Prenatal exposure to paracetamol and the risk of autism and attention-deficit/hyperactivity disorder: An umbrella review and meta-meta-analysis.

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.