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.

Benzodiazepine receptor agonists (BZRAs) are commonly used clinically and data on their hazardous use from large populations of psychiatric patients is limited.

To assess the current status of hazardous BZRA use and related factors in Chinese out-patient psychiatric settings.

The study included out-patients with at least one BZRA prescription from five psychiatric settings in east, central and west China in 2018. Demographic and prescription information were extracted from the electronic prescription database. We defined the co-occurrence of overdose and long-term use as hazardous use, and patients whose recorded diagnoses did not meet any indications approved by the Chinese Food and Drug Administration as over-indication users. Additionally, 200 hazardous users were randomly selected for follow-up interview to confirm the actual situation.

Among 720 054 out-patients, 164 450 (22.8%) had at least one BZRA prescription; 55.9% of patients were prescribed over-indication and 3% were defined as hazardous users. Multilevel multivariate regression analysis with hospital as a random effect showed that factors associated with hazardous use were older age (18–64 years: β = 0.018; 95% CI 0.013–0.023; >65 years: β = 0.015; 95% CI 0.010–0.021), male (β = 0.005, 95% CI 0.003–0.007), over-indication (β = 0.013, 95% CI 0.012–0.015), more out-patient visits (β = 0.006, 95% CI 0.006–0.006) and more visits to different doctors (β = 0.007, 95% CI 0.007–0.008); 98.5% of hazardous users (197/200) could not be contacted.

BZRAs are commonly used and there is a relatively large proportion of over-indication users among Chinese psychiatric out-patients. However, only a small proportion of hazardous users were detected. The study highlights how to use prescription data to support improvements in clinical practice.