Researchers found in this study of 1.5m children that after adjusting for possible confounders and accounting for possible parental genetic or familial factors, benzodiazepine exposure during pregnancy was not associated with increased risks of autism spectrum disorder or attention-deficit/hyperactivity disorder.
These results challenge current assumptions of a potential association of neurodevelopmental disorders with maternal benzodiazepine use before or during pregnancy.
Approximately 10% to 30% of pregnant women experience mental disorders, including mood or anxiety spectrum disorders. Benzodiazepine agents may be considered at this point to help ameliorate symptoms of anxiety or depression; the prevalence of prescribed benzodiazepine use during pregnancy has been estimated at 1.9% globally.
However, the safety of these agents to the developing foetus and newborn has been called into question. In particular, benzodiazepines are able to cross the placenta, have been found to be present in amniotic fluid and breast milk, and have been listed in the US Food and Drug Administration (FDA) pregnancy category of “potential benefits may warrant use of the drug in pregnant women despite potential human foetal risks” or “the risks outweigh potential benefits”, indicating potential harm to the foetus.
The findings of this cohort study, by a team of scientists from Taiwan, and published in JAMA Network Open, suggests that previously described adverse neurodevelopmental outcomes associated with benzodiazepine exposure during pregnancy were probably accounted for by maternal genetic confounding.
Study details
Association of Prenatal Exposure to Benzodiazepines With Development of Autism Spectrum and Attention-Deficit/Hyperactivity Disorders
Vincent Chin-Hung Chen, Shu-I Wu, Chiao-Fan Lin, et al.
Published in JAMA Network Open on 22 November 2022
Key Points
Question
Is exposure to benzodiazepines in utero associated with development of autism spectrum or attention-deficit/hyperactivity disorders?
Findings
This cohort study of 1 516 846 children found that, after adjusting for possible confounders and accounting for possible parental genetic or familial factors, benzodiazepine exposure during pregnancy was not associated with increased risks of neurodevelopmental disorders.
Meaning
Knowledge of outcomes among offspring associated with prenatal exposure to benzodiazepines can help inform their use during pregnancy.
Abstract
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 analysed 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.
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