A Hong Kong cohort study of 708,020 mother‑child pairs published in JAMA Internal Medicine found no causal link between prenatal paracetamol exposure and autism or ADHD after sibling‑matched analyses, reinforcing acetaminophen’s safety profile in pregnancy.
Written By: Mayuresh Salvi, PharmD
Reviewed By: Pharmacally Editorial Team
A large population-based cohort study has found that prenatal exposure to paracetamol (acetaminophen) was not associated with an increased risk of autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) in offspring after controlling for shared genetic and environmental factors using a sibling-matched design.
Published in JAMA Internal Medicine, the findings provide further reassurance regarding the safety of clinically indicated acetaminophen use during pregnancy and clarify a long-standing safety concern that has generated considerable public and clinical debate.
The study analyzed de-identified electronic health records from Hong Kong spanning January 2001 through December 2023. Among 708,020 mother-child pairs, approximately 43.3% had documented prenatal paracetamol exposure. Researchers then constructed sibling-matched cohorts comprising 124,333 children for ASD analyses and 97,285 children for ADHD analyses to minimize familial confounding that may have influenced earlier observational studies.
Why Researchers Revisited the Safety Question
Paracetamol remains the first-line analgesic and antipyretic recommended during pregnancy because of its established safety profile and the limited number of alternative medicines considered appropriate for pregnant patients. However, several conventional observational studies have reported modest associations between prenatal exposure and neurodevelopmental disorders, including ASD and ADHD, raising concerns about whether the medication itself contributes to these outcomes or whether the findings reflect underlying maternal or familial factors.
The debate intensified after the US Food and Drug Administration highlighted a potential neurodevelopmental safety signal while emphasizing that available evidence had not established a causal relationship, prompting renewed scientific and public discussion.
Sibling Analysis Found No Increased Risk
Initial analyses of the overall study population reproduced findings similar to previous observational studies, showing an apparent association between prenatal paracetamol exposure and both ASD and ADHD. However, those associations disappeared when researchers compared siblings with different prenatal exposure histories.
Prenatal paracetamol exposure was not associated with ASD (adjusted hazard ratio [aHR], 1.00; 95% CI, 0.91-1.11) or ADHD (aHR, 1.01; 95% CI, 0.93-1.08). The findings remained consistent regardless of trimester of exposure, cumulative dose, or patterns of use, including sporadic, intermittent, and persistent exposure, and were confirmed in multiple sensitivity analyses.
Additional Analyses Strengthened the Findings
Researchers also performed negative-control analyses examining maternal paracetamol use before pregnancy and after delivery, periods during which the medication could not plausibly affect fetal brain development. Similar positive associations observed during these periods suggested that the signals seen in conventional cohort studies were more likely explained by shared familial or environmental factors than by prenatal paracetamol exposure itself.
Together, the sibling-matched and negative-control analyses provide strong evidence that residual familial confounding, rather than a direct intrauterine effect of paracetamol, accounts for previously reported associations.
Clinical Implications
The findings are consistent with previous sibling-controlled studies from Sweden and large population-based cohorts from Taiwan and Denmark, which also found no causal association between prenatal acetaminophen exposure and autism or ADHD.
Overall, the study reinforces current clinical recommendations that acetaminophen remains the preferred treatment for pain and fever during pregnancy when clinically indicated. The authors conclude that accounting for familial confounding provides reassuring evidence that the medication is unlikely to increase the risk of ASD or ADHD in offspring, while further studies in diverse populations may continue to refine understanding of prenatal medication safety.
What This Means for Patients
For pregnant women who need treatment for pain or fever, these findings provide additional reassurance that acetaminophen remains an appropriate option when used as recommended by a healthcare professional. Patients should continue to use the lowest effective dose for the shortest necessary duration and consult their clinician before starting or stopping any medication during pregnancy.
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About the Writer
Mayuresh Sunil Salvi (Linkedin) is a PharmD professional and healthcare writer with a strong interest in pharmacovigilance, drug safety, and emerging medical research. He is passionate about exploring new drug discoveries, clinical research, and advances in evidence-based medicine. His interests also include ward rounds, prescription audits, and treatment analysis to support rational pharmacotherapy and improved patient care.