Prenatal smoking, alcohol and caffeine exposure and maternal reported ADHD symptoms in childhood: triangulation of evidence using negative control and polygenic risk score analyses

Abstract

Background and aims: Several 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. Design: First, 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. Setting: We 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. Participants: Phenotype data available for children was: N(ALSPAC)=7,850; N(GENR)=3,849 and N(MOBA)=43,512. Genotype data available for mothers was: N(ALSPAC)=7,074 and N(MOBA)=14,583. Measurements: Offspring 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. Findings: The pooled estimate for maternal prenatal substance use showed an association with ADHD risk (OR_SMOKING=1.11, 95%CI 1.00-1.23; OR_ALCOHOL=1.27, 95%CI 1.08-1.49; OR_CAFFEINE=1.05, 95%CI 1.00-1.11), while not for fathers (OR_SMOKING=1.03, 95%CI 0.95-1.13; OR_ALCOHOL=0.83, 95%CI 0.47-1.48; OR_CAFFEINE=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. Conclusions: Our results do not provide support for a causal intrauterine effect of maternal prenatal substance use on offspring attention-deficit hyperactivity disorder risk.

“Maternal and offspring genetic risk score (GRS) analyses of fetal alcohol exposure and ADHD risk in offspring”

“…We used maternal and offspring variants in the ADH and ALDH genes linked to alcohol use and metabolism to investigate whether there is a causal effect of fetal alcohol exposure on childhood ADHD risk. Consistently with previous work, we did not find evidence for a causal effect (Haan et al, 2021). We observed only weak evidence in one cohort (MoBa) of a negative association between maternal GRS and maternal reported offspring symptoms, in the hyperactivity domain only.…”

“…This is not unexpected, as several studies had previously shown informant discrepancies in the assessment of children mental health problems which may be affected by factors such as mothers own mental health and socioeconomic status (Collishaw et al, 2009; De Los Reyes and Kazdin, 2005). Different findings in previous studies and our study may be also related to scales used for ADHD symptom assessment as observed in our previous study (Haan et al, 2021) and the study by Eilertsen and colleagues. The child’s age at the time of assessment and severity of the ADHD symptoms may as well have an impact on the observed results.…”

“…In addition, a common limitation of previous studies reporting a positive association between PAE, conduct disorder and ADHD symptoms (eg Murray et al (2016), Lund et al (2019), D’Onofrio et al (2007) and Eilertsen et al, 2017) is that they were based on outcomes that were measured only using maternal report. We have previously found inconsistent results for a potential causal effect when offspring ADHD symptoms were reported by mothers compared to teachers (Haan et al, 2021). This is not unexpected, as several studies had previously shown informant discrepancies in the assessment of children mental health problems which may be affected by factors such as mothers own mental health and socioeconomic status (Collishaw et al, 2009; De Los Reyes and Kazdin, 2005).…”

“…ADHD was measured around age 7-8 years in each cohort. As in our previous study (Haan et al, 2021) we wanted to explore whether we observe differences in ADHD hyperactive-impulsive and inattention symptom domains, if ADHD symptoms were reported by mother or teacher, and whether results depended on the questionnaire used for ADHD assessment.…”

“…Our recent report using a combination of negative control and polygenic risk score (PRS) analyses, did not find evidence for a causal effect of PAE on offspring ADHD risk (Haan et al, 2021). In this previous study, the alcohol PRS was derived using SNPs identified from the latest GWAS on alcohol consumption per week (Liu et al, 2019).…”