Acetaminophen use during pregnancy and the risk of attention deficit hyperactivity disorder: A causal association or bias?

Background The association between acetaminophen use during pregnancy and the development of attention deficit hyperactivity disorder (ADHD) in the offspring may be due to bias. Objectives The primary objective was to assess the role of potential unmeasured confounding in the estimation of the association between acetaminophen use during pregnancy and the risk of ADHD, through bias analysis. The secondary objective was to assess the roles of selection bias and exposure misclassification. Data sources We searched MEDLINE, Embase, Scopus, and the Cochrane Library up to December 2018. Study selection and data extraction We included observational studies examining the association between acetaminophen use during pregnancy and the risk of ADHD. Synthesis We meta-analysed data across studies, using random-effects model. We conducted a bias analysis to studies that did not adjust for important confounders, to explore systematic errors related to unmeasured confounding, selection bias, and exposure misclassification. Results The search resulted in seven studies included in our meta-analysis. When adjusted estimates were pooled across all studies, the risk ratio (RR) for ADHD was 1.35 (95% confidence interval [CI] 1.25, 1.46; I-2 = 48%). Sensitivity analysis for unmeasured confounding in this meta-analysis showed that a confounder of 1.69 on the RR scale would reduce to 10% the proportion of studies with a true effect size of RR >1.10. Unmeasured confounding bias analysis decreased the point estimate in five of the seven studies and increased in two studies, suggesting that the observed association could be confounded by parental ADHD. Unadjusted and bias-corrected risk ratios (bcRRs) were: RR = 1.34, bcRR = 1.13; RR = 1.51, bcRR = 1.17; RR = 1.63, bcRR = 1.38; RR = 1.44, bcRR = 1.17; RR = 1.16, bcRR = 1.18; RR = 1.25, bcRR = 1.05; and RR = 0.99, bcRR = 1.18. Conclusions Bias analysis suggests that the previously reported association between acetaminophen use during pregnancy and an increased risk of ADHD in the offspring may be due to unmeasured confounding. Our ability to conclude a causal association is limited.