Background: Anxiety disorders are common in pregnancy, and benzodiazepines are often prescribed to treat anxiety. Yet, few data exist on the safety of benzodiazepine use in pregnancy.
Objectives: To evaluate the risk of congenital malformations following first-trimester benzodiazepine exposure.
Methods: This population-based cohort study used US nationwide samples of publicly (2000-2018) and privately (2003-2020) insured pregnancies linked to liveborn infants. We estimated the relative risk (RR) of any major congenital malformation and organ-specific congenital malformations, respectively, associated with first-trimester benzodiazepine exposure (defined as >=1 medication dispensation). Outcomes were ascertained using highly specific, validated algorithms. We used propensity score fine stratification (50 strata) to adjust for potential confounders across several domains, including psychiatric and chronic comorbid conditions, use of other substances and medications, healthcare utilization, and demographic characteristics. RRs were pooled across data sources using fixed effects meta-analysis.
Results: 51,473 (2.1%) of 2,483,515 publicly insured and 27,777 (1.6%) of 1,750,721 privately insured pregnancies were exposed to benzodiazepines in the first trimester. The prevalence of comorbid conditions was generally higher among exposed compared to unexposed pregnancies; however, all characteristics were well balanced after propensity score weighting.
Among publicly insured pregnancies, the unadjusted absolute risk of any congenital malformation was 4.1% (95% confidence interval [CI]:3.9-4.3%) among exposed pregnancies and 3.4% (3.3-3.4%) among unexposed pregnancies. Among privately insured pregnancies, the risks were 4.9% (4.6-5.2%) and 3.7% (3.7-3.8%), respectively.
Pooled unadjusted RRs were elevated for any malformation (RR=1.26, 95% CI:1.22-1.30), as well as for several organ-specific malformations (e.g., cardiac RR=1.38, 95% CI:1.30-1.46; oral cleft RR=1.30, 95% CI:1.09-1.55). However, after adjustment, no increase in risk was observed for malformations overall (RR=0.98, 95% CI:0.94-1.02), or for any organ-specific malformation (e.g., cardiac RR=1.00, 95% CI:0.94-1.07; oral cleft RR=0.90, 95% CI:0.73-1.10).
Conclusions: Results from this large, US population-based study of publicly and privately insured pregnancies suggests that benzodiazepine use early in pregnancy does not increase the risk for congenital malformations.
