Peer-reviewed article
Maternal Acetaminophen Use and Offspring's Neurodevelopmental Outcome: A Nationwide Birth Cohort Study.
Okubo Y, Hayakawa I, Sugitate R, Nariai H ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This study examines whether mothers' use of acetaminophen during pregnancy is associated with neurodevelopmental disorders in children, using health records from over 217,000 children. The analysis found small increases in risk for ADHD and composite neurodevelopmental outcomes, but sensitivity analyses suggested these associations may be due to confounding, misclassification, or other biases rather than a true effect. The findings are inconclusive about whether acetaminophen use during pregnancy actually harms child development.
Key points
- 39.5% of children in the study were exposed to maternal acetaminophen use during pregnancy
- Propensity score-matched analyses showed a hazard ratio of 1.08 for composite neurodevelopmental outcomes and 1.22 for ADHD
- Sibling comparison analyses showed hazard ratios in the opposite direction, suggesting confounding
- Probabilistic bias analysis indicated overestimation due to unmeasured over-the-counter use
- Negative exposure controls suggested potential positive bias in the observed associations
Limitations
The study relies on administrative health records which may not capture all acetaminophen use (particularly over-the-counter purchases), and multiple sensitivity analyses suggest the observed associations may reflect biases rather than causal effects. The findings cannot establish causation and may not generalise beyond the Asian population studied.
Abstract
Background Maternal acetaminophen use during pregnancy is common globally. However, its potential risks for neurodevelopmental disorders in offspring, including attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID), remain uncertain in Asian populations. Objective We examined the association between maternal acetaminophen use during pregnancy and diagnoses of neurodevelopmental disorders in offspring. Methods This nationwide birth cohort study included 217,602 children contributing 966,546 person-years using a nationwide administrative database from 2005 to 2022. We investigated the association between maternal acetaminophen use during pregnancy and offspring's neurodevelopmental outcomes using Cox proportional hazards models, with primary analyses based on 1:1 propensity score (PS) matching. The robustness of the primary findings was evaluated through alternative statistical approaches (adjusted model and inverse probability of treatment weighting [IPTW]), sibling comparison, probabilistic bias analyses for exposure misclassification, and negative exposure control methods. Results Of the 217,602 children, 85,853 (39.5%) were exposed to acetaminophen during pregnancy. PS-matched analyses (N = 42,123 children per comparator) yielded hazard ratios of 1.08 (95% CI 1.00, 1.16) for composite neurodevelopmental outcomes, 1.22 (95% CI 1.09, 1.36) for ADHD, 1.06 (95% CI 0.98, 1.15) for ASD, and 1.02 (95% CI 0.90, 1.19) for ID. Similar findings were observed in adjusted models and IPTW methods. Sibling comparisons (n = 23,593) showed point estimates in the opposite direction (e.g., HR of ADHD, 0.86 95% CI 0.52, 1.44). Probabilistic bias analysis for exposure misclassification suggested overestimation due to unrecorded over-the-counter acetaminophen use, with effect estimates shifting towards the null as misclassification increased. Negative exposure controls (e.g., NSAIDs and acetaminophen use after pregnancy) indicated potential positive bias in the observed associations. Conclusions Although PS-matched analyses indicated small increases in risk, sensitivity analyses suggested that unmeasured confounding, misclassification and other biases may partially explain these associations.