The following is an editorial in the American Journal of Bioethics, March 2022 issue. It can be found here: https://www.tandfonline.com/toc/uajb20/current
Advancements in fetal assessment and therapeutic intervention in medical practice and clinical research call for corresponding progress in regulatory and ethical guidance. In “A new ethical framework for assessing the unique challenges of fetal therapy trials,” Hendriks et al. (2022) propose a new way of thinking about the ethics of clinical research on fetal therapies, which necessarily involve both the pregnant woman and the fetus. They reject the current view that we should look only at the clinical risks and benefits. Instead, they argue that psychosocial factors are crucial and recommend that considering such factors is the only adequate way to address the asymmetrically distributed risks and benefits that accrue to the fetus and the pregnant woman.
Current US Health and Human Service regulations limit research to studies where the risk to the fetus is minimal unless it holds out the prospect of a direct benefit to the fetus or the pregnant woman (45 C.F.R. 46.204 (b)). Hendricks et al. (2022) argue for an alternative where individual risks for the pregnant woman and the fetus should be justified by both the benefits for each of them and also by the study’s social value, ultimately permitting research with a mildly unfavorable risk–benefit ratio for pregnant women and/or the fetus. Federal regulations guiding pediatric research, based on the Belmont Report and elaborated in the Common Rule Subpart D, offer an instructive perspective and rely heavily on two distinctions (21 C.F.R. 50 (d)). The first is between research and clinical practice. To be considered research, there must be a formal protocol designed to produce generalizable knowledge. Innovative therapy is not necessarily research, and medical practice involves clinical recommendations made in the best interest of an individual patient (Earl 2019).
In pediatric research, there is a further distinction between projects that have a prospect of direct benefit to the child and those that do not (Bhatnagar et al. 2021). With a prospect of direct benefit, protocols must consider whether potential benefits outweigh potential risks. In the absence of this prospect, protocols are only permissible if they involve minimal (or minor increase over minimal) risk. Additionally, many congenital and genetic diseases require intervention before certain stages of maturation or disease progression. The inability to study therapies in adults or even assenting adolescents means we must instead resolve which protocols are permissible for fetal research with no applicable adult model or limited preliminary data.
Despite parallels between pediatric and fetal therapy, the pediatric framework is insufficient to guide the ethical conduct of fetal therapy protocols with pregnant participants. There are important ways in which fetal therapy and fetal therapy research differ from therapy and research involving children. First, almost all fetal research has a prospect of direct benefit which simplifies the analysis. As minimal risk becomes irrelevant, the risk-benefit ratios take priority. The second unique feature of fetal therapy is the more evident one: usually, there are risks to the pregnant woman with no balancing direct medical benefits to her. There are, however, significant indirect benefits. A pregnant woman who consents to a potentially risky antenatal intervention likely does so in the hope that her presumed baby will be better off, the prospect of which is beneficial to her. The medical risks of therapy are balanced by the psychological benefits to the pregnant woman. Outside the scope of traditional medical benefits are intangible aims such as identifying as a “good mother,” benefitting other family members, or the satisfaction that comes from advancing knowledge that may help others. The key threshold question, then, requires a balancing of potential clinical risks and benefits to both fetus and pregnant woman, as well as less tangible though compelling psychological benefits to the pregnant woman. As Hendriks et al. (2022) note, “there is a point at which highly unfavorable risk-benefits to the pregnant women make research unacceptable,” yet precisely how that threshold is established remains unclear.
As members of the Pediatric Gene Therapy and Medical Ethics (PGTME) Working Group housed in NYU Grossman School of Medicine’s Division of Medical Ethics, we examine this issue from the perspective of pediatric gene therapy research in children. In this area too, risk-benefit analysis is one of the main challenges, given the uncertainty of investigational gene therapy products’ curative potential and lack of alternative treatment options for many rare diseases (Webb et al. 2021). We have found that many parents are motivated by ethical commitments not only to their own child but also to the research enterprise devoted to finding cures for other children with the same disease. Parents share that participation in clinical research can provide hope or the psychological benefit of believing that “…she [or he] has done everything she [or he] could,” (Hendriks et al. 2022) and provides the satisfaction of helping to advance genetic interventions for their rare disease community. Pregnant participants may make similar arguments for fetal therapy, especially once the possibility of fetal gene therapy is introduced.
IRBs and investigators must make an independent assessment of the potential risks and magnitude of benefits to the fetus/child-to-be while also considering medical risks and psychological risks and benefits to the pregnant person and her family. Outcomes like decisional regret following therapeutic intervention are a possibility for families. As Crombag et al. (2022) point out, the potential for psychological harm exists along with psychological benefit, with both outcomes being notably subjective.
The role of clinical ethics consultants in exploring these considerations with potential participants is emphasized by both Bartlett et al. (2022)—who note the importance of time, space, and clinical ethics expertise in navigating patient preferences like moral and religious values—and by Riggan et al. (2022), who outline a multidisciplinary approach pioneered by their fetal surgery advisory board. The latter articulate how considerations beyond immediate medical benefits, such as psychosocial benefit to the family, impact on siblings, financial burden, and balance of autonomy may currently be beyond the scope of an IRB and may “hinder timely access to gestational-age-sensitive, maternal-fetal interventions.” They further highlight that while some maternal fetal surgeries are strictly regulated under IRB frameworks, “other procedures are no longer considered experimental, and may even be a new standard of care.” The advisory board serves as an independent third party and additionally offers a “life course perspective” with attention to clinical journeys that may require long-term support in later childhood and adulthood, affecting quality of life.
In “Considering reprogenomics in the ethical future of fetal therapy trials,” Farrell and Michie (2022) discuss how genomic interventions can cause modifications extending beyond the human genome to the epigenome and maternal microbiome. They suggest that updated frameworks explicitly consider that modifications may have “lifelong effects for the fetus, the pregnant patient, and indeed any future offspring.” Risks, they note, may include effects to the pregnancy via obstetric complication or impact on initial developmental stages as well as health and well-being of participants after pregnancy. Here they bring attention to the postpartum state and findings that genomically modified material may persist in participants with far reaching effects. Furthermore, they acknowledge the diverse configurations of families or pregnant persons. These may entail donor sperm, egg or embryos among other guardianship dynamics like surrogacy. These complexities beyond heteronormative cis-gendered biological and wanted pregnancies are not acknowledged at all by federal regulatory guidance and scarcely by the proposed framework.
The most notable element lacking from the Hendriks et al. framework is the significance of reproductive rights. Fry and Premkumar (2022) raise the concern that if abortion is not accessible, there may be potential for greater coercion toward prenatal intervention, and that experimental maternal-fetal therapy, “falsely equates engagement in research with a maternal desire for pregnancy continuation at all costs, thereby stripping pregnant people of reproductive justice.” Regarding access to abortion, Farrell and Michie (2022) note that “in any clinical trial, a plan for adverse effects almost certainly will need to include the possibility of spontaneous or induced abortions among participation,” though jurisdictions have differential access to safe and legal abortions. In “Restrictions on abortion, social justice and the ethics of research in maternal-fetal therapy trials,” Marshall et al. (2022) note that operating on a fetus may be considered among other options including termination of pregnancy or post-birth surgery and raise the question of “what interests accrue to fetuses in involuntary pregnancies.” They demonstrate the imperatives to prioritize reproductive autonomy, call for the routine collection of immediate and long-term outcomes for pregnant trial participants, and raise concerns about fair access, especially for persons of color and socioeconomically disadvantaged populations.
Federal regulations governing IRBs need to consider such elements with consequently critical analysis and update current regulatory and ethical frameworks to keep pace with advancements in fetal therapy research. The risk thresholds of research interventions must be evaluated not just against the potential benefits of the intervention but also against the risks of not doing research or not carefully evaluating therapies especially as we expand our notion of the pregnant woman and fetus beyond an insular dyad. The duty to protect research participants must be balanced with the duty to carefully study the risks and benefits of innovative fetal therapies and to carefully consider the psychosocial impact of these therapies on parents and families with appreciation for reproductive rights and access.
Hunt and Bateman-House report unrestricted funding from Parent Project Muscular Dystrophy that supports their PGTME-related work.