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 step-by-step 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 gyne-oncology 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 long-term 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, Long-term 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 Long-term 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 Long-term studies, the Swedish group has published on medical and psychological outcome up to 3 years after UTx, with results showing that there are no or minor negative consequences of the procedure,8 and with two thirds of the participants of the initial UTx trial4 having achieved the goal of becoming parents by UTx.2 Moreover, an international registry, under the governance of the International Society of Uterus Transplantation (ISUTx) is up and running with the first annual report expected in 2021 (personal communication J. Fronek, president of ISUTx). Taken together, human UTx has been introduced in accordance with Moore's criteria6 and the IDEAL concept.7 The Swedish UTx project is, from an international perspective, regarded as a master example of how a new transplantation procedure, as well as an infertility treatment, should be introduced. The major step now is to carry out a safe transition of UTx from an experimental to a clinical procedure. There is a demand from AUFI patients to undergo UTx as an infertility treatment, but a societal unwillingness to offer the procedure because of its complexity, possible complications/adverse effects, and the presumed high costs involved. Only one publication exists on the cost-effectiveness of the UTx procedure; this was in a Swedish context and with the initial trial4 as a base for cost evaluations.9 We found that the cost of an LD UTx procedure, including preoperative screening of donor and recipient, IVF, surgeries, postoperative care, medication, and societal costs for the sick leave for donor and recipient was about € 70 000.9 Around a quarter of the expenses were connected to the costs of sick leave for the donor and recipient, so our current development with minimal invasive surgery by robotics,5 with the associated short time of convalescence, will most likely reduce the costs in future. The cost analysis9 could be used by decision-makers, politicians, and the public in discussions of whether UTx should be incorporated into clinical procedures that are covered by public health or by a national/private insurance system. However, full data on costs will only be available when complete data of reproductive and obstetrical outcome are available. To my knowledge, there are currently two centers in the world that offer UTx as a clinical procedure and these are Tübingen University Hospital in Germany (covered by health insurance) and Baylor University Medical Center in the USA (privately funded), with the price tag at the latter institution being as high as US$ 200 000, for surgery and postoperative care.10 The Nordic countries have comparable public health systems, with practically free-of-cost infertility treatments and transplantations. My opinion is that as UTx has proven to be an effective and safe infertility treatment, groups of women with AUFI, in many instances due congenital malformation or cancer, should also be offered UTx within a public health system. The demand for UTx within the Nordic countries, with an estimated prevalence of 5000 women with AUFI,3 is difficult to predict. Based on the interest of entering the second Swedish UTx study of 2017,5 the Swedish team predicts that during the initial years of clinical UTx within the Nordic countries, no more than a total of 20 procedures per year would be carried out. This number may slowly grow in the coming years. Within the Nordic countries, transplantations are centralized to national centers in Norway and Finland. In Denmark and Sweden, transplantations of liver and thoracic organs are centralized to two centers in each country. These centralizations have given center-volumes of transplantations of the liver and each thoracic organ of above 80 and 20 procedures, respectively. These center volumes of specific transplantations are essential to build up expert multidisciplinary teams, for cost-effectiveness, and to form a base for future clinical development as well as research. This analysis would also apply to UTx. Hence, a preferred scenario would be to initially have only one of the major transplantation centers within the Nordic countries to also carry out UTx surgery. This would be most suited to Sahlgrenska University Hospital in Gothenburg, Sweden, which has the world's most extensive and longest experience of this procedure. In the future, if demand increases, especially within one specific nation, another center could open with the knowledge of the complex UTx surgeries being transferred through structured learning rotations at the existing center. This scenario is similar to when LD liver transplantation and pancreas transplantation were established at several Nordic centers. However, the more standardized screening and IVF preparations, as well as the postsurgical follow up, including monitoring, immunosuppression, pregnancy attempts by embryo transfer, and obstetrics, could be carried out at any other tertiary hospital from the start, provided there is experience in general transplantation surgery, reproductive medicine, and perinatal medicine.