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CC BY 4.0 · Am J Perinatol
DOI: 10.1055/a-2764-2202
Original Article

The Ethics of Clinical Research on Diseases of the Fetus and Newborn: Balancing Benefit–Risk, Autonomy, and Maternal–Fetal Interests

Authors

  • Robert M. Nelson

    1   Pediatric Drug Development, Child Health Innovation Leadership Department, Johnson & Johnson, Raritan, New Jersey, United States

  • Karla Childers

    2   Bioethics-Based Science and Technology Policy, Office of the Chief Medical Officer, Johnson & Johnson, New Brunswick, New Jersey, United States

  • Leona E. Ling

    3   Translational Science (Autoantibody), Johnson & Johnson, Cambridge, Massachusetts, United States

  • Lori Alquier

    4   Global Regulatory Affairs, Johnson & Johnson, Raritan, New Jersey, United States

  • Yosuke Komatsu

    5   Department of Maternal Fetal Immunology, Johnson & Johnson, Spring House, Pennsylvania, United States

  • Lisa Schwartz

    6   Department of Immunology, Johnson & Johnson, Raritan, New Jersey, United States

  • Anne M. Stevens

    7   Department of Clinical Development, Century Therapeutics, Seattle, Washington, United States

  • May Lee Tjoa

    8   Global Medical Affairs, Johnson & Johnson, Cambridge, Massachusetts, United States

  • Kenneth J. Moise  Jr

    9   Department of Women's Health, Dell Medical School, Austin, Texas, United States

  • Sara F. Goldkind

    10   Goldkind Consulting, LLC, Chevy Chase, Maryland, United States

Funding Information This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Abstract

Objective

Pregnant persons historically have been excluded from clinical trials. Recently, there has been a shift from exclusion toward inclusion of pregnant persons in research while acknowledging the complexity of reproductive ethics and the intertwined interests of the pregnant person and fetus. Our objective was to use a principle-based approach to review the ethics of clinical research concerning pregnancy-related disorders that predominantly affect fetal well-being.

Study Design

Ethical principles are applied to the design of interventional trials in two rare conditions of pregnancy, hemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT).

Results

Severe HDFN and FNAIT are fetal and neonatal diseases caused by maternal alloantibodies with potential outcomes including maternal and neonatal morbidity, preterm delivery, and fetal or neonatal death. Early-onset severe HDFN was the initial indication for a phase 2 open-label study of nipocalimab in pregnancy, given poor outcomes after prior severe HDFN pregnancy(s). After establishing proof of concept, a phase 3 randomized placebo-controlled study was initiated based on the ethical principles of equipoise and generating socially valuable data to support the efficacy and safety of nipocalimab in severe HDFN. However, off-label use of antenatal intravenous immunoglobulin (IVIg) in standard-risk FNAIT pregnancies made a randomized placebo-controlled study challenging. Thus, the FNAIT clinical program for nipocalimab in pregnant persons with standard-risk FNAIT includes a randomized, placebo-controlled study limited to sites that do not use antenatal IVIg, and a global randomized open-label study of nipocalimab or IVIg.

Conclusion

Knowledge of the clinical course and management of severe HDFN and FNAIT, the non-clinical and non-pregnant human clinical evidence, and input from physicians, patients, and health authorities permitted the design of clinical protocols that satisfy the principles of beneficence and non-maleficence in these rare and complex diseases.

Key Points

  • Ethical principles apply to pregnancy-related disorders affecting fetal well-being.

  • Placebo-controlled randomized trials in HDFN are based on equipoise.

  • FNAIT programs must account for the off-label use of IVIg.

Keywords

pregnancy - fetal and neonatal alloimmune thrombocytopenia - hemolytic disease of the fetus and newborn - ethics, research - nipocalimab - Fc receptor, neonatal


Publication History

Received: 06 February 2025

Accepted: 03 December 2025

Article published online:
30 December 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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