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Introduction

Uterus transplantation
  • Mats Brännström
    Correspondence
    Correspondence: Mats Brännström, M.D., Ph.D., Department of Obstetrics and Gynecology, University of Gothenburg, Goteborg, Sweden.
    Affiliations
    Department of Obstetrics and Gynecology, University of Gothenburg, Göteborg, Sweden

    Stockholm IVF-EUGIN, Stockholm, Sweden
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      Uterus transplantation is the first available treatment for absolute uterine factor infertility. Live births have been reported after transplantation of uteri both from live and deceased donors. Although this novel infertility treatment is still at its experimental stage, with human attempts performed within clinical trials, there is a rapid development in the field. Up until June 2019 more than 60 human uterus transplantation attempts have been performed and the scientific data of the published cases will be reviewed in relation to surgery and outcome. The assisted reproductive technologies that are used before and after uterus transplantation have to be modified for this patient group. The special demands for in vitro fertilization in a patient with no uterus and with embryo transfer in a transplanted uterus will be discussed. Traditionally, uterus transplantation has been performed through laparotomy in both the donor and the recipient. There is now a move to introduce minimally invasive surgery in live donor surgery transplantation, and in the future this may also be applied to recipient surgery. There is a continuous debate whether live donor or deceased donor uterus is the organ source for optimal outcome. Ongoing studies and the general development of the uterus transplantation field will shed light on the pros and cons of each donor source.

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      Infertility treatment has been revolutionized during the last 40 years, primarily by introduction of in vitro fertilization (IVF) and intracytoplasmic sperm injection. Most causes of female and male infertility have become treatable, but the group of women with absolute uterine factor infertility (AUFI) has remained untreatable. The option for these women to acquire genetic motherhood has been the use of gestational surrogacy, a procedure that is not allowed in most parts of the world.
      Absolute uterine factor infertility is due to either uterine absence (congenital/surgical) or uterine abnormality (anatomic/functional) that prevents implantation of an embryo or completion of a viable pregnancy. Surgical uterine absence in women of reproductive is after hysterectomy due to symptomatic and inoperable large leiomyoma, cervical/endometrial cancer, sarcoma or because of life-threatening obstetric bleeding from uterine atony, uterine rupture, or malplacentation. Congenital uterine absence is part of the Mayer-Rokitansky-Küster-Hauser syndrome, also named Müllerian agenesis.
      A present uterus may also be associated with AUFI, such as in some types of congenital uterine malformations. A great majority of women with a hypoplastic uterus and fractions of women with unicornuate and bicornuate uterus will be irreversibly infertile. Other groups of women with uterine presence and AUFI are portions of women with adenomyosis, intrauterine adhesions or previous radiation over the pelvis. There is also the cohort of women with unexplained uterine factor infertility, who experience a great number of implantation failures after IVF. These women have no history of uterine disease and imaging/hysteroscopy reveal normal results.
      The concept of uterus transplantation (UTx) to treat AUFI was first tested in 2000, when an attempt to perform live donor UTx to treat AUFI, caused by peripartum hysterectomy, was performed (
      • Fageeh W.
      • Raffa H.
      • Jabbad H.
      • Marzouki A.
      Transplantation of the human uterus.
      ). That historic UTx attempt ended in removal of a necrotic uterus after three months, but the case indubitably stimulated research activity within this new field of infertility research. The first organized clinical UTx trial was performed in Sweden in 2013, and the live donor trial included nine UTx procedures (
      • Brännström M.
      • Johannesson L.
      • Dahm-Kähler P.
      • Enskog A.S.
      • Mölne J.
      • et al.
      First clinical uterus transplantation trial: a six-month report.
      ). From that cohort, the first successful UTx procedure was established by demonstration of the first live birth in 2014 (
      • Brännström M.
      • Johannesson L.
      • Bokström H.
      • Kvarnström N.
      • Mölne J.
      • Dahm-Kähler P.
      • et al.
      Livebirth after uterus transplantation.
      ). This important proof-of-concept of UTx, as an infertility treatment has been followed by several more live births (
      • Mölne J.
      • Broecker V.
      • Ekberg J.
      • Nilsson O.
      • Dahm-Kähler P.
      • Brännström M.
      Monitoring of human uterus transplantation with cervical biopsies: a provisional scoring system for rejection.
      ), including one after deceased donor UTx (
      • Ejzenberg D.
      • Andraus W.
      • Baratelli Carelli Mendes L.R.
      • Ducatti L.
      • Song A.
      • et al.
      Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility.
      ). Unlike transplantation of most solid organs, UTx is not a-life-saving procedure but rather a quality-of-life enhancing and life-creating type of transplantation. Moreover, UTx is the first ephemeral type of transplantation, where the transplanted graft is not intended for life-long use but rather for a restricted time-frame, typically around five years so that there will be time for pregnancies with live births. The advantage of this restricted period for an allograft is that the length of immunosuppression medication is limited, thereby reducing the risk for long-term side effects such as development of nephrotoxicity, hypertension, diabetes and malignancy. The UTx procedure should not be considered successful until the birth of a healthy baby and this will normally occur around one and a half years after UTx.
      The successful introduction of UTx marks a new era in infertility treatment and may also be a renaissance for reproductive surgery. Even though UTx has many similarities with transplantation of the traditional solid abdominal organs, such as the kidney, liver and pancreas, a general concept is that the future field of UTx should be led by doctors with the specialty of obstetrics and gynecology. Reasons for the future dominance of obstetricians/gynecologists in this field are that we are the doctors that identify the potential patients, do most of the screening procedures of the donors and recipients, perform IVF before transplantation, are important surgeons at surgeries (transplantation, c-section, hysterectomy), are responsible for post-transplantation follow-up, perform embryo transfer after transplantation, and are responsible for obstetric care during pregnancies. However, the success of the complete UTx procedure depends on close collaboration within a multidisciplinary team, including also transplant surgeons, nephrologists, anesthesiologist and psychologists.
      Thus, our specialists in gynecology surgery, reproductive medicine and feto-maternal medicine should develop this field further in close collaboration with transplant surgeons. Concerning the gynecology surgeons, they should be trained in advanced pelvic surgery, and ample experience in robotic-assisted laparoscopy is beneficial to be able to take part in the future development of minimally invasive surgery in UTx. These gynecology surgeons can preferably have long experience in gynecologic oncology surgery or surgery for advanced endometriosis, with good knowledge in extra-peritoneal dissection and vascular anatomy in the lower pelvic region.
      The field of UTx is rapidly expanding and clinical trials have started or are in the start-up-phase in all continents. The published scientific literature, team-training in animal models, and exchange of data/site visits between groups with demonstrated successful UTx procedures and groups in the planning/start-up-phase, will be the most important tools to transfer knowledge and to get a safe and effective spread of this infertility treatment.
      This month's “Views and Reviews” provide an updated analysis of the clinical field of human UTx. One article sets the stage by reviewing the surgery and outcome of the published UTx cases, both from live donors and deceased donors. There are indications that reported graft failures are related to inclusion of suboptimal donor uteri and the modalities that should be used for pre-transplantation screening of donors are discussed in the article mentioned above. There exist special demands on assisted reproduction in relation to UTx, and that filed is covered in another article. Minimally invasive surgery will clearly have an impact also in the field of UTx, especially concerning live donor surgery. The present and the future of traditional laparoscopy and robotic-assisted laparoscopy in the UTx field is covered in one article that reviews the surgical results in detail. Lastly, the importance of increasing the donor pool with use of both live and deceased uterus donors is discussed. It is my hope that this series provides the reader with a good overview of the field and also inspires young doctors within our field to initiate research and clinical activity within the field of UTx.

      References

        • Fageeh W.
        • Raffa H.
        • Jabbad H.
        • Marzouki A.
        Transplantation of the human uterus.
        Int J Gynaecol Obstet. 2002; 76: 245-251
        • Brännström M.
        • Johannesson L.
        • Dahm-Kähler P.
        • Enskog A.S.
        • Mölne J.
        • et al.
        First clinical uterus transplantation trial: a six-month report.
        Fertil Steril. 2014; 101: 1228-1236
        • Brännström M.
        • Johannesson L.
        • Bokström H.
        • Kvarnström N.
        • Mölne J.
        • Dahm-Kähler P.
        • et al.
        Livebirth after uterus transplantation.
        Lancet. 2015; 14: 607-616
        • Mölne J.
        • Broecker V.
        • Ekberg J.
        • Nilsson O.
        • Dahm-Kähler P.
        • Brännström M.
        Monitoring of human uterus transplantation with cervical biopsies: a provisional scoring system for rejection.
        Am J Transplant. 2017; 17: 1628-1636
        • Ejzenberg D.
        • Andraus W.
        • Baratelli Carelli Mendes L.R.
        • Ducatti L.
        • Song A.
        • et al.
        Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility.
        Lancet. 2019; 392: 2697-2704