The vaginal microbiome in uterine transplantation.

Women with congenital absolute uterine factor infertility (AUFI) often need vaginal restoration to optimise sexual function. Given their lack of procreative ability, little consideration has previously been given to the resultant vaginal microbiome (VM). Uterine transplantation (UTx) now offers the opportunity to restore these women's reproductive potential. The structure of the VM is associated with clinical and reproductive implications that are intricately intertwined with the process of UTx. Consideration of how vaginal restoration methods impact VM is now warranted and assessment of the VM in future UTx procedures is essential to understand the interrelation of the VM and clinical and reproductive outcomes. TWEETABLE ABSTRACT: The vaginal microbiome has numerous implications for clinical and reproductive outcomes in the context of uterine transplantation.

Human uterine transplantation: a review of outcomes from the first 45 cases.

Uterine transplantation restores reproductive anatomy in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The number of cases being performed is increasing exponentially, with detailed outcomes from 45 cases, including nine live births, now available. In light of the data presented herein, including detailed surgical, immunosuppressive and obstetric outcomes, the feasibility of uterine transplantation is now difficult to refute. However, it is associated with significant risk with more than one-quarter of grafts removed because of complications, and one in ten donors suffering complications requiring surgical repair. TWEETABLE ABSTRACT: Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication.

First live birth after uterus transplantation in the United States.

Uterus transplantation has proven to be a successful treatment for women with absolute uterine infertility, caused either by the absence of a uterus or the presence of a nonfunctioning uterus. We report the first birth of a healthy child following uterus transplantation in the United States, from a recipient of a uterus allograft procured from an altruistic living donor. Two major modifications from the previously reported live births characterized this uterus transplant. First, the transplanted uterus relied upon and sustained the pregnancy while having only the utero-ovarian vein as venous outflow. The implication is a significantly simplified living donor surgery that paves the way for minimally invasive laparoscopic or robot-assisted techniques for the donor hysterectomy. Second, the time from transplantation to embryo transfer was significantly shortened from prior protocols, allowing for an overall shorter exposure to immunosuppression by the recipient and lowering the risk for potential adverse effects from these medications.

Live nondirected uterus donors: Psychological characteristics and motivation for donation.

Emerging research suggests that uterus transplantation is a viable option for women without a uterus who want to become pregnant and carry a child to term. Currently, no knowledge exists regarding nondirected uterus donors. This study (NCT 02656550) explored the baseline psychological characteristics of nondirected uterus donors at a single study site. Of the 62 potential donors who underwent initial screening, 6 nondirected donors were chosen and participated in uterus donation. Participants received a comprehensive evaluation, which included clinical history and psychological assessments. The mean age of the donors was 42 years; most (83%) were white/not Hispanic, and all had a college degree. Current depression was reported by 2 participants, past depression was reported in 2 participants, and past anxiety was reported in 3 participants. Based on several different psychological measures, donors had a higher general well-being than the normative sample, and none of the participants' scores indicated psychological distress. All 6 women indicated that giving another woman an opportunity to carry her own child was a motivation for pursuing uterus donation. Further research on potential psychological motives and gains for the donor as well as long-term effects on donors is crucial for ethical practice.

Deceased donor uterus retrieval: A novel technique and workflow.

Uterus transplantation has proven successful when performed with a living donor. Subsequently, interest in the novel field of reproductive transplantation is growing. The procedure is still considered experimental, with fewer than 25 cases performed worldwide, and the techniques of both uterus procurement and transplantation are still developing. We detail a new approach to deceased donor uterus procurement. In contrast to reported techniques and our own initial experience, in which the deceased donor uterus was procured post cross-clamp and after other organs were procured, our approach now is to perform the uterus procurement prior to the procurement of other organs in a multiorgan donor and hence prior to cross-clamp. We describe our practical experience in developing and implementing the logistical workflow for deceased donor uterus procurement in a deceased multiorgan donor setting.

Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned From Early Setbacks to Technical Success.

Uterus transplantation is a vascularized composite allograft transplantation. It allows women who do not have a uterus to become pregnant and deliver a baby. In this paper, we analyze the first five cases of living donor uterus transplantation performed in the United States. The first three recipients lost their uterus grafts at days 14, 12, and 6, respectively, after transplant. Vascular complications, related to both inflow and outflow problems, were identified as the primary reason for the graft losses. Two recipients, at 6 and 3 mo, respectively, after transplant, have functioning grafts with regular menstrual cycles. Ultimate success will be claimed only after a live birth. This paper is an in-depth analysis of evaluation, surgical technique, and follow-up of these five living donor uterus transplants. The lessons learned were instrumental in allowing us to evolve from failure to technical and functional success. We aim to share our conclusions and build on knowledge in the evolving field of uterus transplantation.

Living Donor Uterus Transplant and Surrogacy: Ethical Analysis According to the Principle of Equipoise.

The uterus is the most recent addition to the list of organs that can be successfully transplanted in humans. This article analyzes living donor uterus transplantation according to the ethical principle of equipoise. A comparison is made between living donor uterus transplantation and gestational surrogate motherhood. Both are solutions to absolute uterine infertility that allow the transfer of genetic material from intended parents to a child. The analysis concludes that living donor uterus transplantation does not violate the ethical principle of equipoise and should be considered an ethically acceptable solution to absolute uterine infertility.

Preclinical report on allogeneic uterus transplantation in non-human primates.

STUDY QUESTION: Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection? SUMMARY ANSWER: Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used. WHAT IS KNOWN ALREADY: UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 female baboons as uterus recipients. The follow-up time was 5-8 weeks. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Uterus retrieval was performed with extended hysterectomy including bilateral uterine and internal iliac arteries and ovarian veins. After UTx, with vascular anastomoses unilateral to the internal iliac artery and the external iliac vein, the uterus recipients received one of the following: no immunosuppression (n = 4); monotherapy (oral slow release tacrolimus) (n = 4) or induction therapy (antithymocyte globulin) followed by triple therapy (tacrolimus, mycophenolate, corticosteroids; n = 10). Surgical parameters, survival, immunosuppression and rejection patterns were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: The durations of uterus retrieval and recipient surgery were around 3 and 3.5 h, respectively. The total ischemic time was around 3 h. All the recipients and the donors survived the surgery. All the recipients presented rejection to some extent within the first weeks following UTx. In one recipient, the uterus was of normal appearance at the end of the study period. In spite of occasional high (>60 ng/ml) blood levels of tacrolimus, there was no evidence of nephrotoxicity. LIMITATIONS AND REASONS FOR CAUTION: This initial non-human primate allogeneic UTx study indicates that further research is needed to optimize immunosuppression protocols in order to avoid uterine rejection. WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that allogeneic UTx in primate species is feasible but continued work on this issue is needed. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Swedish Research Council, ALF University of Gothenburg, Hjalmar Svensson Foundation and by Jane and Dan Olsson Research Foundation. The authors do not have any competing interest.

Uterus transplantation in a non-human primate: long-term follow-up after autologous transplantation.

BACKGROUND: Uterus transplantation (UTx) may provide the first available treatment for women affected by uterine infertility. The present study aimed to further develop a surgical technique for autologous UTx in a non-human primate species and to assess long-term function. METHODS: Female baboons (n= 16) underwent autologous transplantation of the uterus with the Fallopian tubes and ovaries, performed with a previously published surgical technique (n= 6, Group 1) or using a modified technique (n= 10; Group 2). The uterine arteries were dissected to the proximal end of the anterior branch (Group 1) or the entire (Group 2) internal iliac artery, and the ovarian veins were dissected to the crossing over the ureter (Group 1) or further cranially to include greater lengths and patches of the cava/renal vein (Group 2). Back-table preparation created common venous and arterial ends with arterial anastomosis either end-to-side to the left external iliac artery (Group 1) or end-to-end to the left internal iliac artery (Group 2). RESULTS: Overall short-time survival of the animals was 88% (66% in Group 1 and 100% in Group 2). Of all the operated animals, 75% (66% in Group 1 and 80% in Group 2) resumed ovarian cyclicity. Regular menstruation after UTx was demonstrated only in Group 2 (60%). Menstruating animals (n= 6) were each exposed to timed mating for ≥5 menstrual cycles, but pregnancy did not occur. Adhesions and tubal blockage were seen in post-mortem analysis. CONCLUSIONS: The modified UTx model of Group 2 is a safe procedure and shows resumed long-term uterine function in a majority of the animals, although pregnancy could not be demonstrated.

Uterine transplantation research: laboratory protocols for clinical application.

The aim of this review is to summarize the state-of the-art methods that are used in clinical organ transplantation today, as well as the major findings of recent experimental uterus transplantation (UTx) research regarding organ donation/retrieval, ischemic preservation, surgical techniques for anastomosis, immunosuppression and pregnancy. Absolute uterine factor infertility lacks treatment despite the major developments in infertility treatment and assisted reproduction. Concerning uterine factor infertile patients, genetic motherhood is only possible through gestational surrogacy. The latter can pose medical, ethical and legal concerns such as lack of control of life habits during surrogate pregnancy, economic motives for women to become surrogate mothers, medical/psychological pregnancy-related risks of the surrogate mother and uncertainties regarding the mother definition. Thus, surrogacy is non-approved in large parts of the world. Recent advances in the field of solid organ transplantation and experimental UTx provide a favourable and safe background in a scenario in which a human clinical UTx trial can take place. Protocols based on animal research over the last decade are described with a view to providing a scientifically guided approach to human UTx as an experimental procedure in the future.

Uterus transplantation in the baboon: methodology and long-term function after auto-transplantation.

BACKGROUND: Techniques for uterus transplantation (UTx) have been developed in rodent/domestic animals towards future clinical introduction of UTx to treat uterine factor infertility. The aim of this study was to extend the UTx research into a non-human primate species by developing surgical techniques for uterus retrieval and transplantation in the baboon. METHODS: Female baboons (n = 15) underwent surgery, with the initial five animals used for studies of pelvic vascular anatomy. Retrieval surgery included isolation of the ovarian veins and the uterine arteries together with the anterior branches of the internal iliacs. The utero-tubal-ovarian specimen was removed, flushed and kept ex vivo for 2 h when the two arterial ends and two venous ends were anastomosed side-to-side to construct one arterial and one venous end. These were, at auto-transplantation, anastomosed end-to-side to the external iliacs and the animals (n = 10) were evaluated concerning cyclicity and later by laparoscopy/laparotomy. RESULTS: The total duration of organ retrieval, backtable preparation and transplantation was around 6 h with an overall ischaemic time of the specimen of about 3 h. One animal died due to cardiomyopathy. Five out of the nine surviving animals resumed cyclicity, as a sign of re-established ovarian function. Only two out of these five animals exhibited resumed menstruation, indicating re-established ovarian and uterine function. Laparoscopy confirmed normal-sized uteri in these two animals. CONCLUSIONS: This study demonstrates the feasibility of UTx by vascular anastomosis in a non-human primate species. The low success rate demonstrates the complexity involved in UTx surgery and the need for further methodological developments.

Evaluation of the significance of dietary folate from wild vegetables in Vietnam.

Data on the overall dietary folate intakes among high-risk groups in poor countries is very limited. Vegetables are considered good sources but the evaluation of their contribution is hampered by the lack of data on folate concentrations in many traditional foods. Data on the analysis of folate concentrations in 16 wild vegetables used in the Mekong Delta and the Central Highlands in Vietnam and an evaluation of the relative importance of different foods in folate intakes of women is presented. Vegetable samples were collected in four study villages, blanched and frozen samples were transported to Sweden for analysis. Freeze-dried samples were analysed for total folate quantification using a commercial radio protein binding assay. Daily folate intakes among women were estimated from 7-day food frequency interviews with 213 women. The folate concentration in the vegetable samples ranged from 10 to 96 microg/100 g. The mean estimated daily folate intake among the 213 women in the study areas was 251 microg. Vegetables contributed approximately one-third of the daily folate intake, of which 72% and 42%, respectively, in the two regions was from wild vegetables. A majority of the women (87%) got some dietary folate from wild vegetables and nearly one-third had mean daily folate intakes of > 50 microg from such hidden food sources. The evaluation of dietary folate is complicated by data gaps in food composition tables, the unreliability of existing food data, variations between methods used for folate analysis and limited understanding of the bioavailability of food folate.