Use of Paracetamol in Pregnancy Is Not Associated with an Increased Risk of Neurodevelopmental Disorders in Offspring

Paracetamol is an analgesic and antipyretic widely recommended and used for the management of pain and fever during pregnancy. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) consider paracetamol to carry minimal risk during pregnancy (1,2). However, in 2021, a group of 91 experts published a consensus statement recommending avoidance of paracetamol use in pregnancy due to the possibility of various adverse outcomes for the newborn (3).

The consensus statement summarized research suggesting unfavorable neurological, urogenital, and reproductive outcomes associated with maternal and perinatal use of paracetamol, particularly disorders such as autism and attention-deficit/hyperactivity disorder (ADHD). Based on a review of experimental and epidemiological literature, the experts cautioned that pregnant women should refrain from paracetamol use unless it is medically indicated. At the same time, the statement acknowledged the clear limitations of the existing epidemiological literature, emphasized the need for rigorous meta-analyses, and noted that multiple biases could explain the observed associations between paracetamol use and neurodevelopmental anomalies/disorders.

The results of a study published in April 2024 in the Journal of the American Medical Association (JAMA) (4) are therefore significant. This was a national sibling-controlled cohort study that included over 2.4 million children born in Sweden between 1995 and 2019, with follow-up through December 31, 2021. Paracetamol use during pregnancy was determined from the national Medical Birth Register, and information on early exposure to the drug was prospectively collected throughout pregnancy. The primary outcomes were autism, ADHD, and diagnoses of intellectual disability, identified using International Classification of Diseases (ICD) codes.

Although the study had several strengths (a large, nationally representative sample; an extensive control group with adjustment for numerous potential confounders; systematic, prospective recording of paracetamol use and clinical diagnoses of neurodevelopmental disorders), there were also limitations. First, in a small proportion of patients, diagnoses of autism and ADHD were not confirmed, and the mean age of diagnosis was higher than in other studies. In addition, information on paracetamol use was not entirely precise (dose, duration, or timing in relation to pregnancy), and prescription records may not fully reflect over-the-counter use. Therefore, more specific aspects of exposure could not be evaluated, and it cannot be definitively excluded that use of paracetamol above a certain dose at a critical time point might represent a potential risk.

Nevertheless, the conclusion of the study is important: paracetamol use during pregnancy was not associated with an increased risk of autism, ADHD, or intellectual disability in sibling-controlled analyses.

References

1. US Food and Drug Administration. FDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy. January 9, 2015. Accessed March 19, 2024. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-has-reviewed-possible-risks-pain-medicine-use-during-pregnancy

2. Pharmacovigilance Risk Assessment Committee. PRAC recommendations on signals: adopted at the 12–15 March 2019 PRAC meeting. European Medicines Agency. April 8, 2019. Accessed March 19, 2024. Available at: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-12-15-march-2019-prac-meeting_en.pdf

3. Bauer AZ, Swan SH, Kriebel D, et al. Paracetamol use during pregnancy: a call for precautionary action. Nat Rev Endocrinol. 2021;17(12):757-766. doi:10.1038/s41574-021-00553-7

4. Ahlqvist VH, Sjoqvist H, Dalman C, et al. Acetaminophen Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability. JAMA. 2024;331(14):1205-1214. doi:10.1001/jama.2024.3172