Benzodiazepine Prenatal Exposure No Risk for Autism Spectrum Disorder and ADHD

Analysis revealed similar findings of no significant differences in risks for ASD or ADHD among differently exposed children born from the same mother exposed to benzodiazepines.

Prenatal benzodiazepine exposure is not associated with increased risks for autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD), according to study findings published in the Journal of the American Medical Association Network Open.

Estimates claim up to 30% of pregnant women experience mood or anxiety spectrum disorders and worldwide prescription use of benzodiazepine during pregnancy may be 1.9%. Benzodiazepines can cross the placenta and have been found in amniotic fluid and breast milk.

Investigators sought to determine if benzodiazepine exposure during pregnancy was associated with development of ASD or ADHD in exposed fetuses and newborns. The primary endpoint was ASD or ADHD.

Exposure to benzodiazepine during first trimester to third trimester was defined as having a benzodiazepine prescription dispensed at least once beginning 90 days prior to the first trimester through the end of the third trimester. A link to the Taiwan Maternal and Child Health Database enabled investigators to measure paternal benzodiazepine exposure from January 2004 through December 2014.

Our results challenge current assumptions of a potential association of neurodevelopmental disorders with maternal benzodiazepine use before or during pregnancy.

Investigators conducted a population-based observational cohort study that included more than 1.1 million mothers (mean gestational age 38.5±1.8 years) in Taiwan presenting more than 1.5 million live births from January 2004 through December 2017. There were almost as many distinct fathers as mothers.

Investigators used linked data from the Taiwan National Health Insurance Research Database and birth certificate registration. (All Taiwan residents are required to join the National Health Insurance program). Among all births, investigators found 789,455 (52.0%) boys born full term and followed up to 2017 (younger than 14 years of age). They noted 5% of the children (76,411) had benzodiazepine exposure during pregnancy.

While investigators noted benzodiazepine exposure during pregnancy was associated with increased risks for ASD (first trimester exposure: hazard ratio [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) and associated with increased risks for ADHD (first trimester exposure: 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), sibling comparison models used to address potential maternal genetic confounding (parallel comparison by paternal exposure status) showed no significant associations of benzodiazepine exposure during pregnancy for 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) or 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).

Stratification analysis of short-acting and long-acting benzodiazepines revealed similar findings of no significant differences in risks for ASD or ADHD among differently exposed children born from the same mother exposed to short-acting or long-acting benzodiazepines.

Significant study limitations include the observational design, use of prescriptions to define exposure status, unmeasured confounding factors (lifestyle or use of illicit substances), no validation study with the Taiwan National Health Insurance Research Database for ASD or ADHD, no dose-response analysis, conflicting investigator statements including live births through December 2017 and including only children born before 2014, failure to capture adolescent or adult ADHD not measured in study-age participants (3-13 years), sibling comparison created an underpowered sample size particularly for third trimester maternal benzodiazepine exposure, and unestablished generalizability to other countries.

Investigators concluded “Our key finding was that, although benzodiazepine exposure during pregnancy may be associated with increased risks of ADHD or ASD when compared with nonexposed population-wide controls, no significant increase in such risks was found when compared with sibling controls.” This suggests to investigators that associations with in utero benzodiazepines may be confounded by environmental factors or other maternal genetic factors. They added “Our results challenge current assumptions of a potential association of neurodevelopmental disorders with maternal benzodiazepine use before or during pregnancy.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

References:

Chen VCH, Wu SI, Lin CF, Lu ML, Chen YL, Stewart R. Association of prenatal exposure to benzodiazepines with development of autism spectrum and attention-deficit/hyperactivity disorders. JAMA Netw Open. Published online November 22, 2022. doi:10.1001/jamanetworkopen.2022.43282