Prenatal smoking, alcohol and caffeine exposure and ADHD risk in childhood: parental comparisons and polygenic risk score (PRS) analyses

Background and aimsSeveral studies have indicated that maternal prenatal substance use may be associated with offspring ADHD via intrauterine effects. We investigated associations between maternal prenatal smoking, alcohol and caffeine consumption with childhood ADHD risk accounting for shared familial factors. DesignFirst, we used a negative control design comparing maternal and paternal substance use. Three models were used for negative control analyses: unadjusted (without confounders); adjusted (including confounders) and mutually adjusted (including confounders and partners substance use). The results were meta-analysed across the cohorts. Second, we used polygenic risk scores (PRS) as proxies for exposures. Maternal PRS for genetic variants of smoking, alcohol and coffee consumption were regressed against ADHD risk. We triangulated the results across the two approaches to infer causality. SettingWe used data from three longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK, Generation R study (GenR) in the Netherlands and Norwegian Mother, Father and Child Cohort study (MoBa) in Norway. ParticipantsPhenotype data available for children was: NALSPAC=7,850; NGENR=3,849; NMOBA=43,512. Genotype data available for mothers was: NALSPAC=7,074 and NMOBA=14,583. MeasurementsOffspring ADHD risk around age 7-8 was derived by dichotomising symptom scores from multiple questionnaires and parental self-reported substance use was measured at the 2nd pregnancy trimester. FindingsThe pooled estimate for maternal prenatal substance use showed an association with ADHD risk (ORSMOKING=1.11, 95%CI 1.00-1.23; ORALCOHOL=1.27, 95%CI 1.08-1.49; ORCAFFEINE=1.05, 95%CI 1.00-1.11), while not for fathers (ORSMOKING=1.03, 95%CI 0.95-1.13; ORALCOHOL=0.83, 95%CI 0.47-1.48; ORCAFFEINE=1.02, 95%CI 0.97-1.07). However, maternal associations did not persist in sensitivity analyses (substance use before pregnancy, adjustment for maternal ADHD in MoBa). The PRS analyses did not show evidence of association in ALSPAC or MoBa. ConclusionsOur results do not provide support for a causal intrauterine effect of maternal prenatal substance use on offspring attention-deficit hyperactivity disorder risk.