Gestational Exposure to Benzodiazepines and Z-Hypnotics and the Risk of Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder in Offspring

Abstract

Two recent cohort studies, one from Norway and the other from Taiwan, examined for perhaps the first time whether gestational exposure to benzodiazepines and to z-hypnotics was associated with a clinical diagnosis of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in offspring. The studies had important methodological strengths that are not often seen; these included actual assessment during pregnancy of whether drugs prescribed were used, and, if so, when; adjustment of analyses for postbaseline time-varying covariates; inclusion of discordant sibling pair and paternal exposure analyses; inclusion of pre-pregnancy vs intrapregnancy analyses; and others. The studies also had important limitations; these included inadequate statistical power resulting in a failure to identify potential associations in even unadjusted analyses; lack of information on intermittent use vs daily dosing; and others. The strengths and limitations are identified and explained to empower readers to identify similar issues in other studies. Important findings apparent in these studies are that benzodiazepine exposure may be associated with an increased risk of both ASD and ADHD, regardless of the trimester of exposure. The magnitude of increased risk is small and diminishes to statistical nonsignificance in adjusted analyses. The risks appear elevated in association with paternal exposure. In discordant sibling pair analyses, risks do not appear to be significantly higher in the exposed sib relative to the unexposed sib. These findings imply that observed associations, if any, between gestational exposure to benzodiazepines and ASD or ADHD in offspring may be due to maternal and paternal genetic factors, to family environmental variables, and to confounding by indication, rather than to benzodiazepine exposure itself. Nevertheless, decision-making should be tailored to individual context and shared between prescriber and patient. Finally, no conclusions can be drawn regarding the neurodevelopmental safety of z-drug exposure during pregnancy.