Association of Prenatal Acetaminophen Exposure Measured in Meconium With Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity

Abstract

IMPORTANCE Despite evidence of an association between prenatal acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD) in offspring, the drug is not contraindicated during pregnancy, possibly because prior studies have relied on maternal self-report, failed to quantify acetaminophen dose, and lacked mechanistic insight.OBJECTIVE To examine the association between prenatal acetaminophen exposure measured in meconium (hereinafter referred to as meconium acetaminophen) and ADHD in children aged 6 to 7 years, along with the potential for mediation by functional brain connectivity. DESIGN, SETTING, AND PARTICIPANTSThis prospective birth cohort study from the Centre Hospitalier Université de Sherbrooke in Sherbrooke, Québec, Canada, included 394 eligible children, of whom 345 had meconium samples collected at delivery and information on ADHD diagnosis. Mothers were enrolled from September 25, 2007, to September 10, 2009, at their first prenatal care visit or delivery and were followed up when children were aged 6 to 7 years. When children were aged 9 to 11 years, resting-state brain connectivity was assessed with magnetic resonance imaging. Data for the present study were collected from September

Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts

“…Whilst acetaminophen is considered the safest analgesic/antipyretic for pregnant women and children, mounting evidence has linked prenatal acetaminophen exposure to worse cognitive performance [4][5][6], more behavioural problems [1,7,8], Autism Spectrum Conditions (ASC) [6,9] and Attention-Deficit/ Hyperactivity Disorder (ADHD) symptoms [1,3,6,10]. Recently, detection of acetaminophen in meconium has associated with increased odds of ADHD and altered frontoparietal connectivity at ages 9-10 years [11].…”

Prenatal Acetaminophen, Adverse Birth Outcomes, and ADHD: Mediation Analysis in a Prospective Cohort

“…In this cohort, we have previously shown an association of prenatal acetaminophen with increased odds for ADHD, 22 and associations of ADHD with adverse birth outcomes including preterm birth and lower birthweight. 27 Here, we additionally assessed whether birth outcomes mediated the relationship between prenatal acetaminophen exposure and ADHD, in separate models for each birth outcome, using the 'mediation' R package, 42 which implements a quasi-Bayesian Monte Carlo method with 1,000 simulations.…”

“…To the best of our knowledge, all but two cohort studies investigating the effects of prenatal acetaminophen exposure on children's health have relied on mothers to self-report their acetaminophen use during pregnancy. 21,22 Furthermore, the only studies to show associations of prenatal acetaminophen with birth outcomes administered questionnaires during pregnancy and postpartum to assess maternal acetaminophen use. 10,14 Consequently, adverse birth outcomes could have influenced maternal responses in the postpartum interviews; when outcomes are suboptimal, women might be more likely to recall any potential explanatory behavior.…”

“…Measuring chemicals in meconium, the first feces of newborn infants, has proven to be an effective, non-invasive method to assess cumulative prenatal exposures. 22,26,27 Chemicals in meconium are known to have passed through the fetus and into the fetal intestinal tract, [28][29][30][31] making meconium an ideal substrate for measuring in utero exposures. Furthermore, meconium measurements reflect cumulative exposures during the 2 nd and 3 rd trimesters of pregnancy, as xenobiotics and their metabolites are deposited in meconium throughout that period.…”

The need for studies of acetaminophen’s impact on risk-taking in daily life; reply to Ross and Holstege (2021)

“…In a recent study, acetaminophen levels in meconium (the first feces of newborn infants) predicted hyperactivity levels at age 10. The relationship between in utero exposure and hyperactivity was mediated by alterations in dorsolateral prefrontal connectivity ( Baker et al. , 2020 )—a region implicated in performance on the risk-taking task used in our study ( Schonberg et al.…”