A New Ethical Framework for Assessing the Unique Challenges of Fetal Therapy Trials

Hendriks, Saskia; Grady, Christine; Wasserman, David; Wendler, David; Bianchi, Diana W.; Berkman, Benjamin E.

doi:10.1080/15265161.2020.1867932

Cited by 22 publications

(43 citation statements)

References 96 publications

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“…As such, we argue the interests of the pregnant person and the fetus–though aligned in some ways—can diverge enough that they should be considered separately. We also believe that it can be appropriate to consider well‐being more broadly in the assessment of fetal therapy trials 5 . However, we recognize that this is controversial.…”

Section: A New Ethical Frameworkmentioning

confidence: 97%

“…Various ethical frameworks have been proposed for assessing fetal therapy trials (see Table 2 for three commonly cited frameworks). However, their proposed criteria diverge, 5 which can cause uncertainty and inconsistency for investigators and IRB members. More importantly, we disagree substantively with these existing frameworks, largely because they can preclude appropriate and important trials.…”

Section: Existing Ethical Frameworkmentioning

confidence: 99%

“…This commentary is not about therapies that primarily aim to benefit pregnant persons and that may or may not additionally have fetal benefits.) Balancing the interests of fetuses and pregnant persons to determine whether the asymmetrically distributed risks and benefits are acceptable is the main ethical challenge in assessing fetal therapy trials 5–7 . Suprisingly, regulatory guidance on this ethical challenge is limited, and – in our view – insufficiently protects pregnant persons and fetuses.…”

Section: Introductionmentioning

confidence: 99%

“…Suprisingly, regulatory guidance on this ethical challenge is limited, and – in our view – insufficiently protects pregnant persons and fetuses. Various ethical frameworks have been proposed, although most are at least a decade old and consensus remains elusive 5 . Importantly, many of these frameworks include restrictive criteria (e.g., fetal therapies are only acceptable for severe diseases) that are uncommon in bioethics and would block the development of many new fetal therapies.…”

Section: Introductionmentioning

confidence: 99%

“…We need new ethical guidance that protects research participants but permits important and appropriate research 7–9 . After reviewing the existing ethical and regulatory guidance and using conceptual analysis to consider alternatives, we recently proposed a new framework to help investigators and Institutional Review Boards (IRBs) assess the risks and benefits of fetal therapy trials 5 . This commentary explains why new guidance is needed and further clarifies our proposed framework.…”

Section: Introductionmentioning

confidence: 99%

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A new ethical framework to determine acceptable risks in fetal therapy trials

et al. 2022

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Objective Fetal therapy trials pose complex ethical challenges because risks and benefits to both fetuses and pregnant persons must be considered. Existing regulatory guidance is limited and many proposed ethical frameworks have unnecessarily restrictive criteria that would block the development and implementation of important new fetal therapies. We aimed to develop a new ethical framework for assessing the risks and benefits of fetal therapy trials. Methods We reviewed existing regulatory and ethical guidance on fetal therapy trials. We used conceptual analysis to design a new ethical framework, which is grounded in general ethical principles for clinical research. Results We propose a new framework for assessing the risks and benefits of fetal therapy trials. We suggest that the potential benefits of a fetal therapy trial – for the fetus, the pregnant person, and society – should outweigh the risks for the fetus and the pregnant person. Furthermore, the risk‐benefit profile for just the fetus and the risk‐benefit profile for just the pregnant person should be appropriate. Conclusions We hope that this new framework will permit important studies while protecting pregnant persons and fetuses from disproportionate harms.

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Section: A New Ethical Frameworkmentioning

confidence: 97%

Section: Existing Ethical Frameworkmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A new ethical framework to determine acceptable risks in fetal therapy trials

et al. 2022

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Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis

Miller,

Baschat,

Rosner

et al. 2023

JAMA

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ImportanceEarly anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival.ObjectiveTo assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia.Design, Setting, and ParticipantsProspective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies.ExposureEnrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks’ gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age.Main Outcomes and MeasuresThe primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement.ResultsThe trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks’ gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks).Conclusions and RelevanceSerial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden.Trial RegistrationClinicalTrials.gov Identifier: NCT03101891

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Precarious hope: Ethical considerations for offering experimental fetal therapies outside of research after initial studies in humans

Hendriks,

Althaus,

Atkinson

et al. 2023

Prenatal Diagnosis

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ObjectiveRisks and benefits of experimental fetal therapies can remain uncertain after initial clinical studies, especially long‐term effects. Nevertheless, pregnant individuals may request them, hoping to benefit their future child. Guidance about offering experimental fetal therapies outside research (as “innovative therapy”) is limited, despite their ethical complexity. We propose points for clinicians and reviewers to consider when deciding whether and how to offer experimental fetal therapies as innovative therapies after initial clinical studies.MethodWe used conceptual analysis and a current case to develop points for consideration, grounded in broader debates on innovative therapy and the unique challenges associated with experimental fetal therapies.ResultsClinicians should evaluate whether offering experimental fetal therapies as innovative therapy is appropriate for a pregnant individual and their fetus. The anticipated risk‐benefit ratio for the fetus should be favorable. For the pregnant individual, risks may outweigh benefits, within reasonable limits. Medical resources should be sufficient to ensure appropriate care. Clinicians should support pregnant individuals in making informed choices. Clinicians offering innovative therapies with more than minimal risk should collect and report data on outcomes. Independent review should take place.ConclusionConsidering these points may advance the interests of fetuses, future children, and their families.

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A New Ethical Framework for Assessing the Unique Challenges of Fetal Therapy Trials

Cited by 22 publications

References 96 publications

A new ethical framework to determine acceptable risks in fetal therapy trials

A new ethical framework to determine acceptable risks in fetal therapy trials

Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis

Precarious hope: Ethical considerations for offering experimental fetal therapies outside of research after initial studies in humans

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