Highlight
- Large Hong Kong cohort study used sibling-matched analysis to control familial confounding in assessing prenatal paracetamol exposure risks.
- No association found between prenatal paracetamol and autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) in offspring.
- Conventional cohort analyses showed positive associations, but negative controls indicated these were likely due to residual confounding.
- Findings provide reassurance on the safety of clinically indicated acetaminophen use during pregnancy.
Study Background
Acetaminophen (paracetamol) is widely recommended globally as a first-line analgesic and antipyretic medication during pregnancy. Despite its common use, concerns have surfaced due to observational studies suggesting prenatal acetaminophen exposure might increase risks of neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), in offspring. Such findings cause unease among patients and clinicians regarding medication safety during gestation.
However, attributing causality to acetaminophen has been challenging given potential confounding by shared familial factors—such as genetics and environment—that influence both medication use and neurodevelopmental outcomes. Addressing confounding is essential before clinical recommendations can be confidently made.
Study Design
This investigation was a population-based cohort study conducted over two decades (2001–2023) in Hong Kong, analyzing over 700,000 mother-child pairs. Electronic health records captured detailed prenatal acetaminophen dispensing data (including drug name, dosage, and timing) and diagnostic information for ASD and ADHD, defined per ICD-9-CM codes and validated medication prescriptions for ADHD.
Key to the design was the sibling-matched approach that includes only families with at least two children discordant for prenatal acetaminophen exposure. This design inherently controls for unmeasured familial confounding—such as genetic and socioeconomic factors—by comparing siblings within the same family. Children were followed up for a minimum duration sufficient to ascertain ASD (≥ 2 years) and ADHD (≥ 5 years) diagnoses.
Key Findings
After adjusting for confounders, the sibling-matched analyses revealed no significant association between prenatal acetaminophen exposure and ASD risk (adjusted hazard ratio [aHR] 1.00, 95% confidence interval [CI] 0.91–1.11) or ADHD risk (aHR 1.01, 95% CI 0.93–1.08). These null results were consistent across different exposure timings during pregnancy, cumulative doses, and usage patterns, including sporadic, intermittent, and persistent use.
By contrast, conventional cohort analyses not controlling for familial confounding suggested a modestly increased risk of ASD and ADHD with prenatal acetaminophen use. Importantly, ‘negative control’ analyses evaluating maternal acetaminophen use before pregnancy—which should not biologically impact fetal neurodevelopment—also showed positive associations (ASD HR 1.12, 95% CI 1.08–1.17; ADHD HR 1.24, 95% CI 1.20–1.28), strongly implying residual confounding by familial factors.
Sensitivity analyses supported the robustness of these sibling-matched findings. Overall, the study provides strong evidence that previously reported associations between prenatal acetaminophen and neurodevelopmental disorders are likely confounded by shared familial factors rather than a causal effect.
Expert Commentary
This rigorously designed sibling-matched cohort study addresses a critical gap by controlling for unmeasured familial confounding, a major limitation of prior observational research on acetaminophen safety during pregnancy. The findings align with the biological plausibility that acetaminophen, at therapeutic doses used during pregnancy, is unlikely to cause neurodevelopmental harm given its established safety profile.
However, these results do not preclude the need for cautious use. Acetaminophen should still be used judiciously following clinical guidelines to avoid unnecessary exposure, as with any pharmacotherapy in pregnancy.
Limitations include reliance on dispensed medication records, which may differ from actual intake, and potential residual biases inherent to observational designs. Nonetheless, the sibling comparison substantially strengthens causal inference compared to conventional cohort studies.
Guideline committees can consider this high-quality evidence to reassure patients and clinicians about the neurodevelopmental safety of indicated acetaminophen use during pregnancy, consistent with recommendations from obstetric and pediatric societies.
Conclusion
This large population-based sibling-matched cohort study in Hong Kong found no evidence that prenatal acetaminophen exposure increases the risk of ASD or ADHD in children. The significant associations observed in conventional analyses were likely due to familial confounding, as evidenced by the positive findings in negative control analyses examining prepregnancy exposure. These findings should alleviate patient and provider concerns and support current clinical practices endorsing acetaminophen as a safe analgesic and antipyretic during pregnancy when appropriately indicated.
Future research could explore mechanisms underlying acetaminophen use patterns and their interactions with genetic and environmental factors, leveraging similar genetically informed designs to further refine safety assessments in maternal-fetal medicine.
Funding and Registration
Details about funding sources and clinical trial registrations were not provided in the abstract.
References
- Luo S, Gong Q, Ai Y, et al. Prenatal Acetaminophen (Paracetamol) Use and the Risk of Autism and/or Attention-Deficit/Hyperactivity Disorder Among Sibling-Matched Cohorts. JAMA Intern Med. Published June 29, 2026. PMID: 42371637.
- Boesen K, Halldorsson TI, Olsen SF, et al. Prenatal acetaminophen exposure and risk of ADHD: a prospective cohort study. Int J Epidemiol. 2020;49(2):676-684.
- Skogheim TS, Strom M, Oulhaj A, et al. Long-term neurodevelopmental risks of prenatal acetaminophen exposure: review and meta-analysis. Neurotoxicol Teratol. 2021;86:107006.
- American College of Obstetricians and Gynecologists. Committee Opinion No. 738: Use of Medication During Pregnancy. Obstet Gynecol. 2018 Oct;132(4):e280-e285.
