Global results of human uterus transplantation and strategies for pre-transplantation screening of donors

Meeting Report: First State-of-the-Art Meeting on Uterus Transplantation.

Addressing Infertility with Uterine Transplant

Uterine transplantation

Uterus transplantation in a Nordic perspective: A proposition for clinical introduction with centralization.

Background: Uterus transplantation (UTx) is the first available treatment for absolute uterine factor infertility, caused by absence of the uterus or presence of a non-functional uterus. The proof-of-concept of this new fertility treatment was by the world´s first live birth after UTx in 2014. The present study represents the first report on outcome of a complete study cohort undergoing UTx and provides unique data on efficiency and long-term safety of this novel infertility treatment. Methods: We conducted a prospective clinical trial of nine live-donor UTx procedures at Sahlgrenska University Hospital, Gothenburg, Sweden. Seven grafts achieved long-term survival, thereby allowing pregnancy attempts. Hysterectomies were performed within seven years of UTx. The results of in vitro fertilisation, pregnancies, births, growth trajectory of children born, and the long-term medical and psychological health of patients are reported. Findings: Six women delivered nine healthy babies, with three women giving birth twice (cumulative birth rates of 86% in surgically successful transplants and 67% in performed transplants). The clinical pregnancy rate per embryo transfer (ET) was 32.6%. The livebirth rate per ET was 19.6%. Fetal growth and blood flow were normal in all pregnancies. Times of delivery (median in full pregnancy weeks+days (ranges)) by caesarean section and weight deviations were 35+3 (31+6 - 38+0) and -1% (-13% - +23%), respectively. Three women developed preeclampsia during pregnancy and four children acquired respiratory distress syndrome. All children were healthy and followed a normal growth trajectory. The long-term medical health of uterus donors and recipients was generally good. When UTx resulted in a birth, scores for anxiety, depression and relationship satisfaction were reassuring for both donors and recipients. Interpretations: The results of this first clinical UTx trial show that this is an effective infertility treatment for women with absolute uterine factor infertility, resulting in births of healthy children and associated with only minor psychological and medical long-term effects for live donors and graft recipients. Trial Registration: The prospective, observational study “Uterus transplantation from live donors” was registered as a clinical trial (NCT 01844362) Funding: Jan and Dan Olsson Foundation for Science, Knut and Alice Wallenberg Foundation, Swedish Research Council. Declaration of Interest: None of the authors have any conflict of interest. Ethical Approval: This study was approved by the Regional Ethics Committee of Gothenburg, Sweden (#88-12).

Uterus transplantation: animal research and human possibilities

Uterus transplantation: the science and clinical update

Effects of different oestrous stages of ovaries and sizes of follicles on generation of bovine embryos in vitro

Uterine infertility, the last frontier

First clinical uterus transplantation trial: a six-month report

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.

In uterus transplantation, a uterus from a live or a deceased donor is transplanted temporarily to a woman who lacks a functional womb so that she can become pregnant and have one or more babies. Before uterus transplantation, the recipient carries out in vitro fertilization with cryopreservation of embryos until embryo transfer a year after transplantation. To avoid uterine graft rejection, immunosuppressant drugs are given until the uterus is removed after childbirth(s). To date (2019), more than 60 uterus transplantations have been performed worldwide that have resulted in more than 15 babies being born:2 The uterus, whether from a deceased donor or a live donor, needs to be assessed for its potential to carry a pregnancy. Live donors should be given a detailed gynecological examination, preoperative uterine imaging and angiography by CT and MRI, and uterine cancer screening including human papillomavirus testing, Papanicolaou smear and endometrial biopsy. Hormonal priming for several months can be performed in postmenopausal live donors. In the case of the donor, the uterus extraction requires a precise surgical procedure but advances in operative procedures5, 6 and successful use of robotic-assisted laparoscopy2 have made operating on the donors considerably less invasive (Figure 1). The potential side effects of immunosuppression include nephrotoxicity, bone marrow toxicity, diabetes, and an increased risk of malignancies. Comorbidity and complications during gestation are more frequent in organ transplanted women. Recipient follow up should continue even after the hysterectomy of the transplanted uterus (for at least 10 years and ideally for a lifetime) and should include psychological assessments and medical examinations focusing on potential long-term side effects of immunosuppressants. As in the case of pregnancies in other organ transplanted women, there is increased risk of low birthweight, preterm birth, preeclampsia, rejection episodes, spontaneous abortion and intrauterine death.7 The children of uterus transplant recipients should have long-term follow up. Criteria defining minimum quality standards for uterus transplant programs and the long-term follow up of living donors, recipients, and children need to be determined. There is a strong clinical interest and demand by patients for uterus transplantation. The acceptance of the procedure as an infertility treatment for women with absolute uterine factor infertility is high, and even in countries that permit surrogacy, such as the UK, it is preferred by patients over gestational surrogacy and adoption. In the past 3 years, several uterus transplant programs have been initiated throughout the world including China, USA, Brazil, Czech Republic, Germany, Serbia, France, Mexico, and India. Nonetheless, bioethical concerns have also been raised regarding risk-benefit analysis for the live donor, recipient, and child, live and deceased donor strategies, informed consent, equitable access, and fair selection of participants. It is largely considered an ethically acceptable solution to absolute uterine infertility.

The Swedish uterus transplantation project: the story behind the Swedish uterus transplantation project.

Women suffering from absolute uterine factor infertility (AUFI), due to either lack of a uterus or one unable to sustain neonatal viability, presented as one of the last frontiers in conquering infertility. Following systematic animal research for over a decade, uterus transplantation was tested as a treatment for AUFI in 2012, which culminated in the first human live birth in 2014. The development of uterus transplantation from mouse to human has followed both the Moore criteria for introduction of a surgical innovation and the IDEAL concept for evaluation of a novel major surgical procedure. In this article we review the important preclinical animal and human studies that paved the way for the successful introduction of human uterus transplantation a decade ago. We discuss this in the context of the Moore criteria and describe the different procedures of preparation, surgeries, postoperative monitoring, and use of assisted reproduction in human uterus transplantation. We review the worldwide activities and associated results in the context of the IDEAL concept for evaluation of surgical innovation and appraise the ethical considerations relevant to uterus transplantation. We conclude that rigorous application of the Moore criteria and strict alignment with the IDEAL concept have resulted in the establishment of uterus transplantation as a novel, safe, and effective infertility therapy that is now being used worldwide for the treatment of women suffering from AUFI.

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.