Association of Prenatal Exposure to Benzodiazepines With Development of Autism Spectrum and Attention-Deficit/Hyperactivity Disorders

Importance: Prenatal exposure to benzodiazepines is reported to be associated with neurodevelopmental disorders among children, but associations of maternal genetic confounding with neurodevelopmental disorders among children have not been taken into consideration. Objective: To ascertain whether prenatal benzodiazepine exposure was associated with development of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Design, Setting, and Participants: This cohort study used linked data from birth certificate registration and the Taiwan National Health Insurance Research Database from January 1, 2004, to December 31, 2017, on 1 138 732 mothers with 1 516 846 live births between January 1, 2004, and December 31, 2017. Data were analyzed between February 20, 2021, and September 19, 2022. Exposure: Benzodiazepine exposure during pregnancy (first trimester to third trimester) was defined as having at least one benzodiazepine prescription dispensed. Main Outcomes and Measures: The main outcomes were ADHD and ASD. Results: There were 1 516 846 children (mean [SD] gestational age, 38.5 [1.8] years; 789 455 boys [52.0%]) born full term who were younger than 14 years of age and followed up to 2017; 5.0% of the children (n = 76 411) were exposed to a benzodiazepine during pregnancy. Benzodiazepine exposure during pregnancy was associated with increased risks of ADHD (first trimester exposure: hazard ratio [HR], 1.24 [95% CI, 1.20-1.28]; second trimester exposure: HR, 1.27 [95% CI, 1.21-1.34]; third trimester exposure: HR, 1.25 [95% CI, 1.14-1.37]) and ASD (first trimester exposure: HR, 1.13 [95% CI, 1.05-1.21]; second trimester exposure: HR, 1.10 [95% CI, 0.98-1.22]; third trimester exposure: HR, 1.21 [95% CI, 1.00-1.47]). However, no differences were found with unexposed sibling controls during the same time frame for ADHD (first trimester exposure: HR, 0.91 [95% CI, 0.83-1.00]; second trimester exposure: HR, 0.89 [95% CI, 0.78-1.01]; third trimester exposure: HR, 1.08 [95% CI, 0.83-1.41]) or ASD (first trimester exposure: HR, 0.92 [95% CI, 0.75-1.14]; second trimester exposure: HR, 0.97 [95% CI, 0.71-1.33]; third trimester exposure: HR, 1.07 [95% CI, 0.53-2.16]). Similar findings were also noted in the stratification analysis of short-acting and long-acting benzodiazepines. Conclusions and Relevance: This cohort study suggests that previously described adverse neurodevelopmental outcomes associated with benzodiazepine exposure during pregnancy were likely to be accounted for by maternal genetic confounding.