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CC BY 4.0 · Am J Perinatol 2025; 42(12): 1576-1587
DOI: 10.1055/a-2512-9387
Original Article

Urinary Acetaminophen Metabolites and Clinical Outcomes in Extremely Premature Infants

Authors

  • Miguel Guardado

    1   Department of Biological and Medical Informatics, University of California, San Francisco, San Francisco, California

  • Dara Torgerson

    2   Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California

  • Cheryl Chapin

    3   Department of Pediatrics, University of California, San Francisco, San Francisco, California

  • Azuka Atum

    2   Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California

  • Ryan D. Hernandez

    4   Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California

  • Ronald Clyman

    3   Department of Pediatrics, University of California, San Francisco, San Francisco, California

  • Rebecca Simmons

    5   Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

  • Samuel Parry

    6   Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

  • Philip L. Ballard

    3   Department of Pediatrics, University of California, San Francisco, San Francisco, California

Funding This work was supported by NIH grants R01HL153429 (PLB, DT) and RO1GM142112 (RH). MG is a recipient of a Howard Hughes Medical Institute Gilliam Fellowship, an Achievement Award for College Scientists Foundation Scholarship, and a UCSF Discovery Fellows Program Award. RAS and SP are supported by the March of Dimes Prematurity Research Center at the University of Pennsylvania.
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Abstract

Objective

Extremely premature infants are treated with acetaminophen (APAP) for pain and patent ductus arteriosus. High doses of APAP in adults are toxic, and a recent study found an association between APAP metabolite levels in mothers' breast milk and both bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) in their premature infants. In this study, we determined levels of APAP metabolites in the urine of infants at high risk for BPD and ROP.

Study Design

Biorepository urine samples from 314 infants <29 weeks' gestation in the multicenter TOLSURF and PROP studies were analyzed by untargeted UHPLC:MS/MS (Metabolon, Inc.). We performed multivariate logistic regression and meta-analysis to examine associations between APAP metabolite levels and clinical outcomes.

Results

4-APAP sulfate was the most abundant of eight detected APAP metabolites and was present in 95% of urines. There were high correlations between levels of 4-APAP sulfate and the other APAP metabolites. In longitudinal studies on a subgroup of infants (day 6–56), periods of elevated 4-APAP sulfate occurred in 24/28 infants and were of longer duration (10.5 vs. 4.2 days, p = 0.001) with higher levels (13.3 vs. 5.6, p = 0.01) in infants after transition to enteral from total parenteral nutrition. Episodes of elevated metabolite did not differ by BPD status. On both days 10 and 28 there were no significant associations between levels of APAP metabolites and either BPD or ROP for all infants or for infants exclusively on parenteral or enteral nutrition.

Conclusion

In two cohorts of extremely premature infants, levels of urinary APAP metabolites were not associated with increased risk for two adverse clinical outcomes.

Key Points

  • Safety of acetaminophen (APAP) in extremely premature infants has not been established.

  • The major urinary APAP metabolite was detected in the majority of urine samples.

  • No association was found between APAP levels and either bronchopulmonary dysplasia or retinopathy of prematurity.

Keywords

acetaminophen - paracetamol - metabolomics - extremely premature infant - bronchopulmonary dysplasia - retinopathy of prematurity

Note

The research protocols for all parent clinical trials were approved by the Institutional Review Boards of the participating institutions, and a parent of each infant provided written informed consent.


Authors' Contributions

Trial conception and design, data acquisition, data analysis/interpretation, critical revision of the manuscript, and final approval: All authors.


Drafting the article: P.L.B.




Publication History

Received: 05 August 2024

Accepted: 19 December 2024

Accepted Manuscript online:
09 January 2025

Article published online:
31 January 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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