Uterus transplantation (UTx) is a young, albeit rapidly growing field in medicine in which multidisciplinary efforts of transplantation surgery, gynecology, and assisted reproduction technologies are synergized. The first clinical transplantation trial was launched in 2012 in Sweden following extensive preparatory work in small and large animals.1,2 The first baby born to a recipient of a live donor uterus transplant in Sweden had been the third attempt, preceded by a live donor procedure in Saudi Arabia (2000) and a deceased donor procedure in Turkey (2011). Attempts in Saudi Arabia and Turkey had failed due to surgical complications or have not resulted into the birth of a healthy baby.3,4
The mother of this first baby born after a uterus transplant suffered from absolute uterine infertility due to Mayer-Rokitansky-Kuester-Hauser (MRKH) syndrome. She was 35 year old and had received a living donor (unrelated) uterus transplant (LDUTx) from a 61-year-old donor in Gothenburg. A first attempt of an embryo transfer had been successful and the embryo had been cryopreserved at the 8-cell stage. This transplant had been part of a series of 9 living donor transplants in Sweden and initiated activities at several centers around the world to set up clinical UTx studies with variations regarding major surgical techniques and donor selection.5 Additional key events have been the first healthy baby born to a recipient of a nondirected living donor in the United States6 and the first baby born to a recipient of a deceased donor uterus transplant (DDUTx) in Sao Paulo, Brazil.7
INTERNATIONAL SOCIETY OF UTERUS TRANSPLANTATION (ISUTX)
ISUTx (www.isutx.org) has been founded in Gothenburg, Sweden (2016), with participants from centers worldwide with an interest in clinical and experimental UTx. The ISUTx is truly multidisciplinary with members representing gynecology, reproductive medicine, transplantation surgery, nephrology, maternal-fetal medicine, psychology, and medical ethics. The society aims to exchange data efficiently, to foster clinical and experimental research, to facilitate the communication between all disciplines advancing the field, and to maintain an international registry to assure quality and safety.
UTx is recognized in most countries as a vascularized allotransplant comparable to solid organ transplants or other vascularized transplant such as face and hand transplants. The society emphasizes on the importance of this determination as the allocation and jurisdiction for tissue transplants will not allow to utilize established organ allocation principles.8 During the last 2 years, most vascularized allotransplant procedures in Europe and the United States have been UTx. Notably, there is a large contribution of altruistic donors.9 Moreover, surveys have shown a broad acceptance of deceased uterus donation.10
Facing the rapidly evolving field, the American Society for Reproductive Medicine has recently published a position paper summarizing indications and guidelines.11 Relevant aspects of clinical and experimental research in addition to open questions have been summarized in a recent review.12
At the first international congress of ISUTx in Gothenburg in 2017, the society agreed on having biannual international congresses and in the alternating years state-of-the-art (SOTA) meetings providing centers around the world with updates of the rapidly advancing field, this to assure safe and effective treatments.
The first SOTA meeting on UTx took place in Ghent, Belgium, on October 19–20, 2018, and was attended by some 120 participants. A clear majority of teams who are known to be involved in a program for UTx were present at this meeting (Figure 1). As of this meeting, approximately 20 clinical studies on UTx have been registered and 52 transplants have been performed worldwide, showing not only a broader acceptance but also an exponentially increasing rate of the procedure. To our knowledge, 13 healthy babies have been born in Europe (9 babies after LDUTx), North America (2 babies after LDUTx), South America (1 baby after DDUTx), and Asia (1 baby after LDUTx).
In this report, we summarize the most relevant recommendations, surgical implications, immunosuppressive strategies, reproductive aspects, and future perspectives related to UTx that were presented and discussed at the meeting in Ghent.
UTX AND UTERINE FACTOR INFERTILITY
Uterine factor infertility (UFI), either congenital or acquired, affects 1 in 500 fertile-aged women. This abnormality urges women to consider surrogacy or adoption. The most frequent congenital reason for UFI is MRKH syndrome and more than 90% of all UTx procedures have been in recipients with MRKH syndrome. The syndrome typically involves the agenesis of vagina and uterus linked to a defect of the Müllerian ducts. The vaginal aplasia is generally corrected in the late teenage years with the surgical creation of a neovagina or self-dilation to create a vagina of normal length that enables normal intercourse. The syndrome is a heterogeneous disorder with variable penetrance and expression due to one or multiple germline mutations. Epigenetic signatures contribute to the MRKH phenotype with monozygotic twins being discordant for the MRKH phenotype. Surrogacy, as an alternative for genetic children is either illegal or heavily restricted in most countries. For those who do not consider adoption as an alternative, UTx represents the only option for UFI.
LIVING VERSUS DECEASED DONOR PROCEDURE
UTx has thus far mostly been performed with living donors. The most important advantage of a living donor procedure is the opportunity for a thorough work-up of the donor and the elective timing of surgery. The main disadvantage is the exposure of the donor to a challenging surgery. Especially the retrieval of the uterine veins remains intricate and time-consuming. Deceased donor transplantation, on the other hand, has limitations as well. Overall, pregnancy rates of DDUTx have been inferior, potentially related to the injury of the uterus during recovery that may impact on the receptivity of the uterus. The experience in Sao Paulo however has demonstrated that DDUTx can be successful and it may very well be that the current experience for this procedure is too limited to draw more definite conclusions. Teams with both living and deceased donor programs experience, report to prefer the living donor approach. Indeed, in DDUTx there are remaining challenges of the procurement procedure as part of a multiorgan retrieval, particularly in getting an adequate length and quality for the venous outflow. Interesting is a report by the Dallas team on an approach that procures the uterus before the multiorgan retrieval.13 Moreover, in DDUTx, procurement of the ovarian veins is easily achieved.
Current evidence is scarce for standardized mandatory or recommended preoperative screening. Broad strokes for inclusion and exclusion criteria have been provided recently.11 Nevertheless, detailed screening and assessment of both donor and recipients appears critical for successful outcome. At a minimum, screening should include a physical and gynecological examination; imaging; blood tests; immunological testing; viral, bacterial, fungal, and hormonal testing. A thorough evaluation by a social worker, psychiatrist, or psychologist should be performed as women hoping to achieve pregnancy are frequently highly motivated but also under emotional stress. Additionally, living donors need to understand the extent of the surgery and potential complications, but also that the UTx may not be successful. Recipients also need to understand that there is a limited experience with DDUTx. The availability of deceased donors and waiting times are unclear at this point.
Detailed imaging of the donor vasculature is of critical relevance and may consist of computed tomography angiography (CTA), magnetic resonance angiography (MRA), and digital subtraction angiography (DSA). It is essential to evaluate the uterine artery lumen both proximally and distally. In the Swedish experience, MRA did not identify the uterine arteries in 35% of cases, CTA provided a better visualization, while DSA provided the best information on uterine arteries with accurate measurements (Brännström M, unpublished data, 2018). A small number of graft failures have been reported in living donor cases and have mostly involved uteri with signs of pathological changes of the vasculature, especially those from older donors. However, it should be noted that the donor of the uterus that resulted in the first live birth was 61 years at donation and 63 years at childbirth, indicating that chronological age is a relative contraindication.
For future evaluations of donors, it has been suggested that MRA is sufficient if the uterine arteries can be properly visualized and measured; additional CTA imaging may be necessary and invasive DSA would only be recommended if MRA and CT imaging were inconclusive.
The UTx transplant requires expert microsurgical techniques due to the small diameter of arteries and thin walls of the veins. The preferred venous outflow continues to be debated. Most centers have used the deep uterine veins, including segments/patches of the internal iliac veins. The dissection of the uterine veins, often with a venous plexus around the ureter, remains surgically challenging in live donors. The surgery takes place deep in the funnel-shaped pelvic cavity and the deep uterine veins are tightly attached to the ureters and the parametrial tissue. In deceased donors, however, the isolation of the uterine vein is somewhat less complicated. To date, more than 10 transplantations have been performed using only ovarian veins. That approach will make the surgery easier; however, an adequate blood supply of the ovaries of the donor needs to be assured. Most recently, the utero-ovarian vein has been used by some teams as the only venous outflow, leading to at least one normal pregnancy with birth so far.13
More recently it has become obvious that vaginal strictures at the anastomosis site are frequent and prevention of these strictures has been discussed. An optimal condition and length of the (neo-)vagina before UTx surgery appears relevant to prevent this complication. There was consensus that the recipient vagina should have a minimal length of 7 cm; in order to prevent vaginal strictures, the length of the donor vagina should not exceed 1.5 cm. In patients with vaginal strictures, visualization of the cervix challenges gynecological examinations in particular for cervical biopsies and embryo transfers. Some centers suggested that diathermic sealing devices, used when opening the vaginal cuff, may compromise blood supply and recommended dividing the vagina with regular scissors. Other relevant factors may include matching the size of donor and recipient vagina, the use of interrupted versus continuous sutures, in addition to recommending regular intercourse after transplantation and/or using vaginal dilators. Vaginal strictures may be treated with the implantation of stents which seems safe and efficient.
Sutures fixating the graft should be placed prior to implantation using non-absorbable sutures. When a uterine remnant is present, it can be used as additional paracervical support after it has been split above the neovaginal vault. At a minimum, the transplanted uterus should be fixated with the round, the uterosacral ligaments, and the uterine remnants (MRKH) or the paravaginal tissue (non-MRKH). Most teams suggested that a large peritoneal bladder flap from the donor promotes optimal fixation of the lower uterine part and the cervix and may prevent internal hernias.
Immediate postoperative care should include imaging of the graft with abdominal ultrasound and Doppler flow. The use of a disposable probe for immediate postoperative microvascular surveillance does not seem to be mandatory but may be useful. Protocol cervical biopsies are recommended at weekly intervals for the first posttransplantation month and then at monthly intervals. During pregnancy, biopsies are recommended once per trimester. The Swedish grading system for rejections has been useful.14
All centers advocate for an induction of immunosuppression including polyclonal T-cell antibodies (antithymocyte globulin) or a monoclonal antibody directed against the interleukin 2 receptor on activated T cells (basiliximab). First-line treatment for acute rejections are steroid boluses, while antithymocyte globulin may be used for steroid-resistant rejections. However, most rejections diagnosed by protocol biopsies have been subclinical and do not necessitate treatment. On the basis of large expertise from pregnancies of other solid organ transplants, the currently used maintenance immunosuppressive regimen including tacrolimus and azathioprine seems safe during pregnancy. As in solid organ transplantation, side effects of immunosuppressants require careful monitoring. The infection risk is increased after UTx although epidemiological data are lacking.
Infections with human papillomavirus and cytomegalovirus warrant specific attention; there have been cases of graft loss linked to uterine infections. Alloimmune responses after UTx will require further research and the optimal immunosuppressive regimens will need to be defined. Also, there is an ongoing debate on the time interval between transplantation and embryo transfer: most teams still advocate a 1-year interval, although some teams have abbreviated this period to 6 months.
Donor surgeries have been done with a conventional open approach in most cases. Laparoscopic approaches have been used by some. The group in Gothenburg has recently initiated a robotic-assisted laparoscopic approach that may support the complex dissection of the uterine vessels, particularly the deep uterine veins and the dissection around the ureter. Early unpublished results show an improved exposure with less blood loss; the time for the surgery, however, has not been reduced.
Establishing an international registry was considered of critical importance to move the field forward while assuring safety and quality. A structure of a registry was introduced at the meeting and participants felt that a mandatory participation was necessary. A template was introduced that will collect key information on donor, recipient, surgery, immunosuppression and microbial prophylaxis, prepregnancy follow-up, in vitro fertilization protocol, pregnancy, uterine removal, and complications.
Finally, at the end of this meeting it was decided that the second international congress of ISUTx is scheduled to take place in Cleveland, OH, in 2019 (chaired by Andy Tzakis and Rebecca Flyckt), while the second SOTA meeting will be organized in Prague, Czech Republic, in 2020 (chaired by Jiri Fronek).
Overall, this has been a very productive meeting that updated participants on the SOTA of a rapidly expanding field. Currently more than 20 teams are engaged in a Utx program, and both LDUTx and DDUTx are being used. Although the pros and cons of both techniques are becoming more and more clear, it is clear that many open questions still remain. It is expected that the very near future will answer some of the most pressing questions, not only on the role of deceased versus living donation but also on surgical techniques and the availability of deceased donors. Although UTx is still to be seen as an experimental procedure, it is the ethical and moral duty of everyone involved in a program around UTx to report on their results and to enter their data in the soon-to-be available registry.
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