Risks of prematurity and low birth weight associated with trimester-specific prenatal benzodiazepine exposure

Background: Intrauterine exposure of the developing fetus or neonate to bendodiazepine may lead to fetal abnormalities or adverse reactions. We sought to investigate whether benzodiazepine use before or during different trimesters of pregnancy had different associations with incident preterm births (PTB) or small for gestational age (SGA) infants. Methods: We conducted a 13-year longitudinal cohort study incorporating population-wide, sibling, and paternal comparisons. We used nation-wide population-based data on diagnoses and drug prescriptions from the Taiwan National Health Insurance Research Database, with linkages to the Taiwan Birth Certificate Registration and the Taiwan Maternal and Child Health Database between 2004 and 2016. We obtained data on live births to mothers exposed or unexposed to benzodiazepine. Children born by the same mother without benzodiazepine exposures before or during pregnancy were ascertained to create the sibling comparison cohort. We also gathered information on newborns with benzodiazepine-exposed or unexposed fathers. We determined the risks of subsequent PTB and SGA during the 13-year follow-up period. Results: We included data on 2 572 125 births to mothers exposed to benzodiazepine and 2 265 685 births to mothers unexposed to benzodiazepine. After adjustments and from our sibling comparison group, the increased risks of preterm births (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.53–1.91) and SGA (OR 1.47, 95% CI 1.14–1.89) were significant only among children born from mothers exposed to benzodiazepine in the third trimester. Limitations: Our results are subject to unmeasured confounding factors, such as smoking and the severity of parental mental illness, which were not available in the administrative claims data. Conclusion: Benzodiazepine exposure during the third trimester, but not the first or second trimesters, increased the risks of PTB and SGA. This result may reflect the direct effects of benzodiazepine on fetal development or the intrauterine environment.