Transfer of paracetamol across the placenta and fetal blood–brain barriers and its safety for use in pregnancy

Paracetamol (acetaminophen) is the most widely used analgesic and antipyretic during pregnancy and has long been considered safe at recommended doses by national health authorities. However, recent preclinical and epidemiological studies have prompted renewed scrutiny of its pharmacology and safety profile in the context of fetal development. This review summarizes current evidence on the pharmacokinetics of paracetamol in pregnancy, placental transfer and permeability across the fetal brain barriers. We also examine findings from both experimental and population-based studies investigating short- and long-term prenatal exposure on offspring outcomes. Despite a great deal of research, evidence linking prenatal paracetamol exposure to adverse neurodevelopmental effects remains inconsistent and no conclusive causality has been established. Uncertainty and public confusion over the safety of paracetamol use in pregnancy is exacerbated by the heterogeneity of study designs, exposure assessment and confounding factors. Nonetheless, data from preclinical models suggest potential pathways that prenatal exposure may influence neurodevelopment, such as oxidative stress and endocrine modulation. However, alternative drug treatments or reasons for use, such as fever, if left untreated have stronger associations with detrimental physical and neurodevelopmental outcomes. Therefore, use of paracetamol when clinically indicated and at the lowest dose for the shortest duration necessary may be safest for maternal and fetal health. Nonetheless, ongoing research integrating mechanistic and epidemiological approaches is still essential to clarify the developmental consequences of fetal paracetamol exposure and to inform evidence-based recommendations for safe dosing regimens for maternal analgesic and antipyretic use.