First-trimester exposure to benzodiazepines and risk of congenital malformations in offspring: A population-based cohort study in South Korea

Abstract

Background: Benzodiazepines are frequently prescribed during pregnancy; however, evidence about possible teratogenicity is equivocal. We aimed to evaluate the association between first-trimester benzodiazepine use and the risk of major congenital malformations.

Methods and findings: Using Korea's nationwide healthcare database, we conducted a population-based cohort study of women who gave birth during 2011 to 2018 and their live-born infants. The exposure was defined as one or more benzodiazepine prescriptions during the first trimester. We determined the relative risks (RRs) and confidence intervals (CIs) of overall congenital malformations and 12 types of organ-specific malformations. Infants were followed from birth to death or 31 December 2019, whichever came first (up to 8 years of age). Propensity score fine stratification was employed to control for 45 potential confounders. Among a total of 3,094,227 pregnancies, 40,846 (1.3%) were exposed to benzodiazepines during the first trimester (mean [SD] age, 32.4 [4.1] years). The absolute risk of overall malformations was 65.3 per 1,000 pregnancies exposed to benzodiazepines versus 51.4 per 1,000 unexposed pregnancies. The adjusted RR was 1.09 (95% CI 1.05 to 1.13, p < 0.001) for overall malformations and 1.15 (1.10 to 1.21, p < 0.001) for heart defects. Based on mean daily lorazepam-equivalent doses, the adjusted RRs for overall malformations and heart defects were 1.05 (0.99 to 1.12, p = 0.077) and 1.12 (1.04 to 1.21, p = 0.004) for <1 mg/day and 1.26 (1.17 to 1.36, p < 0.001) and 1.31 (1.19 to 1.45, p < 0.001) for >2.5 mg/day doses, respectively, suggesting a dose-response relationship. A small but significant increase in risk for overall and heart defects was detected with several specific agents (range of adjusted RRs: 1.08 to 2.43). The findings were robust across all sensitivity analyses, and negative control analyses revealed a null association. Study limitations include possible exposure misclassification, residual confounding, and restriction to live births.

Conclusions: In this large nationwide cohort study, we found that first-trimester benzodiazepine exposure was associated with a small increased risk of overall malformations and heart defects, particularly at the higher daily dose. The absolute risks and population attributable fractions were modest. The benefits of benzodiazepines for their major indications must be considered despite the potential risks; if their use is necessary, the lowest effective dosage should be prescribed to minimize the risk.

Trial registration: ClinicalTrials.gov NCT04856436.

Conflict of interest statement

We have read the journal’s policy and the authors of this manuscript have the following competing interests: YN received a grant from the National Research Foundation of Korea, outside the submitted work. J-YS received grants from the Ministry of Food and Drug Safety, the Ministry of Health and Welfare, the National Research Foundation of Korea, the Government-wide R&D Fund for Infectious Disease Research and pharmaceutical companies, including Amgen, Pfizer, GSK, Hoffmann-La Roche, Dong-A ST, and Yungjin, outside the submitted work.

Figures

Fig 1. Absolute and relative risks of congenital malformations in infants following maternal exposure to benzodiazepines during the first trimester.

CI, confidence interval; PAF, population attributable fraction; PS, propensity score; *RD1000, risk difference per 1,000 births.

Fig 2. Risks of individual categories of heart and digestive system defects in infants following maternal exposure to benzodiazepines during the first trimester.

CI, confidence interval; PAF, population attributable fraction; PS, propensity score; *RD1000, risk difference per 1,000 births.

Fig 3. Risks of congenital malformations in infants according to individual benzodiazepine exposure during the first trimester.

BZD, benzodiazepine; CI, confidence interval; RR, relative risk; PS, propensity score. Clorazepate was not analyzed owing to the small sample size (n = 14).

Fig 4. Risks of congenital malformations in infants following maternal exposure to benzodiazepines in the first trimester: subgroup analyses.

CI, confidence interval; PS, propensity score. *Mean daily dose based on the lorazepam-equivalent dose.

Fig 5. Risks of congenital malformations in infants following maternal exposure to benzodiazepines in the first trimester: sensitivity analyses.

CI, confidence interval; PS, propensity score.