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Association of Prenatal Exposure to Benzodiazepines With Development of Autism Spectrum and
Vincent Chin-Hung Chen1,2, Shu-I Wu3,4, Chiao-Fan Lin2,5
1Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.
Insights
Prenatal benzodiazepine exposure in pregnancy did not increase risks for autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) when controlling for maternal genetic factors. Previous associations were likely due to genetic confounding, not the medication itself.
Area of Science:
- Neurodevelopmental disorders
- Pharmacogenetics
- Perinatal health
Background:
- Prenatal exposure to benzodiazepines has been linked to neurodevelopmental disorders in children.
- The role of maternal genetic confounding in these associations has not been adequately addressed.
- Understanding these links is crucial for accurate risk assessment and counseling.
Purpose of the Study:
- To investigate the association between prenatal benzodiazepine exposure and the development of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).
- To determine if maternal genetic factors confound the observed associations.
- To clarify the neurodevelopmental risks associated with prenatal benzodiazepine use.
Main Methods:
- A large cohort study utilizing linked birth certificate and national health insurance data from Taiwan (2004-2017).
- Included over 1.5 million live births, defining benzodiazepine exposure by prescription dispensing during pregnancy.
- Analyzed outcomes of ADHD and ASD, comparing exposed children with unexposed sibling controls to account for genetic and familial factors.
Main Results:
- Initial analysis showed increased risks for ADHD and ASD with prenatal benzodiazepine exposure across trimesters.
- However, when using unexposed sibling controls, no significant differences in ADHD or ASD risks were observed.
- Stratification by short-acting and long-acting benzodiazepines yielded similar findings, suggesting no medication-specific risk.
Conclusions:
- The study suggests that previously reported associations between prenatal benzodiazepine exposure and adverse neurodevelopmental outcomes are likely explained by maternal genetic confounding.
- This finding challenges the direct causal link between benzodiazepine exposure and increased risks of ADHD and ASD.
- Re-evaluation of risks and clinical guidance may be necessary, emphasizing the importance of considering genetic factors in perinatal research.
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 analyzed 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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