Association of Prenatal Acetaminophen Exposure Measured in Meconium With Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".