Benzodiazepine exposure during early pregnancy and risk of miscarriage: dose–response, half-life classification, and individual agents

PURPOSE: To evaluate the association between benzodiazepine exposure during early pregnancy and the risk of miscarriage, with a focus on dose-response, half-life, and individual agents. METHODS: This nested case-control study was conducted using a large Japanese administrative database. Cases were defined as pregnancies ending in miscarriage between 2005 and 2023. Controls were randomly selected through risk-set sampling with replacement and matched in a 3:1 ratio. Conditional logistic regression, adjusted for confounders, was used to assess the associations. RESULTS: Overall, 44,118 cases were matched with 132,317 controls, with a mean age of 33.2 years. The prevalence of benzodiazepine exposure was 1.7% and 1.2% among cases and controls, respectively. Etizolam (0.3%) had the highest prevalence, followed by alprazolam (0.3%) and brotizolam (0.2%) in both groups. Adjusted odds ratio (OR) for benzodiazepine exposure during early pregnancy was 1.241 (95% confidence interval: 1.136-1.357). Adjusted ORs for high-dose (1.212 [1.050-1.400]) and medium-dose (1.189 [1.037-1.363]) exposure were numerically higher than that for low-dose exposure (1.111 [0.934-1.322]). Adjusted OR for long-acting benzodiazepines (1.308 [1.124-1.522]) was numerically higher than those for intermediate- (1.132 [0.999-1.284]) and short-acting (1.157 [1.030-1.300]) agents. Adjusted ORs for etizolam, alprazolam, and brotizolam were 0.929 (0.782-1.103), 0.853 (0.707-1.030), and 1.454 (1.180-1.791), respectively. CONCLUSIONS: Benzodiazepine exposure during early pregnancy was modestly associated with an increased risk of miscarriage. Although associations tended to be stronger with higher dose levels and longer half-life categories, estimates across subgroups lacked precision and should be interpreted with caution.