Prenatal polysubstance use and attention-deficit/hyperactivity disorder (ADHD)

Introduction

Six million US children/adolescents (9.8%) have attention deficit/hyperactivity disorder (ADHD).¹ Prenatal substance use is a potential etiology of ADHD.² Up to 31% of pregnant people report polysubstance use, most commonly alcohol, tobacco and cannabis,³ but few studies have examined patterns of prenatal polysubstance use and ADHD outcomes.⁴ This study aimed to identify patterns of polysubstance use associated with ADHD outcomes. Determining hazardous patterns of prenatal substance use is important for prevention to reduce impact on fetal neurodevelopment.

Methods

The study used baseline through 3^rd year follow-up data (2016 to 2020) from the Adolescent Brain Cognitive Development (ABCD) Study, a large (N=11,874) longitudinal study designed to assess brain and cognitive development from childhood (age 9/10 years old) through adolescence.⁵ Ethics approval for the study was obtained by the Thomas Jefferson University Institutional Review Board.

Parent reported ADHD symptoms were defined by the annual Child Behavioral Checklist (CBCL) Diagnostic and Statistical Manual (DSM) 5-oriented scales⁶ with youth scoring at or above clinical range (i.e. t-score ≥70) at baseline or any follow up (ages 9–13 years old); sources and rationale for this assessment have been described elsewhere.⁷ Maternal substance use (i.e., tobacco, alcohol, cannabis, cocaine/crack, heroin/morphine, oxycodone, other drug) was assessed at baseline by asking if the biological mother used those substances once knowing of pregnancy.

Sociodemographic variables included maternal/child race and ethnicity, household income, maternal education, and maternal age and child’s gestational age at birth. Biological maternal mental health history included any problems due to alcohol, drugs, and depression.

Binary logistic regression models (STATA [StataCorp], version 17.0) were used to estimate odds ratios (ORs), adjusted odds ratios (AORs) and 95% confidence intervals (CIs). All logistic regression models estimating AORs simultaneously controlled for sociodemographic variables (Table 1). Logistic regression models assessing the association between clinically significant levels of ADHD and maternal substance use were fitted using generalized estimating equations (GEE) with an exchangeable correlation structure (Table 1). All analyses accounted for clustering across the 21 research sites and within families. Missing data were handled using listwise deletion. The range of missing data among the items used in the analyses was between 0.03% (i.e., child’s age) and 5.1% (i.e., maternal history of drug related problems).

Table 1.

Association between maternal substance use and clinically significant levels in ADHD

Variables	Unadjusted Model	Adjusted Modelc
	ADHD T-score >=70	ADHD T-score >=70
	N = 11520	N = 10665
	OR (95% CI)	aOR (95% CI)
Substance use when knowingly pregnantd
No Use	Reference	Reference
Alcohol Use Only	0.400 (0.134–1.192)	0.548 (0.186–1.619)
Tobacco Use Only	1.707 (1.151–2.532)	1.019 (0.663–1.567)
Cannabis Use Only	3.555 (1.994–6.338)	2.097 (1.152–3.817)
Other Illicit Substance Use Only	1.366 (0.240–7.794)	1.000 (0.178–5.607)
Alcohol and Tobacco Use	7.567 (3.082–18.581)	4.272 (1.623–11.247)
Cannabis and Alcohol Use	2.857 (0.533–15.307)	1.541 (0.274–8.652)
Cannabis and Tobacco Use	3.436 (1.625–7.265)	2.183 (0.965–4.935)
Cannabis, Alcohol and Tobacco Use	3.630 (0.668–19.728)	1.188 (0.204–6.921)
Other Polysubstance use (other drug with at least alcohol use, tobacco use or cannabis use)	2.631 (0.946–7.317)	0.523 (0.099–2.766)
Age in years
(9–10 years old)	Reference	Reference
(10–11 years old)	0.877 (0.767–1.002)	0.834 (0.722–0.964)
(11–12 years old)	0.804 (0.688–0.938)	0.785 (0.664–0.927)
(12–13 years old)	0.764 (0.641–0.911)	0.779 (0.646–0.939)

^a.Boldface indicates statistical significance (p<0.001)

^b.Abbreviations: ADHD- Attention Deficit-Hyperactivity Disorder

^c.All adjusted models control for age of follow-up, sex of child, child’s race, whether the child is Hispanic, Household income, maternal age of mother when she gave birth to the respondent, age of the child at baseline, highest level of parental education (mother or father), whether the child was preterm, whether the child’s mother had a history of alcohol related problems, whether the child’s mother had a history of drug related problems, and whether the child’s mother had a history of depression.

^d.It should be noted that models assessing the association between clinically significant levels in ADHD and each of the four maternal substance use items separately (and in combination [each of the four variables were included in the model simultaneously]) only found cannabis use to be statistically significant (when controlling for the factors outlined in the current analysis). The odds of clinically significant ADHD were roughly 2 times higher (aOR = 1.91, 95% CI = 1.18, 3.09) among mothers that knowingly used cannabis during pregnancy when compared to mothers who did not use cannabis during pregnancy (controlling for maternal alcohol, tobacco, and other illicit substance use).

Results

Within the sample of 11,874 children, 626 (5.27%) had parent reported ADHD (CBCL t-score ≥70). Alcohol and tobacco co-use after knowing of pregnancy was associated with roughly four times greater odds (aOR=4.27, 95% CI=1.62, 11.24) of parent reported ADHD, and cannabis-only use after knowing of pregnancy was associated with roughly two times greater odds (aOR=2.09, 95% CI= 1.15–3.82) of parent reported ADHD in the child compared to children whose mothers did not use any substances during pregnancy (Table 1). Several factors were associated with maternal substance use while knowing of pregnancy (Appendix Table 1).

Discussion

Alcohol and tobacco co-use and cannabis-only use after knowledge of pregnancy was associated with parent reported ADHD. This association remained robust after adjusting for confounding factors suggesting these patterns of substance use are independently associated with ADHD. Alcohol and tobacco co-use had the strongest association with ADHD, which is concerning given that they are the most accessible substances. The association with cannabis only-use is also concerning given that increasing cannabis legalization has contributed to greater acceptance of prenatal cannabis use⁸ without a thorough understanding of its effects on the developing fetus. Prevention efforts should include education for pregnant people on the neurodevelopmental risks associated with common and readily accessible substances.

Limitations

Study limitations include lower prevalence of ADHD and maternal substance use in the sample compared to national estimates.³ Low ADHD prevalence may be due to use of CBCL scores, which may not capture effectively treated children (e.g., those receiving medication therapy). Low prevalence of maternal substance use may be due to retroactive report, stigmatizing language of the question, or by proxy report from another caregiver (e.g.., biological father, foster parent). Finally, other potential genetic/environmental factors were not accounted for in analyses.

Conclusions

In this large sample of US children, prenatal alcohol and tobacco co-use and cannabis-only use was associated with development of ADHD symptoms in offspring. Prevention efforts should be geared towards education.