Prenatal Paracetamol Exposure and Autism Spectrum Disorder: A Critical Review of Proposed Mechanisms, Epidemiological Evidence, and Causal Inference.

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by persistent deficits in social communication and restricted, repetitive patterns of behavior. Recent claims linking prenatal exposure to paracetamol (acetaminophen), the most commonly analgesic during pregnancy, to increased risk of ASD. This review aims to critically evaluate the validity of these associations, clarify potential biological mechanisms, and provide a balanced, evidence-based perspective to inform clinical practice. Although several observational cohort studies report statistical associations between in utero paracetamol exposure and ASD, these findings are often limited by confounding. Maternal conditions necessitating pain treatment, such as infection or fever, are themselves established risk factors for adverse neurodevelopmental outcomes. Greater emphasis here is therefore placed on robust study designs, particularly sibling-comparison analyses, which account for shared genetic and environmental influences. These epidemiological studies control for unmeasured confounders and consistently demonstrate attenuation or absence of previously reported associations, suggesting that paracetamol exposure is unlikely to be causative. This review also examines proposed mechanistic pathways, including mitochondrial dysfunction and inhibition of ribonucleotide reductase, but finds insufficient evidence to support a clinically meaningful effect in humans. Given the known risks of alternative therapies, particularly non-steroidal anti-inflammatory drugs during pregnancy, paracetamol remains the recommended first-line treatment for pain and fever. Overall, current evidence does not support a significant increase in ASD risk, and clinical guidelines should remain unchanged.