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.

Uterus Transplantation: Revisiting the Question of Deceased Donors versus Living Donors for Organ Procurement.

Uterus transplantation is a surgical treatment for women with congenital or acquired uterine factor infertility. While uterus transplantation is a life-enhancing transplant that is commonly categorized as a vascular composite allograft (e.g., face or hand), it is similar to many solid organ transplants (e.g., kidney) in that both living donors (LDs) and deceased donors (DDs) can be utilized for organ procurement. While many endpoints appear to be similar for LD and DD transplants (including graft survival, time to menses, livebirth rates), there are key medical, technical, ethical, and logistical differences between these modalities. Primary considerations in favor of a LD model include thorough screening of donors, enhanced logistics, and greater donor availability. The primary consideration in favor of a DD model is the lack of physical or psychological harm to a living donor. Other important factors, that may not clearly favor one approach over the other, are important to include in discussions of LD vs. DD models. We favor a stepwise approach to uterus transplantation, one in which programs first begin with DD procurement before attempting LD procurement to maximize successful organ recovery and to minimize potential harms to a living donor.

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.

Benign course of residual inflammation at end of treatment of liver transplant recipients after sofosbuvir based therapy.

BACKGROUND: Persistent inflammation on histology after successful hepatitis C (HCV) treatment has been reported. However, data regarding the long-term impact in liver transplant recipients is limited, particularly after using direct-acting antiviral (DAA) therapies. AIM: To evaluate the impact of successful treatment with DAAs on histological changes and occult HCV and to describe the clinical course of residual inflammation in liver transplant recipients. METHODS: We conducted a case series of 13 chronic HCV infected liver transplant recipients successfully treated with DAAs between December 2013 and May 2014. All patients were treated for 24 wk and had non-detectable serum HCV RNA by the time of biopsy. Only patients with at least one liver biopsy at or after treatment were included. We examined liver biopsies for evidence of residual inflammation and the presence of intrahepatic HCV RNA. RESULTS: Persistent inflammation was seen in 12/13 patients on end of treatment biopsy. Inflammation was still seen in the available five follow-up biopsies (range 38-48 wk after the end of treatment). Intrahepatic HCV RNA was undetectable in all biopsies. All patients had preserved graft function for a mean follow-up of 2.5 years, except one that developed chronic rejection. CONCLUSION: After successful HCV treatment with DAAs, liver transplant recipients may have persistent inflammation on biopsy without evidence of intracellular RNA. The clinical outcome remained favorable in most patients. Further studies with a larger number and longer follow-up are needed to establish the implication of this finding on long-term graft function.

Pilot study to determine the safety and feasibility of deceased donor liver natural killer cell infusion to liver transplant recipients with hepatocellular carcinoma.

Liver transplantation (LT) is a viable treatment option for cirrhosis patients with hepatocellular carcinoma (HCC). However, recurrence is the rate-limiting factor of long-term survival. To prevent this, we conducted the phase I study of the adoptive transfer of deceased donor liver-derived natural killer (NK) cells. Liver NK cells were extracted from donor liver graft perfusate and were stimulated in vitro with IL-2. The patient received an intravenous infusion of NK cells 3-5 days after LT. Eighteen LT recipients were treated. There were no severe cell infusion-related adverse events or acute rejection episodes. One patient withdrew from the study because the pathological observation revealed sarcoma instead of HCC. All patients who received this immunotherapy completed the follow-up for at least 2 years without evidence of HCC recurrence (median follow-up, 96 months [range, 17-121 months]). Considering that 9 (52.9%) of the 17 patients pathologically exceeded the Milan criteria, liver NK cell infusion is likely to be useful for preventing HCC recurrence after LT. This is the first-in-human immunotherapy study using deceased donor liver-derived NK cells to prevent HCC recurrence after LT. This treatment was well tolerated and resulted in no HCC recurrence after LT.Clinical trial registration www.clinicaltrials.gov ; NCT01147380; registration date: June 17, 2010.

Uterus transplantation: state of the art in 2021.

PURPOSE: To provide a comprehensive review of uterus transplantation in 2021, including a discussion of pregnancy outcomes of all reported births to date, the donor and recipient selection process, the organ procurement and transplant surgeries, reported complications, postoperative monitoring, preimplantation preparation, and ethical considerations. METHODS: Literature review and expert commentary. RESULTS: Reports of thirty-one live births following uterus transplantation have been published from both living and deceased donors. The proper selection of donors and recipients is a labor-intensive process that requires advanced planning. A multidisciplinary team is critical. Reported complications in the recipient include thrombosis, infection, vaginal stricture, antenatal complications, and graft failure. Graft rejection is a common occurrence but rarely leads to graft removal. While most embryo transfers are successful, recurrent implantation failures in uterus transplant patients have been reported. Rates of preterm delivery are high but appear to be declining; more data, including long-term outcome data, is needed. CONCLUSIONS: Uterus transplantation is an emerging therapy for absolute uterine factor infertility, a condition previously without direct treatment options. It is paramount that reproductive health care providers are familiar with the uterus transplantation process as more patients seek and receive this treatment.

Managing liver transplantation during the COVID-19 pandemic: A survey among transplant centers in the Southeast United States.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic has had a profound worldwide impact. Indeed, it has led to a vast decrease in organ transplantation, including liver transplants (LT). There is little data regarding adjustments made by LT centers as a response to the COVID-19 pandemic. AIM: To assess the experience of LT centers in the United States during the pandemic. METHODS: We performed an observational survey study from May 11, 2020 to June 5, 2020. We sent out a 13 question survey to 15 LT centers across the southeastern United States. RESULTS: Eleven LT centers responded to the survey. We found that (11/11) 100% of transplant centers made adjustments because of the COVID-19 pandemic. At least 50% of transplant centers had at least one transplant recipient infected with COVID-19. To adjust, greater than 50% of centers performed fewer LT, 100% of patients were tested for COVID-19, and most centers implemented a virtual platform. CONCLUSION: The COVID-19 pandemic greatly affected liver transplantation in the southeastern United States. It was evident that a concerted effort was made by LT centers to protect their patients and employees from COVID-19 but also to continue the life-saving procedure of LT in this sick patient population. Further studies are needed to assess how LT centers around the world managed the pandemic in order to learn strategies to continue life-saving procedures in this patient population.

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.

Guidelines for standardized nomenclature and reporting in uterus transplantation: An opinion from the United States Uterus Transplant Consortium.

Uterus transplantation is a nascent but growing field. To support this growth, the United States Uterus Transplant Consortium proposes guidelines for nomenclature related to operative technique, vascular anatomy, and donor, recipient, and offspring outcomes. In terms of anatomy, the group recommends reporting donor arterial inflow and recipient anastomotic site delivering inflow to the graft and offers standardization of the names for the 4 veins originating from the uterus because of current inconsistency in this particular nomenclature. Seven progressive stages with milestones of success are defined for reporting on uterus transplantation outcomes: (1) technical, (2) menstruation, (3) embryo implantation, (4) pregnancy, (5) delivery, (6) graft removal, and (7) long-term follow-up. The 3 primary metrics for success are recipient survival (as reported for other organ transplant recipients), graft survival, and uterus transplant live birth rate (defined as live birth per transplanted recipient). A number of secondary outcomes should also be reported, most of which capture stage-specific milestones, as well as data on graft failure. Outcome metrics for living donors include patient survival, survival free of operative intervention, and data on complications and hospitalizations. Finally, we make specific recommendations on follow-up for offspring born from uterine grafts, which includes specialty surveillance as well as collection and reporting of routine pediatric outcomes. The goal of standardization in reporting is to create consistency and improve the quality of evidence available on the efficacy and value of the procedure.

First birth from a deceased donor uterus in the United States: from severe graft rejection to successful cesarean delivery.

Uterus transplantation is the only known potential treatment for absolute uterine factor infertility. It offers a unique setting for the investigation of immunologic adaptations of pregnancy in the context of the pharmacologic-induced tolerance of solid organ transplants, thus providing valuable insights into the early maternal-fetal interface. Until recently, all live births resulting from uterus transplantation involved living donors, with only 1 prior birth from a deceased donor. The Cleveland Clinic clinical trial of uterus transplantation opened in 2015. In 2017, a 35 year old woman with congenital absence of the uterus was matched to a 24 year old parous deceased brain-dead donor. Transplantation of the uterus was performed with vaginal anastomosis and vascular anastomoses bilaterally from internal iliac vessels of the donor to the external iliac vessels of the recipient. Induction and maintenance immunosuppression were achieved and subsequently modified in anticipation of pregnancy 6 months after transplant. Prior to planned embryo transfer, ectocervical biopsy revealed ulceration and a significant diffuse, plasma cell-rich mixed inflammatory cell infiltrate, with histology interpreted as grade 3 rejection suspicious for an antibody-mediated component. Aggressive immunosuppressive regimen targeting both cellular and humoral rejection was initiated. After 3 months of treatment, there was no histologic evidence of rejection, and after 3 months from complete clearance of rejection, an uneventful embryo transfer was performed and a pregnancy was established. At 21 weeks, central placenta previa with accreta was diagnosed. A healthy neonate was delivered by cesarean hysterectomy at 34 weeks' gestation. In summary, this paper highlights the first live birth in North America resulting from a deceased donor uterus transplant. This achievement underscores the capacity of the transplanted uterus to recover from a severe, prolonged rejection and yet produce a viable neonate. This is the first delivery from our ongoing clinical trial in uterus transplantation, including the first reported incidence of severe mixed cellular/humoral rejection as well as the first reported placenta accreta.

Evolving ethical issues with advances in uterus transplantation.

While uterus transplantation was once considered only a theoretical possibility for patients with uterine factor infertility, researchers have now developed methods of transplantation that have led to successful pregnancies with multiple children born to date. Because of the unique and significant nature of this type of research, it has been undertaken with collaboration not only with scientists and physicians but also with bioethicists, who paved the initial path for research of uterus transplantation to take place. As the science of uterus transplantation continues to advance, so too must the public dialogue among obstetrician/gynecologists, transplant surgeons, bioethicists, and other key stakeholders in defining the continued direction of research in addition to planning for the clinical implementation of uterus transplantation as a therapeutic option. Given the rapid advances in this field, the time has come to revisit the fundamental questions raised at the inception of uterus transplantation and, looking forward, determine the future of this approach given emerging data on the procedure's impact on individuals, families, and society.

New Frontier: Role of the Radiologist in Uterine Transplantation.

Uterine transplantation (UT) is a novel treatment for absolute uterine factor infertility (AUFI) that is currently being performed under experimental protocols in multiple medical centers worldwide. At the time of this publication, there have been at least 10 live births by women with a transplanted uterus. As successful outcomes from this innovative procedure increase, it is likely that more centers will perform UT. Imaging is performed in multiple steps of the UT process, including preoperative imaging of potential donors and recipients, posttransplant surveillance, and monitoring of pregnancy. Fetal imaging is performed by maternal-fetal medicine professionals, but most imaging examinations in UT are performed by radiologists. Given the significant role of imaging in this groundbreaking surgery, radiologists must be familiar with the causes of AUFI and the role of imaging in establishing this diagnosis. Radiologists working in medical centers where UT is performed should understand the role of imaging in preoperative planning and postoperative surveillance. While data regarding complications of UT are preliminary at best, radiologists must be aware of the risk of vascular compromise and graft failure and their imaging features. The authors provide a brief history of UT and define the radiologist's role in pre- and postoperative imaging assessments.©RSNA, 2019.

Transplantation of HCV Viremic Livers into HCV Viremic Recipients Followed by Direct-acting Antiviral Therapy.

Background and Aims: Hepatitis C virus (HCV)-infected organs are underutilized. We aimed to assess the safety and efficacy of direct-acting antiviral agents (DAAs) therapy in HCV viremic patients who are transplanted with a liver from a HCV viremic donor. Methods: We conducted a retrospective study, including patients seen from July 2015 to April 2017. HCV viremic patients transplanted with a liver from a HCV viremic donor and subsequently treated with DAAs were included. Outcomes assessed included undetectable viral load at 12 weeks after completing DAA therapy (sustained virologic response, SVR12), adverse events, and interactions with immunosuppression. Results: Twenty-four HCV viremic recipients received livers from HCV viremic donors. Median age was 63 years, and the majority (79.2%) were genotype 1a. Donors and recipients were viremic at the time of transplant. Median modified model for end-stage liver disease score was 19, and median time on the waitlist was 81 days. Median time from transplant to initiation of DAA therapy was 123 days. Several DAA regimens were used and 15 (62.5%) patients did not receive ribavirin. Treatment duration ranged from 12 to 24 weeks. Twenty-three (95.8%) patients achieved SVR12. Five (20.8%) patients developed adverse events; however, none required DAA discontinuation. Conclusions: DAA therapy was efficacious and well tolerated in HCV viremic recipients who underwent liver transplantation from a HCV viremic donor.

Liver Transplantation Following Life-threatening Abdominal Trauma: A Case Series of 5 Patients at a Single Institution.

Managing traumatic liver injury (TLI) is always challenging and demands precise clinical judgment. Currently, treatment of TLI in most circumstances is non-operative; however, surgical therapy might be required for severe TLI, particularly those that result in extensive blood loss. In the current institutional study carried out from June 1995 to April 2017, we describe our experience with 5 patients who received an orthotopic liver transplant for severe TLI. One patient passed away postoperatively from cerebral edema; 1 patient died of renal failure 4 years after the liver transplantation, and 3 patients are still alive. Based on our experience, we conclude that in patients with TLI, especially those with uncontrollable bleeding or those who develop liver failure, liver transplantation should be taken into consideration.

Framing the diagnosis and treatment of absolute uterine factor infertility: Insights from in-depth interviews with uterus transplant trial participants.

BACKGROUND: Despite procedural innovations and increasing numbers of uterus transplant attempts worldwide, the perspectives of uterus transplant (UTx) trial participants are lacking. METHODS: We conducted a mixed-methods study with women with absolute uterine factor infertility (AUFI). Participants included women who had previously contacted the Cleveland Clinic regarding the Uterine Transplant Trial and met the initial eligibility criteria for participation. In-depth interviews were conducted in conjunction with FertiQoL, a validated and widely used tool to measure the impact of infertility on the quality of life of infertility patients. RESULTS: All (n = 19) rated their overall health as good; some experienced grief and social isolation. AUFI is a life-framing experience that influences acceptance by family, partners, peers, and one's self. UTx is a means to gain control of reproductive autonomy. UTx allows family-building and the ability to play an active role in prenatal health and well-being. Establishing and maintaining a supportive relationship is a key issue of AUFI and when considering UTx. Risks of UTx are perceived relative to risks to self/child/family posed by adoption/surrogacy. Participants had no overall preference regarding living or deceased donor. CONCLUSIONS: The ways in which women with AUFI conceptualize this condition in their lives and choices around UTx and participating in a study of the procedure are multifaceted and textured. These perspectives are critical to understanding its ethical, legal, and social implications.