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

Abstract

The Nordic countries have been at the international forefront in developments within the area of assisted reproduction for many decades. The latest major contribution is uterus transplantation (UTx) in combination with in vitro fertilization (IVF), with the world s first eight live births taking place in Sweden between 2014 and 2017.1,2 Uterus transplantation is a unique method to treat absolute uterine factor infertility (AUFI), which is caused by uterine absence (surgical/ congenital) or by a nonfunctional uterus. Based on estimations of the prevalence of AUFI in the United Kingdom,3 this infertility condition affects around 5000 women in the Nordic countries. Gestational surrogacy has, for some decades, been an alternative for women with AUFI to achieve genetic, but not gestational, motherhood. Gestational surrogacy arrangements are not allowed in any Nordic country and are practiced in only a restricted number of countries worldwide. We are now in a transitional period of UTx, moving from the research setting into the clinical arena. At this stage, it is important to discuss how UTx should be clinically established and the requirements of an institution looking to start a clinical UTx program. It is of the utmost importance that the transition of UTx, from an experimental infertility treatment into a clinical procedure, will be safe. The discussion below applies not only to the Nordic countries but also to the establishment of clinical UTx programs in any country or region worldwide. Uterus transplantation is a very complex surgical procedure, especially when carried out as a live donor (LD) transplantation. The donor hysterectomy can take up to 10 hours to procure the uterine graft with long vascular segments.4 The transplantation in the recipient takes around 4 hours. There is a shortage of deceased donors with acceptable uteri, so approximately nine out of ten of all the UTx procedures carried out so far in the world have been performed as LD UTx procedures.2 It is likely that LDs will remain the dominant source of uteri for transplantation in the future, especially with the introduction of minimal invasive surgery in donor hysterectomy5 and because nondirected altruistic donation of a uterus, at an age after the fertile period, may become more common. An LD UTx procedure, with advanced surgery in two women, is far from a standard infertility treatment and is surgically more complex than other major LD transplantation procedures, such as kidney and partial liver transplantations. As a result, meticulous preparation and an optimal setting are necessary components in a responsible introduction of UTx. Already in 1970, Francis D. Moore, at that time a professor of surgery at Harvard Medical School, stated the importance of laboratory background, field strength, and institutional stability for successful implementation of any new, major surgical procedure.6 The laboratory background in the UTx field in Sweden was initiated in the late 1990s, inspired by this suggestion of fertility restoration by a young woman undergoing a radical hysterectomy for cervical cancer. Through a stepbystep approach, with progressively more advanced animal models, all essential facets of the UTx procedure were investigated and optimized by the Swedish team during a period of more than a decade, before launching the first human trial in 2013.4 The concept of field strength implies that any institution that plans to implement a new major surgical innovation should have a long tradition and strength in all the clinical fields that may apply. Concerning UTx, such field strength should include a multidisciplinary team of proficient gyneoncology surgeons mastering the complicated retroperitoneal surgery, as well as transplant surgeons, specialists in reproductive medicine, experienced obstetricians, psychologists, pathologists, immunologists, and transplantation physicians to care for the complicated immunosuppression. Such field strength is only available at a tertiary hospital, which in most cases would be a university hospital, with a large division of transplantation surgery. The institutional stability implies that the institution carrying out a new major surgical innovation, such as UTx, should provide longterm institutional support, including resources and commitment to care for the patients, for many years. Regarding an LD UTx procedure, the patients to follow and care for are the donor, the recipient, the partner of the recipient, and the children born from the transplanted uterus. The care and follow up involve both medical and psychological domains. In 2009, the IDEAL (Idea, Development, Exploration, Assessment, Longterm study) concept was launched in a series of papers in Lancet, as an initiative to improve the quality of research in surgery, especially at the introduction of a new innovative surgical procedure.7 The experimental introduction of human UTx has followed this concept and the UTx field is now in the stages of Assessment and Longterm study, by several ongoing and some completed prospective observational studies. Needless to say, randomized controlled studies would not apply to UTx, as there is no alternative treatment or proper control group. Concerning Longterm studies, the Swedish group has published on medical and psychological