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 participants: This 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 25, 2007, to January 18, 2020, and analyzed from January 7, 2019, to January 22, 2020.

Exposures: Acetaminophen levels measured in meconium.

Main outcomes and measures: Physician diagnosis of ADHD was determined at follow-up when children were aged 6 to 7 years or from medical records. Resting-state brain connectivity was assessed with magnetic resonance imaging; attention problems and hyperactivity were assessed with the Behavioral Assessment System for Children Parent Report Scale. Associations between meconium acetaminophen levels and outcomes were estimated with linear and logistic regressions weighted on the inverse probability of treatment to account for potential confounders. Causal mediation analysis was used to test for mediation of the association between prenatal acetaminophen exposure and hyperactivity by resting-state brain connectivity.

Results: Among the 345 children included in the analysis (177 boys [51.3%]; mean [SD] age, 6.58 [0.54] years), acetaminophen was detected in 199 meconium samples (57.7%), and ADHD was diagnosed in 33 children (9.6%). Compared with no acetaminophen, detection of acetaminophen in meconium was associated with increased odds of ADHD (odds ratio [OR], 2.43; 95% CI, 1.41-4.21). A dose-response association was detected; each doubling of exposure increased the odds of ADHD by 10% (OR, 1.10; 95% CI, 1.02-1.19). Children with acetaminophen detected in meconium showed increased negative connectivity between frontoparietal and default mode network nodes to clusters in the sensorimotor cortices, which mediated an indirect effect on increased child hyperactivity (14%; 95% CI, 1%-26%).

Conclusions and relevance: Together with the multitude of other cohort studies showing adverse neurodevelopment associated with prenatal acetaminophen exposure, this work suggests caution should be used in administering acetaminophen during pregnancy. Research into alternative pain management strategies for pregnant women could be beneficial.

Conflict of interest statement

Conflict of Interest Disclosures: Mr Baker reported receiving grants from the National Institute of Environmental Health Sciences during the conduct of the study. Dr Lugo-Candelas reported receiving personal fees from Allergan plc outside the submitted work. Dr Bellenger reported receiving grants from the National Institutes of Health during the conduct of the study and grants from the Natural Sciences and Engineering Research Council of Canada outside the submitted work. Dr Posner reported receiving grants from Aevi Genomic Medicine, Inc, and Takeda Pharmaceutical Company Limited outside the submitted work and consultancy fees from Innovative Science Corporation. No other disclosures were reported.

Figures

Figure 1.. Differences in Resting-State Functional Connectivity Associated With Prenatal Acetaminophen Exposure

Seed-based functional connectivity contrasts detected differences in resting-state connectivity between children with (n = 25) and without (n = 23) prenatal acetaminophen exposure. Compared with the unexposed group, children with prenatal acetaminophen exposure demonstrated increased negative connectivity between the medial prefrontal cortex gyrus (default mode network seed) and 6 clusters covering regions of bilateral precentral and postcentral gyri, superior parietal lobules, and supramarginal gyri (A), as well as increased negative connectivity between the left lateral prefrontal cortex (frontoparietal network seed) and a cluster spanning portions of the right precentral and frontal gyri (B). Analyses were thresholded at a voxel level of P < .001 (uncorrected) and at a cluster level of P < .05 (corrected for false discovery rate). Colored areas show increases in negative (blue) connectivity between the groups. Values above each image indicate the brain section being displayed.

Figure 2.. Causal Mediation by Frontoparietal Network–Frontal Cortex Connectivity

Individual values (points), median (horizontal lines), and interquartile range (boxes) depict significant differences in connectivity between the frontoparietal network and right precentral/frontal gyrus in children with vs without prenatal exposure to acetaminophen (A) and connectivity between the frontoparietal network and right precentral/frontal gyrus in children with hyperactivity above vs below the median (B). Mediation by connectivity of the association between acetaminophen detected in meconium and child hyperactivity at ages 9 to 11 years (C) shows the average causal mediation effect (CME) and average direct effect (DE) from causal mediation analysis. Connectivity is expressed as a Pearson correlation between the 2 brain regions with Fisher z transformation. BASC3-PRS indicates Behavioral Assessment System for Children Parent Report Scale.