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Acetaminophen for the patent ductus arteriosus: has safety been adequately demonstrated?

Journal of Perinatology volume 43, pages 1230–1237 (2023)Cite this article

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Abstract

Patent ductus arteriosus (PDA) is the most common cardiovascular condition diagnosed in premature infants. Acetaminophen was first proposed as a potential treatment for PDA in 2011. Since that time acetaminophen use among extremely preterm neonates has increased substantially. The limited available data demonstrate that acetaminophen reduces PDA without evident hepatotoxicity. These findings have led some to suggest that acetaminophen is a safe and effective therapy for PDA closure. However, the lack of apparent hepatoxicity is predictable. Acetaminophen induced cellular injury is due to CYP2E1 derived metabolites; and hepatocyte CYP2E1 expression is low in the fetal and neonatal period. Here, we review preclinical and clinical data that support the hypothesis that the lung, which expresses high levels of CYP2E1 during fetal and early postnatal development, may be particularly susceptible to acetaminophen induced toxicity. Despite these emerging data, the true potential pulmonary risks and benefits of acetaminophen for PDA closure are largely unknown. The available clinical studies in are marked by significant weakness including low sample sizes and minimal evaluation of extremely preterm infants who are typically at highest risk of pulmonary morbidity. We propose that studies interrogating mechanisms linking developmentally regulated, cell-specific CYP2E1 expression and acetaminophen-induced toxicity as well as robust assessment of pulmonary outcomes in large trials that evaluate the safety and efficacy of acetaminophen in extremely preterm infants are needed.

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Fig. 1: Acetaminophen metabolizing pathways.
Fig. 2: Zonated pattern of hepatocyte injury after toxic acetaminophen exposure.
Fig. 3: Pdgfr-α positive cells are present throughout the developing murine lung.

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Funding

This work was supported by NIH grants R01HL132941 and R01HD107700 to CJW, NIH grant R01HL146859 to DJM.

Author information

Authors and Affiliations

  1. Section of Neonatology, Department of Pediatrics, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA

    Clyde J. Wright

  2. Division of Neonatology, Department of Pediatrics, University of California, San Diego, CA, USA

    David J. McCulley

  3. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Dalhousie University and IWK Health Centre, Halifax, NS, Canada

    Souvik Mitra

  4. Division of Neonatology, Department of Pediatrics, The Children’s Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Erik A. Jensen

Authors
  1. Clyde J. Wright
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  2. David J. McCulley
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  3. Souvik Mitra
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  4. Erik A. Jensen
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Contributions

CJW and EAJ responsible for the initial draft. CJW, EAJ, DJM and SM edited the draft. All authors agree with submission of final version.

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Correspondence to Clyde J. Wright.

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Wright, C.J., McCulley, D.J., Mitra, S. et al. Acetaminophen for the patent ductus arteriosus: has safety been adequately demonstrated?. J Perinatol 43, 1230–1237 (2023). https://doi.org/10.1038/s41372-023-01697-2

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