Maternal Acetaminophen Use and Offspring's Neurodevelopmental Outcome: A Nationwide Birth Cohort Study.

This large study looked at whether taking paracetamol during pregnancy affects children's brain development. While initial results suggested small increases in ADHD risk, detailed follow-up analyses found these results were likely due to study limitations rather than paracetamol itself. When comparing siblings, the pattern reversed. The researchers concluded that factors other than paracetamol use likely explain any observed differences.

This nationwide birth cohort study examined 217,602 children to investigate associations between maternal acetaminophen use during pregnancy and neurodevelopmental outcomes in offspring. While propensity score-matched analyses suggested small increased risks for ADHD (HR 1.22) and composite neurodevelopmental outcomes (HR 1.08), extensive sensitivity analyses raised significant concerns about these findings. Sibling comparisons showed opposite effects, probabilistic bias analyses suggested overestimation due to unrecorded over-the-counter use, and negative exposure controls indicated potential positive bias. The authors concluded that unmeasured confounding, exposure misclassification, and other biases may partially explain the observed associations, questioning the causal nature of any relationship.

Results do not support strong causal associations between maternal acetaminophen use and neurodevelopmental disorders. Multiple bias analyses suggest observed associations may be spurious. Clinical decisions should consider the extensive sensitivity analyses that challenged the primary findings.

Potential exposure misclassification from unrecorded over-the-counter acetaminophen use, unmeasured confounding factors, positive bias indicated by negative exposure controls, and conflicting results between different analytical approaches limit confidence in causal interpretations.

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. We examined the association between maternal acetaminophen use during pregnancy and diagnoses of neurodevelopmental disorders in offspring. 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. 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.

Although PS-matched analyses indicated small increases in risk, sensitivity analyses suggested that unmeasured confounding, misclassification and other biases may partially explain these associations.