HISTORY OF UTERUS TRANSPLANTATION
Until the recent rise in successful uterus transplantation, options for women affected by congenital or acquired absolute uterine factor infertility (AUFI) have been limited. Although varying significantly by geographic region, some women with AUFI have been able to achieve motherhood through adoption, foster parenthood, or in vitro fertilization with the use of a gestational carrier. Sadly, these options are either financially challenging or come at the cost of personal, religious, or philosophical conflict. These obstacles to parenthood can be prohibitive. Women born with Mayer–Rokitansky–Kuster–Hauser (MRKH, or congenital absence of a uterus) describe this to be a life-framing diagnosis that has critical impact on their relationships, work, and sense of self.1 Alternatives are desirable for the treatment of AUFI.
Since the first baby born from a live donor uterus transplant from living donor uterus transplant (LDUTx) in Sweden (2015),2 developments in the field have proceeded at a rapid pace. In just a few years, the first live birth from a deceased donor uterus (DDUtx) was announced3 and the first successful robotic and laparoscopic uterus transplants have been reported.4-6 Moreover, numerous centers have either embarked upon or are in the process of establishing clinical trials in uterus transplantation.7,8
HISTORY OF THE INTERNATIONAL SOCIETY OF UTERUS TRANSPLANTATION
The International Society of Uterus Transplantation (ISUTx) (www.isutx.org) held their World Congress in Cleveland, Ohio on September 6–7, 2019. The Cleveland meeting was the fourth meeting of the ISUTx since it was founded in 2016 in Gothenburg, Sweden. This meeting was the second biannual international World Congress for the Society; the first World Congress was held in Gothenburg, Sweden in 2017. Given the expedited pace of changes in the field, the Society has agreed to meet on alternate years for state-of-the-art meetings to ensure updated communications from active centers. At the Cleveland meeting, there were over 120 attendees representing transplant teams from almost every continent (Figure 1). Membership of the ISUTx is broad and multidisciplinary, including specialists, scientists, and researchers in transplant surgery, gynecologic surgery, reproductive medicine, maternal fetal medicine, biomedical ethics, and other associated disciplines. The mission of the ISUTx includes facilitating networking and research collaboration, improving education and advocacy, sharing knowledge and new discoveries, promoting research in the field, and establishing both an international outcome registry and consensus guidelines for uterus transplantation.
ETHICS PRECONGRESS WORKSHOP
The precongress ethics workshop focused on research ethics and human subject protections within the context of innovative uterus transplant and reproductive research. Ethicists at the event underscored the importance of revisiting foundational ethical principles and addressing new ethical questions as transplant teams move to new stages in the evolution of this procedure.9 This has particular importance as minimally invasive approaches and alternate vascular outflow techniques may change risk:benefit for LDUTx.10 As research efforts transition to clinical implementation of the procedure, thoughtful ethical discussions become even more relevant. Ethicists at the meeting spoke about maternal-fetal and pediatric considerations, and the relevance of a yet unknown risk:benefit ratio with current small sample sizes. A true understanding of potential obstetrical and neonatal concerns will only emerge as the number of live births increases substantially and as these neonates are followed into adulthood. With those data becoming available, potential risks to donors, partners, recipients, and neonates can be more fully understood. A registry to ensure accurate and complete reporting of outcomes will be an essential next step.
INCREASE IN TRANSPLANT ACTIVITY AND LIVE BIRTHS
As evidenced on day 1 of the World Congress with individual centers providing updates, there has been a sizeable increase in the number of LDUTx and DDUTx performed worldwide. To the best of our knowledge, there have now been at least 70 uterus transplants performed, and 20 healthy infants delivered. Teams from Europe, North America, South America, and Asia have reported live births. Mats Brännström and the Gothenburg team opened the session on the first day with data from the first robotic trial of uterus transplant. Since the last state-of-the-art meeting in Ghent in 2018, increased activities from US teams have been noted, with transplants occurring at Baylor (LDUTx and DDUTx), Cleveland Clinic (DDUTx), and University of Pennsylvania (DDUTx). Reports of the first live births in the United States from both living donor11 and deceased donor12 were presented. The Czech team shared a unique perspective from a large series of 9 deceased and living donor transplants.13 Additional teams from Brazil, Germany, Lebanon, and France reported on their experience as well. A discussion of the commonly encountered complication of vaginal stricture in the recipient highlighted challenges in this area. Transplants are known to have occurred in Belgium, China, and India; however, these teams were not present at the meeting. As more transplants are performed, acceptance of uterus transplant by both professional groups and by the public is similarly increasing.14-16
RISE OF MINIMALLY INVASIVE TECHNIQUES FOR UTERUS TRANSPLANTATION
The cultivation of minimally invasive techniques for LDUTx procurements was a significant topic of discussion at the Congress. Both the Gothenburg and Baylor teams are actively performing this approach in clinical trials with favorable results; transplant success and pregnancies were reported at the meeting. Surgical times appear to be improving with experience, as has been noted throughout the robotics literature in other areas. The Baylor team reported a completely robotic uterus recovery with removal of the specimen using a transvaginal bag. The optimal selection of vessels, including developing the use of the utero-ovarian vessels, for venous drainage has been another discussion. Collection and reporting of additional data regarding surgical times, donor complications with minimally invasive surgeries, and reproductive outcomes are of high importance in ensuring the quality and safety of such an approach. Further, concerns regarding bilateral oophorectomy with living donor hysterectomy was raised at the meeting, highlighting the potential morbidity and mortality for living donors undergoing hysterectomy and oophorectomy in their 4th to 6th decade.17
INCREASE IN USE OF DECEASED DONORS
Although still representing less than one-quarter of the transplants performed around the world, deceased donor uterus transplant intensified in 2018–2019. With recent reports of live births from 2 separate groups (Brazil and Cleveland), the safety and efficacy of the DDUTx is becoming more established. Both the Cleveland and Czech groups have performed >5 DDUTx. Although initial results presented at the meeting identified surgery times and success rates that compare satisfactorily with LDUTx, long term data will ultimately help determine the efficiency and efficacy of deceased versus living donors. The ethical benefits obtained through avoidance of donor risk and the removal of potential “donor guilt” with a failed transplant or unsuccessful pregnancies are clear advantages. Concerns with deceased donor uterus transplant remain limited opportunity to evaluate the graft and patient history before procurement, and limited availability of deceased donors within a suitable geographic radius.18
As more embryo transfers, pregnancies, and live births develop, discussions in uterus transplantation will naturally move to issues relevant to embryo selection, preparation for and timing of embryo transfers, and obstetrical considerations in the uterus transplant recipient. Groups with pregnancy experience shared their data regarding IVF and pregnancy outcomes, which overall show high embryo implantation and successful pregnancies with healthy neonates. Reported challenges included recurrent implantation failures, miscarriages, cervical incompetence, placenta accreta, preeclampsia, and preterm delivery. Another discussion at the Congress focused on CMV in uterus transplantation, and there were variations noted by center in protocols for identification and surveillance for CMV. An area of uncertainly remains management of the CMV+Donor/CMV-Recipient. There was also uncertainty on the use of prenatal genetic testing for aneuploidy for embryos (PGT-A), identifying the optimal interpregnancy interval and determining how long to delay embryo transfer after an episode of rejection. Renal function and blood pressure must be carefully monitored during pregnancy, especially with the known nephrotoxic effects of immunosuppression. Observed changes in renal function that occur during transplantation and pregnancy are expected to resolve postpartum and following removal of the graft; however, long-term data in this area must be carefully monitored.
AREAS FOR RESEARCH
In parallel to establishing clinical uterus transplantation, the field is moving forwarding in identifying and starting to tackle important and unique research questions. From a basic research perspective, uterus transplantation provides a unique “model” with the interaction of recipient, uterus allograft, and semiallogeneic embryo. Consequences on the maternal-fetal interface in this scenario with the addition of immunosuppression will represent an exciting novel area that may provide important and critical data with relevance for and beyond uterus transplantation. For deceased donor uterus transplantation, it will be relevant to understand the impact of unspecific injuries including prolonged ischemia and reperfusion injury on outcomes and alloimmunity. Somewhat surprising have been analyses showing that the availability of donors is limited. Novel approaches of “rejuvenating” organs or alternative preservation methods may thus also be relevant in uterus transplantation and help to improve organ allocation and utilization.
CONCLUSIONS AND FUTURE DIRECTIONS
The 2019 ISUTx World Congress was well attended, dynamic, and collaborative in spirit. There were >20 active and developing uterus teams present from around the world. Key topics in this quickly progressing field were discussed in depth, with each center sharing its experiences to develop a more complete picture for all attendees. Based on data presented at the meeting, it appears that transplant activity has intensified since the last meeting (especially in DDUTx), and that minimally invasive approaches can yield successful grafts with acceptable donor risk. It also appears that both LD and DD can provide suitable uteri for the delivery of healthy neonates. New surgical approaches can and should prompt both technical and ethical questions. Most fundamentally, as this treatment remains relatively new, long-term follow up of donors, recipients, and neonates is essential in deepening our understanding of the procedure and its risks and benefits.
The ISUTx registry must be supported and maintained diligently. Dr Brännström and Dr Dahm-Kähler reviewed the structure and flow of the registry data at the meeting. The new ISUTx board (Figure 2) concluded the meeting and scheduled the next state-of-the-art meeting of the ISUTx in Prague, Czech Republic in 2020 (chaired by Jiri Fronek, incoming ISUTx President). The next World Congress will be held in Boston in the Fall of 2021, chaired by Stefan G. Tullius.
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