Re-evaluating the Link Between Prenatal Paracetamol and Neurodevelopmental Outcomes: A โCritical Review
recent concerns have been raised regarding a potential connection between maternal paracetamol (acetaminophen)โค use during pregnancy and an increased risk of neurodevelopmental disorders in children, โขspecifically Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). However, a comprehensiveโข new analysisโฃ 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 assessโค the strength and reliability of the evidence. Researchers meticulously searched a wide range of databases,including Embase,Medline,and PsycINFO,alongside gray literature,to โidentify relevant studies. The reviewโ focused on studies examining the association between prenatal paracetamolโ 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 โฃon paracetamol use throughout pregnancy, a key limitation was the scarcity โฃof research considering both prenatal and postnatal exposure. Crucially, the quality assessment, utilizing the AMSTAR-2 framework, revealedโฃ pervasive methodological flaws.A โsignificant number of reviews lacked pre-registered protocols, comprehensive search strategies, and clear justifications for excluding โขstudies. Furthermore, robust risk of bias assessments were largelyโค absent, with none employing standardized tools like ROBINS-I โor ROBINS-E. statistical analysisโ was frequently enough inadequate, with limited pooling of adjusted estimates.โ Consequently,the overall confidence in the findings was โrated as low in two reviews and critically low in seven.
Despite reporting positive associations between prenatal paracetamol exposureโข and adverse neurodevelopmental outcomes – with oddsโข ratios or relative risks for ADHD ranging from 1.2 to 1.4, and smaller effects for ASD โค- the review uncovered critical nuances.Sensitivity analyses indicated โstrongerโฃ 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 โthe observed links are likely driven byโข confounding factors rather than a directโ effectโข of the drug. โค The high degree of overlap (23%) between primary studies further complicated interpretation. Notably, seven of the reviewedโ studies explicitly cautioned against drawing โคcausal conclusions,โฃ acknowledging the potential for bias โคand 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 โADHD or โฃASD. The observed associations inโค broader populationโ 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 carefullyโข considering the methodological limitations of observational studies when interpreting potential โrisk 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: umbrellaโ review ofโค systematic reviews. BMJ, 391, e088141. DOI: 10.1136/bmj-2025-088141. https://www.bmj.com/content/391/bmj-2025-088141
