Benzodiazepine Use in Pregnancy and the Risk of Pregnancy Outcomes.

Abstract

Benzodiazepine use during pregnancy has increased despite concerns about potential risks to pregnancy outcomes, including abortion, stillbirth, preterm birth, and small for gestational age. Existing evidence remains limited by unclear clinical interpretation and methodological biases. To evaluate the associations between benzodiazepine use and risk of preterm birth and small for gestational age while considering the risks of abortion and stillbirth as competing events. Using the National Health Insurance Research Database of Taiwan from January 1, 2011, to December 31, 2021, a sequence of open-label, randomized trials during gestational weeks 0 to 36 was emulated. Eligibility criteria for each trial included pregnancy in gestational weeks 0 to 36, maternal age between 15 and 55 years, with no benzodiazepine use during the preceding 6 months. The data were analyzed from November 2024 through April 2025. Benzodiazepine use or nonuse. Abortion (spontaneous abortion and elective abortion), stillbirth, preterm birth, and small for gestational age. Relative risks (RRs) were estimated across the sequence of trials. To address potential competing events (abortion or stillbirth), stabilized inverse probability of censoring weights was applied that incorporated postbaseline prognostic factors across all pregnancies. Analyses were stratified by gestational periods: first (weeks 0-13), second (weeks 14-26), and third trimester (weeks 27-36). The mean (SD) age of the individuals in the benzodiazepine group (59 521 pregnancies) and nonuse group (394 956 pregnancies) was 31.9 (5.8) and 31.6 (5.3) years, respectively. Benzodiazepine use was associated with an increased risk of abortion (RR, 1.58; 95% CI, 1.50-1.66), spontaneous abortion (RR, 1.65; 95% CI, 1.55-1.76), and elective abortion (RR, 1.83; 95% CI, 1.70-1.98) and showed no association with stillbirth (RR, 0.96; 95% CI, 0.78-1.17). After accounting for competing risks, benzodiazepine use was associated with increased risks of preterm birth (RR, 1.20; 95% CI, 1.18-1.23) and small for gestational age (RR, 1.06; 95% CI, 1.00-1.09), with more pronounced effects observed after exposure during the second trimester. The results of this cohort study, after considering the association of competing events, suggested that benzodiazepine use was associated with increased risks of preterm birth and may also be associated with increased risk of small for gestational age; however, the latter association was small and sensitive to the analytic method.