Individual and Combined Association Between Prenatal Polysubstance Exposure and Childhood Risk of Attention-Deficit/Hyperactivity Disorder

Henri M. Garrison-Desany, MSPHXiumei Hong, MD, PhDBrion S. Maher, PhDTerri H. Beaty, PhDGuoying Wang, MD, PhDColleen Pearson, BALiming Liang, PhDXiaobin Wang, MD, MPH, ScDChristine Ladd-Acosta, PhD

JAMA Netw Open. 2022;5(3):e221957. doi:10.1001/jamanetworkopen.2022.1957

Key Points

Question  Is prenatal exposure to multiple substances, alone or in combination, associated with the risk of attention-deficit/hyperactivity disorder (ADHD) in childhood?

Findings  In this cohort study of 3138 children with and without ADHD, prenatal opioid exposure was significantly associated with the highest childhood risk of ADHD among all substances measured. Interactions between exposure to opioids and cannabis as well as opioids and alcohol were also associated with ADHD risk.

Meaning  This study’s findings suggest that it is important to consider prenatal exposure to multiple substances and the interactions between these substances when counseling women regarding substance use during pregnancy.


Importance  Polysubstance use among pregnant women has increased because of the opioid epidemic and the increasing legalization of cannabis along with persistent tobacco and alcohol consumption. Previous research on prenatal substance use and the child’s risk of attention-deficit/hyperactivity disorder (ADHD) has mostly focused on single-substance exposures; simultaneous examination of multiple substance use and assessment of their synergistic health consequences is needed.

Objectives  To assess the consequences of the use of specific substances during pregnancy, investigate whether the interaction of multiple prenatal substance exposures is associated with increases in the risk of childhood ADHD, and estimate the aggregate burden of polysubstance exposure during gestation.

Design, Setting, and Participants  This cohort study analyzed data from the Boston Birth Cohort from 1998 to 2019. The sample of the present study comprised a multiethnic urban cohort of mother-child pairs who were predominantly low income. A total of 3138 children who were enrolled shortly after birth at Boston Medical Center were included and followed up from age 6 months to 21 years.

Exposures  Substance use during pregnancy was identified based on self-reported tobacco smoking, alcohol consumption, and use of cannabis, cocaine, or opioids in any trimester of pregnancy. Diagnostic codes for neonatal opioid withdrawal syndrome or neonatal abstinence syndrome from the International Classification of Diseases, Ninth Revision, and the International Classification of Diseases, Tenth Revision, were also used to identify opioid exposure during gestation.

Main Outcomes and Measures  ADHD diagnosis in the child’s electronic medical record.

Results  Among 3138 children (1583 boys [50.4%]; median age, 12 years [IQR, 9-14 years]; median follow-up, 10 years [IQR, 7-12 years]) in the final analytic sample, 486 (15.5%) had an ADHD diagnosis and 2652 (84.5%) were neurotypical. The median postnatal follow-up duration was 12 years (IQR, 9-14 years). Among mothers, 46 women (1.5%) self-identified as Asian (non–Pacific Islander), 701 (22.3%) as Hispanic, 1838 (58.6%) as non-Hispanic Black, 227 (7.2%) as non-Hispanic White, and 326 (10.4%) as other races and/or ethnicities (including American Indian or Indigenous, Cape Verdean, Pacific Islander, multiracial, other, or unknown). A total of 759 women (24.2%) reported the use of at least 1 substance during pregnancy, with tobacco being the most frequently reported (580 women [18.5%]). Cox proportional hazards models revealed that opioid exposure (60 children) had the highest adjusted hazard ratio (HR) for ADHD (2.19; 95% CI, 1.10-4.37). After including main statistical effects of all individual substances in an elastic net regression model, the HR of opioids was reduced to 1.60, and evidence of a statistical interaction between opioids and both cannabis and alcohol was found, producing 1.42 and 1.15 times higher risk of ADHD, respectively. The interaction between opioids and smoking was also associated with a higher risk of ADHD (HR, 1.17).

Conclusions and Relevance  The findings of this study suggest that it is important to consider prenatal concurrent exposure to multiple substances and their possible interactions when counseling women regarding substance use during pregnancy, the future risk of ADHD for their children, and strategies for cessation and treatment programs.

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