In View: Game Changer
Organ transplantation has come a long way: life-saving procedures in solid organ transplantation have made way to vascular composite allotransplantation (VCA) as a “life-giving” treatment. This treatment has initially been offered for hand and face transplantation, most recently also for uterus transplantation (UTx) in patients suffering from absolute uterine factor infertility (AUFI).
Following a pioneering series of life donor procedures by the group in Gothenburg,1 the first healthy baby has recently been born to a mother in São Paulo after a uterus transplant from a deceased donor.2 This first successful delivery represents a new milestone, making UTx also possible for patients with AUFI who do not have the option for living-donor procedure while avoiding the risks linked to a complex life donor hysterectomy. Reducing the time between transplantation and embryo transfer to 6 months and showing that the deceased donor uterus tolerated a total ischemic time of close to 8 hours were additional important findings by the group in São Paulo. Thus, the success of Ejzenberg et al2 bears the potential to spark another era in this new field that synergizes transplantation, gynecology, and reproductive medicine.
As with many pioneering steps, opportunities and challenges arise. Although numbers on actual organ availability are lacking, an unfavorable discrepancy between demand and supply for deceased donor uterus transplants can be assumed. In the United States, AUFI can be approximated to affect 1 20 000 women of childbearing age (with an estimated prevalence of 1:5001); based on Organ Procurement and Transplantation Network data, however, there have only been 2200 deceased female donors aged 18 to 49 in 2017. Notably, those numbers do not include data on donor papilloma virus infection, pregnancies, history of a hysterectomy, or the geographic distance between procurement and transplant institution resulting into prolonged ischemic times. Although the number of patients ultimately seeking UTx despite the option of surrogacy, adoption, or childlessness will be much lower, a significant deceased donor organ shortage is expected, shared by experts in the field3 and supported additional model calculations.4 Establishing deceased donor UTx as a clinical procedure will therefore require the successful implication of distinct key factors:
- Donor selection: Deceased donor uterus procurement needs to be standardized and promoted, requiring to homogenize medical criteria in the process of donor identification and evaluation. Donor age, for instance, seems to be an important factor affecting uterine graft function. Although the first healthy baby born after living-donor uterus transplant was carried in a womb that was 63 at the time of delivery,5 the impact of uterus age in both deceased and live donor uterus transplants is expected to play an important role for the success of the procedure. Ideally, a deceased donor’s medical history should indicate healthy pregnancies to assure a functioning uterus. This approach, however, will put additional limitations to the amount of available donors. To this end, there is an urgent need to define distinct preprocurement criteria in order to achieve a reasonable balance between deceased donor quality and quantity. Should donors of increased risk be considered as uterus or VCA donors in general? Many may consider this as an unreasonable risk for a non–life-saving procedure. Nevertheless, the risk to transmit donor-derived diseases when utilizing organs from increased risk donors is very small6 and novel treatment options for Hepatitis C have led some institutions to implement programs for life-saving organs (hearts, lungs, livers, and kidneys) utilizing organs from Hepatitis C positive donors in Hepatitis C negative recipients that receive an effective antiviral treatment after transplantation. Indeed, some uterus transplant programs are currently considering organs from Public Health Services increased risk donors to expand the amount of deceased donor uterus availability. Moreover, establishing a generally accepted and feasible deceased donor examination protocol based on time limitations will be important.
- Assuring graft quality: We know only little about tolerable ischemic times. Although the results by Ejzenberg et al2 together with preclinical data7 suggest tolerable ischemia times of 8 hours, further research is required as prolonged ischemic times may not only impact uterus viability but also fertility. Moreover, refining graft storage or graft conditioning and applying methods such as machine perfusion (hypothermic or normothermic) might help to assess and optimize deceased organ quality. An additional aspect of utmost importance will be to get the donor’s consent. Given the nonvital character of UTx together with the sensible nature of fertility and motherhood, a donor’s approval for donation of the uterus cannot be undoubtedly derived from the consent for life-saving solid organs. Therefore, a legal framework is needed, acknowledging this special prerequisite, for example, by implementing an additional UTx donor registry or by extending the consent on organ donor identity cards. Donors and the next-of-kin also need to understand that in vitro fertilization is a critical portion of the process. Naturally, this must be accompanied by providing comprehensive information to the public, raising general awareness, and seeking a maximum of transparency.
- Uterus allocation: Establishing an allocation system will need to incorporate specific ethical requirements associated with UTx. Valuable experience can hereby be derived from the field of VCA with the transplantation of non–life-saving organs. UTx specific criteria have been recently proposed by Bruno and Arora8 in addition to Bayefsky and Berkman,9 and comprise, amongst others, the motivation to parent compared with solely restoring body integrity, child-rearing capacity, successful in vitro fertilization before UTx listing, and prioritizing of yet childless couples. Further aspects may encompass, from a more utilitarian perspective, the number of children designated parents intend to have or a preferential treatment of patients who have experienced a miscarriage in their medical history, which can be associated with a particular severe psychological burden.
In summary, unleashing the potential of deceased donor UTx will rely on multiple challenges that are yet to overcome. At the same time, special caution must also be paid to a potential psychological pressure on AUFI patients linked to societal perceptions and expectations of femininity and motherhood.10 Comprehensive and reasonable implementation of the procedure will therefore require close interdisciplinary cooperation between the areas of transplant surgery, gynecology, reproductive medicine, and psychological assistance, embedded in a legal framework acknowledging specific medical and ethical idiosyncrasies.
1. Brännström M, Johannesson L, Dahm-Kähler P, et al. First clinical uterus transplantation trial: a six-month report. Fertil Steril. 2014;101:1228–1236.
2. Ejzenberg D, Andraus W, Baratelli Carelli Mendes LR, et al. Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility. Lancet. 2019;392:2697–2704.
3. Williams N. Should deceased donation be morally preferred in uterine transplantation trials? Bioethics. 2016;30:415–424.
4. Lavoué V, Vigneau C, Duros S, et al. Which donor for uterus transplants: brain-dead donor or living donor? A systematic review. Transplantation. 2017;101:267–273.
5. Brännström M, Johannesson L, Bokström H, et al. Livebirth after uterus transplantation. Lancet. 2015;385:607–616.
6. Ison MG, Nalesnik MA. An update on donor-derived disease transmission in organ transplantation. Am J Transplant. 2011;11:1123–1130.
7. Del Priore G, Stega J, Sieunarine K, et al. Human uterus retrieval from a multi-organ donor. Obstet Gynecol. 2007;109:101–104.
8. Bruno B, Arora KS. Uterus transplantation: the ethics of using deceased versus living donors. Am J Bioeth. 2018;18:6–15.
9. Bayefsky MJ, Berkman BE. The ethics of allocating uterine transplants. Camb Q Healthc Ethics. 2016;25:350–365.
10. Catsanos R, Rogers W, Lotz M. The ethics of uterus transplantation. Bioethics. 2013;27:65–73.
Following a pioneering series of life-donor procedures by the group in Gothenburg, the first healthy baby has recently been born to a mother in São Paulo after a uterus transplant from a deceased donor.