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

Abstract

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. K E Y W O R D Sacetaminophen, ADHD, bias, confounding, pregnancy

Simple twist of fate: In utero exposure to acetaminophen and risk of childhood Attention Deficit Hyperactivity Disorder

“…In summary, this study has several serious internal and external validity issues that preclude meaningful conclusions be drawn. This study does not substantiate a causal association between in utero exposure to acetaminophen and risk of childhood ADHD and does present new evidence challenging the findings and position of Masarwa et al…”

“…The present quantitative bias analysis from Masarwa et al convincingly demonstrates that parental ADHD and maternal migraine are essential confounders that must be accounted for in when studying in utero exposure to acetaminophen and subsequent risk of childhood ADHD. Their paper provides a timely, sobering, and much needed perspective on this controversial subject . In my opinion, their findings also command pause and reflection on drawing causal inferences from these studies.…”

“…Using quantitative bias analysis, Masarwa et al explore unmeasured confounding, selection bias, and exposure misclassification in each of seven individual studies. A set of fixed assumptions was applied to address biases due to unmeasured confounding and selection, while range of sensitivities and specificities were considered to address exposure misclassification.…”

“…Of the seven studies included in either the original or updated meta‐analysis by Masarwa et al , only two used sufficiently robust diagnostic outcome criteria; that is, either a having physician assigned diagnosis of ADHD or having filled a prescription for an ADHD drug (ie methylphenidate, atomoxetine or lisdexamphetamine). Two studies using these outcome definitions have more recently been published …”

“…In this issue of Paediatric and Perinatal Epidemiology, Masarwa and colleagues apply a meticulous and comprehensive quantitative bias analysis to the controversial issue of in utero acetaminophen exposure and subsequent risk of childhood Attention Deficit Hyperactivity Disorder (ADHD) . As witnessed by other contributions in this special issue of Paediatric and Perinatal Epidemiology , many aspects of childhood neurodevelopment following in utero exposure to acetaminophen have raised professional and public health concerns on the safety of use of acetaminophen in pregnancy.…”