Maternal Acetaminophen Use and Offspring's Neurodevelopmental Outcome: A Nationwide Birth Cohort Study
Yusuke Okubo, Itaru Hayakawa, Ryo Sugitate, Hiroki Nariai
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.