Treatment For Uterine Factor Infertility Research Articles

Determination of Maximum Tolerable Cold Ischemia Time in a Mouse Model of Cervical Heterotopic Uterus Transplantation.

Uterus transplantation (UTx) is an emerging treatment for uterine factor infertility. Determining the maximum tolerable cold ischemia time is crucial for successful UTx. However, the limit for cold ischemia in the uterus is unclear. This study aimed to examine cold ischemia's effects on mouse uteri and identify the maximum cold ischemia duration that uteri can endure. We systematically assessed the tolerance of mouse uteri to extended cold ischemia, 24 h, 36 h, and 48 h, using the cervical heterotopic UTx model. Multiple indicators were used to evaluate ischemia-reperfusion injury, including reperfusion duration, macroscopic examination, oxidative stress, inflammation, and histopathology. The function of transplants was evaluated through estrous cycle monitoring and embryo transfer. Mouse uteri subjected to 48 h of cold ischemia exhibited significant delays and insufficiencies in reperfusion, substantial tissue necrosis, and loss of the estrous cycle. Conversely, uteri that underwent cold ischemia within 36 h showed long survival, regular estrous cycles, and fertility. Our study demonstrated that mouse uteri can endure at least 36 h of cold ischemia, extending the known limits for cold ischemia and providing a pivotal reference for research on the prevention and treatment of cold ischemic injury in UTx.

Availability of Deceased Donors for Uterus Transplantation in the United States: Perception vs. Reality

Uterus transplantation (UTx) is a rapidly evolving treatment for uterine factor infertility. New centers offering this treatment must decide whether to utilize living donors, deceased donors, or both. Although limiting UTx to deceased donors eliminates the surgical risks for living donors, an adequate supply of suitable deceased uterus donors in the United States is an emerging concern. Previous studies describing the paucity of deceased uterus donors failed to consider key donor characteristics, potentially overestimating the available organ pool. To estimate the United States’ supply of deceased donor uteri; we extrapolated detailed clinical and demographic information from the regional donor datasets available from three organ procurement organizations to the national Organ Procurement and Transplantation Network donor pool. We estimate there are approximately 3700 possible and 400 optimal uterus donors annually in the United States. Given these projections and the number of women with uterine factor infertility in the U.S. who pursue parenthood through alternative strategies, we conclude that, as uterus transplant transitions from research to established clinical care, demand could quickly exceed the deceased donor supply. The liberalization of deceased donor selection criteria may be insufficient to address this imbalance; therefore, fulfilling the anticipated increased demand for uterus transplantation may require and justify greater use of living donors.

Uterus transplantation: a rescue technique to save the viability and functionality of the graft after intra-operative outflow thrombosis

ObjectiveTo Study a surgical approach to venous vascular thrombosis after Uterus transplantation (UTx). UTx is the only treatment for uterine factor infertility when conventional therapies are not possible. One of the major limitations of UTx is the high incidence of vascular thrombosis that in most series reaches approximately 20%. DesignCase report SubjectsWe report here a technique used in a 30-year-old female with congenital absence of the uterus who developed intraoperative thrombosis after a UTx from a brain-dead donor. InterventionThe UTx was performed by revascularizing the graft through bilateral donor internal iliac vessels (artery and vein) anastomosed end-to-side to the external iliac vessels of the recipient. The superior uterine veins were not anastomosed and were left unreconstructed. An end-to-end graft to the recipient vaginal anastomosis was performed. After uterus reperfusion, congestion of the organ was noted and bilateral venous thrombosis of the internal iliac veins of the graft was found. A “Y-shaped” venous jump graft was used to restore venous outflow of the left superior uterine vein and the internal iliac vein of the graft after thrombectomy. Main Outcome MeasuresViability and functionality of the uterus graft after intraoperative bilateral venous thrombosis ResultsThe post-operative course was uneventful, and this Utx resulted in the delivery of a healthy baby. ConclusionThis is the first successful rescue technique utilized to restore venous outflow and save the viability and functionality of a transplanted uterus. We demonstrated that a transplanted uterus from a deceased donor with a monolateral outflow could succeed in pregnancy and delivering of a healthy baby.

Effect of Pressure Conditions in Uterine Decellularization Using Hydrostatic Pressure on Structural Protein Preservation.

Uterine regeneration using decellularization scaffolds provides a novel treatment for uterine factor infertility. Decellularized scaffolds require maximal removal of cellular components and minimal damage to the extracellular matrix (ECM). Among many decellularization methods, the hydrostatic pressure (HP) method stands out due to its low cytotoxicity and superior ECM preservation compared to the traditional detergent methods. Conventionally, 980 MPa was utilized in HP decellularization, including the first successful implementation of uterine decellularization previously reported by our team. However, structural protein denaturation caused by exceeding pressure led to a limited regeneration outcome in our previous research. This factor urged the study on the effects of pressure conditions in HP methods on decellularized scaffolds. The authors, therefore, fabricated a decellularized uterine scaffold at varying pressure conditions and evaluated the scaffold qualities from the perspective of cell removal and ECM preservation. The results show that by using lower decellularization pressure conditions of 250 MPa, uterine tissue can be decellularized with more preserved structural protein and mechanical properties, which is considered to be promising for decellularized uterine scaffold fabrication applications.

SURGICAL AND REPRODUCTIVE OUTCOMES IN A LARGE DECEASED DONOR UTERUS PROGRAM: CLEVELAND CLINIC'S SIX YEAR REPORT

To report the latest surgical and reproductive outcomes for the ongoing Cleveland Clinic Trial of Uterine Transplantation for the Treatment of Uterine Factor Infertility (ClinicalTrials.gov identifier NCT02573415), the oldest uterus transplant trial in the United States and to our knowledge the largest deceased donor trial. While use of deceased donors eliminates risk to a living donor, it is unclear whether outcomes are similar.

Uterus transplantation worldwide: clinical activities and outcomes.

Women with absolute uterine factor infertility, because of uterine absence, or the presence of a nonfunctional uterus, were regarded as being untreatable until 2014 when the first birth following uterus transplantation (UTx) took place in Sweden. This proof-of-concept occurred in a woman with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHs) with congenital uterine absence, who received a uterus from a 61-year-old live donor (LD). Since then, several births after UTx have occurred in Sweden and subsequently in other countries, including both LD and deceased donor (DD) transplants. A great majority of the recipients were women with MRKHs. The efficiency and safety of UTx can be determined only when a complete study cohort of transplanted women have reached the definitive endpoint of graft hysterectomy. The different outcomes of transplanted women include graft failure, as well as graft survival with failure to achieve livebirth, or livebirth(s). Published data from a completed trial are not yet available. The results that we have to rely on are reports of completed surgeries and interim outcomes that may be as early as a few months after surgery and up to several years after UTx. The purpose of this review is to give an update on all published clinical UTx data and major results, including live births up to mid 2021. The interim results of a number of UTx studies have been published. LD UTx procedures have been reported from four European countries (Sweden, the Czech Republic, Germany, Spain), four Asian nations (Saudi Arabia, India, China, Lebanon), as well as some from the USA. DD UTx procedures have been reported from Turkey, the Czech Republic, the USA and Brazil. To our knowledge, there also exist unpublished UTx cases from some of the countries mentioned above and from at least four other countries (Serbia, France, Mexico, Italy). We estimate that at least 80 UTx procedures have been performed, resulting in more than 40 births. The present study includes only data from published, peer-reviewed, research papers. The results of 62 UTx cases show an overall surgical success rate, as defined by a technically successful transplantation with a subsequent regular menstrual pattern, of 76%. The success rates for LD and DD UTx procedures were 78% and 64%, respectively. The rate of serious postsurgical complications requiring invasive or radiological intervention was 18% for LDs and 19% for recipients. The cumulative live birth rate in successful UTx procedures is estimated to be above 80%. Twenty-four births after UTx have been reported and the results show a high rate of preterm birth, with an associated high proportion of respiratory distress syndrome. UTx has proven to be a successful treatment for uterine factor infertility at several centers around the world. The modest success rate and the fairly high complication rate among LDs, indicate that further research and development under strict governance are needed before this option should be widely offered.

Preimplantation genetic testing for aneuploidy in uterus transplant patients.

Uterus transplantation is an emerging treatment for uterine factor infertility. In vitro fertilization with cryopreservation of embryos prior is required before a patient can be listed for transplant. Whether or not to perform universal preimplantation genetic testing for aneuploidy should be addressed by centers considering a uterus transplant program. The advantages and disadvantages of preimplantation genetic testing for aneuploidy in this unique population are presented. The available literature is reviewed to determine the utility of preimplantation genetic testing for aneuploidy in uterus transplantation protocols. Theoretical benefits of preimplantation genetic testing for aneuploidy include decreased time to pregnancy in a population that benefits from minimization of exposure to immunosuppressive agents and decreased chance of spontaneous abortion requiring a dilation and curettage. Drawbacks include increased cost per in vitro fertilization cycle, increased number of required in vitro fertilization cycles to achieve a suitable number of embryos prior to listing for transplant, and a questionable benefit to live birth rate in younger patients. Thoughtful consideration of whether or not to use preimplantation genetic testing for aneuploidy is necessary in uterus transplant trials. Age is likely a primary factor that can be useful in determining which uterus transplant recipients benefit from preimplantation genetic testing for aneuploidy.

Outcome of Recipient Surgery and 6-Month Follow-Up of the Swedish Live Donor Robotic Uterus Transplantation Trial.

Uterus transplantation has proved to be a feasible treatment for uterine factor infertility. Herein, we report on recipient outcome in the robotic uterus transplantation trial of 2017–2019. The eight recipients had congenital uterine aplasia. The donors were six mothers, one sister, and one family friend. Donor surgery was by robotic-assisted laparoscopy. Recipient surgery was by laparotomy and vascular anastomoses to the external iliacs. The duration (median (ranges)) of recipient surgery, blood loss, measured (left/right) uterine artery blood flow after reperfusion, and length of hospital stay were 5.15 h (4.5–6.6), 300 mL (150–600), 43.5 mL/min (20–125)/37.5 mL/min (10–98), and 6 days (5–9), respectively. Postoperative uterine perfusion evaluated by color Doppler showed open anastomoses but restricted blood distribution in two cases. Repeated cervical biopsies in these two cases initially showed ischemia and, later, necrosis. Endometrial growth was not seen, and hysterectomy was later performed, with pathology showing partly viable myometrium and fibrosis but necrosis towards the cavity. The other six patients acquired regular menstrual cyclicity. Surgery was performed in two patients to correct vaginal stenosis. Reversible rejection episodes were seen in two patients. In conclusion, the rate of viable uterine grafts during the initial 6-months of the present study (75%) leaves room for improvement in the inclusion/exclusion criteria of donors and in surgical techniques. Initial low blood flow may indicate subsequent graft failure.

Use of Laser Speckle Contrast Analysis during pelvic surgery in a uterine transplantation model.

Aim:Uterine transplantation (UTx) is proposed for treatment of uterine factor infertility. Our aim was to assess whether Endoscopic Laser Speckle Contrast Analysis (eLASCA) could evaluate pelvic blood flow at anastomotic sites required for sheep and rabbit UTx.Results/methodology:eLASCA detected blood flow in rabbit UTx #7 and #9. In sheep UTx #2, #3 and #5, the results allowed us to conclude that blood flow was present in the uterine graft following transplantation; and post-UTx, the animal had heart and respiratory rates, and oxygen saturation compatible with a normal hemodynamic status.Conclusion:These preliminary results establish the potential of Laser Speckle Contrast Analysis as noncontact and real-time tool for observation of spatially-resolved blood flow from which other parameters can be derived.

A Survey of Public Opinion in the United States Regarding Uterine Transplantation

Study ObjectiveTo evaluate the opinions and attitudes of the general public regarding uterine transplantation (UTx) in the United States. DesignA cross-sectional study (Canadian Task Force classification II-2). SettingA Web-based survey. PatientsA nationally representative sample of adult US residents by age and sex. InterventionsA Web-based questionnaire administered in November 2016. Measurements and Main ResultsRespondents who supported UTx were compared with those who were opposed using log binomial regression to calculate relative risk ratios and 95% confidence intervals. Of the 1444 respondents recruited, 1337 (93%) completed the survey. Ninety respondents (6%) disagreed with the use of in vitro fertilization for any indication and were excluded. Of the remaining 1247 respondents, 977 (78%) supported and 48 (4%) opposed allowing women to undergo UTx. Respondents with higher yearly incomes and education level were more likely to agree that “taking the uterus from one person and putting it into another person is ethical.” Respondents who answered that UTx is safe for the donor, recipient, and baby were more likely to believe that UTx is an acceptable, ethical alternative to a gestational carrier. Forty-five percent of respondents believed that UTx should be covered by insurance, whereas 24% did not. ConclusionThe majority of respondents in a sample of US residents support UTx, find it ethical, and believe that it is an acceptable alternative to a gestational carrier although support varies. These findings suggest that the US public is in favor of uterine transplantation as a treatment for uterine factor infertility.

A survey of public opinion in the United States regarding uterine transplantation

Abstract Study Objective To evaluate the opinions and attitudes of the general public regarding uterine transplantation (UTx) in the United States. Design A cross-sectional study (Canadian Task Force classification II-2). Setting A Web-based survey. Patients A nationally representative sample of adult US residents by age and sex. Interventions A Web-based questionnaire administered in November 2016. Measurements and Main Results Respondents who supported UTx were compared with those who were opposed using log binomial regression to calculate relative risk ratios and 95% confidence intervals. Of the 1444 respondents recruited, 1337 (93%) completed the survey. Ninety respondents (6%) disagreed with the use of in vitro fertilization for any indication and were excluded. Of the remaining 1247 respondents, 977 (78%) supported and 48 (4%) opposed allowing women to undergo UTx. Respondents with higher yearly incomes and education level were more likely to agree that “taking the uterus from one person and putting it into another person is ethical.” Respondents who answered that UTx is safe for the donor, recipient, and baby were more likely to believe that UTx is an acceptable, ethical alternative to a gestational carrier. Forty-five percent of respondents believed that UTx should be covered by insurance, whereas 24% did not. Conclusion The majority of respondents in a sample of US residents support UTx, find it ethical, and believe that it is an acceptable alternative to a gestational carrier although support varies. These findings suggest that the US public is in favor of uterine transplantation as a treatment for uterine factor infertility.

Uterine Transplantation: Surgical Innovation in the Treatment of Uterine Factor Infertility.

Uterine factor infertility (UFI) is a condition that affects thousands of women and is estimated to have a prevalence as high as one in five hundred reproductive-aged women. A wide range of circumstances can lead to UFI and include women with congenital absence of a uterus (Mayer Rokitansky Kuster Hauser or MRKH syndrome), women who have undergone iatrogenic removal of the uterus, or women who have uteri that are in situ but have been damaged by infection or surgical instrumentation. There have been 17 published reports of human uterine transplantation in the world. This article will summarize the history of human uterine transplantation and discuss our current understanding of the medical, surgical, and ethical considerations surrounding this innovative procedure.

Uterus transplantation and beyond

Uterus transplantation is today the only available treatment for absolute uterine factor infertility which is caused by either congenital/surgical uterine absence or that a present uterus is non-functioning. Structured animal-based research, from rodents to nonhuman primates, was the scientific basis for a successful introduction of uterus transplantation as a clinical procedure. The patient groups for uterus transplantation, the preclinical research and data from the published human cases will be covered herein. During recent years the concept of bioengineering of organs and tissues has emerged. Creation of a bioengineered uterus is in the initial research state, with experiments performed in rodents. The research that has been performed to create a bioengineered uterus will be summarized. In conclusion, uterus transplantation is now a clinical experimental procedure for treatment of uterine factor infertility. In parallel to the establishment of this combined assisted reproduction technique and transplantation procedure as a routine clinical procedure, we predict that uterus bioengineering will develop further towards introduction within the human setting, but that this process will take several years.

Deceased donor uterine transplantation

To share our experience in performing the first-ever deceased-donor uterine transplant in the United States. This video uses an animation and footage from a uterine transplantation procedure to review the steps and techniques involved in performing a uterine transplant. Academic, multisite medical center. A reproductive-age patient with Mayer-Rokitansky-Kuster-Hauser syndrome. Transplantation of a viable uterus from a deceased donor. Assessment of posttransplantation uterine graft viability. This video article describes the essential steps in the uterine transplant process, including selecting an appropriate donor with no history of infertility or uterine malformations. Furthermore, a deceased donor should exhibit brain death but not cardiac death. We also review our inclusion criteria for suitable recipients. In this video we outline the key steps in a uterine transplantation procedure and demonstrate footage from an actual transplant procedure. These steps include establishing bilateral end-to-side vascular anastomoses between the donor uterine artery and vein and the recipient's external iliac vessels. Once this has been completed and reperfusion noted of the donor uterus, connection to the recipient vaginal cuff is then performed. Uterine transplantation, although currently experimental, has gained the potential to become the first true treatment for uterine factor infertility. This procedure can become a promising option for the approximately 1.5 million women worldwide for whom pregnancy is not possible because of the absence of the uterus or presence of a nonfunctional uterus. Deceased donor uterine transplantation will further serve to broaden accessibility for this procedure.

Uterus Transplantation: Medical Considerations

Background Uterine transplantation is a novel treatment for uterine factor infertility (UFI), a condition which affects women who have an absent or nonfunctioning uterus and cannot carry their own biological children. Traditionally, surrogacy and adoption have been the only options for women with UFI. With recent successful living donor transplants in a clinical trial from Sweden, there is new hope for women with UFI to be able to experience pregnancy.

Deceased Donor Uterine Transplantation: Innovation and Adaptation.

This commentary endeavors to share our practical experience in developing and implementing the first uterine transplant clinical trial in the United States. Uterine transplant is a promising novel treatment for uterine factor infertility. After reported successful live births after uterine transplant in Sweden, research teams around the world are either embarking on or are considering the development of uterine transplant protocols. Our observations on the applied rather than theoretical aspects of uterine transplantation research in human subjects are detailed in this article. Important among these considerations are composing a broad and experienced multidisciplinary team as well as performing adequate preclinical preparations, including ideally animal studies and practice organ procurements. Ethical preparation is tantamount to clinical preparation for the complexities inherent in uterine transplant, and our suggestions for updating the current ethical criteria for uterine transplant are outlined here. We also describe our perspectives on the strengths and weaknesses of living compared with deceased donor models. Finally, we describe how a strong program can recover and adapt in the face of setbacks to continue a path toward innovation.

Psychological aspects in pre-transplantation assessments of patients prior to entering the first uterus transplantation trial.

Uterus transplantation is a treatment of uterine factor infertility. It raises questions of psychological aspects and well-being among the participants, which is of great importance as this is a new type of a major surgical procedure. This commentary focuses on the psychology surrounding this novel type of transplantation and the importance of patient selection. In addition, psychological aspects of events during the first postoperative year and the follow-up are discussed.

Livebirth after uterus transplantation

Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus. Eleven human uterus transplantation attempts have been done worldwide but no livebirth has yet been reported. In 2013, a 35-year-old woman with congenital absence of the uterus (Rokitansky syndrome) underwent transplantation of the uterus in Sahlgrenska University Hospital, Gothenburg, Sweden. The uterus was donated from a living, 61-year-old, two-parous woman. In-vitro fertilisation treatment of the recipient and her partner had been done before transplantation, from which 11 embryos were cryopreserved. The recipient and the donor had essentially uneventful postoperative recoveries. The recipient's first menstruation occurred 43 days after transplantation and she continued to menstruate at regular intervals of between 26 and 36 days (median 32 days). 1 year after transplantation, the recipient underwent her first single embryo transfer, which resulted in pregnancy. She was then given triple immunosuppression (tacrolimus, azathioprine, and corticosteroids), which was continued throughout pregnancy. She had three episodes of mild rejection, one of which occurred during pregnancy. These episodes were all reversed by corticosteroid treatment. Fetal growth parameters and blood flows of the uterine arteries and umbilical cord were normal throughout pregnancy. The patient was admitted with pre-eclampsia at 31 full weeks and 5 days, and 16 h later a caesarean section was done because of abnormal cardiotocography. A male baby with a normal birthweight for gestational age (1775 g) and with APGAR scores 9, 9, 10 was born. We describe the first livebirth after uterus transplantation. This report is a proof-of-concept for uterus transplantation as a treatment for uterine factor infertility. Furthermore, the results show the feasibility of live uterus donation, even from a postmenopausal donor. Jane and Dan Olsson Foundation for Science.

The First Clinical Trial of Uterus Transplantation: Surgical Technique and Outcome.

Uterus transplantation may become a treatment for uterine factor infertility, which affects > 200,000 women only in Europe. The only option for these women, with no functional uterus, to gain genetic motherhood is by a surrogate mother. The latter procedure is not allowed in most countries due to ethical, religious or legal reasons. Our team has developed a procedure for uterus transplantation from live donor, through extensive research in several animal species. In May 2012 we were granted human IRB approval for a clinical study of 9 human transplantation cases with the uterus from live donors. The recipients and donors had been investigated for >12 months before the trial. This included IVF treatment. The donors were mothers (n=5), close relatives (n=3) or family friend and the ages were 35-62 years. Eight recipients were born with no uterus (MRKH syndrome) and one had been hysterectomized 7 years prior to the study because of cervical cancer. The ages of the recipients were between 27 and 38 years. The surgery of the donor involved isolation of the uterus with vascular pedicles including the uterine vessels and segments of the internal iliac vessels. The surgery of the recipient involved bilateral end-to-side anastomosis to the external iliacs, vagino-vagino anastomosis and uterine fixation to several pelvic ligaments. The surgical procedures will be discussed in detail. Durations of donor and recipient surgery ranged from 10 to 13 h and 4 to 6 h, respectively. The recipients received standard induction and initial triple maintenance immunosuppression.The 2nd uterus donor was diagnosed with a uterovaginal fistula on postoperative day 10. All other donor surgeries went without complications. No immediate perioperative complication occured among the recipients. However, one uterus had to be removed around 72 h after surgery due to bilateral uterine vessel thrombosis. Another uterus was removed 3.5 months after surgery due to persistent intrauterine infection and later development of an intrauterine abscess. Menstruation started after around 1-2 months in 7 recipients. In conclusion, the results demonstrate the surgical feasibility of live uterus transplantation. It remains to be determined what the pregnancy potential is in a transplanted uterus. Pregnancy results of our study population are expected in 2014.

Uterine Transplantation as a Clinical Application for the Treatment of Uterine Factor Infertility: 11 Years of Experimental Research

Uterine Transplantation as a Clinical Application for the Treatment of Uterine Factor Infertility: 11 Years of Experimental Research Ramirez ER, Ramirez Nessetti DK, Nessetti MBR, Guido RS, AbuElmagd KM, Ramirez HA. Obstetrics and Gynecology, St. Johns Regional Medical Center, Oxnard, California; Obstetrics and Gynecology, Nebraska Comprehensive Health Care/Nebraska Mental Health Centers, Lincoln, Nebraska; Family Medicine, Medical Psychology and Psychopharmacology, Nebraska Comprehensive Health Care/Nebraska Mental Health Centers, Lincoln, Nebraska; Obstetrics and Gynecology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Director, Intestinal Rehabilitation & Transplantation, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Obstetrics and Gynecology, Universidad de La Sallle, Bogota, Santa Fe, Colombia