Uterus Transplantation: A Rapidly Expanding Field : Transplantation

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Uterus Transplantation

A Rapidly Expanding Field

Brännström, Mats MD, PhD1,2; Dahm Kähler, Pernilla MD, PhD1; Greite, Robert MS3; Mölne, Johan MD, PhD4; Díaz-García, César MD, PhD5,6; Tullius, Stefan G. MD, PhD3

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doi: 10.1097/TP.0000000000002035
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Assessing the indication for uterus transplantation, it appears important to distinguish between a congenital uterine agenesis (Mayer-Rokitansky-Küster-Hauser syndrome [MRKHS]) or a surgically absent uterus due to acquired conditions, such as intrauterine adhesions, large leiomyomas that are related to uterine malfunction, causing implantation failure or defect a placentation.1

MRKHS is characterized by the genetic absence of a uterus or the presence of a rudimentary solid bipartite uterus; the syndrome is linked to a normal female karyotype, thus supporting healthy off-springs in surrogate carriers.2 MRKH syndrome accounts for less than 3% of all Müllerian malformations3 and is present in 1:4500 women.4

Hysterectomies are the most frequent gynecological surgery with approximately 600 000 procedures/per year performed in the United States; more than 40% of patients undergoing hysterectomies are younger than 44 years.5 Cervical cancer affects a large proportion of women and approximately 30% of cervical cancer patients are diagnosed at a young age (<40 years).6-8 Other malignancies of the uterus, such as sarcoma or endometrial cancer, are less frequent at a young age (<3%).9

Emergency hysterectomies peripartum due to uterine rupture, uterine atony, invasive malplacentation, or uncontrolled bleeding are rare but significant (approximately 5 in 10 000 deliveries).10 Moreover, 3.5% of all women younger than 39 years undergo hysterectomy for large fibroids.11

An anatomically present, however, dysfunctional uterus represents an additional indication for a uterus transplant: dysfunctionality may be linked to (i) radiation damage; (ii) myoma not requiring hysterectomy with an annual incidence up to 26.7% in infertile patients11-14; (iii) intrauterine adhesions (Asherman syndrome, prevalence of 1.5% among fertile-aged females15 with infertility rates of 50%16); and (iv) congenital malformations other than MRKHS associated with different degrees of sterility and adverse perinatal outcomes, such as miscarriage or very early preterm deliveries.13

Overall, the prevalence of uterine malformations in the general population is approximately 5% to 7%, closely reflecting the portion of infertile women (7.3%).17 Although not all of those with anatomical absent or a dysfunctional uterus will be interested in UTx, the number of those seeking the procedure is expected to be substantial.

Definition of Success in UTx

Unique in UTx, success is not only defined by organ function but by the delivery of a healthy offspring. The determination of success will thus not be evident until at least around 18 months after UTx, as pregnancy attempts should be delayed for 12 months. Three stages assessing outcome/success in UTx will therefore need consideration: (i) an early favorable surgical UTx outcome—with a viable graft by 3 month, (ii) graft function by 1 year with several months of regular menstruations, (iii) a successful pregnancy with the delivery of a healthy baby (Figure 1).

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FIGURE 1:
Uterus transplantation is a multidisciplinary effort involving a careful timing from IVF to a successful pregnancy.

Results From the Swedish UTx Trial

The mother delivering the first healthy baby after UTx has been part of a cohort of 9 women that underwent live donor UTx in 2013. By 1 year, 7 of 9 women had a favorable surgical outcome with a functioning graft and menstruations starting by 1 to 2 months.18 Currently, 8 healthy babies have been born from this cohort, with the first and second live births described in detail elsewhere.19,20 The Swedish group has also assessed psychological and medical outcomes in detail.21 All donors were in good physical and psychological health by 1 year after uterus donation. A ureteric-vaginal fistula, presenting around 2 weeks after surgery, was the most severe complication. The fistula was successfully repaired, and the donor recovered completely. Psychological outcomes of recipients and partners during the first posttransplantation year were favorable,22 although the period of the initial 3 months revealed anxiety in some patients largely based on concerns over a potential graft loss and consequences of possible rejections.

UTx Attempts 2015 to 2017

During the recent 2 years, several UTx programs have been initiated throughout the world. A living donor UTx, using a robotic-assisted live-donor hysterectomy with an open UTx based on exclusive ovarian vein drainage, was performed in China in November 2015 with reported 1-year graft survival and function.23 The first 4 attempts in the United States, including 1 deceased donor transplant24 and 3 living donor transplants25 were not successful: early transplant hysterectomies based on infectious complications24 in addition to surgical complications25 have been reported. Two more recent live donor UTx procedures in the United States,25 in addition to a deceased donor UTx in Brazil in 201626 demonstrated early surgical success.

In addition to published reports, attempts of UTx have been communicated through media outlets and personal communications. Several deceased and living donor UTx have been performed in the Czech Republic (2016-2017), 2 living donor cases have been reported from Germany (2016-2017), a living donor identical twin transplant has been performed in Serbia 2017, and 3 living donor UTx have been reported from India (2017); most recently a robotic-assisted laparoscopic living donor uterus transplant has been performed in Gothenburg, Sweden. The Gothenburg group plans on moving forward with a total of 10 robotic hysterectomies, an approach that may provide a significant advantage in safety and recovery for living donors. All published UTx cases, and those that have been communicated to us personally are shown in Table 1.

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TABLE 1:
Uterus transplant experience (as of September 2017) including published and personally communicated cases

To date, more than 30 uterus transplantations have been performed worldwide with most cases during the last 12 months. Although not all uterus transplants have been successful, a careful assessment will be critical for further progress. Creating an international registry documenting all UTx will represent a major advantage, providing a complete picture of activities and results with surgical success/complication, medical, and reproductive outcome.

Of note, the Gothenburg group also led the efforts of several teams around the world by initiating experimental training and clinical programs.

Moving Forward

Uterus transplantation is on the verge toward establishing itself as a clinical treatment for AUFI. Attempts of UTx at several places around the world document the strong clinical interest and demand by patients for this procedure. As for other vascular composite tissue transplants, it will be critical to assure financial coverage for the procedure, a discussion that will potentially also be challenged by alternative approaches that include surrogacy and adoption.

Addressing relevant open clinical and research questions is expected to critically advance the field.

Assessment of Uterine Functionality and Safety

Assessment of uterine quality and function is a prerequisite for a successful UTx. Aspects of donor age are of relevance, although it must be noted that the first healthy baby was born from a uterus that was 63 years at the time of delivery.19 Of note, the first surgically successful deceased donor transplant, with a graft showing regular menstruations, had been from a 23-year-old donor. However, a successful pregnancy has not been reported in this case.27 Blood supply to the uterus after transplantation is usually solely provided through the uterine arteries, because the additional blood flow of a native uterus through bilateral vaginal and ovarian arteries will not be present in the transplanted uterus. The demand of an almost tenfold increased blood flow during pregnancy requires additional consideration. Previous reports have given account to the development of vascular thrombosis and impaired uterine blood flow possibly linked to intimal hyperplasia.25,28

Thus, future research needs to evaluate reliable tests assessing the functionality of the uterus. Different imaging modalities assessing uterine structure and vasculature may be applied both in live and deceased donors. Identifying structural abnormalities that include uterine polyps or—malformations in addition to submucosal or large intramural leiomyomas and adenomyosis will be of critical relevance because they may impair reproductive outcomes. In the Swedish experience, uterus and vasculature had been imaged by magnetic resonance imaging.28 Of note, the single case in this series that resulted into a uterine artery thrombosis had shown a low blood flow during back-table preparation,28 most likely linked to an insufficient lumen of the uterine artery. Thus, a lumen of a certain size may be required for graft success, and different imaging techniques, including 3D ultrasound, Duplex-ultrasound, magnetic resonance imaging, computed tomography, and classical angiography, may provide an advantage in assessing blood supply and structural abnormalities of the uterus.

Functional testing in deceased donors is limited to the availability of a reliable medical history. Endometrial receptivity assays measuring the expression patterns of more than 250 genes, which are typically overexpressed or underexpressed during the implantation window29 can be applied to living donors. Moreover, hormonal priming for several months can be performed in postmenopausal live donors. Testing the microbiota within the uterus before and after transplantation at certain times of the menstrual cycle has recently been reported as functional readouts.30

In addition to other transmittable infections, donors should be tested for high-risk human papilloma virus infections as viral clearance will be limited in immunosuppressed recipients and the risk for cervical neoplasia will be increased substantially.31

Donor Hysterectomies and Uterus Transplantation

An open surgical approach has until recently been the standard technique for live donor hysterectomies.19,20,28 Minimal invasive surgical approaches either through a conventional or robotic-assisted laparoscopic approach have been performed recently and may optimize the live donor procedures allowing a faster recovery while reducing the time of surgery (from 10 to 13 hours for the open procedure).28 Certainly, all new surgical techniques will need to go through a proper evaluation to ensure favorable results for UTx. Of note, up until today, healthy babies have only been delivered in the Gothenburg series using an open live donor hysterectomy and a recipient procedure with a bilateral anastomosis of uterine arteries and veins to the recipient’s iliac vessels.28

Although it is surgically straightforward to isolate the uterine arteries together with the anterior portions of the internal iliac arteries, it is more demanding to isolate the uterine veins to include a segment/patch of the internal iliac vein. Uterine veins, with several connecting branches, are tightly attached to the ureters and several of the connecting branches must be divided to retrieve the uterus while keeping the donor ureters intact. Venous outflow through the ovarian veins has been considered as an alternative.32 Although this approach simplifies the live donor hysterectomy, concerns remain if the venous outflow using the ovarian veins will be sufficient. Moreover, it remains unclear if the venous outflow through the ovarian veins will be compromised with positional and growth changes of the uterus during pregnancy. The experience in few clinical UTx attempts that have either used the ovarian veins solely or a combination of uterine and ovarian veins25 as the venous outflow will help understanding this relevant issue (Figure 2).

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FIGURE 2:
Both uterine and ovarian veins have been used as venous outflow. Shown is the uterus after reimplantation with ovarian vein anastomosed to the external iliac vein on the patient’s right and the uterine vein anastomosed on the patient’s left. Uterine arteries are anastomosed bilaterally to the external iliac arteries.

After the successful reperfusion, the vaginal cuff of the uterus is attached to the recipient’s vagina. Attaching the uterus to the round/sacrouterine ligaments, in addition to the paravaginal connective tissues and the bladder peritoneum provides additional structural support. It remains unclear if the vaginal reconstruction in MRKH patients through either dilatation or mucosal reconstruction will impact the surgical procedure.

Thus, the predominant surgical questions in UTx are related to the live-donor hysterectomy (open vs laparoscopic vs robotic approach) and the recipient approach (using the uterine vs. ovarian vein as a venous out) (Table 2).

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TABLE 2:
Selected open questions in uterus transplanation

Domino procedures have been successfully performed in solid-organ transplantation (SOT). Although it is recognized that domino procedures come with imminent risks, this approach may be of relevance in UTx. With live donor hysterectomies being challenged by the anatomy of the uterine vein, the transplanted uterus is surgically more easily accessible than the native uterus. Moreover, the basic concept of UTx is that of a “temporary” transplant with a planned hysterectomy by approximately 5 years, ideally after the delivery of 2 healthy babies. Questions related to the frequencies of pregnancies and tolerable caesareans will need to be answered.

Ischemia and Reperfusion Injury and Donor-Related Injuries

Consequences of ischemia-reperfusion injury (IRI) impact both, alloimmune responses and transplant outcomes in SOT. Prolonged cold ischemic times (CIT) are associated with higher rates of delayed graft function and higher rates of acute rejections in kidney transplantation.33-35 Importantly, renal graft survival has been compromised if CIT exceeded 18 hours.36 Tolerable ischemic-times vary substantially in an organ-specific fashion37; however, acceptable ischemia times have not been determined clinically.

CIT in the experience of the 9 live donor uterus transplants in Sweden have been brief, not exceeding 2 hours.28 Although most studies investigating the impact of IRI on the uterus have been in animal models, few clinical studies have been brought forward. Major histological changes after prolonged ischemia (up to 24 hours) were absent in human uterine tissue preserved in University of Wisconsin solution or Perfadex. Myometrial contraction, however, was better preserved after 6 hours of cold storage compared with 24 hours of CIT.38 A clinical ex-vivo study assessed 8 uteri procured from brain-dead donors and reported on an absence of histological changes after a CIT of 12 hours.39 In addition, a desquamation of the endometrium of uteri from brain-dead donors has been reported as histologically evident after a cold storage of 24 hours.40

Additional data have been collected in animal models: subsequent to warm ischemic times (WIT) of 4 hours, uteri from cynomolgus macaque monkeys demonstrated an intact morphology with uterine function41; 8 hours of WIT, in contrast, had been linked to amenorrhea and uterine atrophy.41 In a rat uterus transplant model, 4 hours of WIT had been linked to morphological necrosis in 5 of 10 animals,42 whereas a CIT of 24 hours in a mouse uterus transplant model had been well tolerated with excellent function and pregnancy rates.43

IRI can be linked to capillary rarefaction impacting organ perfusion with potential implications on uterine function and pregnancy.44-47 At least in theory, reduced uterine perfusion pressure can cause endothelial dysfunction—a major hallmark of preeclampsia.48 The mechanisms behind endothelial dysfunction in preeclamptic pregnancies are not fully elucidated, but an imbalance between antiangiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFLT-1) and proangiogenic factors like vascular endothelial growth factor and placental growth factor seem to play a role.48 Recently, it has been shown that sFLT-1 increases dramatically in the plasma of patients after renal transplantation.49 Notably, this increase was more pronounced in recipients of deceased compared to living donor kidneys and levels of sFLT-1 correlated with delayed graft function and peritubular capillary loss.49 Elevated sFLT-1 levels have been linked to IRI50 and may therefore, with the downstream hemodynamic consequences, increase the risk for preeclampsia,51,52

Moreover, IRI increases arterial stiffness,53 another risk factor for preeclampsia.54 The Gothenburg group performed successful uterus transplants from 5 postmenopausal donors19 in which an age-related augmented arterial stiffness may be postulated.55 Of note, not only donor factors may increase the risk for preeclampsia in UTx. Approximately, 40% of all patients with MRKH syndrome have a unilateral kidney putting this patient cohort at a higher risk.56

Taken together, acceptable ischemic times and uterine-specific consequences of IRI have not been defined for human UTx. Moreover, studies defining optimal preservation solutions and novel perfusion methods have not been explored for UTx (Table 2).

Implications of Uterine Age on UTx

The consequences of organ age on hormonal responses, age-related sensitivities to prolonged ischemia, the capacity of the uterus to expand, and obstetrical complications, such as preeclampsia, need further exploration.

In SOT, older organs are preferably transplanted into older recipients as the immunogenicity of older organs appears augmented with a less forceful immune response.57-59 Interestingly, the uterus of postmenopausal women contains fewer CD45+ cells within the endometrium60; moreover, the CD8+ T-cell count of the ectocervix has been shown to decline.61 If those findings impact immunogenicity remains unknown.

Arterial stiffness has been linked to an increased risk of preeclampsia with a more advanced arterial stiffness observed in parallel to increasing age.62-64 If those aspects are of relevance for an augmented risk for preeclampsia in UTx remains unclear. Uterus age may also impact the reproductive performance with interesting data obtained from oocyte donation programs, delineating the effects of uterus versus oocyte/sperm donor age. In a typical oocyte donation program, oocytes are obtained from women younger than 30 years; compromised pregnancy rates will mostly likely be related to uterine-specific factors in this scenario as oocytes will be of high quality. In a large retrospective cohort study with greater than 17 000 cycles of oocyte donation, a reduction in pregnancy and implantation rates had been observed in recipients in their “late 40s.”65 These findings have been confirmed by others.66-69 Moreover, in a single-center oocyte donation program with greater than 3000 cycles, implantation and pregnancy rates had been compromised in oocyte recipients older than 45 years.68 In addition, miscarriage rates and adverse perinatal events such as preterm delivery, premature rupture of membranes, lower birth weight, hypertension, and proteinuria were more prevalent in oocyte recipients older than 45 years.68

Immunosuppression

Immunosuppressive protocols in UTx have been based largely on the experience in SOT. Induction treatments have used both polyclonal T-cell and IL-2R antibodies. Maintenance immunosuppression consisted mostly of a triple or dual immunosuppression with calcineurin inhibitors (CNIs) (most frequently tacrolimus) and mycophenolic mofetil (MMF). Steroids have mostly been tapered and reinitiated in some patients with frequent acute rejections. After 10 months and before embryo transfer, MMF is switched to azathioprine to prevent teratogenic side effects of MMF. There is a broad experience with pregnancies and deliveries in recipients of SOT. Although pregnancies in SOT recipients are considered high risk requiring monitoring by an expert multidisciplinary team, outcomes have been excellent. An increased risk of preeclampsia has been reported that appears to be independent from the renal function.70 CNIs, steroids, and azathioprine are considered safe as immunosuppressants, whereas rituximab (an anti-CD-20 antibody) and MMF have been linked to teratogenic side effects while the safety of mechanistic target of rapamycin inhibitors has not been tested.71 Some but not all reports have suggested adjusting CNI doses because circulating drug levels may change during pregnancy.71 This aspect may be of relevance because azathioprine has been linked to inferior graft survival and more frequent acute rejections when compared with MMF.72

Acute rejections have been observed in the majority of patients in the Gothenburg series.73 Those rejections had been steroid-sensitive in all but 1 patient who required treatment with anti-thymocyte globulin.

The immunosuppressive armamentarium has been broadened in the recent past. Belatacept a costimulatory blockade agent has been used successfully in SOT with favorable long-term outcomes in renal transplantation mostly related to the absence of nephrotoxicity observed with the application of CNIs.74 Alemtuzamab, a humanized monoclonal antibody against CD52 has been used successfully off-label in SOT as an induction agent and as a treatment for steroid-resistant acute rejections. The agent causes a depletion of T and B lymphocytes, monocytes, and NK cells, and may at least in theory be of relevance as an immunosuppressant in uterus transplantation.75 Of note, there is currently not sufficient clinical experience to consider alemtuzamab or belatacept as safe for the application during pregnancy.

Organ-specific aspects appear of relevance. The uterus undergoes cyclical structural and functional changes of the endometrium and the subendometrial stroma, with large variations in density and composition of immunological active cells within the organ.76 Moreover, uterine transplant-specific aspects may be related to the considerably shorter time of immunosuppression (currently considered to be approximately 5 years with up to 2 pregnancies). Thus, characteristic side effects of long-term immunosuppression including nephrotoxicity and diabetes may be substantially less and/or reversible in UTx with a limited exposure time to immunosuppression. Similarly, the risk of malignancy is impacted by the overall amount and time of exposure to immunosuppressants.

Immune modulations through the maternal-fetal interface have been intensively studied. Under healthy conditions, the semiallogeneic fetus is tolerated. This phenomenon has fueled an interest in understanding mechanisms and potentially transferring gained knowledge into the setting of allogeneic transplants.77

Now, it remains unclear if mechanisms of the immune modulating maternal-fetal interface are relevant in UTx. Reducing immunosuppression based on this assumption appears certainly unfounded.

Rejection Diagnosis in UTx

Rejection scores have been established for UTx73; however, mechanisms of alloimmune responses in UTx remain to be explored.

Early diagnosis of rejection is critical. In the Gothenburg experience, protocol biopsies have been obtained weekly for the first month with subsequent monthly intervals for the first year. Protocol biopsies are of importance as possible clinical signs of rejection, such as possible macroscopic signs, such as cervical discoloration, abnormal vaginal discharge, fever or abdominal pain,18,28 would represent rather late signs. In fact, all acute rejection episodes in the Gothenburg series were subclinical and with normal macroscopic appearance of the cervix at gynecological examination. Using a histological rejection score that had been established in Gothenburg, 5 of 7 UTx recipients in this series showed at least 1 episode of rejection.73 As in SOT, one could envision biomarkers assessing the risk for rejections and, ideally, those biomarkers will be replacing biopsies as the criterion standard. Although such parameters have not been established for UTx, cervical smears may provide a source for molecular diagnostics.

Importantly, biopsies thus far have been obtained from the ectocervix.18,28 Of note, data from animal studies suggest that endometrium and myometrium are infiltrated at differing time intervals with the myometrium rejected earlier than the endometrium.78-80 This could possibly be explained by the anatomy of uterine vessels entering the organ through the myometrium and reaching the endometrium lastly. In the human uterus, there is a significantly augmented expression of HLA class I molecules in the endometrium compared with the myometrium, suggesting that the endometrium is the main target for rejection in the human setting.81

Rejections in UTx have mainly revealed T cell–mediated patterns78,80 (Figure 3). Cervical biopsies in the Gothenburg series showed predominantly lymphocytes and some neutrophils to be present during early rejections.73 A study in murine UTx (without immunosuppression) demonstrated that CD3+ T cells can be detected within 5 to 10 days after allogeneic transplantation in both endometrium and myometrium.78 T cells infiltrating the uterus after transplantation are mainly cytotoxic T cells (CD8+) binding to HLA class I with a lower density of T-helper cells (CD4+).80 Cytotoxic T cells were predominantly detected in the myometrium in contrast to T-helper cells that were predominantly detected in the endometrium.80

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FIGURE 3:
Light microscopy of cervical biopsies after uterus transplantation. A, Normal cervical biopsy with very few inflammatory cells (month 9). B, grade 2 rejection by mth 15 with dense, predominantly lymphocytic infiltrates localized between stroma and epithelium; inset with CD3 staining. Arrow marks apoptotic cells with spongiosis and focal loss of the epithelium from the stroma (clefting).

In line with these findings, human uterine CD3+ T cells were found to consist of a larger proportion of cytotoxic CD8+ T cells (66%) and smaller proportion of T-helper CD4+ cells (33%)82,83 in the normal, nontransplanted human uterus.

Moreover, in the allotransplanted mouse uterus, macrophages were the first immune cells to be increased in the uterus after transplantation (by day 2 in the myometrium and by day 5 in the endometrium).80 Macrophage infiltration seemed to overlap with the infiltration of neutrophils by days 5 and 10 in the myometrium and by day 10 in the endometrium.80 Importantly, immune cell density and localization is also impacted by the reproductive cycle in mouse and humans,83,84 suggesting that cellular infiltrates characteristic of rejection may be impacted hormonally.

Of note, little is known about antibody-mediated rejection in UTx thus far.

Long-Term Consequence for Donors, Recipients, and Children

Aspects related to the long-term health of babies, recipients, and donors of UTx have not been studied. Clearly, a multidisciplinary team effort needs to be in place and to continuously follow uterus donors, recipients, and babies.

Long-term effects of living donors will need to be carefully assessed. Recently published 1-year follow-up data showed that few psychological strains had been reversible. All patients continued with their “normal” life, and psychological assessments had been normal. Established psychological tests showed scores slightly higher than in the general population.21 Likewise, minor medical and surgical complications had been reversible.

Future outcomes studies will need to confirm the absence of medical or surgical complications long term. Indeed, the potential for ureteric strictures, compromised innervations of the pelvic floor with potential clinical consequences of pelvic organ prolapse or incontinence need assessment.85 As those conditions are not infrequent in women of postmenopausal age, a detailed gynecological examination with standardized evaluations needs to be performed before the donor hysterectomy.86

Recipient follow-up will need to go beyond the date of transplant hysterectomy (for at least 10 years and ideally for a lifetime) planned after the delivery of the desired number of babies. Follow-up will not only need to include psychological assessments but also medical examinations focusing on potential long-term side effects of immunosuppressants including the potential for malignancies, nephrotoxicity, or diabetes. Long-term follow-up will also need to include children of uterus transplant recipients.

In moving the field forward, a registry will need to provide the basis for the long-term health of living donors, uterus transplant recipients, and babies. Criteria defining minimum quality standards for uterus transplant programs in addition to long-term follow-up of living donors, recipients, and offspring will need to be delineated. For living donors established psychological tests had been implemented in a 1-year follow-up study of all 9 donors in the Gothenburg program.22

CONCLUSIONS

Uterus transplantation has advanced rapidly from an experimental procedure in animals to a successful clinical application. Nevertheless, at this time, UTx should be considered a clinical experimental procedure until a sufficient amount of experience has been collected from clinical trials that are expected to enroll during the next 1 to 2 years. With a significant clinical demand, it is expected that the volume will increase. Indeed, many international centers have already initiated programs. Currently, healthy babies have only been born after live donor uterus transplants. Most recent deceased donor transplants have been surgically successful, and it appears probable that a uterus from a deceased donor will also be able to carry a healthy baby. Pioneering work for UTx comes from the Gothenburg group that has also helped many centers around the world to get started. Most recently, this group has also refined the live donor procedure with a robotic approach.

Many open questions remain that will need to be answered in the future (Table 2). There is a clear demand for a long-term psychological and medical follow-up of donors, recipients, and children. Uterus transplant programs will not only need to assure a multidisciplinary approach but will also need to implement quality assessment and process improvement measures.

Aspects of donor age, consequences of IRI, uterus-specific aspects of rejection, and immunosuppression are some of the critical questions that have not been studied sufficiently.

Uterus transplantation provides a unique opportunity with a limited time for immunosuppression. Nevertheless, consequences need to be followed and documented long term after the discontinuation of immunosuppression.

Although only supported by limited experimental data, uterine decellularization and recellularization protocols have been tested in the rat87 with bioengineered uterine tissue used to cover uterine defects. Of note, patched uteri had been capable to carry pregnancies to term.88 Those studies have recently also been extended into a large animal model.89 This field has to be explored further in several animal models, including nonhuman primates, before any possible clinical trial.

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