Pooled analyses restricted to sibling-comparison designs—accounting for shared genetic and environmental factors—showed no association between prenatal paracetamol exposure and autism spectrum disorder, attention-deficit hyperactivity disorder, or intellectual disability, according to a recent study.
Paracetamol remains the most commonly recommended analgesic and antipyretic during pregnancy, yet questions about its potential neurodevelopmental effects have persisted amid conflicting observational evidence. In sibling-comparison analyses, prioritized as the primary evidence, prenatal paracetamol exposure was not associated with autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), or intellectual disability. These findings remained consistent when analyses were limited to studies at low risk of bias and those with more than 5 years of follow-up.
The researchers conducted a systematic search of MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov from database inception through Sept 30, 2025. Eligible studies used cohort designs and reported adjusted risk estimates comparing neurodevelopmental outcomes among patients exposed to paracetamol in utero vs those unexposed. Outcomes were defined using validated questionnaires or medical records, and studies were required to report maternal comorbidities and concomitant treatments. Studies reporting only unadjusted estimates were excluded to reduce confounding.
Study quality was assessed using the Quality In Prognosis Studies (QUIPS) tool, which evaluates risk of bias across domains including prognostic factor measurement, confounding, outcome assessment, and statistical analysis. Of the 43 studies included in the systematic review, 11 were rated at low risk of bias, 23 at moderate risk, and nine at high risk. Seventeen studies met criteria for inclusion in the meta-analysis.
"Current evidence does not indicate a clinically important increase in the likelihood of ASD, ADHD, or intellectual disability in [patients] who use paracetamol as directed, supporting existing recommendations on its safety," stated lead authors Francesco D'Antonio, PhD, of the Center for Fetal Care and High-Risk Pregnancy, University of Chieti, Italy, and Maria Elena Flacco, PhD, of the Department of Environmental and Preventive Sciences, University of Ferrara, Italy, and colleagues.
Meta-analyses used a random-effects generic inverse variance approach to generate pooled odds ratios. Secondary analyses incorporated all studies reporting adjusted estimates, those judged to be at low risk of bias according to QUIPS, and studies with extended follow-up. Across all analytical approaches, pooled estimates were close to null.
The researchers noted several limitations. Definitions of paracetamol exposure varied substantially, with many studies relying on maternal self-report rather than pharmacy dispensing records or biomarker confirmation, increasing the risk of misclassification and recall bias. Outcome classification differed across diagnostic eras, reflecting changes in diagnostic criteria and assessment tools. In addition, limited stratified reporting restricted analyses by dosage, duration, trimester of exposure, and offspring sex within the most stringent study subsets. Although sibling-comparison designs reduce confounding from shared familial factors, they may have reduced statistical power and remain susceptible to time-varying confounders between pregnancies.
The researchers reported no competing interests and no external funding for this study.
Source: The Lancet: Obstetrics, Gynaecology, & Women’s Health
