Re-evaluating the Link Between Prenatal Paracetamol and Neurodevelopmental Outcomes: A Critical Review
recent concerns have been raised regarding a potential connection between maternal paracetamol (acetaminophen) use during pregnancy and an increased risk of neurodevelopmental disorders in children, specifically Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). However, a comprehensive new analysis published in the BMJ casts important doubt on a causal relationship, highlighting ample limitations in the existing research.
The BMJ study undertook a rigorous “umbrella review” – a systematic evaluation of existing systematic reviews and meta-analyses – to assess the strength and reliability of the evidence. Researchers meticulously searched a wide range of databases,including Embase,Medline,and PsycINFO,alongside gray literature,to identify relevant studies. The review focused on studies examining the association between prenatal paracetamol exposure and the development of ADHD or ASD, encompassing cohort, cross-sectional, case-control, and randomized trial designs.
The analysis identified nine systematic reviews, incorporating data from 40 primary studies. While the majority of these reviews were relatively recent, focusing on paracetamol use throughout pregnancy, a key limitation was the scarcity of research considering both prenatal and postnatal exposure. Crucially, the quality assessment, utilizing the AMSTAR-2 framework, revealed pervasive methodological flaws.A significant number of reviews lacked pre-registered protocols, comprehensive search strategies, and clear justifications for excluding studies. Furthermore, robust risk of bias assessments were largely absent, with none employing standardized tools like ROBINS-I or ROBINS-E. statistical analysis was frequently enough inadequate, with limited pooling of adjusted estimates. Consequently,the overall confidence in the findings was rated as low in two reviews and critically low in seven.
Despite reporting positive associations between prenatal paracetamol exposure and adverse neurodevelopmental outcomes – with odds ratios or relative risks for ADHD ranging from 1.2 to 1.4, and smaller effects for ASD - the review uncovered critical nuances.Sensitivity analyses indicated stronger associations with longer durations of exposure, particularly during the third trimester. Though, and importantly, studies employing sibling-controlled analyses – which effectively neutralize shared genetic and familial influences – found these associations largely disappeared, suggesting the observed links are likely driven by confounding factors rather than a direct effect of the drug. The high degree of overlap (23%) between primary studies further complicated interpretation. Notably, seven of the reviewed studies explicitly cautioned against drawing causal conclusions, acknowledging the potential for bias and design limitations to inflate perceived risks.
The BMJ umbrella review ultimately concludes that the current body of evidence does not support a clear association between prenatal paracetamol exposure and an increased risk of ADHD or ASD. The observed associations in broader population studies are more likely attributable to unmeasured or familial confounding variables than to a direct pharmacological effect of paracetamol. This finding underscores the importance of carefully considering the methodological limitations of observational studies when interpreting potential risk factors for complex neurodevelopmental conditions.
Source: Sheikh J, Allotey J, Sobhy S, et al. (2025). 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, 391, e088141. DOI: 10.1136/bmj-2025-088141. https://www.bmj.com/content/391/bmj-2025-088141
