Unique risk factors for unplanned preterm delivery in the uterus transplant recipient.

STUDY QUESTION: Do characteristics of the lower uterine segment and cervix modify the risk of preterm delivery in uterus transplant (UTx) recipients? SUMMARY ANSWER: The cervical length showed little association with preterm delivery, however, cervical inflammation deserves further exploration as a cause of preterm delivery. WHAT IS KNOWN ALREADY: UTx recipients do not have the risk factors normally used to stratify pregnancies that would benefit from cervical length assessment. In addition, unique factors related to absent tissues, a different blood supply, inflammatory processes of rejection, cervical biopsies, and a different microbiome challenge the normal progressive remodeling of the cervix and thus cervical competence. STUDY DESIGN, SIZE, DURATION: This is a subanalysis of a clinical trial of 20 women undergoing uterus transplantation at Baylor University Medical Center from 2016 to 2020, in addition to two women who received transplantation outside of a research protocol at our institution through September 2022. In this report, the first 16 UTx recipients that achieved live birth are included. PARTICIPANTS/MATERIALS, SETTING, METHODS: The focus of this study was 20 pregnancies that reached the second trimester in 16 women following UTx. We analyzed recipient, transplant, and donor factors to determine if characteristics were associated with delivery outcome. We compared obstetrical outcomes, including planned versus unplanned delivery, by factors such as number of superior venous anastomoses, warm ischemia and cold ischemia times, donor factors including cesarean sections, cervical biopsy results, and cervical ultrasound results. MAIN RESULTS AND THE ROLE OF CHANCE: Planned term deliveries occurred in 44% (8/18) of live births. Of the preterm births, 30% (3/10) were planned and 70% (7/10) were unplanned. Unplanned deliveries occurred in women with spontaneous preterm labor, severe rejection, subchorionic hematoma, and placenta previa. Cervical length in UTx recipients averaged 33.5 mm at 24 weeks and 31.5 mm at 28 weeks, comparable to values from the general population. No relationship was seen between delivery outcome and number of veins used, ischemic time, or number of previous cesarean sections. LIMITATIONS, REASONS FOR CAUTION: The study's small size allows limited conclusions. The obstetric history of all donors was limited to mode of delivery. WIDER IMPLICATIONS OF THE FINDINGS: Cervical length measurements in the UTx population are not expected to deviate from those with a native uterus. While cervical length surveillance remains important, attention must be paid to the results of cervical biopsies which are obtained to monitor rejection. Inflammatory processes seem most predictive of preterm delivery. STUDY FUNDING/COMPETING INTEREST(S): No funding was provided for this study. The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: NCT02656550.

Living uterus donors' perceptions of decision-making and informed consent: a qualitative study of the Dallas Uterus Transplant Study participants.

Uterus transplantation is a growing field, but little is known about living uterus donors' perceptions of informed consent or their decision-making processes. This study used semistructured interviews to collect information regarding uterus donors' experiences with uterus donation, perceptions of the informed consent process, and information on how they decided to pursue uterus donation. Interviews were coded for thematic analysis. Three major themes emerged in this study. First, the decision-making process was based on individuals' motivations, rationale, and considerations of alternative contributions to help other women with infertility. Second, participants described how they felt about the process of informed consent, their decision-making processes, and how their experiences compared with their expectations. Third, participants discussed how uterus donation was a valuable experience. This study found that living uterus donors are motivated to give another woman the opportunity to experience pregnancy and childbirth. They were satisfied with the informed consent process, their experiences were in line with their expectations, and the value of uterus donation was associated with the act of donation itself. Our findings suggest that living donor uterus programs should develop robust informed consent processes that provide detailed information about uterus donation and encourage shared decision-making with potential uterus donors.

OPTN/SRTR 2021 Annual Data Report: Vascularized Composite Allograft.

Year 2020 marked the first OPTN/SRTR Annual Data Report that included a chapter on vascularized composite allograft (VCA), which encompassed reviews of data collected between 2014 (when VCA was included in the Final Rule) and 2020. The present Annual Data Report shows that the number of VCA recipients in the United States continues to be small and trended downward in 2021. While data continue to be limited by sample size, trends continue to show a predominance in White, young/middle-aged, male recipients. Similar to the 2020 report, eight uterus and one non-uterus VCA graft failures were reported from 2014 through 2021. Critical to advancement of VCA transplantation will be the standardization of definitions, protocols, and outcome measures for the different VCA types. Like intestinal transplants, it is likely that VCA transplants will be concentrated and performed at referral transplant centers.

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.

Neonatal Outcomes after Uterus Transplantation: Dallas Uterus Transplant Study.

OBJECTIVE: Limited data are available on the outcome of infants born after uterus transplantation. Our aim was to describe the hospital course and laboratory findings in the first 2 months of life of the 12 infants born in the Dallas UtErus Transplant Study (DUETS). STUDY DESIGN: Based on the trial protocol, information about infants was collected in a prospective fashion, including infant demographics, hospital course, and laboratory values. RESULTS: Twelve infants were delivered, all by cesarean section, from 11 mothers who had undergone uterus transplantation (one mother had two pregnancies and delivered two babies). All pregnancies were singleton. The mothers received immunosuppressive therapy, and one had a rejection episode that was detected during pregnancy. The rejection episode resolved after steroid treatment. The infants had a median gestational age of 366/7 weeks (range: 306/7-380/7 weeks) and median birth weight of 2,920 g (range: 1,770-3,470 g). The lowest Apgar's score at 5 minutes was 8. All infants were appropriate size for gestational age. Two infants presented with bandemia but negative blood cultures. At 2 months of age, all infants achieved the developmental and behavioral milestones outlined by the American Academy of Pediatrics. CONCLUSION: The 12 infants born from mothers with uterus transplants had a neonatal course that reflected the gestational age at delivery. No baby was born with an identified malformation or organ dysfunction. Longer follow-up and a larger number of infants are needed to confirm these observations. KEY POINTS: · Normal fetal development after uterus transplantation.. · No baby was born with malformations or showed any organ dysfunction.. · At 2 months, all infants achieved appropriate developmental and behavioral milestones..

Doppler Flow Indices and Prediction of Embryo Transfer Success and Pregnancy Outcome in Uterus Transplant Recipients.

OBJECTIVE: Doppler velocimetry of the uterine and umbilical arteries is used to predict preeclampsia and monitor fetal outcomes. There have been no reports of Doppler velocimetry indices in pregnancies conceived after uterus transplantation, which differ from traditional pregnancies because of different uterine vascular inflow and outflow and exposure to immunosuppressive agents. We sought to examine whether Doppler indices can be used to predict embryo transfer success after uterus transplantation and whether Doppler indices across pregnancy predict fetal growth restriction. STUDY DESIGN: This was a single-center cohort observational study of 14 uterus transplant recipients who underwent embryo transfer. Of these, 12 women successfully delivered 14 babies. Five Doppler investigations were performed within the cohort: (1) prepregnancy; (2) uterine artery assessment across pregnancy; (3) umbilical artery assessment across pregnancy; (4) successive pregnancies; and (5) fetal growth. RESULTS: Prepregnancy uterine artery Doppler indices did not correlate with successful implantation after embryo transfer. Uterine artery Doppler indices in uterus transplant recipients decreased across pregnancy as described in pregnancies without uterus transplantation. The umbilical artery systolic/diastolic velocity ratio was lower at all weeks of gestation after uterus transplantation compared with values described in pregnancies without uterus transplantation. In those women who delivered two successive babies after uterus transplant, umbilical artery Doppler indices were significantly lower during the second pregnancy. There was always forward flow throughout diastole in the umbilical arteries, and no babies experienced fetal growth restriction. CONCLUSION: In our study, uterus transplantation was not associated with abnormal blood flow indices in either the uterine or umbilical arteries. Although Doppler indices were not predictive of embryo transfer success, they supported the expectation that pregnancies after uterus transplantation at our center result in normally grown babies. KEY POINTS: · Uterus transplantation is not associated with abnormal blood flow indices.. · Prepregnancy uterine artery Doppler indices did not correlate with successful embryo implantation.. · Doppler assessment supports the expectation of normal placentation, fetal growth, and healthy live births after uterus transplantation..

First uterine transplant case at the Royal Prince Alfred Hospital.

Uterine transplantation (UT) is an emerging medical treatment for women affected by absolute uterine factor infertility (AUFI). To date there have been over 90 documented cases of UT performed worldwide, with over 50 live births. UT allows women affected by AUFI the opportunity to carry and deliver a childd. The Royal Prince Alfred Hospital (RPAH) introduced a UT study in 2019; however, due to the impacts of the COVID pandemic the study was placed on hold for two years. In February 2023, RPAH performed the centre's first UT from a living unrelated donor to a 25-year-old woman with Mayer-Rokitansky-Küster-Hauser syndrome. The donor and recipient surgeries were uncomplicated and both are recovering well in the early post-operative period.

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.

Strategic Planning and Essential Steps for Establishing a Uterine Transplant and Rehabilitation Program: From Idea to Reality.

UTx is performed to address absolute uterine infertility in the presence of uterine agenesis, a nonfunctional uterus, or after a prior hysterectomy. After the initial success of UTx resulting in a livebirth (2014) in Sweden, there are over 70 reported UTx surgeries resulting in more than 40 livebirths worldwide. Currently, UTx has been performed in over 10 countries. As UTx is transitioning from an "experimental procedure" to a clinical option, an increasing number of centers may contemplate a UTx program. This article discusses essential steps for establishment of a successful UTx program. These principles may be implemented in cis- and transgender UTx candidates.

Children after uterus transplantation: 2-year outcomes from the Dallas UtErus Transplant Study (DUETS).

OBJECTIVE: To describe outcomes in the first 2 years of life for the children born in the Dallas UtErus Transplant Study. DESIGN: Cohort study comprising all live births from uterus transplantation at a single centre. SETTING: Baylor University Medical Center, Dallas, Texas. POPULATION: A total of 14 children from 12 uterus transplantation recipients. METHODS: Retrospective review of data through 2 years of life. MAIN OUTCOME MEASURES: Information on children's development was collected based on the Bright Futures Guideline and the Bright Futures Previsit Questionnaire. Primary outcomes were anthropometric measures (children's body length, weight, head circumference), neurological status, cognitive status and physical development at 6, 12, 18 and 24 months of age. RESULTS: The median gestational age at delivery was 36+6  weeks, with a median birthweight of 2940 g. Follow-up data were available for 13 offspring. Physical and neurological developmental milestones were met and were age appropriate in all children within the first 24 months. General health was good, and no abnormalities in immune development were found. Cognitive deviations were only mild and temporary and improved with interventions. CONCLUSIONS: The children's growth and physical, neurological and cognitive development were age appropriate within the first 2 years of life. To confirm these outcomes, further data should be collected in collaboration with other centres.

The journey from infertility to uterus transplantation: A qualitative study of the perspectives of participants in the Dallas Uterus Transplant Study.

OBJECTIVE: To assess how absolute uterine factor infertility affects women who undergo uterus transplantation, how uterus transplantation impacts women with absolute uterine factor infertility and how uterus transplant recipients view uterus transplantation in terms of their reproductive autonomy. DESIGN: Qualitative semi-structured interview study. SETTING: Uterus transplant programme in a large academic medical centre in the USA. POPULATION/SAMPLE: Twenty one uterus transplant recipients. METHODS: A medical chart review was conducted to collect patient demographic information and clinical outcomes. Semi-structured interviews collected information regarding participants' experience. MAIN OUTCOME MEASURE(S): The outcomes of interest were participants' experience of infertility, experience with uterus transplantation and general perceptions of uterus transplantation. RESULTS: Six participants were pregnant (one with a second child), six had experienced early graft failure and removal, five had delivered a healthy baby, and four had a viable graft and were awaiting embryo transfer. The primary themes identified were: the negative impact of absolute uterine factor infertility diagnosis on psychological wellbeing, relationships and female identity; the positive impact of uterus transplantation on healing the emotional scars of absolute uterine factor infertility, female identity and value of research trial participation and the perception of uterus transplantation as an expansion of reproductive autonomy. All participants reported that uterus transplantation was worthwhile, regardless of individual outcome. CONCLUSION: Absolute uterine factor infertility has a negative impact on women from a young age, affects multiple relationships and challenges female identity. Uterus transplantation helps to reverse this impact, transforming women's life narrative of infertility and enhancing female identity. TWEETABLE ABSTRACT: Absolute uterine factor infertility (AUFI) adversely affects women. Uterus transplantation helps mitigate the negative impact of AUFI, by transforming women's life narratives of infertility and enhancing female identity.

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.

The Ethical Evolution of Uterus Transplantation From Concept to Clinical Procedure.

Uterus transplantation (UTx) offers women with absolute uterine factor infertility a path to motherhood that enables them to carry their own pregnancy. Debates about the ethics of UTx have evolved in tandem with its clinical evolution: clinical trials have provided evidence regarding risks and benefits to donors and recipients that were initially uncertain; technical advances have altered the balance between risks and benefits; and the experiences of donors and recipients has revealed questions that were not anticipated. As UTx transitions to a clinical procedure, questions remain about long-term risks and benefits, applications beyond carrying a pregnancy, and cost and access.

The Future of Uterus Transplantation: Cost, Regulations, and Outcomes.

Uterus transplantation (UTx) has evolved rapidly since technical success was first demonstrated, and is now practiced worldwide, using both living and deceased donors. As UTx transitions from an experimental to widely available standard clinical procedure, new challenges and questions are becoming more urgent. These include issues of cost and coverage, the establishment of guidelines and registries to ensure quality of care and monitor outcomes, regulatory oversight (including for the allocation organs from deceased donors), and the extent to which indications for UTx should be expanded.

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.

Life underneath the VCA umbrella: Perspectives from the US Uterus Transplant Consortium.

The parallel emergence of uterus transplantation (UTx) and other transplantation innovations including face and hand transplantation led to the categorization of the uterus as a vascular composite allograft (VCA). With >60 transplants and >20 births worldwide, UTx is transitioning rapidly from a research endeavor to an effective treatment option for women with uterine factor infertility. While it originally made sense to group the innovations under one umbrella, it is time to revisit the designation of UTx as a VCA. We describe how UTx needs unique policy, procedural codes, insurance contracts, and educational initiatives. We contend that separating UTx from VCAs may become necessary in the future to avoid hindering the growth and regulation of this field.

Clinical pregnancy rates and experience with in vitro fertilization after uterus transplantation: Dallas Uterus Transplant Study.

BACKGROUND: The clinical pregnancy rates among patients with uterus transplantation have been reported by only a limited number of centers, and those centers have not used preimplantation genetic testing for aneuploidy in their protocol. OBJECTIVE: This study examined clinical pregnancy rates among women with absolute uterine-factor infertility undergoing in vitro fertilization using good-quality, expanded-blastocyst-stage, euploid embryos after uterus transplantation. STUDY DESIGN: This cohort observational study involved 20 women who underwent uterus transplantation over 3 years. Notably, 14 of these patients had successful transplants and were followed prospectively for a median of 14.1 months (range, 11-34.8 months). In vitro fertilization was performed before subjects underwent uterus transplantation, and good-quality expanded-blastocyst-stage euploid embryos were obtained and frozen for future embryo transfer. Interventions consisted of in vitro fertilization, preimplantation genetic testing for aneuploidy, uterus transplantation, and frozen embryo transfer. RESULTS: All 14 subjects with successful transplants underwent single embryo transfer of a warmed, good-quality, euploid, expanded blastocyst and had at least 1 documented clinical pregnancy within the uterus. In 71.4%, the first embryo transfer resulted in clinical pregnancy. The median time from successful uterus transplantation to first embryo transfer was 4.5 months; from successful uterus transplantation to first clinical pregnancy, 7.3 months; and from successful uterus transplantation to first live birth, 14.1 months. A total of 13 live births have occurred in 12 subjects. CONCLUSION: Women with absolute uterine-factor infertility who have surgically successful uterus transplantation and in vitro fertilization using preimplantation genetic testing for aneuploidy can achieve high clinical pregnancy rates. We have reduced the time interval from uterus transplantation to embryo transfer by at least 50% and the interval from uterus transplantation to clinical pregnancy by >6 months compared with previous studies. We believe our approach may shorten the time from transplant to clinical pregnancy and therefore decrease patient exposure to immunosuppressant therapies.

Pregnancy after CMV infection following uterus transplantation: A case report from the Dallas Uterus Transplant Study.

Uterus transplantation is a repeatedly proven treatment for women with absolute uterine-factor infertility, which is the congenital or acquired absence of the uterus, who desire to carry, and ultimately deliver, a child. No stranger to the field of transplant or obstetrics is cytomegalovirus. Cytomegalovirus is both a frequent complication after transplant, presenting as an opportunistic infection, and a common congenital disease in the newborn child from pregnancy. To date, there have been no reported cases of pregnancy following uterus transplantation from cytomegalovirus-positive donors into cytomegalovirus-negative recipients. We present a case report describing our experience of a cytomegalovirus-negative recipient, transplanted with a uterus from a cytomegalovirus-positive living donor, and subsequently diagnosed with active cytomegalovirus infection despite prophylactic treatment. She was treated for infection prior to embryo transfer and carried a healthy child to term. This case suggests transplanting a cytomegalovirus-positive uterus into a negative donor is possible to do safely.

Uterus transplantation and pregnancy induction: Approved protocol at the Royal Prince Alfred Hospital.

Absolute uterine factor infertility (AUFI) is defined as the absence of a uterus or the presence of a non-functional uterus. Before the first live birth from a uterus transplant in 2014, the only fertility options for women with AUFI were surrogacy and adoption. In November 2019, our team was granted approval for the first uterus transplant trial in Australia using known living donors. Our program is based on that of our overseas collaborators in Dallas, Texas; this team will also be proctoring us for our first two cases.

Uterus transplantation - donor and recipient work-up.

PURPOSE OF REVIEW: Uterus transplantation (UTx) is transitioning from an experimental procedure to a clinical treatment for absolute uterine factor infertility (AUFI). Standardized protocols for the evaluation and selection of donors and recipients that maximize chances of success - a healthy live birth - are needed. RECENT FINDINGS: To date, recipient eligibility has been limited to otherwise healthy women with AUFI who are of childbearing age and are good candidates for in-vitro fertilization (IVF). For donors (living or deceased), selection criteria vary, apart from basic requirements of blood-type compatibility and freedom from critical infectious diseases, but generally require a term birth and a uterus free from uterine pathologies. The stepwise evaluation process for candidate recipients and living donors moves through health screening (medical and psychosocial); initial selection committee review; IVF (recipients only); and final selection committee review. This eliminates candidates with poor chances of success before exposure to unnecessary risks. SUMMARY: The currently stringent selection criteria for prospective recipients and donors will likely broaden, as UTx becomes more widely available. Continued research is needed to define the donor, recipient and uterine graft factors associated with successful outcomes, and to support the development of standardized selection criteria.