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Paracetamol use in pregnancy — caution over causal inference from available data

Nature Reviews Endocrinology volume 18, page 190 (2022)Cite this article

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The Consensus Statement by Bauer et al.1 (Bauer, A. Z. et al. Paracetamol use during pregnancy — a call for precautionary action. Nat. Rev. Endocrinol. 17, 757–766 (2021)1) has, not surprisingly, drawn considerable public attention. We agree with the authors’ call for a focused research effort to investigate the reported associations from observational studies concerning prenatal use of paracetamol (also known as acetaminophen or N-acetyl-p-aminophenol (APAP)) and adverse reproductive and neurodevelopmental outcomes. However, we caution against an inference of causality that is based upon inadequate evidence. Here we provide a consensus counterstatement to the conclusion of that paper.

We reviewed the literature on APAP use in pregnancy and adverse outcomes. These studies are limited by serious methodological problems, including failure to account for confounding, and elements of bias that make interpretation of the data challenging. APAP is a common over-the-counter drug that more than 60% of individuals recall having used sometime during pregnancy2. Differential exposure and misclassification of the timing, dose and duration of use of APAP during pregnancy is likely, as well as confusion with other analgesic drugs, which could lead to over-estimation of the true effect. Residual confounding from shared co-morbidities and genetic and environmental factors with exposure and outcome can bias associations away from the null. Pregnant people use APAP for migraine or fever, both of which have been associated with adverse effects on fetal neurological development3,4. Furthermore, individuals who use APAP in pregnancy for longer durations have a higher prevalence of self-reported mental health conditions, including depression and anxiety, and are reported to have more prevalent use of antidepressant medications, compared with pregnant individuals who use APAP for shorter durations2. The potential for a shared underlying genetic susceptibility to neurodevelopmental and psychiatric conditions being passed from parent to child must also be considered5,6. An important problem in combining data from several observational studies is the considerable variability in selection and adjustment of the potential confounders, which intensifies interpretation challenges7. Finally, the quality and validity of neurodevelopmental outcome definitions are problematic8. Attempts to globally quantify neurodevelopmental outcome definitions for clinical interpretation can be highly misleading, given their wide phenotypic presentations.

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Authors and Affiliations

  1. Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, USA

    Sura Alwan

  2. Division of Clinical Genetics, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA

    Elizabeth A. Conover

  3. MotherToBaby North Carolina, Asheville, NC, USA

    Lorrie Harris-Sagaribay

  4. Center for Epidemiology and Maternal-Child Health, Washington, DC, USA

    Steven H. Lamm

  5. MotherToBaby Connecticut, Division of Medical Genetics, UConn Health, Farmington, CT, USA

    Sharon V. Lavigne

  6. Department of Psychiatry and Obstetrics and Gynecology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Shari I. Lusskin

  7. Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Sarah G. Obican

  8. MotherToBaby Utah, Utah Department of Health, Salt Lake City, UT, USA

    Alfred N. Romeo

  9. Reproductive Toxicology Center, A Non-Profit Foundation, Washington, DC, USA

    Anthony R. Scialli

  10. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Katherine L. Wisner

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  1. Sura Alwan
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  2. Elizabeth A. Conover
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Corresponding author

Correspondence to Sura Alwan.

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Competing interests

A.R.S. declares past consulting for Cadence Pharmaceuticals. The other authors declare no competing interests.

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Alwan, S., Conover, E.A., Harris-Sagaribay, L. et al. Paracetamol use in pregnancy — caution over causal inference from available data. Nat Rev Endocrinol 18, 190 (2022). https://doi.org/10.1038/s41574-021-00606-x

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