REVIEW   Open access

Minerva Pediatrics 2022 December;74(6):774-88

DOI: 10.23736/S2724-5276.22.06932-4

Copyright © 2022 THE AUTHORS

This is an open access article distributed under the terms of the CC BY-NC 4.0 license which allows users to distribute, remix, adapt and build upon the manuscript, as long as this is not done for commercial purposes, the user gives appropriate credits to the original author(s) and the source (with a link to the formal publication through the relevant DOI), provides a link to the license and indicates if changes were made.

language: English

The safety of pediatric use of paracetamol (acetaminophen): a narrative review of direct and indirect evidence

Esha PATEL ¹, John P. JONES III ^{1, 2}, Dillan BONO-LUNN ³, Maragatha KUCHIBHATLA ⁴, Antara PALKAR ², Jasmine CENDEJAS HERNANDEZ ^{1, 2}, Joshua T. SARAFIAN ², Victoria G. LAWTON ², Lauren G. ANDERSON ², Zacharoula KONSOULA ¹, Kathryn J. REISSNER ^{5, 6}, William PARKER ^{1, 2} ✉

¹ WPLab, Inc. Durham, NC, USA; ² Department of Surgery, Duke University Medical Center, Durham, NC, USA; ³ Departments of Public Policy, University of North Carolina, Chapel Hill, NC, USA; ⁴ Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA; ⁵ Department of Psychology, University of North Carolina, Chapel Hill, NC, USA; ⁶ Department of Neuroscience, University of North Carolina, Chapel Hill, NC, USA

Paracetamol (acetaminophen) use during pregnancy and early childhood was accepted as safe in the 1970s, but is now a subject of considerable concern. Careful analysis shows that initial acceptance of the drug was based on the false assumption that drug interactions in babies and adults are the same, and on a complete absence of knowledge regarding the impact of the drug on brain development. At least fourteen epidemiological studies now indicate that prenatal exposure to paracetamol is associated with neurodevelopmental problems. Based on these studies, it can be concluded that prenatal exposure to paracetamol causes statistically significant risks of developmental delays, attention deficit hyperactivity disorder, and a subtype of autism spectrum disorder (ASD) associated with hyperkinetic behavior. In contrast, data regarding postnatal exposure to paracetamol are limited, and several factors impede a classic multivariate analysis of epidemiologic data to resolve the issue. However, circumstantial evidence regarding postnatal exposure to the drug is abundant, and includes at least three otherwise unexplained temporal relationships, data from laboratory animal studies, several miscellaneous and otherwise unexplained correlations, and a lack of alternative suspects that fit the evidence-derived profile. Based on this evidence, it can be concluded without any reasonable doubt that oxidative stress puts some babies and children at risk of paracetamol-induced neurodevelopmental injury, and that postnatal exposure to paracetamol in those susceptible babies and children is responsible for many if not most cases of ASD.

KEY WORDS: Acetaminophen; Autism spectrum disorder; Vaccination