Comment on: “Maternal Paracetamol (Acetaminophen) Use During Pregnancy and Risk of Autism Spectrum Disorder and Attention Deficit/Hyperactivity Disorder in Offspring: Umbrella Review of Systematic Reviews”

Paracetamol (acetaminophen) is frequently used during pregnancy to treat pain and fever. Recently, public concern increased after claims by the US president that prenatal exposure to acetaminophen may increase the risk of autism in children. While regulatory agencies and professional organizations have reaffirmed the safety of paracetamol use during pregnancy, systematic reviews of observational studies on this topic vary in their methods, control for confounding, and findings. As a result, the strength and validity of the evidence remain uncertain. This study aims to evaluate the quality of existing evidence and the reported associations between prenatal paracetamol exposure and risks of autism and ADHD in children. This umbrella review conducted searches of Medline, Embase, PsycINFO, the Cochrane Database of Systematic Reviews, Epistemonikos, and gray literature through September 2025 to identify systematic reviews and meta-analyses evaluating maternal paracetamol use during pregnancy and risks of autism spectrum disorder or attention deficit/hyperactivity disorder in offspring. Independent reviewers screened studies and assessed full texts for eligibility. Systematic reviews were included if they evaluated randomized trials or observational studies examining prenatal paracetamol exposure and neurodevelopmental outcomes in children. The AMSTAR 2 tool was used to assess the methodological quality of each review. Data on study characteristics, exposure definitions, outcomes, confounder adjustment, and effect estimates were extracted by 2 independent reviewers. Findings were summarized narratively, and the degree of overlap of primary studies across reviews was accounted for to avoid over-weighting. Among 663 articles identified, 9 systematic reviews met the inclusion criteria. Forty primary studies were represented, most of which were prospective cohort studies. Overall methodological quality was low, with some of the common limitations including a lack of protocol registration, incomplete search strategies, and inadequate assessment of bias in primary studies. There was a considerable overlap of primary studies between reviews. All reviews reported a positive association between prenatal acetaminophen use and adverse neurodevelopmental outcomes, though they recognized a lack of causal association due to residual confounding and other limitations. Meta-analyses reported pooled risk estimates for ADHD of ~1.2 to 1.4, with smaller positive associations for autism. Stronger associations were reported when exposure occurred with higher frequency, longer duration, or later in gestation. However, the few studies that accounted for familial influence using sibling-controlled analyses found attenuated associations, which suggests that unmeasured familial or environmental confounding could explain a significant portion of the observed relationship. The findings suggest that the previously reported association between prenatal paracetamol exposure and autism or ADHD is more likely explained by bias and confounding than a causal effect. Prior systematic reviews often reported small positive associations, but the primary studies included were heterogeneous and frequently lacked adequate control for confounding. In the few studies that accounted for shared familial factors using sibling comparisons, the associations were reduced, suggesting that genetic, environmental, or other family-level factors play a large role in the observed relationship. Strengths of this umbrella review include a comprehensive search strategy and a formal assessment of review quality and study overlap. Limitations include the heterogeneity and generally low methodological quality of the included reviews, as well as reliance on previously published data. (Summarized from Sheikh J, Allotey J, Sobhy S, et al. Maternal paracetamol (acetaminophen) use during pregnancy and risk of autism spectrum disorder and attention deficit/hyperactivity disorder in offspring: umbrella review of systematic reviews. BMJ. 2025;391:e088141. doi:10.1136/bmj-2025-088141).