JAMA Intern Med. 2026 Jun 29. doi: 10.1001/jamainternmed.2026.2215. Online ahead of print.
ABSTRACT
IMPORTANCE: Paracetamol (acetaminophen) is the first-line analgesic and antipyretic recommended globally during pregnancy. Observational studies have reported associations with increased risks of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in offspring, raising public and clinical concern; however, these findings may be substantially confounded by unmeasured familial factors.
OBJECTIVES: To assess the association between prenatal paracetamol exposure and risk of ASD and ADHD in offspring using a sibling-matched study design to control for familial confounding.
DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study, conducted from January 1, 2001, to December 31, 2023, in Hong Kong, used deidentified electronic health records within a triangulation framework. From an initial cohort of 708 020 mother-child pairs (approximately 43.3% with prenatally paracetamol exposure), sibling-matched cohorts were constructed of children from families with discordant prenatal paracetamol exposure and sufficient follow-up (≥2 years for ASD and ≥5 years for ADHD). Data analysis was conducted from October 2, 2025, to March 24, 2026.
EXPOSURE: Prenatal paracetamol exposure, identified from electronic dispensing records (British National Formulary [BNF], section 4.7.1) with data on drug name, strength, dosage, and prescription dates.
MAIN OUTCOMES AND MEASURES: Incident diagnoses per the International Classification of Diseases, Ninth Revision, Clinical Modification, for ASD (code 299) or for ADHD (code 314) or a prescription for ADHD-specific medication licensed in Hong Kong (methylphenidate, atomoxetine, or lisdexamfetamine [BNF, section 4.4]).
RESULTS: The final cohorts comprised 124 333 children for ASD analysis (mean [SD] age, 9.3 [4.7] years; 61 775 females [49.7%] and 62 558 males [50.3%]) and 97 285 for ADHD analysis (mean [SD] age, 7.6 [4.2] years; 48 455 females [49.8%], 48 830 [50.2%]). In the sibling-matched analyses, prenatal paracetamol exposure was not associated with the risk of ASD (adjusted hazard ratio [aHR], 1.00; 95% CI, 0.91-1.11) or ADHD (aHR, 1.01; 95% CI, 0.93-1.08). Null associations were consistent across exposure timing, cumulative dose, and usage patterns (sporadic, intermittent, persistent), and were robust in sensitivity analyses. However, positive associations were observed in conventional cohort analyses, and importantly, also in negative control analyses of prepregnancy exposure for ASD (HR, 1.12; 95% CI, 1.08-1.17) and ADHD (HR, 1.24; 95% CI, 1.20-1.28).
CONCLUSIONS AND RELEVANCE: In this population-based cohort study, a sibling-matched analysis found no evidence of an association between prenatal paracetamol exposure and the risk of ASD or ADHD in offspring. The positive signals observed in conventional studies are likely attributable to residual familial confounding. These findings provide important reassurance regarding the safety of indicated paracetamol use during pregnancy.
PMID:42371637 | DOI:10.1001/jamainternmed.2026.2215