Z-Drug Use in the First Trimester of Pregnancy and Risk of Congenital Malformations

Importance: Sleep disturbances are common in pregnancy and often treated with nonbenzodiazepine sedative hypnotics (Z-drugs). However, there is limited evidence on the fetal safety of Z-drugs. Objective: To evaluate whether Z-drug exposure in the first trimester of pregnancy is associated with an increased risk of congenital malformations. Design, Setting, and Participants: This US population-based cohort study evaluated health care utilization data from publicly insured beneficiaries in the Medicaid database (2000-2018) and commercially insured beneficiaries in the Merative MarketScan database (2003-2020). Participants were pregnant individuals and their liveborn infants, with maternal enrollment from 90 days before pregnancy to 30 days after delivery and infant enrollment for 90 days after birth unless death occurred sooner. Data analysis was performed from November 2023 to April 2025. Exposure: At least 1 dispensing of Z-drugs (zaleplon, eszopiclone, or zolpidem) in the first trimester of pregnancy compared with no dispensing. Main Outcomes and Measures: Major congenital malformations were identified using linked maternal and infant claims. The risks of any major congenital malformation, organ-specific malformations, and individual malformations in pregnancies with Z-drug exposure in the first trimester were compared with the risks in unexposed pregnancies. Relative risks (RRs) and 95% CIs were estimated. Propensity score fine stratification weights were used to control for confounders. Results: A total of 4 281 579 pregnancies were identified (mean [SD] maternal age at delivery, 25.2 [6.0] years in Medicaid and 31.6 [4.6] years in MarketScan). First-trimester Z-drug exposure was identified in 11 652 (0.5%) of 2 506 106 pregnancies in Medicaid and 10 862 (0.6%) of 1 775 473 pregnancies in MarketScan; 92.1% of exposed pregnancies had zolpidem exposure. The adjusted pooled RR for malformations overall was 1.01 (95% CI, 0.95-1.08). While adjusted pooled RRs were increased for abdominal wall defects (1.46; 95% CI, 0.89-2.38), tetralogy of Fallot (1.45; 95% CI, 0.86-2.46), and neural tube defects (1.62; 95% CI, 0.96-2.74), these associations were imprecisely estimated, driven by the Medicaid cohort and not replicated in the MarketScan cohort. Results were consistent across multiple sensitivity analyses. Conclusions and Relevance: These findings suggest that Z-drug exposure in the first trimester of pregnancy is not associated with a meaningful elevation in the risk of congenital malformations overall, nor was there a consistent signal observed for organ-specific or uncommon, individual malformations examined.