Annals of Internal MedicineBenzodiazepine Use Early in Pregnancy and Risk for Congenital Malformations

🧠 Mental Health / Behavioral Sensitivity

This population-based cohort study evaluated whether benzodiazepine exposure during the first trimester of pregnancy was associated with major congenital malformations. Investigators analyzed more than 4.2 million pregnancies across U.S. Medicaid and MarketScan databases from 2000 to 2020. Exposure was defined by at least one benzodiazepine prescription fill during the first trimester. After adjustment for confounding factors using propensity score methods, investigators found no substantial increase in overall malformation risk, no consistent organ-specific safety signal, and no evidence of a dose-response relationship. As an observational study, the findings did not establish causality.

Clinical Considerations

• More than 79,000 pregnancies were exposed to benzodiazepines during the first trimester across the two databases.
• Adjusted absolute risk of any major malformation was 4.0% vs 4.1% in Medicaid and 4.9% vs 4.8% in MarketScan for exposed versus unexposed pregnancies.
• The pooled adjusted relative risk for any major congenital malformation was 0.99 (95% CI, 0.96-1.03).
• Investigators found no consistent association with organ-specific malformations across sensitivity analyses.
• No dose-response relationship was observed across exposure analyses.
• Findings from analyses involving coexposure to benzodiazepines and other psychoactive medications were inconsistent, and a reproducible pattern was not identified.

Practice Applications

• Discuss these findings as part of shared decision-making when weighing benzodiazepine risks and benefits during pregnancy.
• Recognize that this large observational study did not identify a substantial increase in overall congenital malformation risk from first-trimester benzodiazepine exposure.
• Interpret organ-specific findings cautiously because observed signals were inconsistent across analyses.
• Evaluate concurrent psychoactive medication use separately, as coexposure findings remain uncertain.
• Balance medication risks against the potential consequences of undertreated maternal psychiatric illness during pregnancy.