Placenta–Foetus Pharmacology of Acetaminophen in Pregnancy: A Systematic Review of Exposure Biomarkers, Oxidative Stress, Endocrine Disruption and Neurodevelopmental Safety Signals
Wiku Andonotopo, Aloysius Suryawan, Ridwan Abdullah Putra, Theresia Monica Rahardjo, Rizna Tyrani Rumanti, Roland Frederik Lengkey, Arief Setiawan, Julia Windi Gunadi, Muhammad Adrianes Bachnas, Mochammad Besari Adi Pramono, Julian Dewantiningrum, I Nyoman Hariyasa Sanjaya, Dudy Aldiansyah, Laksmana Adi Krista Nugraha, Wibisana Andika Krista Dharma, Waskita Ekamaheswara Kasumba AndanaputraAbstract
Acetaminophen is the most frequently used analgesic and antipyretic during pregnancy, yet its safety for the maternal–placental–foetal unit and subsequent child development remains a subject of ongoing investigation. While previous reviews have largely emphasised neurodevelopmental outcomes, fewer have integrated pharmacokinetic, biomarker, mechanistic and epidemiological evidence within a single maternal–foetal framework. This systematic review synthesised the current evidence on placental transfer, foetal exposure, biological mechanisms and reported developmental outcomes associated with prenatal acetaminophen exposure. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, a systematic search of major biomedical databases and additional sources identified 842 records, of which 29 studies met the predefined eligibility criteria. The included evidence comprised pharmacokinetic and biomarker investigations, population-based cohort studies, sibling-controlled analyses, mechanistic studies, systematic reviews and meta-analyses. Collectively, the available evidence demonstrates that acetaminophen crosses the placenta and is detectable in maternal plasma, placental tissue, cord blood and meconium, confirming foetal exposure throughout pregnancy. Observational studies have reported associations between prenatal exposure and neurodevelopmental outcomes, particularly attention-deficit/hyperactivity disorder and autism spectrum disorder, although these findings remain susceptible to residual confounding related to maternal illness, pain, fever and treatment indication. Proposed biological mechanisms include oxidative stress, endocrine disruption, epigenetic regulation and neuroimmune signalling; however, the current evidence does not establish a causal relationship between prenatal acetaminophen exposure and adverse developmental outcomes. Overall, the evidence supports a maternal–placental–foetal exposure continuum but remains insufficient to infer causality. Future research should prioritise integrated pharmacokinetic, biomarker and longitudinal epidemiological studies to strengthen biological understanding and improve causal inference.