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Living Donor Ethics and Uterus Transplantation
This article provides an in-depth ethical analysis of living donor uterus transplantation, incorporating clinical, psychological, and qualitative study data into the discussion. Although the concept of living organ donors as patients in their own right has not always been present in the field of transplantation, this conceptualization informs the framework for living donor ethics that we apply to living uterus donation. This framework takes root in the principles of research ethics, which include respect for persons, beneficence, and justice. It incorporates an analysis based on eight potential vulnerabilities of living donors: capacitational, juridic, deferential, social, medical, situational, allocational, and infrastructural. Finally, it recognizes that special relationships—such as that of the living donor advocate with the potential donor—require special responsibilities, including identifying vulnerabilities and engaging donors in a shared decision-making process. Directed and non-directed uterus donors require separate ethical analyses because their different relationships with recipients will influence the types of vulnerabilities, they are subject to as well as the potential benefits they may gain from donation.
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A Framework for Living Donor Ethics
When describing his discussion with the first successful living kidney donor in the US, Joseph Murray stated:
The donor, a 23-year-old intelligent person, asked a very pointed question: would the doctors at the Peter Bent Brigham Hospital be willing to take care of him medically for the rest of his life if he gave his kidney? We stated that we neither could nor desired to make a guarantee of that sort: we were there to help his brother and if he (the prospective donor) could help his brother, we felt that the chances of success were quite good.
This conceptualization of the donor as part of the medical team reflected a broader conceptualization of the living donor transplantation as a single medical procedure, during which the donor and recipient risks and benefits were considered cumulatively rather than individually. Moreover, while the organ transplant recipient has always been viewed as a patient, the donor is considered a healthy volunteer but not necessarily a patient. In their new book, The Living Organ Donor as Patient, Drs. Lainie Friedman Ross and J. Richard Thistlethwaite argue for the opposing viewpoint: that living donors should be considered patients in their own right even if they are undertaking clinical risks to benefit a third party (Ross and Thistlethwaite 2022).
Ross and Thistlethwaite base their conceptualization of the living organ donor as a patient on the framework of research ethics where one party is exposed to clinical risks to benefit another party. The starting point for their framework is the three principles of the National Commission's Belmont Report (National Commission 1978): respect for persons, beneficence, and justice. Respect for persons has two unique moral requirements: "the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy" (National Commission 1978, Part B.1). Individuals deemed to have diminished autonomy are generally precluded from living donation, so the primary focus of this principle throughout the book is acknowledging the autonomy of the living donor.
The second principle, beneficence, or the utilitarian calculation of risks and benefits, is an obligation to both the individual research subject and the research enterprise. When applied to living donation, the obligation is to the individual donor as well as the donor-recipient pair, the transplant team, and the transplant program. Ross and Thistlethwaite quote Carl Elliott's work on living donor ethics in their discussion of beneficence, a powerful passage that warrants recounting here:
Finally, it is important to realize that the doctor is not a mere instrument of the patient's wishes. Analyses of living organ donation and risky clinical research are [End Page 196] often simplified needlessly by a failure to acknowledge outright that the doctor is also a moral agent who should be held accountable for his actions. If a patient undergoes a harmful procedure, the moral responsibility for that action does not belong to the patient alone; it is shared by the doctor who performs it. Thus, a doctor is in the position of deciding not simply whether a subject's choice is reasonable or morally justifiable, but whether he is morally justified in helping the subject accomplish it.
Finally, justice in the Belmont Report is related to the fair selection of subjects. As Ross and Thistlethwaite explain, this conceptualization of justice can also be applied to living donation: "The fair selection of subjects means ensuring fair opportunities for participation with additional safeguards for members of vulnerable groups to prevent over-reliance because they are convenient or because of social perception of lower worth" (58). They go on to comment that fair selection of subjects does not mean excluding vulnerable groups from donation if their ability to give voluntary and informed consent can be assured.
To safeguard vulnerable groups or persons, the underlying reason or reasons for vulnerability must be identified. Ross and Thistlethwaite utilize a taxonomy of vulnerabilities devised by Kipnis for research, modifying them to apply to living donor transplantation (Kipnis 2001; Ross and Thistlethwaite 2018). The eight vulnerabilities of living donors are identified as: capacitational, juridic, deferential, social, medical, situational, allocational, and infrastructural.
The final element in the framework for the analysis of living donation is to recognize that "special relationships create special responsibilities" (Ross and Thistlethwaite 2022, 69). In the transplant space, the living donor advocate (LDA) or living donor advocate team (LDAT) has a special relationship with potential living donors to promote their best interests, support informed consent, and advocate on their behalf. The goal of the LDA or LDAT should be to help potential donors address their vulnerabilities and engage them in a shared decision-making process.
After developing this extensive framework for the ethical evaluation of living donation, Ross and Thistlethwaite go on to apply it to various living donor populations, including women, minors, prisoners, and non-directed donors, as well as to clinical scenarios such as acute liver failure and paired exchange. Each application of the framework includes a free-standing analysis of the scenario with an explanation of each element of the framework, a process that we will use in this article. Overall, the focus of the book is on kidney donation, as this is by far the most common living donor surgery, with a few chapters dedicated to living liver donation. In the first chapter, pancreas, lung, intestinal, and uterus donation, are discussed, but these procedures are not ultimately evaluated using the framework for living donor ethics.
As members of the highest volume uterus transplant center in the world, we believe that it is the right time to further examine the ethics of living uterus [End Page 197] donation using the framework put forward by Ross and Thistlethwaite. In their brief discussion of living donor uterus transplantation, the authors state: "Given that the availability of deceased donor organs should not be a limiting factor, an important ethical and policy question that has not been addressed in the US is how much higher the success rate of live births from living donor uterine [sic] transplants compared to deceased donor uterine transplants would have to be to justify the risks to the living donors" (39). We begin our analysis of living donor uterus transplantation with a basic historical overview and description of the current state; provide a rebuttal to Ross and Thistlethwaite, arguing that living donation is a viable option for uterus transplantation regardless of deceased donor organ availability; and then apply the living donor ethics framework to two types of uterus donors, related and non-directed.
Living Donor Uterus Transplantation Background
The first successful living donor uterus transplant was performed in Sweden in 2013, resulting in a healthy live birth in 2014 (Brannstrom et al. 2015). The donor was a close family friend of the recipient, who had a diagnosis of Meyer Rokitansky Küster Houser syndrome (MRKH). In 2022, the International Society of Uterus Transplantation published its first report of a worldwide registry; 45 uterus transplant procedures were reported, 78% of which were from live donors (Brannstrom et al. 2022). At the time of the report, 16 recipients had given birth to at least one child. A review of clinical activities and outcomes of uterus transplantation worldwide in 2021 estimated that at least 80 uterus transplants have been performed, resulting in more than 40 live births. According to this report, the success rate for living donor uterus transplantation was 78%, and for deceased donor uterus transplantation was 64% (Brannstrom, Belfort, and Ayoubi 2021). The largest research trial to perform living donor uterus transplantation is the Dallas Uterus Transplant Study (DUETS), which did a total of 20 uterus transplants, 18 from living donors, 17 of whom were not related to the recipients and one of whom was an acquaintance (Testa et al. 2020).
Why Use Living Donors?
There has been much debate over living versus deceased donors for uterus transplantation, with those in favor of only deceased donors arguing that there should be sufficient supply given the low volume of uterus transplants performed, so there is no reason to put living persons at risk when a viable alternative exists (Bruno and Arora 2018, 2020; Ross and Thistlethwaite 2022). If the deceased donor pool is sufficient and the outcomes are comparable, they argue, then living uterus donation may no longer be ethically justifiable. [End Page 198]
In terms of outcomes, there have been more live births after living donor uterus transplantation than deceased donor uterus transplantation, and the success rate is higher (Brannstrom, Belfort, and Ayoubi 2021). Therefore, the condition of comparable outcomes has not been met. Some may argue that outcomes of deceased donation may be lower but still good enough to be acceptable, and that these outcomes should be tolerated, given that this is a quality-of-life transplant. Moreover, while uterus transplantation is currently a low-volume procedure, deceased donors that would be considered acceptable for uterus donation are also rare. A study in France that evaluated 4,544 female deceased donors over five years found that only 124 were considered "very ideal donors," 264 were considered "ideal donors," and 936 would have been "expanded criteria donors." Thus, the number of potential uterus donors is much smaller than both the number of deceased donors overall and the number of female deceased donors (Dion et al. 2022). The authors of this study concluded that the limited number of deceased donor grafts that would be available for uterus transplantation necessitates a complementary strategy of utilizing both living and deceased donor grafts.
Beyond the quality and quantity issues with deceased donor grafts, there are also concerns about the conduct of deceased donor uterus retrieval, namely the risks to the other organs and the complexity that this procedure adds to the overall procurement. The uterus procurement takes place as part of the thoracic and abdominal multiorgan procurement and requires coordination with the other procurement teams. In most reported cases, the uterus is procured using a standard post cross-clamp technique, in which the uterus is removed after the other abdominal organs (Flyckt et al. 2016; Fronek, Janousek, and Chmel 2016; Ozkan et al. 2013). The downside of this technique is that the vasculature is hard to define after cross-clamp and the uterus is subjected to a longer time in situ, during which it is not adequately cooled. Our center developed a deceased donor procurement technique similar to the in situ split liver technique, in which the dissection is done during the warm dissection phase and the uterus is removed and flushed on the back table before cross-clamping for the other organs (Testa et al. 2018). This technique mitigates the technical and quality concerns about post cross-clamp retrieval, but it adds at least a couple of hours to the procurement, during which a donor could become unstable and the other organs could be compromised. Using either procurement technique adds time and complexity to the deceased donor procurement procedure and adds some risk that the other organs being procured could be compromised.
Even if deceased donor uterus transplantation were to meet the criteria of sufficient supply and comparable outcomes, there are several reasons that living uterus donation may still be considered ethically acceptable. In response to Bruno and Arora's (2018) argument that deceased donors should be favored for uterus transplantation, we provided a three-point argument that supports living uterus donation regardless of whether deceased donation is an option (Wall and Testa 2018). [End Page 199] First, the evaluation of living donor uterus grafts will likely remain safer than deceased donors, because living donors can provide a comprehensive medical history and undergo a more thorough workup, meaning that the likelihood of graft failure from donor-related reasons is lower than with deceased donors. Second, living donor uterus transplantation is an elective scheduled procedure, which can be done when the recipient is physically and emotionally ready and can be timed toward the desired pregnancy timeline. Finally, the donor and recipient operations can be done in an overlapping fashion to minimize the cold ischemic time on the uterus. This theoretically decreases the risk of graft loss or non-utilization, but there is not data to support this claim in uterus transplantation. Therefore, living uterus donation provides unique advantages as compared to deceased uterus donation and may be favored by some recipients and transplant centers even if deceased donor grafts are available. Given these advantages, we believe that there are ethically acceptable reasons for living donor uterus transplantation regardless of the quality or availability of deceased donor uterus grafts.
Living donor hysterectomy procedures have evolved similarly to living donor kidney and liver procedures from open to minimally invasive techniques. Robotic or laparoscopic donor hysterectomy has been performed in the US, Sweden, China, Spain, Brazil, and India (Matoba et al. 2021). After performing the first 13 living donor hysterectomies in the DUETS clinical trial open, the team made the transition to a robotic-assisted approach (Johannesson et al. 2021). While the median operative time was longer with the robotic-assisted approach, the median blood loss, length of hospital stay, and length of sick leave were all less. The first robotic-assisted living donor hysterectomy in Brazil resulted in a technically successful recipient uterus transplant, and the donor was discharged from the hospital 48 hours postoperatively (Vieira et al. 2021). The clinical trial in India performed donor hysterectomies with a laparoscopic minimally invasive approach that utilized the utero-ovarian veins as outflow, which reduced both complexity and operative time but required donor oophorectomy (Puntambekar et al. 2018, 2019).
Transplantation from Directed Donors
In the first uterus transplant clinical trial in Sweden, nine uterus transplants were performed, all from living donors who had a relationship with their respective recipients (Brannstrom et al. 2014). Five of the donors were mothers of their recipients, three were other relatives, and one was a family friend. The Czech uterus transplant trial followed with a similar donor population: four out of five living donors were the mothers of recipients, and one was the mother's sister (Chmel et al. 2019). Mothers were also the donors for two recipients in the clinical trial in India (Puntambekar et al. 2019). Because the majority of related uterus donors to date have been mothers, we will specifically focus on mothers as living donors in our ethical framework analysis of directed donor uterus transplantation. [End Page 200]
Respect for Persons
Respect for persons in the living donor ethics framework "requires that the transplant team employ a shared decision-making process in which they empower patients to make decisions that best reflect their own interests and values, free from undue pressure or influence" (Ross and Thistlethwaite 2022, 55). Mothers of daughters with MRKH may feel internal pressure to donate, as they may feel some level of responsibility for their daughters having absolute uterine factor infertility (Wall et al. 2022). In living donor liver transplantation, parents rarely make a rationally informed decision but rather take an "automatic leap" when they hear of the possibility of donation (Duerinckx et al. 2014; Nadalin et al. 2007). Because uterus transplantation is not a life-saving procedure and the potential recipients are adults, mothers may take more time to consider the option of donation than with other solid organs, but more research is needed to learn about living-related uterus donor decision-making processes.
Beneficence
Because uterus transplantation is a new field, the risks and benefits to uterus donors and recipients are somewhat unknown. Donors undergo a hysterectomy with preservation of the vascular pedicles for recipient implantation. This operation is longer and more complex than a simple hysterectomy, and the risks of donor hysterectomy are greater, with ureteral injuries being the most common complication (Johannesson et al. 2021; Kvarnstrom et al. 2017; Ramani et al. 2020). Two of 18 of the donors from the DUETS study (5.5%) had ureteral complications: one had a blood clot that was treated with stent placement and resolved without further interventions, and the other had bilateral thermal injuries that were treated with stents initially, with one requiring surgical reimplantation (Johannesson et al. 2021; Ramiani et al. 2020). One of the nine living donors from Sweden (5.5%) developed a ureteric vaginal fistula that was initially managed with a stent and eventually required surgical reimplantation (Kvarnstrom et al. 2017). None of these donors have had long-term renal consequences from their ureteral complications.
The benefit to mothers as related living donors for uterus transplantation is that they have the opportunity to become grandmothers to the children born from their donation. The donation itself, even if unsuccessful, may still be of benefit to mothers who feel that they at least did what they could to help their daughters. In a study of the psychological outcomes one year after living donation in Sweden, donors whose recipients had graft failure did not regret their decision to donate (Kvarnstrom et al. 2017). Like liver and kidney donors, we believe that uterus donors must be supported by an LDA or LDAT who helps the donor in a shared decision-making process that allows her to make a decision that is in line with her interests, values, and beliefs. [End Page 201]
Justice
Preferentially selecting mothers as living uterus donors makes sense both relationally and immunologically. Because uterus transplantation is a quality-of-life transplant, there may be increased acceptance of mothers as living donors when compared to altruistic stranger donations, which may be perceived as unacceptable risk-taking similar to living liver donors (Thomas et al. 2014). However, if mothers are the preferred donors, they could be subject to deferential vulnerability, especially if potential recipients are encouraged to look within their family for a related donor, as is required by some uterus transplant programs.
Vulnerability Analysis
Using Ross and Thistlethwaite's framework, we will now address the eight vulnerabilities of living donors. The first vulnerability is capacitational, which hinges on whether the living donor has the capacity to deliberate about donation. There is no urgency to the decision about uterus donation, so potential donors should be given sufficient time and information to make an informed decision about donation. Those who do not have capacity should be categorically denied as living donors. Juridic vulnerability is concerned with whether potential donors are liable to the formal legal authority of others who have an independent interest in donation. This is generally not the case for living-related uterus donors. The third vulnerability is deferential, which is exhibiting behaviors that may mask an unwillingness to participate. This can be self-imposed and may apply to mothers as living uterus donors who want to please their family or "make up" for their daughters' infertility. The challenge with deferential vulnerability is "to devise a process that eliminates as much as possible the social pressures that the potential living donors 'may feel even if, in reality, they are not being imposed'" (Ross and Thistlethwaite 2022, 61, citing Kipnis 2003, 113). Transplant centers can decrease the risk of deferential vulnerability by accepting non-directed as well as directed living donors and offering the option of deceased donor uterus transplantation so that mothers do not feel that being a donor for their daughters is the only possibility. Social vulnerability refers to donors who are in groups whose rights and interests have been socially disvalued. In their discussion of women as living donors, Ross and Thistlethwaite comment that women are less commonly the wage earners in their families, so when families look to members for organ donation, women may be favored so that wage earners can continue to financially support their families. Even if families do not put pressure on non-wage earners, the non-wage earners themselves may volunteer to donate in order to contribute to the family. The options for familial uterine donors are exclusively women. However, as motioned above, mothers may volunteer as donors because of a feeling of responsibility for their daughters' infertility as well as a social desire to be a grandparent. [End Page 202]
Medical vulnerability occurs when a donor is selected because of a serious health-related condition in the recipient for which less satisfactory alternative options exist. In this part of the analysis, it is important to note that infertility is defined as a disease by the World Health Organization, and that they define fertility care as one of the core elements of reproductive health (WHO 2020). Moreover, the psychological impact of infertility is similar to that of serious medical illnesses such as cancer, hypertension, and HIV (Domar, Zuttermeister, and Friedman 1993). Therefore, while absolute uterine factor infertility may not be a life-threatening condition, it is a serious medical illness for which some women feel that adoption and surrogacy are less satisfactory options (Wall et al. 2022). Mothers may be subject to medical vulnerability if their daughters have decided that uterus transplantation is their preferred option for parenthood. Situational vulnerability refers to time constraints on the donation. Living donor uterus transplantation is an elective procedure that can be scheduled when the donor and recipient are ready, so there should not be time constraints that create situational vulnerability. Allocational vulnerability asks if the living donor is lacking in subjectively important social goods that will result from being a donor. Mothers of recipients may feel that they are lacking in the social good of being a grandparent and that a uterus donation would allow them to obtain this social good, so there may be some level of allocational vulnerability even though there are alternative pathways to parenthood, such as adoption and surrogacy, for potential recipients. Finally, infrastructural vulnerability is related to the political, organizational, economic, and social context of the donor care setting. For living uterus donors, the institution must have processes in place to support potential donors pre- and post-donation, as well as provide long-term follow-up for donors.
Special Relationships
The concept of the importance of special relationships described by Ross and Thistlethwaite is based on Goodin's (1985) work on vulnerability, which argues that "we bear special responsibilities for protecting those who are particularly vulnerable to us" (109). Specifically, doctors have a responsibility to protect the interests of their patients. Ross and Thistlethwaite argue that LDAs or LDATs have a special relationship with the potential living donor and therefore have special responsibilities to protect them. The goal of the LDA or LDAT is to examine the potential vulnerabilities of the living donor and help with shared decision-making about donation that focuses on ensuring adequate informed consent. For mothers as living donors, the LDA or LDAT need to ensure that potential living donors are not under undue personal or familial pressure to donate and are making decisions that are well-informed and in line with their personal goals and values. [End Page 203]
Transplantation from Non-Directed Donors
Baylor University Medical Center, which performed the DUETS study, utilized non-directed living uterus donors for 17 of 18 living donor uterus transplants in their clinical trial. The choice to proceed with non-directed living donors was due to the overwhelming number of volunteers that applied to the clinical trial to be potential uterus donors (Johannesson et al. 2018; Testa et al. 2020). All potential donors underwent detailed medical and psychological screening (Johannesson et al. 2018). Potential donors were motivated to donate to give another woman the opportunity to carry her own child (Warren et al. 2018). In the clinical trial protocol, donors and recipients were allowed to meet if they mutually agreed to do so, but only after the recipient had either had a graft hysterectomy or at least one successful live birth. The ethical framework analysis of non-directed living uterus donation differs from living-related uterus donation because the donors are not influenced by their knowledge of the recipients' struggle with infertility or their relationship with the recipients.
Respect for Persons
Respect for persons in the living donor ethics framework "requires that the transplant team employ a shared decision-making process in which they empower patients to make decisions that best reflect their own interests and values, free from undue pressure or influence" (Ross and Thistlethwaite 2022, 55). Unlike mothers as directed donors, non-directed donors have no relationship with their recipients so they do not experience familial or personal pressure to donate to a particular person. While the LDA or LDAT should be involved in the donor evaluation, there is a lower likelihood of undue pressure from others toward non-directed uterus donation.
Beneficence
The living donor hysterectomy procedure is the same for directed and non-directed donors. Donors undergo a hysterectomy with preservation of the vascular pedicles for recipient implantation. This operation is longer and more complex than a simple hysterectomy, and the risks of donor hysterectomy are greater, with ureteral injuries being the most common complication (Johannesson et al. 2021; Kvarnstrom et al. 2017; Ramani et al. 2020). The benefit to non-directed living donors is the knowledge that they gave another woman the opportunity to carry her own child, even if they never meet their recipient or the recipient's offspring.
Justice
In terms of preferential selection of particular groups of donors for uterus transplantation, the obvious shared characteristic is that all donors are women, and as discussed in relation to directed donors, women are more commonly donors [End Page 204] for other organs due to social pressure and family constructs. In the case of non-directed donation, potential donors are not subject to social or family pressure to donate to benefit a particular recipient. However, as uterus transplantation expands throughout the world, centers must be careful to make sure that non-directed uterus donors are not motivated by financial or other incentives that create undue pressure to donate. Currently, living uterus donors do not receive any financial incentives or compensation for uterus donation.
Vulnerability Analysis
Using Ross and Thistlethwaite's framework, we will again address the eight vulnerabilities of living donors with attention to the non-directed uterus donor. The first two vulnerabilities are the same between directed and non-directed uterus donors, so this initial part of the analysis is repetitive with the directed uterus donor evaluation. The first vulnerability is capacitational, which asks if the living donor has the capacity to deliberate about donation. Since there is no urgency to the decision about uterus donation, potential donors should be given sufficient time and information to make an informed decision about donation. Those who do not have capacity should be categorically denied as living donors. Juridic vulnerability asks if potential donors are liable to the authority of others who have an independent interest in donation, and this is generally not the case for non-directed uterus donors.
The third vulnerability is deferential, which is exhibiting behaviors that may mask an unwillingness to participate. Unlike directed donors, potential non-directed donors do not have a relationship with the potential recipient and therefore should not be subject to deferential vulnerability through familial or internal pressure. Social vulnerability refers to donors who are in groups whose rights and interests have been socially disvalued. While women are commonly donors in familial donation, non-directed female donors are not in a position of social dis-value. Medical vulnerability occurs when a donor is selected because of a serious health-related condition in the recipient for which less satisfactory alternative options exist. Because non-directed donors do not have a relationship with their potential recipients, they should not be biased by medical vulnerability concerns about the recipient. Situational vulnerability refers to time constraints on the donation. Because uterus transplantation is an elective procedure, there are no time constraints on non-directed donors. Allocational vulnerability asks if the living donor is lacking in subjectively important social goods that will result from being a donor. The characteristics of the first six live non-directed uterus donors in the DUETS trial include income over $60,000 per year and a bachelor's degree or higher, suggesting as with other groups of non-directed donors that they do not have a serious allocational vulnerability (Kumar et al. 2017; Warren et al. 2018). Finally, infrastructural vulnerability is related to the political, organizational, economic, and social context of the donor care setting. Just as with directed [End Page 205] uterus donation, centers that accept non-directed uterus donors should have the resources to follow these patients long-term.
Special Relationships
LDAs or LDATs have a special relationship with the potential living donor and therefore have special responsibilities to protect them. It is the responsibility of the LDA or LDAT to ensure that potential non-directed uterus donors give informed and voluntary consent for the procedure, and particularly that the donors are aware that even non-directed donors can have negative outcomes, including having to face the challenge of telling others why they decided to donate, as well as financial, physical, and mental health problems (Balliet et al. 2019; Rodrigue et al. 2011; Ross and Thistlethwaite 2022).
Conclusion
The framework for living donor ethics developed by Ross and Thistlethwaite is an excellent tool for the evaluation of individual clinical cases, as well as for new advancements in living donation, such as living donor uterus transplantation. In this article, we applied the framework to directed and non-directed uterus donors, using current evidence about donor outcomes and experiences. Directed uterus donors, specifically those who are mothers to their recipients, may be subject to social, deferential, and allocational vulnerabilities, all of which are less likely to be concerns with non-directed living uterus donors. These vulnerabilities can be identified and addressed by LDAs or LDATs, still allowing for voluntary informed consent for uterus donation.
We believe that living uterus donation is an ethically acceptable option for uterus transplantation based on the unique advantages of living donation over deceased donation, but that it must be done with attention to potential vulnerabilities and safeguards in place to protect the interests of potential donors.
anji.wall@bswhealth.org
