While we have a body of literature examining the risk of major malformations in children exposed to benzodiazepines during pregnancy (which is largely reassuring), there is considerably less information on the effects of this class of medications on long-term neurodevelopmental outcomes. Earlier this year, a systematic review from Wang and colleagues pulled together the limited information on neurodevelopmental outcomes in children with in utero exposure to benzodiazepines.
The review from Wang and colleagues noted that while there was not a strong signal to indicate risk of worse neurodevelopmental outcomes in benzodiazepine-exposed children, the data regarding long term neurodevelopmental outcomes was, up to that point, very limited.
New Data from Taiwan Health Insurance Database
In a study published last week, researchers used linked data from birth certificates and the Taiwan National Health Insurance Research Database (2004-2017) to examine the prevalence of autism spectrum disorder and attention-deficit/hyperactivity disorder in children with and without benzodiazepine exposure. The cohort study included 1,138,732 mothers with a total of 1,516,846 live births.
Pharmacy dispensation records were used to identify exposed pregnancies. ICD-9 and 10 codes in the medical record were used to identify children with ASD and ADHD. The mean (SD) follow-up time for the full child sample was 8.5 (SD 3.2) years.
About 5.0% of the children (n = 76,411) were exposed to a benzodiazepine during pregnancy. Benzodiazepine exposure during pregnancy was associated with a small but statistically significant increase in risk of ADHD; trimester of exposure did not affect risk (first trimester exposure: unadjusted hazard ratio [HR], 1.24 [95% CI, 1.20-1.28]; second trimester: HR, 1.27 [95% CI, 1.21-1.34]; third trimester: HR, 1.25 [95% CI, 1.14-1.37]).
The risk of ASD was also slightly increased in children with benzodiazepine exposure (first trimester exposure: HR, 1.13 [95% CI, 1.05-1.21]; second trimester: HR, 1.10 [95% CI, 0.98-1.22]; third trimester: HR, 1.21 [95% CI, 1.00-1.47]).
Adjusted Analyses Show No Increase in Risk of ADHD or ASD
Previous studies examining child outcomes have documented the many challenges in calculating risk in exposed versus unexposed children. Estimates of risk are by necessity derived from non-randomized studies, in which there are important differences between the women who elect to take a particular medication during pregnancy and the women who do not use the medication. Most obviously the two groups differ in terms of the reason (or indication) for taking a particular medication. Confounding by indication is an important consideration, and we have seen in many studies observing that, after adjusting for potential confounding factors, many risks attributed to medication exposure are no longer significant.
In the current study, the researchers were able to adjust for many different potential confounding factors, including year of birth, gestational age, maternal and paternal age, maternal and paternal history of psychiatric illness, maternal smoking, and maternal use of opioids. After adjustment, there was no longer a difference between exposed and unexposed children in terms of risk for ASD or ADHD.
In addition, the researchers were able to control maternal genetic and environmental factors by comparing risk in exposed versus unexposed siblings. They observed no differences between the two groups in terms of risk for ADHD or ASD.
This is the largest study to date examining neurodevelopmental outcomes in children exposed to benzodiazepines during pregnancy, including over 76,000 children. It is also the study with the longest follow-up. While these are considerable strengths, there are some limitations. This study does not include information regarding frequency of dosing or dosage. Depending on the disorder being treated, benzodiazepines are prescribed across a wide range of dosages and may be used continuously or intermittently. Neurodevelopmental outcomes may vary depending on the dose and type of benzodiazepine used.
While this study cannot completely rule out the possibility that prenatal exposure to benzodiazepines may affect neurodevelopmental outcomes, this study, combined with previous smaller studies, provides reassuring information to women with questions regarding the use of benzodiazepines during pregnancy.
So what do we tell our patients? The current study and previous systematic reviews do not show a strong signal indicating risk of worse neurodevelopmental outcomes in children with prenatal exposure to benzodiazepines.
Ruta Nonacs, MD PhD
Chen VC, 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. 2022 Nov 1;5(11):e2243282.
Wang X, Zhang T, Ekheden I, et al. Prenatal exposure to benzodiazepines and Z-drugs in humans and risk of adverse neurodevelopmental outcomes in offspring: a systematic review. Neurosci Biobehav Rev. 2022 Jun; 137:104647.