How Surgical Research Gave Birth to a New Clinical Surgical Field: A Viewpoint from the Dallas Uterus Transplant Study

Since the turn of the millennium, uterus transplantation (UTx) has progressed from an experimental animal model to successful human clinical trials to being offered as a clinical nonexperimental procedure [1, 2], to treat absolute uterine infertility in women desiring to carry their own pregnancies. This rapid development was enabled in part by groundwork laid more generally for solid organ transplantation during the late 19th and 20th centuries, including the development of blood vessel anastomosis techniques [3‒5], establishment of the tenets of transplantation immunology, and the related development of techniques for antibody screening, as well as identification of effective protocols of chemical immunosuppression to enable graft survival [4]. Other more general developments from which UTx research benefited include the development of minimally invasive surgery and its application to living donor surgeries [6] and the availability of registry data of women who experienced pregnancy after solid organ transplantation, from which UTx immunosuppression regimens were developed with drugs approved by the FDA for use during pregnancy [7‒9].

UTx differs significantly from other solid organ transplants in that not only must it be technically and immunologically feasible, but also the transplanted uterus must be able to support pregnancy and a healthy live birth (Fig. 1). Although the first human UTx was attempted in 2000 [10] with little evidence from or experience with animal studies [11], the clinical trials and UTx programs that have demonstrated success were built on a significant foundation of animal research, and animal studies have continued in tandem with the human UTx trials, both for team training purposes and to test new and evolving UTx techniques [11].

UTx animal research has been detailed extensively elsewhere [7, 11]. Briefly, however, they have included key demonstrations and advances in understanding pivotal to the success of human UTx: rodent studies established the proof of concept of pregnancy in a transplanted uterus [12] and allogeneic transplanted uteri [13], that implantation and miscarriage rates were similar in transplanted and native uteri [14], that the uterus tolerates extended cold ischemic times [15], that use of the immmunosuppressants cyclosporin and tacrolimus before and during pregnancy decreases implantation rates and increases miscarriage rates [13, 16, 17], that the uterine denervation and/or vaginal stricture resulting in UTx recipients requires cesarean delivery to achieve similar rates of live births to native uterine pregnancies [18], and that birthweights and growth trajectories in offspring of allogeneic UTx were similar to those in offspring of native uterine pregnancies [17]. Sheep studies demonstrated the first live births (via cesarean section) after UTx in a large animal species [19] and that pregnancy proceeded normally in an allogeneic uterine graft in a large animal species with a relatively long gestation period [20], as well as establishing the tolerance for up to 24 h cold ischemic time in a uterus of similar size to the human uterus [21], and the need for induction and maintenance of immunosuppression protocols similar to those used after renal, hepatic, and cardiac transplantation in humans (but discontinuing components known to cause fetal malformations before pregnancy) to prevent graft rejection [22, 23]. Nonhuman primate studies were critical to establishing the safety and effectiveness of the UTx technique before initiating human trials [11]. The first primate study was an autologous baboon model in which technical success of the UTx was achieved in only 2 of the 10 baboons, demonstrating the need for further methodological developments [24]. Modifications to the surgical technique, including procuring entire internal iliac arteries and utero-ovarian veins and using histidine-tryptophan-ketoglutarate for flushing, improved technical success to 60%, but no pregnancies occurred despite multiple rounds of mating likely due to pelvic adhesions and non-patent oviducts [25], leading to the conclusion that oviducts should not be transplanted with the uterus in human UTx [11]. Studies conducted in cynomolgus macaques examined vascular anatomy of the uterus, establishing that venous drainage occurred through deep uterine veins, superficial uterine veins, and ovarian veins [26], and demonstrated technical success with autologous UTx using different venous vascular pedicles [26, 27] as well as the first natural pregnancy and live birth in a primate following UTx [27]. Nonhuman primate allogeneic UTx studies demonstrated the challenges of achieving adequate immunosuppression, confirming the need for induction immunosuppression and the use of combination maintenance immunosuppression [28‒30]. One of the allogeneic UTx baboon studies also established that cervical biopsies were sufficient to diagnose rejection, leading to the development of a uterine rejection scoring system [28] that was modified for use in human UTx [31].

Nonhuman primate studies continued after clinical trials of human UTx began, contributing evidence regarding alternative venous vascular pedicles and vascular anastomoses relevant to the continued evolution of UTx surgical techniques. For example, studies in cynomolgus macaques demonstrated that use of ovarian veins meaningfully reduced the operative time for living donors [32] and that duration of vascular anastomoses to the iliac vessels was superior to the aorta and vena cava [33].

The first technically successful human UTx was performed in Turkey in 2011 using a deceased donor, and a live birth was reported 9 years after transplant [34‒37]. The first human clinical trial was established in Sweden in 2012, enrolling 10 donor-recipient pairs [38], within which context the first live birth after UTx occurred in 2014 [39]. The first live birth following deceased donor UTx was reported in 2018 [40]. As of 2022, more than 80 UTx procedures have been performed in almost 20 centers in Europe, North America, Latin America, and Asia, resulting in more than 40 live births [41, 42]. In the decade that has followed the initiation of the first human clinical trial, there has been substantial evolution and innovation in the donor and recipient procedures and protocols, aimed at the dual goals of decreasing morbidity for living donors and recipients and increasing success rates of achieving live births.

Alongside the technical advancements in UTx, work was done on building ethical consensus around this procedure. Early work in the development of the Montreal Criteria proposed the first set of standards for recipients, donors, and the healthcare team [43, 44]. Recipient criteria included being a genetic female, having a contraindication to surrogacy and adoption, seeking UTx solely for gestational purposes, passing a psychological evaluation, and being suitable for motherhood. As data have been gathered on recipient experiences, further evidence of the unique benefits of UTx over alternatives as well as the value that patients gain from UTx are shifting the ethical conversation away from UTx as a last resort and toward UTx as one of multiple options for women with AUFI [45].

In the USA, four institutions have started UTx programs since 2015/2016, but only two programs have performed more than three cases each [46]. This reflects the challenges associated with establishing, financing, and maintaining a uterus transplant program. Thus, a systematic evaluation of regional need, local expertise, and institutional resources is beneficial to any center considering the addition of a uterus transplant program. In 2015, when Baylor University Medical Center, Dallas, established a uterus transplant program (The Dallas Uterus Transplant Study [DUETS]), the uterus transplant scene was novel and small. Only three centers worldwide (one in Europe and two in the Middle East) had performed uterus transplantations in humans, only one of these centers had performed more than a single case, and only one center had a successful live birth in a uterus transplant recipient [47]. So, at the point when the DUETS trial started, proof of concept had been achieved with uterine grafts from a living donor at a single center [48]. A successful procedure had not been reproduced at another center and the donor and recipient surgeries were all done using an open technique.

The DUETS has pushed the field of UTx forward in terms of volume, outcomes, technical innovation, and academic productivity. The infrastructure utilized to foster innovation in all aspects of UTx was based on the experience gained in advancing solid organ transplantation through the process of clinical trials [49]. In addition, we built on the experience and concepts from other medical specialties such as obstetrics and gynecology, reproductive endocrinology, pathology, and radiology, in areas unique to UTx that were not comparable to solid organ transplantation. Herein, we present our research trial experience, the innovations that we spearheaded, and the process of moving UTx from a research endeavor to a durable, successful clinical uterus transplant program (Fig. 2).

The Baylor Scott & White Research Institute Institutional Review Board (IRB) approved DUETS in 2015. In addition to the IRB, the study proposal was discussed and approved by the Institutional Ethical Committee and clinical operations. After approval, the study was listed on clinicaltrials.gov (NCT02656550). The initial 20 cases were completely funded by the Baylor Scott & White Research Institute. The study protocol was designed for both living and deceased donor transplantations. Although no guidelines existed for UTx, our program followed all rules and regulations set by the United Network for Organ Sharing for living and deceased donor abdominal organ transplantation [50].

We discovered in this process that a uterus transplant program requires an intricate network of physicians, nurses, technicians, and administrators to function smoothly and effectively. Due to the medical and surgical complexity and need for long-term follow-up in UTx, the composition of the team is imperative. Key representatives were identified from transplant surgery, gynecologic surgery, obstetrics, maternal-fetal medicine, reproductive endocrinology, psychology, neonatology, pathology, nursing, and radiology. In addition, we collaborated with an already active UTx center in Sweden to develop protocols, review selection criteria, approve candidates, and proctor the initial operations.

After IRB approval, potential recipients and donors started contacting our center. The initial recruitment experience for UTx recipients and donors, the screening protocol, and demographic data (i.e., age, body mass index, current smoking, and number of children) have been previously published [51]. Twenty recipients and 18 living donors were enrolled in the study and underwent transplantation or donation procedures. Prior to final enrollment, the 20 potential recipients who met enrollment criteria and wanted to proceed with UTx underwent in vitro fertilization [52].

In 2016, we performed the first 5 uterus transplants in the DUETS trial [53]. The first four UTx were performed with the assistance of part of the team from Sweden and were the 11th to 14th living donor UTx performed in the world. The first three uterus transplants in our trial failed and had to be removed within days of the index operation [53]. During 2016, several changes were made to the operative techniques and approaches because of these early graft failures (Table 1).

Ultimately, the focus of these first 5 cases was on the technical details of the donor and recipient operations, with a goal of improving techniques to achieve technical success. Immunosuppression regimens utilized institutional protocols for kidney transplantation and protocols from earlier uterus transplant trials. Based on cervical biopsies, we developed a histopathological grading system and treatment strategy [54]. Embryo transfer (ET) was planned 6 months after UTx, which was shorter than the traditional 12-month wait that other UTx centers had utilized [55].

With two technically successful transplants by the end of 2016, the next year of the study added three more successes and one early graft failure. The first case of 2017 was the first deceased donor operation at our center and one of the first in the world, during which a technique for deceased donor hysterectomy that mimicked the living donor approach was pioneered [56]. In addition to this innovation in deceased donor, refinements were made to the recipient clinical protocol this year (see Table 1) to improve chances of success and reduce risk to the recipients. The former included addition of routine intraoperative intravenous heparin prior to reperfusion to the recipient protocol, based on our experience with the eighth transplant, which remained ischemic after vascular clamp removal despite visually and Doppler-tested patent anastomoses. The importance of anticoagulation, as well as strategies such as intraoperative assessment of anastomotic site patency by Doppler velocimetry and postoperative ultrasound monitoring, to mitigate graft loss due to thrombosis is emphasized by early reports from the UTx registries/consortia, in which thrombosis was the leading cause of graft loss [41, 42]. Refinements to the DUETS protocol aimed at reducing risk to the recipients involved changes to the immunosuppression protocol that allowed ET as early as 3 months after induction therapy [55].

Four more UTx were performed at our center in 2018. Unfortunately, the tenth recipient had early graft failure secondary to ischemia of the graft attributed to atherosclerotic disease in the donor, based on which we altered the inclusion criteria and evaluation protocol for living donors to avoid repeated occurrences (see Table 1) [57, 58]. The subsequent three uterus transplants that year were technically successful, and with the change in immunosuppression regimen instituted in 2017, two recipients from 2018 were able to achieve a live birth less than a year after UTx.

The final year of the clinical trial was both the highest volume year and the most innovative with the introduction of robotic technology (Table 1). For the last 5 living donors of the 7 done this year, the donor hysterectomy was performed using a robot-assisted technique with extraction of the uterus graft through the vagina.

Other UTx centers were similarly introducing minimally invasive living donor surgeries around this time with the aim of decreasing morbidity for donors – including an early report from China in 2017 describing a robotic-assisted donor hysterectomy (RADH) [59] and reports from India [60, 61] and Sweden [62, 63] of approaches in which part of the dissection and the uterus extraction were done via an abdominal incision [61, 64]. The DUETS approach was unique in that it was fully robotic-assisted with transvaginal extraction of the graft using a sterile bag (Endo-catch) for graft removal and demonstrated no damage to the uterine grafts or their vascular pedicles with this extraction method [65, 66]. This same approach to the donor hysterectomy was used in the first successful UTx in Spain, in late 2020 [67]. In addition to the DUETS RADHs, one recipient graft hysterectomy was performed 2 months after delivery using a robotic-assisted approach in 2019.

Technical success was achieved in 14 of 20 UTx recipients. Of the 6 graft failures, 5 occurred early in the series. The first three living donor grafts (cases 1, 2, and 3) were lost to vascular complications (2 to venous outflow obstruction and 1 to arterial thrombosis). Two subsequent grafts, 1 from a living donor (case 10) and 1 from a deceased donor (case 8), remained ischemic after vascular clamp removal despite visually and Doppler-tested patent anastomoses. One living donor graft (case 14) failed due to ischemia caused by hemorrhagic hypovolemia secondary to bleeding from the stump of the obturator branch of the donor internal iliac artery, recognized 6 h postoperatively. No graft failures occurred more than 7 days post-UTx. Twelve of the 14 recipients with graft survival beyond 1 year have delivered one or two healthy babies [68, 69]. Notably, the first live birth in the DUETS trial was for the same recipient who had the first operation utilizing the superior uterine veins [70]. The remaining 2 women are either pregnant or undergoing ET.

After completion of the first 20 transplants, the outcomes were thoroughly evaluated by a committee of clinical staff, hospital administration, and ethics experts. After 8 months of systematic review, a decision was made to continue the uterus transplant program outside of a research study. One of the main barriers to offering UTx as a clinical procedure is that it is not covered by insurance in the USA, as is common to infertility care. Therefore, we had to conduct a financial analysis to determine the projected cost of the clinical procedure which included direct and indirect costs associated with the entire process of UTx from evaluation of the recipient and donor to live birth and graft hysterectomy. With these data, a committee of clinical staff, financial staff, and hospital administration explored the option of offering self-pay uterus transplant services. The team considered various pricing models and decided on a package pricing model where a complete deposit is paid up-front. In addition, our treatment protocols were streamlined to avoid unnecessary interventions, testing, and medications. Whereas the research patients had to relocate to a radius of 50 miles of Dallas, this did not apply to the patients in the clinical program. This gave our program the opportunity to reach out to collaborators in centers close to the patient’s home so they could be remotely managed by our team during parts of the postoperative and pregnancy courses. Our collaborators included national and international centers of transplant surgery, gynecology, maternal-fetal medicine, obstetrics, and reproductive endocrinology. All the work done during this year was in preparation for starting the clinical program. Due to the COVID-19 pandemic, no UTx was performed in 2020, even though the program was ready to start.

From 2021 to May 2022, the first 3 clinical program cases of UTx were performed utilizing uteri from non-directed living donors, all of which were technically successful. All donor hysterectomies were performed using our robot-assisted technique with extraction of the uterus graft through the vagina. Moreover, the first live birth from the clinical program occurred in 2022. There has continued to be a high level of interest from both potential recipients and potential living donors, and more UTx have been approved and are planned for 2022.

The DUETS clinical trial shows how innovation in surgical technique, the use of technology, and immunosuppression have progressed the field of uterus transplantation, building off the strong foundations of research-based clinical practice across the fields of transplantation, obstetrics and gynecology, and reproductive endocrinology. We show how the innovations happened over time and how the outcomes improved with these innovations.

One of the first major innovations that we made in the approach for uterus donation and transplantation was to procure both the superior and inferior uterine veins from donors and use the best option in terms of size and location for outflow [71]. The premise of being able to choose which vein to use is based on experiences from kidney transplantation, in which one of the veins in a kidney with multiple veins can be performed without impacting graft function, and on experience with trachelectomies [72]. Because veins will drain the entire organ rather than specific territories, having the choice of outflow is key to success in terms of both procuring a donor graft that can be used for transplantation and implanting the graft into the recipient. Moreover, the ability to utilize the superior uterine veins allows for both sparing of the ovaries in the donor and a more straightforward donor operation, both of which are key to the transition to the robotic-assisted living donor technique [64, 65].

Another major innovation in living uterus donation that we introduced was the RADH with transvaginal extraction of the uterus [65, 66]. Other UTx trials have reported minimally invasive living donor hysterectomy but with some differences compared to our technique, such as removal of donor ovaries as part of the procedure [60, 73], conversion to open surgery [62, 63], and/or extraction of the graft through an abdominal incision [59, 60, 62, 63, 73]. Our technique has improved the donor experience by decreasing the length of stay and time away from work, and we believe it represents a safe and reproducible minimally invasive approach to this operation [65, 66]. The choice of moving from an open technique directly to robotic rather than laparoscopic minimally invasive donor hysterectomy was based on prior experience with both robotic living donor nephrectomy and robotic radical hysterectomy at our center. We felt that the better visualization and wrist manipulation of the robotic platform improved our ability to mobilize and preserve the vessels needed for implantation [74]. With the success of robotic donor hysterectomy, we expanded the use of robotics to include graft hysterectomies in selected cases.

A third major innovation from our center was shortening of the time between UTx and ET and, consequently, the time from UTx to graft hysterectomy. This offers two advantages: (1) a shorter graft-recipient time and (2) a longer time to achieve the goal of a second pregnancy for those who desire it within the 5-year graft-recipient time limitation set by most UTx programs [55]. Compared to other UTx studies, the shortened time interval from UTx to ET alone reduced the time from UTx to the first live birth by an average of 7 months in our recipients [55, 69].

Not only did the DUETS trial introduce medical and surgical innovations, we also demonstrated a novel pathway to provide UTx as a clinical option. Unlike other solid transplant organs, the main barriers to UTx as clinical option were cost along with lack of insurance coverage, regulation, and oversight. As a first step toward future administrative management such as claims processing, Current Procedural Terminology (CPT) codes were established for UTx and donation in 2020 [75]. Effective in 2021, membership requirements for UTx programs were established under the US Department of Health and Human Services (DHHS) Organ Procurement and Transplantation Network (OPTN) [76]. These requirements establish universal expectations in terms of (1) quality control of the performing facilities and personnel, (2) protocols for candidate wait-listing and organ allocation, and (3) collection of standardized data elements [77].

Even as UTx is offered more widely as a clinical option, opportunities persist for research to continue to improve the experience and outcomes for both recipients and living donors. The duration of living donor hysterectomy, for example, frequently exceeds 10 h, increasing the risk for postoperative complications; some centers have, however, been able to reduce the surgical time to 4–6 h, offering the opportunity to compare the approaches used and outcomes achieved to establish best practices that can then be standardized across programs, particularly as the volumes of data become available to compare recipient outcomes according to choice of venous outflow vessel, which has substantial implications for living donor hysterectomy time [41]. Improvements in transplant-related complications for recipients may also be achieved. Current reports indicate that 43–52% of recipients with 10- to 12-month graft survival experience 1 or more episodes of rejection [41, 42], and rejection episodes during pregnancy have been reported [42]. While most episodes of rejection were successfully resolved with steroid cycles, others required more intensive treatment, and in some patients, they recurred frequently (up to 5 episodes in 10 months) [41, 42]. Continuing advancement in immunosuppression protocols – and/or prediction of recipients or donor-recipient pairings likely to experience severe or recurrent episodes of rejection – could reduce the associated morbidity for recipients. Likewise, vaginal stricture is a common complication for UTx recipients, with as many as half of those developing this complication requiring surgical intervention, which carries risks of genitourinary injury [42]. Strategies to reduce the incidence of this complication continue to be investigated [78]. Additional areas for continued research include pregnancy complications – which have been noted to be more frequent than expected [41], although successfully managed following standard obstetrical care [42] – and impact of donor characteristics such as age and chronic conditions on recipient outcomes [41].

In conclusion, our center has demonstrated that UTx can be reproducible, result in live births from both living and deceased donors, and be safely introduced as a clinical option. The success of UTx at our center and multiple institutions worldwide supports expanding UTx to other centers, which follows the footsteps of other solid organ transplants. Due to the complexity of UTx as well as the need for long-term multidisciplinary care, we suggest that any center implementing an UTx program have an established abdominal transplant program, a gynecologic surgery program, high-risk obstetric and neonatal care, and institutional support and oversight. We also recommend that new centers partner with established programs for protocol development and operative proctoring.

The authors have no conflicts of interest to declare.

No funding was received for this work.

Liza Johannesson and Anji Wall: conceptualization, methodology, writing-original draft preparation, reviewing, and editing. Briget da Graca: writing-original draft preparation. Giuliano Testa: methodology, reviewing, and editing.