1.25, 95% confidence interval (CI) 0.93-1.67]. Similarly, the risk of late-onset preeclampsia was not decreased among mothers exposed during the second trimester compared with unexposed women (RRpooled: 0.99, 95% CI 0.81-1.22). CONCLUSION: Contrary to the hypothesis, exposure to TNF-α inhibitors during pregnancy did not appear to be associated with a reduced risk of early-onset or late-onset preeclampsia. These findings do not support consideration of the use of TNF-α inhibitors for the prevention of preeclampsia.

Trends in Use and Evidence of Adherence to Risk Evaluation and Mitigation Strategy Pregnancy Testing Requirements for Thalidomide, Lenalidomide, and Pomalidomide in the USA, 2000-2020.

INTRODUCTION: Lenalidomide, pomalidomide, and thalidomide are effective treatments for multiple myeloma but are teratogenic. To mitigate this risk, the US Food and Drug Administration (FDA) required risk evaluation and mitigation strategy (REMS) programs for these drugs, which include pregnancy testing among women of childbearing potential-twice before initiation, weekly in the first month on treatment, and every 2-4 weeks thereafter. OBJECTIVE: We evaluated dispensing trends of lenalidomide, pomalidomide, and thalidomide and assessed adherence to REMS pregnancy testing requirements among at-risk patients taking these drugs. METHODS: Using three US health insurance claims databases (Optum Clinformatics® [2004-2020], Merative Marketscan [2003-2019], and Medicaid [2000-2018]), we assessed monthly use of the drugs, patient characteristics and treatment persistence among drug initiators, and claims-based evidence for adherence to pregnancy testing requirements among initiators with child-bearing potential. RESULTS: Lenalidomide was the most prescribed agent following its approval in 2006 and through the end of the study period. A total of 48,311 lenalidomide (mean age = 59 years [standard deviation (SD) = 16]), 17,550 thalidomide (mean age = 65 years [SD = 12]), and 6560 pomalidomide initiators (mean age = 65 years [SD = 11]) were identified; 45% of initiators of each drug were women. Among initiators under follow-up on day 90, 70% were still on therapy. Initiators of childbearing potential comprised 3% (N = 1,920) of all initiators; among this cohort, 12% had evidence in claims data of two pregnancy tests before initiation, and 9% with at least 33 days of follow-up of four tests during the first month of treatment. By contrast, 52% who received a refill had claims-based evidence of a pregnancy test within 7 days of dispensing. CONCLUSION: Although most patients who initiated lenalidomide, pomalidomide, and thalidomide were not of child-bearing potential, further investigation into actual non-adherence to pregnancy testing is needed.

Internal validation of gestational age estimation algorithms in healthcare databases using pregnancies conceived with fertility procedures.

Fertility procedures recorded in healthcare databases can be used to estimate the start of pregnancy, which can serve as a reference standard to validate gestational age estimates based on International Classification of Diseases (ICD) codes. In a cohort of 17,398 pregnancies conceived by fertility procedures in MarketScan (2011-2020), we estimated gestational age at the end of pregnancy using algorithms based on (1) days since fertility procedure (the reference); (2) ICD-9/ICD-10 (before/after October 2015) codes indicating gestational length recorded at the end of pregnancy (method A); and (3) ICD-10 enhanced with Z3A codes denoting specific gestation weeks recorded at prenatal visits (method B). We calculated the proportion of pregnancies with an estimated gestational age within 14 days of the reference. Method A accuracy was similar for ICD-9 and ICD-10 codes. After 2015, method B was more accurate than method A: For term births, within-14-day-agreements were 90.8% for method A and 98.7% for method B. Corresponding estimates were 70.1% and 95.6% for preterm births; 35.3% and 92.6% for stillbirths; 54.3% and 64.2% for spontaneous abortions; and 16.7% and 84.6% for elective terminations. ICD-10-based algorithms that incorporate Z3A codes improve the accuracy of gestational age estimation in healthcare databases, especially for preterm and non-live births.

Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure.

BACKGROUND: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use. METHODS: We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control. RESULTS: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine. CONCLUSIONS: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.).

Accounting for Twins and Other Multiple Births in Perinatal Studies Conducted Using Healthcare Administration Data.

The analysis of perinatal studies is complicated by twins and other multiple births even when they are not the exposure, outcome, or a confounder of interest. Common approaches to handling multiples in studies of infant outcomes include restriction to singletons, counting outcomes at the pregnancy-level (i.e., by counting if at least one twin experienced a binary outcome), or infant-level analysis including all infants and, typically, accounting for clustering of outcomes by using generalised estimating equations or mixed effects models. Several healthcare administration databases only support restriction to singletons or pregnancy-level approaches. For example, in MarketScan insurance claims data, diagnoses in twins are often assigned to a single infant identifier, thereby preventing ascertainment of infant-level outcomes among multiples. Different approaches correspond to different causal questions, produce different estimands, and often rely on different assumptions. We demonstrate the differences that can arise from these different approaches using Monte Carlo simulations, algebraic formulas, and an applied example. Furthermore, we provide guidance on the handling of multiples in perinatal studies when using healthcare administration data.

Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy.

BACKGROUND AND OBJECTIVES: Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy. METHODS: We conducted a population-based cohort study using linked national registers from Denmark, Finland, Iceland, Norway, and Sweden and administrative health care data from the United States and New South Wales, Australia. We described first trimester use of ASM combinations among pregnant people with epilepsy from 2000 to 2020. We compared the risk of MCM after first trimester exposure to ASM combinations vs valproate monotherapy and low-dose valproate plus lamotrigine or levetiracetam vs high-dose valproate (≥1,000 mg/d). We used log-binomial regression with propensity score weights to calculate adjusted risk ratios (aRRs) and 95% CIs for each dataset. Results were pooled using fixed-effects meta-analysis. RESULTS: Among 50,905 pregnancies in people with epilepsy identified from 7.8 million total pregnancies, 788 used lamotrigine and levetiracetam, 291 used lamotrigine and topiramate, 208 used levetiracetam and topiramate, 80 used lamotrigine and zonisamide, and 91 used levetiracetam and zonisamide. After excluding pregnancies with use of other ASMs, known teratogens, or a child diagnosed with MCM of infectious or genetic cause, we compared 587 exposed to lamotrigine-levetiracetam duotherapy and 186 exposed to lamotrigine-topiramate duotherapy with 1959 exposed to valproate monotherapy. Pooled aRRs were 0.41 (95% CI 0.24-0.69) and 1.26 (0.71-2.23), respectively. Duotherapy combinations containing low-dose valproate were infrequent, and comparisons with high-dose valproate monotherapy were inconclusive but suggested a lower risk for combination therapy. Other combinations were too rare for comparative safety analyses. DISCUSSION: Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with epilepsy treated in the first trimester of pregnancy, the risk of major congenital malformations is lower with lamotrigine-levetiracetam duotherapy than with valproate alone, but similar with lamotrigine-topiramate.

Short-Term Increases in NO2 and O3 Concentrations during Pregnancy and Stillbirth Risk in the U.S.: A Time-Stratified Case-Crossover Study.

Associations between gaseous pollutant exposure and stillbirth have focused on exposures averaged over trimesters or gestation. We investigated the association between short-term increases in nitrogen dioxide (NO2) and ozone (O3) concentrations and stillbirth risk among a national sample of 116 788 Medicaid enrollees from 2000 to 2014. A time-stratified case-crossover design was used to estimate distributed (lag 0-lag 6) and cumulative lag effects, which were adjusted for PM2.5 concentration and temperature. Effect modification by race/ethnicity and proximity to hydraulic fracturing (fracking) wells was assessed. Short-term increases in the NO2 and O3 concentrations were not associated with stillbirth in the overall sample. Among American Indian individuals (n = 1694), a 10 ppb increase in NO2 concentrations was associated with increased stillbirth odds at lag 0 (5.66%, 95%CI: [0.57%, 11.01%], p = 0.03) and lag 1 (4.08%, 95%CI: [0.22%, 8.09%], p = 0.04) but not lag 0-6 (7.12%, 95%CI: [-9.83%, 27.27%], p = 0.43). Among participants living in zip codes within 15 km of active fracking wells (n = 9486), a 10 ppb increase in NO2 concentration was associated with increased stillbirth odds in single-day lags (2.42%, 95%CI: [0.37%, 4.52%], p = 0.02 for lag 0 and 1.83%, 95%CI: [0.25%, 3.43%], p = 0.03 for lag 1) but not the cumulative lag (lag 0-6) (4.62%, 95%CI: [-2.75%, 12.55%], p = 0.22). Odds ratios were close to the null in zip codes distant from fracking wells. Future studies should investigate the role of air pollutants emitted from fracking and potential racial disparities in the relationship between short-term increases in NO2 concentrations and stillbirth.

First Trimester Use of Buprenorphine or Methadone and the Risk of Congenital Malformations.

Importance: Use of buprenorphine or methadone to treat opioid use disorder is recommended in pregnancy; however, their teratogenic potential is largely unknown. Objective: To compare the risk of congenital malformations following in utero exposure to buprenorphine vs methadone. Design, Setting, and Participants: This population-based cohort study used health care utilization data from publicly insured Medicaid beneficiaries in the US from 2000 to 2018. A total of 13 360 pregnancies with enrollment from 90 days prior to pregnancy start through 1 month after delivery and first trimester use of buprenorphine or methadone were included and linked to infants. Data were analyzed from July to December 2022. Exposure: A pharmacy dispensing of buprenorphine or a code for administration of methadone in the first trimester. Main Outcomes and Measures: Primary outcomes included major malformations overall and malformations previously associated with opioids (any cardiac malformations, ventricular septal defect, secundum atrial septal defect/nonprematurity-related patent foramen ovale, neural tube defects, clubfoot, and oral clefts). Secondary outcomes included other organ system-specific malformations. Risk differences and risk ratios (RRs) were estimated comparing buprenorphine with methadone, adjusting for confounders with propensity score overlap weights. Results: The cohort included 9514 pregnancies with first-trimester buprenorphine exposure (mean [SD] maternal age, 28.4 [4.6] years) and 3846 with methadone exposure (mean [SD] maternal age, 28.8 [4.7] years). The risk of malformations overall was 50.9 (95% CI, 46.5-55.3) per 1000 pregnancies for buprenorphine and 60.6 (95% CI, 53.0-68.1) per 1000 pregnancies for methadone. After confounding adjustment, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). Risk was lower with buprenorphine for cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), including both ventricular septal defect (RR, 0.62; 95% CI, 0.39-0.98) and secundum atrial septal defect/nonprematurity-related patent foramen ovale (RR, 0.54; 95% CI, 0.30-0.97), oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and clubfoot (RR, 0.55; 95% CI, 0.32-0.94). Results for neural tube defects were uncertain given low event counts. In secondary analyses, buprenorphine was associated with a decreased risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared with methadone. These findings were consistent in sensitivity and bias analyses. Conclusions and Relevance: In this cohort study, the risk of most malformations previously associated with opioid exposure was lower in buprenorphine-exposed infants compared with methadone-exposed infants, independent of measured confounders. Malformation risk is one factor that informs the individualized patient decision regarding medications for opioid use disorder in pregnancy.

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children.

Importance: Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain. Objective: To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD. Design, Setting, and Participants: This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan). Exposures: Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy. Main Outcomes and Measures: Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure. Results: The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD. Conclusions and Relevance: The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.