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Maternal paracetamol intake and fetal ductus arteriosus constriction/closure: comprehensive signal evaluation using the Austin Bradford Hill criteria

  • Pharmacoepidemiology and Prescription
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Abstract

Purpose

Acetaminophen (APAP) is available over-the-counter and widely regarded as safe for use in pregnancy. APAP has been used to close a persistently patent ductus arteriosus. Fetal constriction/closure of the ductus arteriosus (FCCDA), of public health interest given the drug’s widespread use during pregnancy, is being monitored globally, including by the European Medicines Agency Pharmacovigilance Risk Assessment Committee. Our objective was to share a comprehensive signal evaluation of FCCDA with in utero APAP exposure to determine if the totality of evidence is sufficiently more consistent with one of the following two possibilities: (1) APAP never contributes to FCCDA (null hypothesis or HO) versus (2) APAP may in some cases be at least a contributory cause of in utero DA narrowing (alternative hypothesis or HA) to justify risk communication.

Methods

To assess the relative support for HO versus HA, we synthesize and interpret within an Austin Bradford Hill criteria framework a comprehensive, cross-disciplinary set of published information and de novo analysis, including toxicology, epidemiology, clinical pharmacology, and clinical and quantitative pharmacovigilance analysis of spontaneous reports.

Results

While residual uncertainty remains, the totality of information is more compatible with HA than H0, to the extent that it is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA.

Conclusion

It is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA, and this should therefore be communicated to stakeholders.

Trial registration

ClinicalTrials.gov registration: Not applicable

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Data availability

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Acknowledgments

The authors wish to thank Susan Mattano, PhD, DABT, for her contribution to the animal toxicology results section.

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Funding

This signal evaluation exercise was conducted in the course of Pfizer Inc.’s ongoing drug safety surveillance activities. The publication of this analysis, including editorial support in the form of quality checking, formatting assistance, and electronic submission performed by Peloton Advantage, LLC, an OPEN Health company, was funded by Pfizer. On August 1, 2019, Pfizer Consumer Healthcare became part of GSK Consumer Healthcare.

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Authors

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Study design: KL, MH

Data analysis/interpretation: All authors

Critical revision and review of the manuscript: All authors

Project/data management: MH

Statistical analyses: MH, EH

Approval of final draft for submission: All authors

Statistics: MH, EH

Data collection: VPZ, MH, EH, SB

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Correspondence to Manfred Hauben.

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Conflict of interest

Manfred Hauben, MD, MPH, is a full-time employee of Pfizer Inc. and owns stocks and stock options in Pfizer and stocks in other pharmaceutical companies that may manufacture and/or market drugs mentioned in this article.

Stephen Bai, PhD, is a clinical pharmacology consultant for Pfizer Inc. He is employed by Atrium Staffing, a company Pfizer contracts with for staffing needs.

Eric Hung, PharmD, is a full-time employee of Pfizer Inc. and owns stocks and stock options in Pfizer.

Kasia Lobello, MD, is a full-time employee of Pfizer Inc. and owns stocks and stock options in Pfizer.

Charles Tressler, MD, was a full-time employee of Pfizer Inc. at the time that this study was conducted and owned stocks and stock options in Pfizer.

Vincent P. Zucal, PharmD, is a contractor through Atrium Staffing. He owns Pfizer stock and mutual fund holdings that include other pharmaceutical companies.

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Hauben, M., Bai, S., Hung, E. et al. Maternal paracetamol intake and fetal ductus arteriosus constriction/closure: comprehensive signal evaluation using the Austin Bradford Hill criteria. Eur J Clin Pharmacol 77, 1019–1028 (2021). https://doi.org/10.1007/s00228-020-03039-z

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