Miracles of science: Birth after uterus transplantation.

AIM: The concept of regaining childbearing ability via uterus transplantation (UTx) motivates many infertile women to pursue giving birth to their own children. This article provides insight into maternal and neonatal outcomes of the procedure globally and facilitates quality of care in related medical fields. METHODS: The authors searched ISI Web of Science, MEDLINE, non-PubMed-indexed journals, and common search engines to identify peer-review publications and unpublished sources in scientific reference databases. RESULTS: The feasibility of the procedure has been proven with 46 healthy children in 88 procedures so far. Success relies upon dedicated teamwork involving transplantation surgery, obstetrics and reproductive medicine, neonatology, pediatrics, psychology, and bioethics. However, challenges exist owing to donor, recipient, and fetus. Fetal growth in genetically foreign uterine allograft with altered feto-maternal interface and vascular anatomy, immunosuppressive exposure, lack of graft innervation leading to "unable-to-feel" uterine contractions and conception via assisted reproductive technology create notable risks during pregnancy. Significant portion of women are complicated by at least one or more obstetric problems. Preeclampsia, gestational hypertension and diabetes mellitus, elevated kidney indices, and preterm delivery are common complications. CONCLUSIONS: UTx has short- and long-term satisfying outcome. Advancements in the post-transplant management would undoubtedly lead this experimental procedure into mainstream clinical practice in the near future. However, both women and children of UTx need special consideration due to prematurity-related neonatal problems and the long-term effects of transplant pregnancy. Notable health risks for the recipient and fetus should be discussed with potential candidates for UTx.

Uterus transplantation: from research, through human trials and into the future.

Women suffering from absolute uterine factor infertility (AUFI) had no hope of childbearing until clinical feasibility of uterus transplantation (UTx) was documented in 2014 with the birth of a healthy baby. This landmark accomplishment followed extensive foundational work with a wide range of animal species including higher primates. In the present review, we provide a summary of the animal research and describe the results of cases and clinical trials on UTx. Surgical advances for graft removal from live donors and transplantation to recipients are improving, with a recent trend away from laparotomy to robotic approaches, although challenges persist regarding optimum immunosuppressive therapies and tests for graft rejection. Because UTx does not involve transplantation of the Fallopian tubes, IVF is required as part of the UTx process. We provide a unique focus on the intersection between these two processes, with consideration of when oocyte retrieval should be performed, whether, and for whom, preimplantation genetic testing for aneuploidy should be used, whether oocytes or embryos should be frozen and when the first embryo transfer should be performed post-UTx. We also address the utility of an international society UTx (ISUTx) registry for assessing overall UTx success rates, complications, and live births. The long-term health outcomes of all parties involved-the uterus donor (if live donor), the recipient, her partner and any children born from the transplanted graft-are also reviewed. Unlike traditional solid organ transplantation procedures, UTx is not lifesaving, but is life-giving, although as with traditional types of transplantation, costs, and ethical considerations are inevitable. We discuss the likelihood that costs will decrease as efficiency and efficacy improve, and that ethical complexities for and against acceptability of the procedure sharpen the distinctions between genetic, gestational, and social parenthood. As more programs wish to offer the procedure, we suggest a scheme for setting up a UTx program as well as future directions of this rapidly evolving field. In our 2010 review, we described the future of clinical UTx based on development of the procedure in animal models. This Grand Theme Review offers a closing loop to this previous review of more than a decade ago. The clinical feasibility of UTx has now been proved. Advancements include widening the criteria for acceptance of donors and recipients, improving surgery, shortening time to pregnancy, and improving post-UTx management. Together, these improvements catalyze the transition of UTx from experimental into mainstream clinical practice. The procedure will then represent a realistic and accessible alternative to gestational surrogacy for the treatment of AUFI and should become part of the armamentarium of reproductive specialists worldwide.

The first Australian uterus transplantation procedure: A result of a long-term Australian-Swedish research collaboration.

AIMS: The aim is to report the results of Australia's first uterus transplantation (UTx). METHODS: Following long-standing collaboration between the Swedish and Australian teams, Human Research Ethics approval was obtained to perform six UTx procedures in a collaborative multi-site research study (Western Sydney Local District Health 2019/ETH13038), including Royal Hospital for Women, Prince of Wales Hospital, and Westmead Hospital in New Souh Wales. Surgeries were approved in both the live donor (LD) and deceased donor models in collaboration with the inaugural Swedish UTx team. RESULTS: This is the first UTx procedure to occur in Australia, involving a mother donating her uterus to her daughter. The total operative time for the donor was 9 h 54 min. Concurrently, recipient surgery was synchronised to minimise graft ischaemic time, and the total operative time for the recipient was 6 h 12 min. Surgery was by laparotomy in the LD and recipient. The total warm ischaemic time of the graft was 1 h 53 min, and the cold ischaemic time was 2 h 17 min (total ischaemic time 4 h 10 min). The patient's first menstruation occurred 33 days after the UTx procedure. CONCLUSION: Twenty-five years of Swedish and Australian collaboration has led to Australia's first successfully performed UTx surgery at The Royal Hospital for Women, Sydney, Australia.

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

BACKGROUND: Uterus transplantation (UTx) has come of age in the 21st century, building on the 20th century developments in vascular anastomosis and effective immunosuppressive protocols that have enabled solid organ transplantation to become the life-extending and life-improving treatment option we know today. However, UTx has the goal of enabling reproduction, meaning that research has focused on establishment of pregnancy and healthy live birth in addition to surgical technique and immunosuppression. SUMMARY: The Dallas Uterus Transplant Study (DUETS), established at Baylor University Medical Center in 2015, is one of four UTx programs in the USA, and it holds the distinction of being home not only to the first US live birth but also the highest volume UTx program worldwide, with 23 uterus transplants performed to date, resulting in 15 live births. Innovations pioneered at our center span all aspects of the UTx process, all seeking to improve success for recipients in terms of achieving pregnancy and live birth, while also minimizing the burden on donors and recipients. They have included the following: (1) a deceased donor hysterectomy approach that allows the uterus to be procured prior to cross clamp; (2) proof of concept with use of only superior uterine veins after procuring both the superior and inferior uterine veins during the donor surgery, enabling the choice of the best option in terms of size and location for outflow, while also preserving ovary viability in living donors; (3) contribution to robot-assisted technique/minimally invasive technique with vaginal extraction of the uterus graft for living donor surgeries, shortening donor recovery times; (4) developing a robot-assisted technique for graft hysterectomies, improving recovery times for recipients at the end of their UTx journey; (5) refining immunosuppression protocols to enable embryo transfer as early as 3 months after induction therapy, increasing recipients' chances for achieving up to two live births during the 5 years posttransplant the UTx protocol specifies; and (6) building on our clinical trial experience to now offer UTx in the U.S. outside the setting of a clinical study. KEY MESSAGES: Our center along with others throughout the world 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. Due to the complexity of UTx as well as the need for long-term multidisciplinary care, centers implementing UTx should have an established abdominal transplant program, a gynecologic surgery program, high-risk obstetric and neonatal care, and institutional support and oversight, and should partner with established UTx programs for protocol development and operative proctoring.

Procedures and technical considerations of robotic-assisted human uterus transplantation.

BACKGROUND: Uterus transplantation is the only treatment for absolute uterine factor infertility. Complex vascular anatomy, long operation time, and intraoperative injuries are the main factors that limit progress in uterus transplantation. Moreover, robot-assisted uterus transplantation is not popular at present due to technical difficulties, with only a few countries reporting success. METHODS: In this paper, we present the key technical points of robot-assisted uterine transplantation by analyzing and summarizing our surgical experience and other successful cases of robot-assisted uterine transplantation. This study provides an evidence-based reference for clinicians planning robot-assisted uterine transplantation procedures. CONCLUSION: Minimally invasive technologies can shorten the operation time, reduce injuries, and contribute to analyzing the anatomy of complex blood vessels. Therefore, robot-assisted uterine transplantation is an important direction for the future of uterine transplantation, and the findings and procedures reported herein contribute to the standardization and promotion of robot-assisted uterine transplantation operations.

Registry of the International Society of Uterus Transplantation: First Report.

BACKGROUND: Uterus transplantation (UTx) is a novel type of transplantation to treat infertility in women with an absent or nonfunctioning uterus. The International Society of Uterus Transplantation (ISUTx) has developed a registry to monitor worldwide UTx activities while serving as a repository for specific research questions. METHODS: The web-based registry has separate data fields for donor, recipient, surgeries, immunosuppression, rejections, pregnancies with live birth(s), and transplant hysterectomies. Data are prospectively registered. RESULTS: A total of 45 UTx procedures have been registered; the majority (78%) of those procedures were live donor (LD) transplants. Median age of the LDs, deceased donors, and recipients were 50 y (range 32-62), 38.5 y (19-57), and 29 y (22-38), respectively. The duration of LD surgery was approximately twice as long as the recipient surgery. Postoperative complications of any Clavien-Dindo grade were registered in 20% of LDs and 24% of recipients. Rejection episodes were more frequent (33%) early after transplantation (months 1-5) compared with later time points (months 6-10; 21%). Healthy neonates were delivered by 16 recipients, with 3 women giving birth twice. The total live birth rate per embryo transfer was 35.8%. Median length of pregnancy was 35 gestational weeks. Twelve uteri were removed without childbirth, with 9 transplant hysterectomies occurring during the initial 7 mo post-UTx. CONCLUSIONS: A mandatory registry is critical to determine quality and process improvement for any novel transplantation. This registry provides a detailed analysis of 45 UTx procedures performed worldwide with a thorough analysis of outcomes and complications.

Meeting Report: Third International Congress of the International Society of Uterus Transplantation, Tübingen.

Uterus transplantation (UTx) is currently the only available treatment for absolute uterine factor infertility. The International Society of Uterus Transplantation (ISUTx) was formally founded in 2017 and joined the Transplantation Society as a formal section in 2021. The Third International Congress of the ISUTx was held in Tübingen, Germany, in October 2021, as a hybrid meeting, attended virtually by about 450 delegates and in person by 35 delegates. This report summarizes the Tübingen meeting and complementary topics of relevance presented at the Second ISUTx state-of-the-art webinar meeting, held in Prague, in October 2020. Main topics covered included surgical considerations, including dissection of veins in living donors and the pros and cons of minimally invasive surgery; managing immune risks; UTx during the COVID-19 pandemic; lessons learnt in the areas of imaging and cytomegalovirus infection; long-term psychological outcomes; opportunities to increase organ availability; and new horizons in UTx, including potential reuse of transplants and the utilization of robotic approaches. Implementation of an International UTx Registry was discussed and considered crucial to assure quality, safety, and further progress in UTx. Attempts made thus far have been promising.

The First 5 Years of Uterus Transplant in the US: A Report From the United States Uterus Transplant Consortium.

Importance: Uterus transplant is a viable surgical treatment for women affected by absolute uterine-factor infertility, which affects 1 in 500 women. Objective: To review transplant and birth outcomes of uterus transplant recipients in the US since the first case in 2016. Design, Setting, and Participants: In this cohort study, 5 years of uterus transplant outcome data were collected from the 3 centers performing uterus transplants in the US: Baylor University Medical Center, Dallas, Texas; Cleveland Clinic, Cleveland, Ohio; and University of Pennsylvania, Philadelphia. A total of 33 women with absolute uterine-factor infertility who underwent uterus transplant between February 2016 and September 2021 were included. Main Outcomes and Measures: Graft survival, live birth, and neonatal outcome. Results: Of the 33 included uterus transplant recipients, 2 (6%) were Asian, 1 (3%) was Black, 1 (3%) was South Asian, and 29 (88%) were White; the mean (SD) age was 31 (4.7) years; and the mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 24 (3.6). Most uterus transplant recipients (31 of 33 [94%]) had a congenitally absent uterus (Mayer-Rokitansky-Küster-Hauser syndrome), and 21 of 33 (64%) received organs from living donors. Mean (range) follow-up was 36 (1-67) months. There was no donor or recipient mortality. One-year graft survival was 74% (23 of 31 recipients). Through October 2021, 19 of 33 recipients (58%) had delivered 21 live-born children. Among recipients with a viable graft at 1 year, the proportion with a live-born child was 83% (19 of 23). The median (range) gestational age at birth of neonates was 36 weeks 6 days (30 weeks, 1 day to 38 weeks), and the median (range) birth weight was 2860 (1310-3940) g (median [range], 58th [6th-98th] percentile). No congenital malformations were detected. Conclusions and Relevance: Uterus transplant is a surgical therapy that enables women with uterine-factor infertility to successfully gestate and deliver children. Aggregate data from US centers demonstrate safety for the recipient, living donor, and child. These data may be used to counsel women with uterine-factor infertility on treatment options.

A multi-institutional study of renal outcomes and renal-related pregnancy outcomes in uterus transplant recipients.

Uterus transplantation (UTx) is an effective treatment option for uterine factor infertility. However, the need for immunosuppression and congenital renal anomalies that coexist with uterine agenesis in about 30% of women with Mayer-Rokitansky-Kuster-Hauser syndrome create a risk for renal dysfunction. We therefore examined renal function trajectory and related pregnancy complications in an international cohort of 18 UTx recipients from September 2016-February 2020 who had at least one live birth. All UTx recipients had a diminution in their renal function that was apparent starting at 30 days posttransplant and in half the reduction in eGFR was at least 20%; the decrease in eGFR persisted into the early post-partum period. Half met criteria for Stage 1 acute kidney injury (AKI) as defined by the AKI Network criteria during their pregnancy. Overall, 28% of UTx recipients developed pre-eclampsia. eGFR was lower at embryo transfer and throughout pregnancy among those who developed pre-eclampsia, reaching statistical significance at week 16 of pregnancy. This effect was independent of tacrolimus levels. Mean eGFR remained significantly lower in the first 1-3 months after delivery. In the subgroup who reached 12 months of postpartum follow up and had a graft hysterectomy (n = 4), there was no longer a statistical difference in eGFR (pretransplant 106.7 ml/m ± 17.7 vs. 12 mos postpartum 92.6 ml/m ± 21.7, p = .13) but the number was small. Further study is required to delineate long term renal risks for UTx recipients, improve patient selection, and make decisions regarding a second pregnancy.

Directed and conditional uterus donation.

Uterus transplantation (UTx) is highly anticipated for the benefits that it might bring to individuals wanting to carry a pregnancy in order to reproduce who do not have a functioning uterus. The surgery-now having been performed successfully in several countries around the world-remains experimental. However, UTx is at some point expected to become a routine treatment for people without a uterus and considering themselves in need of one: women with absolute uterine factor infertility; transgender women; and even cisgender men who wish to gestate. Given the unique benefits UTx offers, uteri are likely to be 'in demand', and such demand, we suggest, will feasibly outstrip supply. Therefore, allocation of those uteri available for transplant may become a pressing issue. In this paper, we consider one aspect of organ allocation-the preferences of donors in making a directed or conditional donation of their uterus. To what extent, in the context of uterus donation, would such donations be ethically permissible?

Uterus transplantation in the treatment of female infertility: the pathologists perspective.

Uterus transplantation is a new experimental treatment method of absolute uterine factor infertility which affects 3-5% of infertile women. Absolute uterine factor infertility includes infertile women with agenesis or severe malformation of the uterus, several acquired uterine diseases causing infertility, and patients of fertile age after hysterectomy because of various causes. Uterus transplantation is considered a new method of assisted reproduction which allows women with absolute uterine factor infertility to have own biological offspring. However, uterus transplantation is considered a radical method of reproduction by some ethicists. Nevertheless, recent analysis of newborns from transplanted uterus has shown high level of childbirths of mature and near-to-term newborns and did not confirm increased risk for both babies and mothers. Therefore, together with gestational surrogacy and adoption, uterus transplantation is nowadays considered promising and unique solution for women with absolute uterine factor infertility. Similarly to other solid organ transplants, the pathologist should be an integral part of the multidisciplinary uterus transplantation research teams. The primary role of the pathologist is histopathological evaluation of rejection changes in the biopsy samples from the ectocervix of the uterine allografts that is based on the provisional scoring system suggested by Swedish pioneers in uterus transplantation research. As the word provisional suggests, this scoring system is continuously studied and the principles of the evaluation of rejection after uterus transplantation could be adjusted in the future.

Birth of a Healthy Baby 9 Years After a Surgically Successful Deceased Donor Uterus Transplant.

OBJECTIVE: To describe surgical procedures, previous failed pregnancies, methods for overcoming pregnancy failure and, most importantly, birth of a healthy infant, in a uterus transplantation from a deceased donor. BACKGROUND: Majority of uterus transplants have involved live donors, but several advantages make deceased donor transplantation a practicable option, principally by eliminating surgical risks to the live donor. METHODS: Uterus transplantation from a deceased donor was performed in September 2011 in Turkey. After 5 miscarriages, perfusion computed tomography revealed an obstructed blood-outflow. To overcome this blood flow obstruction, a saphenous vein graft was anastomosed between utero-ovarian and left ovarian vein with laparotomy. Follow-up computed tomography confirmed resolution of venous congestion and a decrease in uterine volume. RESULTS: Following vascular augmentation surgery, fetal cardiac activity were observed 28 days after the first embryo transfer attempt. Preterm premature rupture of the membranes was diagnosed at 19 weeks' gestation. Cesarean section was planned at 28 weeks' gestation due to intrauterine growth restriction and suspected preeclampsia. A healthy 760 g male baby was delivered. The baby was discharged from the neonatal intensive care unit 79 days after delivery in good condition weighing 2475 g. CONCLUSIONS: Deceased donor uterus transplantation is a reasonable approach for treating uterine factor-related infertility. In case of recurrent miscarriages, regional vascular augmentation by arterial or venous supercharging may be required to overcome regional misperfused regions determined by imaging studies.

Technological Advancements in Uterus Transplantation.

Uterus transplantation is barely a decade old and in a young, evolving field it is hard to identify "technological advances" since it is, in of itself, a technological advance. Nonetheless, one can still identify advances in diagnostic imaging that have improved donor screening to avoid graft losses, highlight the adoption of robotic surgery to make the living donor uterus procurement more minimally invasive, and look to a future of biotechnology like perfusion pumps and bioengineering such as synthetic uterus to increase donor supply. Additional technologies are on the horizon and promise to shape the field further.

Robotic Donor Hysterectomy Results in Technical Success and Live Births After Uterus Transplantation: Subanalysis Within the Dallas Uterus Transplant Study (DUETS) Clinical Trial.

Minimally invasive procurement of uterine grafts for transplantation can decrease living donor recovery time. We examined recipient outcomes for grafts procured by robotic-assisted donor hysterectomies with transvaginal extraction in the Dallas UtErus Transplant Study (DUETS). All 5 grafts were successfully transplanted. Recipients had a median 4.5-hour surgical time, 0.25 L estimated blood loss, and 4-day hospital stay. Four recipients had grade III surgical complications and three had acute cellular rejection. At 18 months, graft viability was 100%, with an 80% live birth rate. This report demonstrates the feasibility and reproducible success of using uterus grafts from living donors who underwent robotic-assisted donor hysterectomy.

Donor robotic-assisted laparoscopy for uterus transplantation.

OBJECTIVE: Uterine transplantation has proven to be a viable solution in cases of absolute uterine factor infertility. Performing uterine explant surgery is one of the most difficult gynecologic surgical challenges owing to the complexity of the uterine vascular system. The goal of this video is to demonstrate uterine explant surgery and highlight the critical anatomy involved in this procedure. DESIGN: In this video, we display, narrate, and illustrate key portions of right pelvic dissection, which was subsequently performed bilaterally to achieve hysterectomy from a living donor for the purpose of uterine transplantation. SETTING: University hospital. PATIENT(S): The donor was a 39-year-old woman, and the receptor sister suffers from Rokitansky syndrome. A careful right site pelvic dissection was visualized in this operation during a hysterectomy with the aim of performing a uterine graft implantation in a living donor (Research Ethics Committee and the Assistance Ethics Committee of Hospital Clínic de Barcelona [HCB/2016/0111] and Bioethics Committee of Catalunya Study included in ClinicalTrials.org registry [NCT04314869]). INTERVENTION(S): The donor's surgery was performed entirely using robotic surgery (DaVinci Xi, Intuitive Survival Inc.). MAIN OUTCOME MEASURE(S): Assessment of uterine graft transplant viability. RESULT(S): Good quality arterial and venous pedicles were obtained during the surgery. The difficulty of this procedure is the extensive vascular dissection that has to be done to isolate the veins that drain the uterus until the hypogastric vein. CONCLUSION(S): Pelvic anatomy dissection for obtaining the graft from the donor in uterus transplantation is complex, and robotic-assisted laparoscopic surgery may help to provide a clear and more precise visualization.

Evolution and Transformation of Uterine Transplantation: A Systematic Review of Surgical Techniques and Outcomes.

BACKGROUND: Uterine transplantation (UTx) is acknowledged to be on the second (2A) of five steps of development in accordance with the staging system for the evaluation of surgical innovations. Accordingly, we aimed to systematically review the available evidence of the surgical techniques and outcomes of UTx in terms of graft survival. METHODS: A comprehensive search was conducted across PubMed Medline, Cochrane-EBMR, Scopus, Web of Science, and CENTRAL through November 2020. RESULTS: Forty studies, reporting 64 recipients and 64 donors, satisfied inclusion criteria. The surgical time and the estimated blood loss were 515 minutes and 679 mL for graft procurement via laparotomy, 210 minutes and 100 mL for laparoscopic-assisted graft harvest, and 660 minutes and 173 mL for robotic-assisted procedures, respectively. Urinary tract infections (n = 8) and injury to the urinary system (n = 6) were the most common donor complications. Using the donor's internal iliac system, two arterial anastomoses were performed in all cases. Venous outflow was accomplished through the uterine veins (UVs) in 13 cases, a combination of the UVs and the ovarian/uteroovarian veins (OVs/UOVs) in 36 cases, and solely through the OVs/UOVs in 13 cases. Ischemia time was 161 and 258 minutes when using living donors (LD) and deceased donors (DD), respectively. Forty-eight uteri were successfully transplanted or fulfilled the purpose of transplantation, 41 from LDs and 7 from DDs. Twenty-five and four live childbirths from LDs and DDs have been reported, respectively. CONCLUSION: UTx is still experimental. Further series are required to recommend specific surgical techniques that best yield a successful transplant and reduce complications for donors and recipients.

Clinicopathological Analysis of Uterine Allografts Including Proposed Scoring of Ischemia Reperfusion Injury and T-cell-mediated Rejection-Dallas UtErus Transplant Study: A Pilot Study.

BACKGROUND: Uterus transplantation (UTx) enables pregnancy in infertile women. This study describes the histopathological changes of ischemia reperfusion injury and mostly acute T-cell-mediated rejection (TCMR) in UTx and proposes modification toward a working formulation grading system with associated treatments. METHODS: Protocol and indication biopsies from 11 living and 2 deceased donor UTx recipients were analyzed. Serving as a control were 49 age-matched nontransplanted uteri. All posttransplant histopathological specimens were evaluated in a blinded fashion by 3 pathologists. Response to treatment was assessed by follow-up biopsies. Serial serum donor-specific antibody (DSA) responses were also recorded. RESULTS: Changes attributed to ischemia reperfusion resolved within 2 wk of UTx in most of the patients. For TCMR grading, perivascular inflammation, focal capillary disruption, and interstitial hemorrhage were added to interface inflammation, intercellular edema, stromal inflammation, and epithelial apoptotic bodies. Of the 173 protocol biopsies, 98 were classified as negative for TCMR; 34 as indeterminate-borderline; 35 as mild; 3 as moderate; and 3 as severe, 1 of which occurred in a DSA-positive recipient and also showed microvascular injury. Corticosteroids successfully treated all moderate-to-severe TCMR episodes. Mild TCMR was treated by increasing existing baseline immunosuppression. Indeterminate-borderline episodes were not treated. Neither ischemia-reperfusion injury nor TCMR with DSA adversely affected embryo transfer. CONCLUSIONS: Relying on a modified histopathological grading system, we developed a treatment strategy resulting in resolution of TCMR and successful pregnancies.