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of Science, MEDLINE, non-PubMed-indexed journals, and common search engines to identify peer-review publications and unpublished sources in scientific reference databases.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.

Three-year follow-up results of two children born from a transplanted uterus.

AIMS: To evaluate the 3-year follow-up results of two children delivered at our institution in 2019 from mothers with a transplanted uterus. METHODS: Observational data on pregnancy outcomes, neonatal course, and growth trajectory in two children born to mothers after uterus transplantation, including 3-year follow-up and neurodevelopmental status assessed using the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III). RESULTS: Both children were born prematurely via uneventful caesarean sections, to mothers with Mayer-Rokitansky-Küster-Hauser syndrome and a transplanted uterus. An acute caesarean section was performed in one mother because of the onset of regular uterine contractions at 34 weeks and 6 days of pregnancy; in the other mother, an elective caesarean section was performed at 36 weeks and 2 days of gestation. The children were born healthy with no congenital malformations. They had an uneventful postnatal course and showed a normal growth trajectory during 3 years of follow-up. The Bayley-III neurodevelopmental scores of both children were within the normal ranges at ages 2 and 3 years. CONCLUSION: Though pregnancy after uterus transplantation is associated with the risk of premature delivery, no abnormalities were observed in the neonatal course and 3-year follow-up results, including the neurodevelopmental status, of two children born prematurely to mothers with a transplanted uterus. This is the first report on neurodevelopmental outcomes in children born after uterus transplantation. More data on children born after this radical procedure of uterine factor infertility treatment are required to support our promising results.

Psychosocial Outcomes in Nondirected Uterus Donors 1 Y After Donation.

BACKGROUND: As uterus transplantation transitions to a clinical procedure for women with absolute uterine-factor infertility, transplant centers performing uterus transplantation need information about the experience of living donors. This study examined the psychosocial impact on 17 nondirected uterus donors in the Dallas UtErus Transplant Study 1 y following donation. METHODS: A prospective longitudinal study was conducted to measure psychosocial outcomes of depression, anxiety, posttraumatic stress, quality of life, and resilience [measured using the Hospital Anxiety and Depression Scale or Patient Health Questionnaire 9-Item, Generalized Anxiety Disorder 7-Item, Posttraumatic Stress Disorder Checklist for the DSM-5, health-related quality of life Short Form-36, and Connor-Davidson Resilience Scale 10-Item, respectively) assessed at baseline, at 6-mo and 1-y follow-up. Differences among baseline, 6-mo, and 1-y postdonation were analyzed. RESULTS: The median age was 38.0 y, 16 were married, 15 were of non-Hispanic/Latino ethnicity. Most donors did not report psychosocial distress; however, 1 donor reported decline on the role limitations because of Emotional Problems Scale and also showed an increase in depression symptoms at the 6 mo, but at 1 y was below the clinical cutoff for depression. A second donor showed modest decline in emotional well-being. Improvements were seen in other donors on the Physical Functioning Scale and posttraumatic stress symptoms. CONCLUSIONS: Although most nondirected donors appeared to remain stable, both positive and negative changes were observed over the first year. Larger studies are needed to determine psychosocial risks and benefit and what additional resources might be needed to ensure optimal psychosocial outcomes.

Hypothermic machine perfusion for uterus transplantation.

OBJECTIVE: To describe the feasibility of hypothermic machine perfusion (HMP) in uterus transplantation (UT) to potentially improve the preservation of the uterus and enhance graft preservation in the donation after brainstem death (DBD) context. Uterus transplantation is a new surgical approach to treating absolute uterine infertility; it can be performed after living donation or after DBD. In the DBD context, the uterus is typically the last organ removed after other vital organs, with the exception of the Baylor team, which removes the uterus first. This key aspect imposes an unavoidable mild temperature ischemia for >1 hour on the uterus during the removal of the vital abdominal and chest organs. In renal transplantation, the perfusion machine reduces the risk of delayed graft function; thus, we hypothesized that machine perfusion could result in a reduction of uterus graft dysfunction. The uterus graft dysfunction could be expressed by a low embryo implantation rate, pregnancy loss, or vascular pregnancy diseases such as preeclampsia or fetal growth restriction." To date, static cold storage of the uterus is the only standard method for preservation before transplantation. HMP is an emerging method that could potentially improve the preservation of the uterus to enhance graft preservation in the DBD context. DESIGN: This video article shows all the technical details of using the HMP for uterine transplantation. SETTING: University. ANIMALS: Porcine model. INTERVENTION: Porcine uterus was retrieved from a DBD domestic animal model and flushed with KPS MP (Bridge To Life Ltd in UK) at 4 °C. After vascular preparation on the back table, the uterus was perfused using KPS MP through a cannula in the aorta using the VitaSmart device (Bridge To Life Ltd in UK) for 18 hours. Then, the uterus was transplanted to the porcine recipient. MAIN OUTCOME MEASURES: The macroscopic appearance of the uterus at the end of HMP and the assessment of the uterus vascularization after transplantation in the recipient compared with the native uterus. RESULTS: This video shows the cannulation of the iliac vessels, cooling and removal of the uterus on a porcine model, uterus preservation using HMP during 18 hours, and then UT in a new recipient pig with the reperfusion of the transplanted uterus next to the native, intact uterus of the recipient. The macroscopic appearance of the uterus at the end of HMP appeared viable and was perfectly flushed. The assessment of the uterus vascularization after transplantation in the recipient was similar to that of the native uterus. To our knowledge, we describe here for the first time the UT procedure in DBD context on an animal model and the use of HMP for uterus preservation in UT programs; this could increase the number of uterine grafts available for a greater number of female recipients. CONCLUSION: Hypothermic machine perfusion could allow the duration of cold ischemia to be prolonged without altering the uterine graft. Nevertheless, this assertion has to be validated in a human context.

Live Birth from Cryopreserved Oocyte After Uterus Transplantation: A Case Report.

BACKGROUND Important legal and ethical issues must be addressed in the practice of uterus transplantation, because it is a non-life-saving intervention. In all cases reported in the literature so far, uterus transplantation is preceded by oocyte retrieval, fertilization of the collected oocytes, and subsequent freezing of the embryos produced. This element should be considered because of the potential ethical, legal, and moral implications related to the existence and fate of supernumerary embryos in the event of transplantation failure. CASE REPORT The Italian Research Project for Uterus Transplantation from a brain-dead donor was approved in 2018 (No. 1438/CNT2018). A 28-year-old patient with Mayer-Rokitansky-Küster-Hauser syndrome, ectopic ovaries, and good ovarian reserve received uterus transplantation in 2020 after oocyte retrieval with laparoscopic assistance. Metaphase oocytes were cryopreserved and thawed after the successful transplantation to perform in vitro fertilization followed by embryo transfer. The pregnancy course was regular, without symptoms until week 30, when PCR positivity for SARS-CoV-2 was recorded. The patient underwent an emergency cesarean delivery at 34 weeks' gestation because of fever and the appearance of regular uterine contractions. An infant was born alive and vital at 34 weeks of pregnancy and weighed 1725 g. The newborn was discharged in good condition and with a body weight of 2740 g. CONCLUSIONS This case report shows that cryopreservation of oocytes can overcome the ethical issue related to embryo retrieval before a successful uterus transplantation can be demonstrated. Our result supports the possibility of bypassing embryo freezing before ascertaining the success of uterus transplantation.

Imaging of Uterine Transplantation.

Uterus transplantation (UTx) is a novel procedure being studied as a treatment of absolute uterine factor infertility. Imaging plays an important role throughout the life cycle of a uterus transplant. In this review, we will first describe the surgical technique of UTx. The article will then focus on the importance of imaging in the evaluation of potential recipients and donors and during the immediate post-surgical time course as graft viability is established. Imaging as part of including in vitro fertilization, pregnancy, and complications will also be discussed.

Should Uterus Transplantation for Transwomen and Transmen Be Subsidized?

Success in uterus transplantation (UTx) among ciswomen suggests that transwomen and some transmen will also likely have interest in this intervention. It does not seem likely, however, that all parties interested in UTx will have the same standing when it comes to federal subsidies or insurance coverage benefits. This analysis describes the comparative moral strength of claims for financial support for UTx that different parties might make.

Uterus Transplantation as a Surgical Innovation.

Uterus transplantation (UTx) research has been introduced in several countries, with trials in Sweden and the United States producing successful outcomes. The growing interest in developing UTx trials in other countries, such as Spain, the Netherlands, Japan, and Australia, raises important questions regarding the ethics of surgical innovation research in the field of UTx. This paper examines the current state of UTx in the context of the surgical innovation paradigm and IDEAL framework and discusses the ethical challenges faced by those considering the introduction of new trials. We argue that UTx remains an experimental procedure at a relatively early stage of the IDEAL framework, especially in the context of de novo trials, where protocols are likely to deviate from those used previously and where researchers are likely to have limited experience of UTx. We conclude that countries considering the introduction of UTx trials should build on the strengths of the reported outcomes to consolidate the evidence base and shed light on the uncertainties of the procedure. Authorities responsible for the ethical governance of UTx trials are advised to draw on the ethical framework used in the oversight of surgical innovation.

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 artificial uterus: on the way to ectogenesis.

The inability to support the growth and development of a mature fetus up to delivery results in significant human suffering. Current available solutions include adoption, surrogacy, and uterus transplantation. However, these options are subject to several ethical, religious, economic, social, and medical concerns. Ectogenesis is the process in which an embryo develops in an artificial uterus from implantation through to the delivery of a live infant. This current narrative review summarizes the state of recent research focused on human ectogenesis. First, a literature search was performed to identify published reports of previous experiments and devices used for embryo implantation in an extracorporeally perfused human uterus. Furthermore, studies fitting that aim were selected and critically evaluated. Results were synthesized, interpreted, and used to design a prospective strategy for future research. Therefore, this study suggests that full ectogenesis might be obtained using a computer-controlled system with extracorporeal blood perfusion provided by a digitally controlled heart-lung-kidney system. From a clinical perspective, patients who will derive significant benefits from this technology are mainly those women diagnosed with anatomical abnormalities of the uterus and those who have undergone previous hysterectomies, numerous abortions, and experienced premature birth. Ectogenesis is the complete development of an embryo in an artificial uterus. It represents the solutions for millions of women suffering from premature deliveries, and the inability to supply growth and development of embryos/fetuses in the womb. In the future, ectogenesis might replace uterine transplantation and surrogacy.

Surgical Approach, Challenges, and Resolutions for Uterus Transplantation in Rats.

Uterine transplantation (UTx) is a new approach for treating women with absolute uterine factor infertility (AUFI). An estimated 3%-5% of women suffer from AUFI. These women were deprived of the option to have children until the advent of UTx. The clinical application of UTx was driven by experimental studies in animals, and the first successful UTx was achieved in rats. Given their physiological, immunological, genetic, and reproductive characteristics, rats are a suitable model system for such transplants. In particular, their short gestation period is a clear advantage, as the usual endpoint of experimental UTx is successful pregnancy with live birth. The biggest challenge for rat models remains the small anatomy, which requires advanced microsurgical skills and experience. Although UTx has led to pregnancy in the clinic, the procedure is not established and requires continuous experimental optimization. Here, a detailed protocol is presented, including essential troubleshooting for rat UTx, which is expected to make the entire procedure easier to grasp for those without experience in this type of microsurgery.

Transplantation of the Uterus in the Male Rat.

BACKGROUND: Uterus transplantation (UTx) is one of the potential methods to cure absolute uterine factor infertility of transgender. However, this mostly comes with many technological challenges. METHODS: Left inguinal UTx was performed in 13 castrated male rats. End-to-end anastomosis of donor common iliac vessels to recipient femoral vessels was used for transsexual UTx. Sampling was performed on day 30 after transplantation. Grafts were used to analyze the histological changes. TUNEL assay was applied to stain the apoptotic cells. Immunological rejection was judged by flow cytometry. RESULTS: Six uteri, 4 ovaries, and 4 upper vaginas were found at day 30 posttransplantation. Similar histological changes to proestrus, estrus, and diestrus of female rats were examined in the transplanted uteri. The histological changes of transplanted vaginas showed similarity to proestrus, estrus, and metestrus of the female rats. Follicles of different stages and corpus luteum with distinct morphological appearances were also observed. The TUNEL assay revealed a higher apoptosis of granulosa cells in transplanted ovaries compared with normal ovaries. CONCLUSIONS: A rat model of transsexual unilateral inguinal uterine transplantation in castrated rats was established, which will provide a reference for bilateral transsexual UTx in animals and genetically 46 XY individuals who wish to become real women through transsexual UTx.

[Uterine transplantation, ethical and social aspects]. / Aspects éthiques et sociaux de la transplantation utérine.

Uterine transplantation is now a possible treatment for absolute uterine infertility. It is currently proposed to women with Mayer-Rokitansky-Küster-Hauser syndrome but indications will likely to expand in the upcoming years. Despite the progressive standardization of the surgical technique and the reduction in perioperative morbidity for both donors and recipients, the number of transplants performed worldwide remains very low compared to the number of women potentially in need. This is partly due to the singularity of uterine transplantation: the uterus is not a vital organ since one can live without a uterus. It is a temporary transplantation that is not performed to extend life but to improve its quality, responding above all to a desire to conceive and bear a child. Beyond the strictly technical aspect, these particularities raise many ethical questions, both on an individual and social level, which should make us question the real place uterine transplantation should take in our society. Answering these questions will allow us to provide better guidance for future eligible couples and to anticipate ethical problems on the long run.

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.

Is suffering a sufficient legitimation for UTx?

Uterus transplantation is a relatively new intervention. A woman with absolute uterine factor infertility receives, by a surgical procedure, a transplanted uterus, most often by living donation. The uterus recipient may thus become pregnant and conceive her own child. As with any other medical treatment, UTx requires legitimation. The anticipated benefits must outweigh the risks of the medical intervention. The risks and benefits of UTx are by no means unequivocal and cannot be easily determined. The benefits depend on the final evaluation of the suffering to be alleviated by the intervention. In the following, we will analyze the suffering addressed by UTx and discuss its normative value. First, we point out that (a) suffering is generally considered an important normative criterion in medicine as well as in the context of UTx; (b) we then describe the risks and anticipated benefits of UTx for the three persons directly concerned: the child, the donor, and the recipient; (c) we further analyze the suffering addressed by UTx. The intervention addresses a form of existential suffering. We discuss the common notion that existential suffering should be evaluated from the subjective perspective of the sufferer; (d) afterwards, we argue that in a social practice like medicine, a one-sided evaluation stemming from the sufferer alone is not sufficient; and (e) finally, arguments from a societal perspective lead us to the conclusion that the existential suffering addressed by UTx does not possess a sufficiently strong normative value to legitimize a high-risk, expensive procedure.

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.

Immunosuppression in uterus transplantation: from transplant to delivery.

INTRODUCTION: Uterus transplantation introduces unique challenges regarding immunosuppression, including the effects of immunosuppressive drugs on the fetus and graft rejection during pregnancy. Although immunosuppressive regimens are based on protocols used after solid organ transplantation, in recipients of uterus grafts, the physician must consider therapy modifications based on the phase of the transplant, from the intra-operative period through to delivery. AREAS COVERED: This review discusses the current immunosuppressive rationale in uterus transplantation, focusing on the therapy in each phase of the transplant. The authors present an overview of the already approved immunosuppressive medications for solid organ transplantation, their application in uterus transplant prior to pregnancy, during pregnancy and as rejection treatment. EXPERT OPINION: Most medications used for uterus transplant are adopted from solid organ transplantation experience, especially kidney transplantation, and rejection is treated in standard fashion. Research is needed to clarify the drugs' effects on fetal and neonatal well-being and to develop new medications to achieve better tolerance. Early markers of uterus graft rejection need to be identified, and prior rejection episodes should no longer be a cause to remove the graft during delivery in a recipient who wants a further pregnancy.