Prenatal benzodiazepine exposure not directly associated with ASD and ADHD

Cases of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) associated with prenatal exposure to benzodiazepine may be caused by maternal genetic confounding, according to a recent study.

Mental disorders are reported in 10% to 30% of pregnant women, including depression and anxiety disorders. Benzodiazepine is used in some cases to reduce symptoms of anxiety and depression, with a global prevalence of 1.9%.

Concerns have arisen over the use of benzodiazepine, as benzodiazepines can cross the placenta, have been found in amniotic fluid and breast milk, and have been indicated by categorization from the US Food and Drug Administration as potentially causing harm to the fetus.

Investigators hypothesized that the maternal depressive or anxiety disorders leading to benzodiazepine prescription could partly be responsible for the development of neurodevelopmental disorders in children. Untreated anxiety and depression symptoms during pregnancy have been associated with neurodevelopmental disorders in offspring.

To determine the association between benzodiazepine exposure during pregnancy and the development of ASD and ADHD, investigators conducted a study consisting of human patients approved by the research ethics committee of the China Medical University and Hospital.

Children with full-term births from January 1, 2004, to December 31, 2017, were included in the study. Benzodiazepine prescription included Anatomical Therapeutic Chemical Classification codes starting with N05BA, along with long- and short-acting benzodiazepines.

Prescription information was used to determine maternal exposure to benzodiazepine before and during pregnancy, while linkage to the Taiwan Maternal and Child Health Database allowed data on children, their fathers, and paternal benzodiazepine exposure to be collected.

Exposure to benzodiazepine was recorded for all 3 trimesters. The first trimester was defined as 90 days or less after estimated conception, the second as days 91 to 180 after conception, and the third as days 181 to 270 after conception. The date of delivery and gestational age was used to estimate the date of conception.

The incidence of ASD and ADHD was measured in children exposed to benzodiazepine during pregnancy and those not exposed to benzodiazepine during pregnancy. At least 1 inpatient record or 3 outpatient diagnoses were used to determine ASD and ADHD.

Child covariates included gestational age, year of birth, low-income family status, and parity. Maternal covariates included nationality, maternal smoking during pregnancy, age at the index birth, maternal opioid drug use, and history of mental disorders. 

The analysis was restricted to mothers with anxiety disorders or major depressive disorder. The association between paternal benzodiazepine exposure and neurobehavioral outcomes was analyzed through sibling comparisons.

There were 1,516,846 children aged under 14 years in the study, 1,138,732 biological mothers, and 1,134,320 fathers. Prenatal exposure to benzodiazepine was seen in 5% of children, 4.6% exposed in the first trimester, 2.2% in the second, and 0.6% in the third.

The mean follow-up time overall was 8.5 years. ASD and ADHD were more common among individuals exposed to benzodiazepine during pregnancy, with 1.1% of exposed children developing ASD compared to 0.9% of unexposed children, and 4.9% of exposed children developing ADHD compared to 3.9% of unexposed children.

Benzodiazepine exposure was associated with a greater risk of ASD and ADHD development in all 3 trimesters. Covariates more often seen in cases of prenatal benzodiazepine exposure included low-income family status, maternal opioid use, smoking during pregnancy, and maternal and paternal mental disorders.

Sibling comparisons showed no significant association between prenatal benzodiazepine exposure and development of ASD or ADHD. The analysis was restricted to mothers with anxiety disorders or major depressive disorders, and children born of these mothers without prenatal exposure to benzodiazepine saw similar chances of developing ASD and ADHD.

These results showed increased risks of ASD and ADHD for children born after benzodiazepine exposure during pregnancy but did not show a significantly increased risk when compared to sibling controls. This indicates other maternal genetic or environmental factors may contribute to associations between benzodiazepine exposure and risks of ASD and ADHD.

Reference

Chen VC, Wu S, Lin C, Lu M, Chen Y, Stewart R. Association of prenatal exposure to benzodiazepines with development of autism spectrum and attention-deficit/hyperactivity disorders. JAMA Netw Open. 2022;5(11):e2243282. doi:10.1001/jamanetworkopen.2022.43282