Association between gestational hypnotic benzodiazepine receptor agonists exposure and adverse pregnancy outcomes: a systematic review and meta-analysis.

Objective: Hypnotic benzodiazepine receptor agonists (HBRA) are frequently prescribed in pregnancy but little is known about their effects on pregnancy outcomes. Herein, we systematically reviewed the evidence on the effects of HBRA exposure during pregnancy and risk of preterm birth (PTB), small for gestational age (SGA), birth defects, and low birth weight (LBW).

Methods: We reviewed the databases of PubMed, CENTRAL, Embase, Scopus, and Web of Science from the earliest possible date to 17th May 2024 and included all studies examining adverse pregnancy outcomes with gestational exposure to HBRA.

Results: Nine studies were included. Meta-analysis showed that HBRA exposure led to a significant increase in the risk of PTB (OR: 1.28 95% CI: 1.05, 1.56 I² = 73%), SGA (OR: 1.24 95% CI: 1.18, 1.30 I² = 0%), and LBW (OR: 1.51 95% CI: 1.27, 1.78 I² = 26%). We noted no significant association between HBRA exposure in pregnancy and subsequent birth defects (OR: 0.90 95% CI: 0.63, 1.28 I² = 56%). Subgroup analysis based on exposure time, type of HBRA, method of assessment of exposure, control of psychiatric diagnosis, and psychotropic drugs altered the results of PTB and SGA but not for birth defects.

Conclusion: HBRA exposure during pregnancy may lead to a small but significant increase in the risk of PTB, SGA, and LBW. HBRA is not associated with an increased risk of birth defects. There are several limitations of current evidence especially with regards to adjustment for psychiatric illness and co-mediations which need to be overcome by future studies.