Tayebi-Hillali H, Blanco-Suárez M, Rivas-Mundiña B, Limeres-Posse J, Diniz-Freitas M, Diz-Dios P. Prenatal exposure to paracetamol and the risk of autism and attention-deficit/hyperactivity disorder: An umbrella review and meta-meta-analysis. Dev Med Child Neurol. 2026; 00: 1–13. https://doi.org/10.1111/dmcn.70512
Abstract
Aim
To evaluate whether prenatal exposure to paracetamol (acetaminophen) is associated with an increased risk of autism and attention-deficit/hyperactivity disorder (ADHD) in offspring, using a meta-meta-analytical (umbrella review) approach.
Method
We conducted a registered umbrella review (PROSPERO CRD420251243790) of systematic reviews with meta-analyses assessing prenatal paracetamol exposure and autism or ADHD. Searches were performed in six major databases up to November 2025. Methodological quality was appraised using AMSTAR-2, and overlap of primary studies was quantified using the corrected covered area. Random-effects meta-meta-analyses were performed for unrestricted, partially quality-restricted, and fully quality-restricted models. When overlap was high, additional meta-analyses of low-risk primary studies were conducted, with risk of bias assessed using ROBINS-E.
Results
Seven meta-analyses were included, encompassing more than 3 million participants. Unrestricted meta-meta-analyses showed small positive associations between prenatal paracetamol exposure and both autism (risk ratio 1.17) and ADHD (risk ratio 1.29). However, after restricting analyses to higher-quality meta-analyses and low-risk primary studies, effect estimates were substantially attenuated and, in several models, approached the null. High heterogeneity and substantial overlap were observed, particularly in analyses of primary studies.
Interpretation
The observed associations between prenatal paracetamol exposure and neurodevelopmental disorders are probably influenced by methodological limitations, including residual confounding and exposure misclassification. Current epidemiological evidence does not support a robust causal relationship, and paracetamol remains an appropriate first-line treatment during pregnancy when clinically indicated.
Graphical Abstract
This meta-meta-analysis synthesizes evidence on prenatal paracetamol exposure and neurodevelopmental outcomes. Crude analyses suggest small associations with autism and ADHD, but these attenuate substantially when restricting to high-quality meta-analyses and low-bias primary studies. Overall, the findings indicate a lack of robust epidemiological evidence supporting a causal association.
