Prenatal exposure to benzodiazepines, Z-drugs and long-term risk of neurodevelopmental disorders in offspring: nationwide cohort study.

Abstract

Benzodiazepine receptor agonists (BZRAs), including benzodiazepines and Z-drugs, are frequently prescribed during pregnancy but their long-term neurodevelopmental safety remains uncertain. To investigate whether prenatal BZRA exposure is associated with an increased long-term risk of neurodevelopmental disorders (LNDDs) in offspring. This nationwide, population-based cohort study used Korean National Health Insurance Service data on all live births from 2011 to 2014, followed until 2023. Prenatal BZRA exposure was defined as maternal prescriptions during pregnancy. Propensity score matching (1:10) was applied to balance covariates. Sensitivity analyses in the full cohort evaluated exposure intensity (0, 1-6, 7-29 and ≥30 cumulative days), drug class (benzodiazepines versus Z-drugs), trimester of exposure and discordant sibling comparisons with mother fixed effects. Among 1 553 505 eligible births, 5949 BZRA-exposed and 55 015 matched unexposed children were analysed. LNDD incidence was 13.9% in the exposed group versus 11.4% in the unexposed (odds ratio 1.25, 95% CI: 1.16, 1.35). In the full cohort, risks increased with exposure intensity: 1-6 days (odds ratio 1.16, 95% CI: 1.05-1.28), 7-29 days (odds ratio 1.19, 95% CI: 1.04-1.36) and ≥30 days (odds ratio 1.18, 95% CI: 1.01-1.38). By trimester, risks were higher with second- (odds ratio 1.30, 95% CI: 1.07-1.59) and third-trimester (odds ratio 1.27, 95% CI: 1.09-1.48) exposure. Class-specific analyses showed stronger associations for benzodiazepines only (odds ratio 1.19, 95% CI: 1.15-1.23) than for Z-drugs only (odds ratio 1.06, 95% CI: 1.04-1.08). In a discordant sibling analysis including 2572 children this association persisted (odds ratio 1.29, 95% CI: 1.05-1.60), indicating that neither familial nor genetic confounding fully explains the observed effects. Prenatal BZRA exposure was associated with increased long-term risks of LNDDs in offspring, with evidence of dose-response and class-specific effects, and persistence in sibling analyses.