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Evolving clinical challenges in uterus transplantation

      Abstract

      Before the first live birth following uterus transplantation (UTx) in 2014, the 1–2% of women with an absent or non-functional uterus had no hope of childbearing. With 64 cases of UTx and 34 births reported in the scientific literature, this emerging technology has the potential for translation into mainstream clinical practice. However, limitations currently include donor availability, recipient suitability, surgical challenges regarding success and complications, and recipient management after UTx and during pregnancy. This review considers these challenges and ways to overcome them so that UTx could become part of the reproductive specialist's armamentarium when counselling patients with uterine factor infertility.

      KEY WORDS

      Introduction

      Uterine factor infertility (UFI) is classified as either absolute or relative. Absolute UFI (AUFI) implies absence of the uterus and encompasses congenital and acquired forms. Congenital AUFI, otherwise known as the Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome, involves the absence of the uterus and often part of the vagina at birth, and affects 1 in 4500 females (
      • Ledig S.
      • Wieacker P.
      Clinical and genetic aspects of Mayer-Rokitansky-Kuster-Hauser syndrome.
      ). Acquired AUFI results from hysterectomy, which, in the USA alone, is performed annually in over 150,000 women under the age of 40 years (
      • Brett K.M.
      • Higgins J.A.
      Hysterectomy prevalence by Hispanic ethnicity: evidence from a national survey.
      ).
      Relative UFI (RUFI) involves a uterus that is so seriously altered that neither naturally conceived nor IVF pregnancies are likely. The primary cause of RUFI is Asherman syndrome, although certain congenital uterine malformations also cause it. Women suffering from UFI had no hope of childbearing until the feasibility of uterus transplantation was documented in 2014, following the birth in Sweden of a healthy baby after transplantation from a living donor to a recipient with MRKH (
      • Brannstrom M.
      • Johannesson L.
      • Bokstrom H.
      • Kvarnstrom N.
      • Molne J.
      • Dahm-Kahler P.
      • Enskog A.
      • Milenkovic M.
      • Ekberg J.
      • Diaz-Garcia C.
      • Gabel M.
      • Hanafy A.
      • Hagberg H.
      • Olausson M.
      • Nilsson L.
      Livebirth after uterus transplantation.
      ). The ultimate measure of success in UTx is the occurrence of a minimum of side effects for the mother and, if living, the donor, and the safe delivery of a healthy live-born infant. The United States Uterus Transplant Consortium (USUTC) has defined seven progressive stages of success: technical success (defined by established outflow and graft viability 3 months after surgery), menstruation, embryo implantation, pregnancy, delivery, graft removal and long-term follow-up (
      • Johannesson L.
      • Testa G.
      • Flyckt R.
      • Farrell R.
      • Quintini C.
      • Wall A.
      • O'Neill K.
      • Tzakis A.
      • Richards E.G.
      • Gordon S.M.
      • Porrett P.M.
      Guidelines for standardized nomenclature and reporting in uterus transplantation: An opinion from the United States Uterus Transplant Consortium.
      ).
      The complexities and associated challenges of establishing a successful UTx programme currently present barriers to translation into mainstream clinical practice. This review addresses these challenges, proposes ways to overcome them and discusses the required psychological support for living donors and recipients, as well as the ethical questions. The aim is to provide a roadmap for the successful establishment of new UTx centres, so that this unique non-vital transplantation will become more accessible to patients suffering from UFI.

      Summary of published cases

      The first UTx, performed in Saudi Arabia in 2000 and published in 2002 (
      • Fageeh W.
      • Raffa H.
      • Jabbad H.
      • Marzouki A.
      Transplantation of the human uterus.
      ), was a failure. The second case was performed in Turkey in 2011 and published in 2013 (
      • Ozkan O.
      • Akar M.E.
      • Erdogan O.
      • Ozkan O.
      • Hadimioglu N.
      Uterus transplantation from a deceased donor.
      ;
      • Ozkan O.
      • Ozkan O.
      • Dogan N.U.
      • Bahceci M.
      • Mendilcioglu I.
      • Boynukalin K.
      • Ongun H.
      • Kantarci A.M.
      • Yaprak M.
      • Cengiz M.
      • Hadimioglu N.
      • Kafadar Y.T.
      • Celik K.
      Birth of a Healthy Baby 9 years after a Surgically Successful Deceased Donor Uterus Transplant.
      ), and this resulted in a live birth 9 years later (
      • Ozkan O.
      • Akar M.E.
      • Erdogan O.
      • Ozkan O.
      • Hadimioglu N.
      Uterus transplantation from a deceased donor.
      ;
      • Ozkan O.
      • Ozkan O.
      • Dogan N.U.
      • Bahceci M.
      • Mendilcioglu I.
      • Boynukalin K.
      • Ongun H.
      • Kantarci A.M.
      • Yaprak M.
      • Cengiz M.
      • Hadimioglu N.
      • Kafadar Y.T.
      • Celik K.
      Birth of a Healthy Baby 9 years after a Surgically Successful Deceased Donor Uterus Transplant.
      ). The first live birth reported from Sweden, in 2015 (
      • Brannstrom M.
      • Johannesson L.
      • Bokstrom H.
      • Kvarnstrom N.
      • Molne J.
      • Dahm-Kahler P.
      • Enskog A.
      • Milenkovic M.
      • Ekberg J.
      • Diaz-Garcia C.
      • Gabel M.
      • Hanafy A.
      • Hagberg H.
      • Olausson M.
      • Nilsson L.
      Livebirth after uterus transplantation.
      ), was one from a trial of nine cases with living donors that was performed after more than a decade of extensive foundational training and research on animal models (
      • Johannesson L.
      • Kvarnstrom N.
      • Molne J.
      • Dahm-Kahler P.
      • Enskog A.
      • Diaz-Garcia C.
      • Olausson M.
      • Brannstrom M.
      Uterus transplantation trial: 1-year outcome.
      ). In seven of the cases, the grafts were functional. However, two required removal, each because of hypoperfusion and secondary intrauterine infection (
      • Karlsson C.C.
      • Dahm-Kahler P.
      • Kvarnstrom N.
      • Molne J.
      • Broecker V.
      • Brannstrom M.
      Hysterectomy after uterus transplantation and detailed analyses of graft failures.
      ). Six patients had healthy babies (three with successive pregnancies) and one had repeated miscarriages. A second UTx trial performed by the Swedish team introduced robotic-assisted laparoscopy, including in the living donors (
      • Brucker S.Y.
      • Brannstrom M.
      • Taran F.A.
      • Nadalin S.
      • Konigsrainer A.
      • Rall K.
      • Scholler D.
      • Henes M.
      • Bosmuller H.
      • Fend F.
      • Nikolaou K.
      • Notohamiprodjo M.
      • Rosenberger P.
      • Grasshoff C.
      • Heim E.
      • Kramer B.
      • Reisenauer C.
      • Hoopmann M.
      • Kagan K.O.
      • Dahm-Kahler P.
      • Kvarnstrom N.
      • Wallwiener D.
      Selecting living donors for uterus transplantation: lessons learned from two transplantations resulting in menstrual functionality and another attempt, aborted after organ retrieval.
      ;
      • Ayoubi J.M.
      • Carbonnel M.
      • Pirtea P.
      • Kvarnstrom N.
      • Brannstrom M.
      • Dahm-Kahler P.
      Laparotomy or minimal invasive surgery in uterus transplantation: a comparison.
      ;
      • Brannstrom M.
      • Dahm-Kahler P.
      • Ekberg J.
      • Akouri R.
      • Groth K.
      • Enskog A.
      • Broecker V.
      • Molne J.
      • Ayoubi J.M.
      • Kvarnstrom N.
      Outcome of Recipient Surgery and 6-Month Follow-Up of the Swedish Live Donor Robotic Uterus Transplantation Trial.
      ) and resulted in a birth (
      • Brannstrom M.
      • Dahm-Kahler P.
      • Kvarnstrom N.
      • Akouri R.
      • Rova K.
      • Olausson M.
      • Groth K.
      • Ekberg J.
      • Enskog A.
      • Sheikhi M.
      • Molne J.
      • Bokstrom H.
      Live birth after robotic-assisted live donor uterus transplantation.
      ).
      Of the 70 recipients to date, 65 have been women with MRKH, four have had a hysterectomy and one had Asherman syndrome (
      • Brannstrom M.
      • Belfort M.A.
      • Ayoubi J.M.
      Uterus transplantation worldwide: clinical activities and outcomes.
      ). Sixty-four UTx procedures have been reported in peer-reviewed journals (Table 1), although more than 80 have been undertaken by about 20 teams worldwide, according to media reports and personal communications (Figure 1) (
      • Brannstrom M.
      • Belfort M.A.
      • Ayoubi J.M.
      Uterus transplantation worldwide: clinical activities and outcomes.
      ).
      Table 1State of the art of uterus transplantation
      (A)
      RecipientsDonors
      Year published
      Year given is year of first publication.
      CountryNumber of UTx casesCause of uterus infertilityNumber of complications
      Complications: at least one grade III or higher Clavien–Dindo complication.
      Reason for transplantectomyLive/deceasedRelationship to recipientSurgical approachNumber of complications
      Complications: at least one grade III or higher Clavien–Dindo complication.
      Transplant resultClinical outcome
      Fully reported cases
      2002Saudi Arabia11 post-partum hysterectomy1 transplantectomy1 thrombosis1 L1 non-directedOpen1 ureteral laceration1 failureN/A
      2013Turkey11 MRKH0N/A1 D1 non-directedOpenN/A1 success2 SAB, 1 LB
      2015Sweden98 MRKH

      1 hysterectomy for cervical cancer
      2 transplantectomies1 thrombosis 1 hypoperfusion9 L5 mothers

      1 aunt
      Open1 uretero-vaginal fistula7 successes

      2 failures
      9 LB (2 LB from each of 3 UTx cases), 1 with 6 SAB
      1 sister
      1 mother-in-law
      1 friend
      2015China11 MRKH0N/A1 L1 motherRobotic01 success1 LB
      2016USA

      Dallas
      2018 MRKH

      2 hysterectomy for myomas
      6 transplantectomies

      1 haemorrhagic shock
      2 thrombosis

      4 surgical complications
      18 L17 non-directed

      1 mother
      13 open

      5 robotic
      1 faecal impaction

      1 vaginal cuff D-dehiscence

      1 bilateral ureteric vaginal fistulae

      1 blood clot in ureter
      13 successes

      5 failures
      11 LB (2 LB from 1 UTx case)
      2 D2 non-directedOpenN/A1 success

      1 failure
      1 LB
      2016Brazil11 MRKH0N/A1 D1 non-directedOpenN/A1 success1 LB
      2017USA

      Cleveland
      22 MRKH1 transplantectomy1 fungal infection2 D2 non-directedOpenN/A1 success

      1 failure
      1 LB
      2017Germany44 MRKHN/A4 L3 mothers

      1 sister
      Open04 successes2 LB, 1 SAB
      2017Sweden88 MRKH2 transplantectomies2 hypoperfusions8 L6 mothersRobotic1 pyelonephritis with hydronephrosis6 successes

      2 failures
      1 LB, 5 with unpublished outcomes
      2018India43 MRKH

      1 Asherman syndrome
      0N/A4 L4 mothersLaparoscopy04 successes4 with unpublished outcomes
      2018Czech Republic1010 MRKH3 transplantectomies

      3 haemorrhage

      5 vaginal stenosis

      1 vesico-vaginal fistula
      2 thrombosis

      1 HSV infection
      5 L4 mothers

      1 mother's sister
      Open1 ureteral laceration

      1 bladder hypotonia
      4 successes

      1 failure
      2 LB, 1 SAB, 1 recipients with 11 ET and no pregnancies, 1 recipient with 5 ET and no pregnancies
      5 D5 non-directedOpenN/A3 successes

      2 failures
      1 LB, 2 recipients with SAB
      2020Lebanon11 MRKH0N/A1 L1 motherOpen01 success1 LB
      2021Spain11 MRKH0N/A1 L1 sisterRobotic01 successUnpublished
      2021Brazil11 MRKH0N/A1 L1 non-directedRobotic01 successUnpublished
      Cancelled procedure
      2017Germany11 MRKH1 UTx not performed because non-flushable on backtableN/A1L1 motherOpen01 failureN/A
      2018Czech Republic11 MRKH1 UTX not performed due to vein insufficiency on backtableN/A1L1 non-directedOpen01 failureN/A
      Authors’ personal experience (unpublished to date)
      UnpublishedSerbia11 MRKH0N/A1L1 monozygotic twinOpen01 success1 LB
      UnpublishedLebanon11 MRKH0N/A1L1 sister-in-lawOpen01 successNot yet delivered
      UnpublishedSweden11 MRKH1 EBV infection with PTLD high-grade lymphoma needing transplantectomy1 PTLD1D1 non-directedOpenN/A1 failureN/A
      UnpublishedFrance11 MRKH0N/A1L1 motherRobotic1 ureteral injury1 success1 LB
      (B) Summary data
      UTxRecipientsLiving donorsDeceased donors
      Total70Total68Total58Total12
      Success51/70 (72.9%)Complications
      Complications: at least one grade III or higher Clavien–Dindo complication.
      22/68 (32.4%)Success45/58 (77.6%)Success7/12 (58.3%)
      LB/UTx
      2 LB/UTx for 4 recipients. D, Deceased donor; EBV, Epstein–Barr virus; ET, Embryo transfer; HSV, herpes simplex virus; L, Live donor; LB, live birth; MRKH, Mayer–Rokitansky–Küster–Hauser syndrome; N/A, not applicable; PTLD, post-transplant lymphoproliferative disorder; SAB, spontaneous abortion; UTx, uterus transplantation.
      34/70 (48.5%)From transplantectomies16/68 (23.5%)Complications
      Complications: at least one grade III or higher Clavien–Dindo complication.
      10/58 (17.2%)Complications
      Complications: at least one grade III or higher Clavien–Dindo complication.
      N/A
      LB/success
      2 LB/UTx for 4 recipients. D, Deceased donor; EBV, Epstein–Barr virus; ET, Embryo transfer; HSV, herpes simplex virus; L, Live donor; LB, live birth; MRKH, Mayer–Rokitansky–Küster–Hauser syndrome; N/A, not applicable; PTLD, post-transplant lymphoproliferative disorder; SAB, spontaneous abortion; UTx, uterus transplantation.
      33/51 (66.7%)
      a Year given is year of first publication.
      b Complications: at least one grade III or higher Clavien–Dindo complication.
      c 2 LB/UTx for 4 recipients.D, Deceased donor; EBV, Epstein–Barr virus; ET, Embryo transfer; HSV, herpes simplex virus; L, Live donor; LB, live birth; MRKH, Mayer–Rokitansky–Küster–Hauser syndrome; N/A, not applicable; PTLD, post-transplant lymphoproliferative disorder; SAB, spontaneous abortion; UTx, uterus transplantation.
      Figure 1
      Figure 1The current status of uterus transplantation (UTx) worldwide. Circles in blue represent the number of published/personal communication UTx cases per centre; green circles represent centres with ongoing trials and no published data; and red circles represent centres planning UTx within the next 1–2 years.
      The current overall technical success rate of UTx, including four unpublished cases and two cancelled backtable cases, is 72.9% (51/70). Thirty-four healthy children have been born, four being born after a previous birth following UTx (Table 1). Most births (n = 29) involved transplanted uteri from living donors (
      • Brannstrom M.
      • Johannesson L.
      • Bokstrom H.
      • Kvarnstrom N.
      • Molne J.
      • Dahm-Kahler P.
      • Enskog A.
      • Milenkovic M.
      • Ekberg J.
      • Diaz-Garcia C.
      • Gabel M.
      • Hanafy A.
      • Hagberg H.
      • Olausson M.
      • Nilsson L.
      Livebirth after uterus transplantation.
      ;
      • Bokstrom H.
      • Dahm-Kahler P.
      • Hagberg H.
      • Nilsson L.
      • Olausson M.
      • Brannstrom M.
      [Uterus transplantation in Sweden - the 5 first children in the world born. Promising results - all the children are healthy].
      ;
      • Brannstrom M.
      • Bokstrom H.
      • Dahm-Kahler P.
      • Diaz-Garcia C.
      • Ekberg J.
      • Enskog A.
      • Hagberg H.
      • Johannesson L.
      • Kvarnstrom N.
      • Molne J.
      • Olausson M.
      • Olofsson J.I.
      • Rodriguez-Wallberg K.
      One uterus bridging three generations: first live birth after mother-to-daughter uterus transplantation.
      ;
      • Brucker S.Y.
      • Strowitzki T.
      • Taran F.A.
      • Rall K.
      • Scholler D.
      • Hoopmann M.
      • Henes M.
      • Guthoff M.
      • Heyne N.
      • Zipfel S.
      • Schaffeler N.
      • Bosmuller H.
      • Fend F.
      • Rosenberger P.
      • Heim E.
      • Wiesing U.
      • Nikolaou K.
      • Fleischer S.
      • Bakchoul T.
      • Poets C.F.
      • Goelz R.
      • Wiechers C.
      • Kagan K.O.
      • Kramer B.
      • Reisenauer C.
      • Oberlechner E.
      • Hubner S.
      • Abele H.
      • Dahm-Kahler P.
      • Kvarnstrom N.
      • Brannstrom M.
      • Nadalin S.
      • Wallwiener D.
      • Konigsrainer A.
      Living-Donor Uterus Transplantation: Pre-, Intra-, and Postoperative Parameters Relevant to Surgical Success, Pregnancy, and Obstetrics with Live Births.
      ;
      • Chmel R.
      • Cekal M.
      • Pastor Z.
      • Chmel Jr., R.
      • Paulasova P.
      • Havlovicova M.
      • Macek Jr., M.
      • Novackova M.
      Assisted reproductive techniques and pregnancy results in women with Mayer-Rokitansky-Kuster-Hauser syndrome undergoing uterus transplantation: the Czech experience.
      ;
      • Huang Y.
      • Ding X.
      • Chen B.
      • Zhang G.
      • Li A.
      • Hua W.
      • Zhou D.
      • Wang X.
      • Liu D.
      • Yan G.
      • Zhang C.
      • Zhang J.
      Report of the first live birth after uterus transplantation in People's Republic of China.
      ;
      • Johannesson L.
      • Testa G.
      • Putman J.M.
      • McKenna G.J.
      • Koon E.C.
      • York J.R.
      • Bayer J.
      • Zhang L.
      • Rubeo Z.S.
      • Gunby R.T.
      • Gregg A.R.
      Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study.
      ;
      • Richards E.G.
      • Farrell R.M.
      • Ricci S.
      • Perni U.
      • Quintini C.
      • Tzakis A.
      • Falcone T.
      Uterus transplantation: state of the art in 2021.
      ), with only five involving deceased donors (
      • Ejzenberg D.
      • Andraus W.
      • Baratelli Carelli Mendes L.R.
      • Ducatti L.
      • Song A.
      • Tanigawa R.
      • Rocha-Santos V.
      • Macedo Arantes R.
      • Soares Jr., J.M.
      • Serafini P.C.
      • Bertocco de Paiva Haddad L.
      • Pulcinelli Francisco R.
      • Carneiro D'Albuquerque L.A.
      • Chada Baracat E.
      Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility.
      ;
      • Flyckt R.
      • Falcone T.
      • Quintini C.
      • Perni U.
      • Eghtesad B.
      • Richards E.G.
      • Farrell R.M.
      • Hashimoto K.
      • Miller C.
      • Ricci S.
      • Ferrando C.
      • D'Amico G.
      • Maikhor S.
      • Priebe D.
      • Chiesa-Vottero A.
      • Heerema-McKenney A.
      • Mawhorter S.
      • Feldman M.
      • Tzakis A.
      First birth from a deceased donor uterus in the United States: from severe graft rejection to successful cesarean delivery.
      ;
      • Fronek J.
      • Janousek L.
      • Kristek J.
      • Chlupac J.
      • Pluta M.
      • Novotny R.
      • Maluskova J.
      • Olausson M.
      Live Birth Following Uterine Transplantation From a Nulliparous Deceased Donor.
      ;
      • Johannesson L.
      • Testa G.
      • Putman J.M.
      • McKenna G.J.
      • Koon E.C.
      • York J.R.
      • Bayer J.
      • Zhang L.
      • Rubeo Z.S.
      • Gunby R.T.
      • Gregg A.R.
      Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study.
      ;
      • Ozkan O.
      • Ozkan O.
      • Dogan N.U.
      • Bahceci M.
      • Mendilcioglu I.
      • Boynukalin K.
      • Ongun H.
      • Kantarci A.M.
      • Yaprak M.
      • Cengiz M.
      • Hadimioglu N.
      • Kafadar Y.T.
      • Celik K.
      Birth of a Healthy Baby 9 years after a Surgically Successful Deceased Donor Uterus Transplant.
      ) (Table 1). Although the technical success rate is currently higher with living versus deceased donors (77.6% versus 58.3% [7/12];
      • Brannstrom M.
      • Belfort M.A.
      • Ayoubi J.M.
      Uterus transplantation worldwide: clinical activities and outcomes.
      ), this must be balanced against the risks for the living donor. Indeed, some teams choose to work only with deceased donors (
      • Ozkan O.
      • Akar M.E.
      • Erdogan O.
      • Ozkan O.
      • Hadimioglu N.
      Uterus transplantation from a deceased donor.
      ;
      • Ejzenberg D.
      • Andraus W.
      • Baratelli Carelli Mendes L.R.
      • Ducatti L.
      • Song A.
      • Tanigawa R.
      • Rocha-Santos V.
      • Macedo Arantes R.
      • Soares Jr., J.M.
      • Serafini P.C.
      • Bertocco de Paiva Haddad L.
      • Pulcinelli Francisco R.
      • Carneiro D'Albuquerque L.A.
      • Chada Baracat E.
      Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility.
      ;
      • Richards E.G.
      • Farrell R.M.
      • Ricci S.
      • Perni U.
      • Quintini C.
      • Tzakis A.
      • Falcone T.
      Uterus transplantation: state of the art in 2021.
      ) while others work with living donors because extensive pre-transplantation evaluation and planned surgery is possible (
      • Brannstrom M.
      • Enskog A.
      • Kvarnstrom N.
      • Ayoubi J.M.
      • Dahm-Kahler P.
      Global results of human uterus transplantation and strategies for pre-transplantation screening of donors.
      ;
      • Jones B.P.
      • Saso S.
      • Quiroga I.
      • Yazbek J.
      • Smith J.R.
      Re: UK criteria for uterus transplantation: a review.
      ;
      • Richards E.G.
      • Farrell R.M.
      • Ricci S.
      • Perni U.
      • Quintini C.
      • Tzakis A.
      • Falcone T.
      Uterus transplantation: state of the art in 2021.
      ).
      While both technical success and live birth rates after UTx are encouraging, only a few women of the approximately 1 million in the world with UFI have benefited from the procedure to date (
      • Brannstrom M.
      • Belfort M.A.
      • Ayoubi J.M.
      Uterus transplantation worldwide: clinical activities and outcomes.
      ). Numerous reasons exist for this limited translation into clinical practice. UTx involves several unique steps (Figure 2): the recipient must undergo IVF to create embryos, ideally prior to the UTx; the likelihood that a transplanted uterus can support a term pregnancy must be considered; pregnancy management presents unique challenges; and the graft of this transitory transplantation procedure must ultimately be removed. Of note, UTx is still at the experimental stage, and the precautionary principle must be widely applied.
      Figure 2
      Figure 2The steps involved in the uterus transplantation process from donor/recipient screening to hysterectomy.

      Screening and selection of UTx recipients and donors

      Recipients

      Based on the authors’ Swedish and French collaborative experience, the following criteria for UTx recipients include: (i) ideally less than 38 years of age (
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ) (because of the sharp decline in fecundity beyond 37 years (
      American College of, O., P
      Gynecologists Committee on Gynecologic and C. Practice. Female age-related fertility decline. Committee Opinion No. 589.
      )); (ii) a willingness to undergo IVF (because natural conception is not possible due to devascularization of the fallopian tubes during the surgery); (iii) no severe associated comorbidities or chronic or active infections; (iv) a body mass index less than 30 kg/m2; and (v) being in a stable relationship. Although having only one kidney, a condition often associated with MRKH, is not currently an exclusion criterion, some trials have excluded women with a low-lying pelvic position of the kidneys (
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ). Most studies have excluded women with past vaginal reconstruction with sigmoid or jejunal segments because of the risk of inflammation, miscarriage or implantation failure, as exemplified by the first deceased donor UTx procedure reported in 2013 (
      • Erman Akar M.
      • Ozkan O.
      • Aydinuraz B.
      • Dirican K.
      • Cincik M.
      • Mendilcioglu I.
      • Simsek M.
      • Gunseren F.
      • Kocak H.
      • Ciftcioglu A.
      • Gecici O.
      • Ozkan O.
      Clinical pregnancy after uterus transplantation.
      ).
      Loosening the above inclusion criteria might include extending the age beyond 38 years if the woman had frozen oocytes or embryos when younger, and/or if she had frozen embryos when older if the embryos had been shown to be euploid by preimplantation genetic testing for aneuploidies (
      • Munne S.
      • Kaplan B.
      • Frattarelli J.L.
      • Child T.
      • Nakhuda G.
      • Shamma F.N.
      • Silverberg K.
      • Kalista T.
      • Handyside A.H.
      • Katz-Jaffe M.
      • Wells D.
      • Gordon T.
      • Stock-Myer S.
      • Willman S.
      S. S. Group
      Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial.
      ). Expanding access might also be achieved by accepting more women with hysterectomy, uterus malformations incompatible with pregnancy and/or Asherman syndrome. Finally, it would seem reasonable to offer UTx to single women providing they (i) have a reliable support system; (ii) are willing to undergo an IVF cycle with oocyte freezing or embryo freezing with donor spermatozoa; and (iii) plan to achieve pregnancy within a year after their UTx procedure to avoid prolonged immunosuppressive treatment.

      Donors

      The use of living and deceased donors is each associated with advantages and disadvantages, and reasons for exclusions have varied among teams because of unstandardized criteria (
      • Johannesson L.
      • Wallis K.
      • Koon E.C.
      • McKenna G.J.
      • Anthony T.
      • Leffingwell S.G.
      • Klintmalm G.B.
      • Gunby Jr., R.T.
      • Testa G.
      Living uterus donation and transplantation: experience of interest and screening in a single center in the United States.
      ;
      • Taran F.A.
      • Scholler D.
      • Rall K.
      • Nadalin S.
      • Konigsrainer A.
      • Henes M.
      • Bosmuller H.
      • Fend F.
      • Nikolaou K.
      • Notohamiprodjo M.
      • Grasshoff C.
      • Heim E.
      • Zipfel S.
      • Schaffeler N.
      • Bakchoul T.
      • Heyne N.
      • Guthoff M.
      • Kramer B.
      • Reisenauer C.
      • Hoopmann M.
      • Kagan K.O.
      • Brannstrom M.
      • Wallwiener D.
      • Brucker S.Y.
      Screening and evaluation of potential recipients and donors for living donor uterus transplantation: results from a single-center observational study.
      ;
      • Carbonnel M.
      • Revaux A.
      • Menzhulina E.
      • Karpel L.
      • Snanoudj R.
      • Le Guen M.
      • De Ziegler D.
      • Ayoubi J.M.
      Uterus Transplantation with Live Donors: Screening Candidates in One French Center.
      ). Nevertheless, all accepted donors have had an absence of uterine pathology, no previous malignancy, no chronic or active infections and no severe comorbidities.

      Living donors

      Because the use of living donors enables extensive pre-transplantation evaluation and planning, most teams choose to gain their initial experience with this source of a uterus. Moreover, surgical success is currently higher with living donors (78% versus 58%), although this must be balanced against the long and complex surgery needed to harvest the uterus with appropriate vascular pedicles from a healthy person, with significant risks for peri- and post-operative complications. Living donors have been mainly relatives of recipients, often mothers (Table 1), and so have had emotional or genetic relationships with the recipient, as with the kidney transplantation model (
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ). However, current experience shows that 75% of potential related donors are at risk of not fulfilling the current inclusion criteria (
      • Carbonnel M.
      • Revaux A.
      • Menzhulina E.
      • Karpel L.
      • Snanoudj R.
      • Le Guen M.
      • De Ziegler D.
      • Ayoubi J.M.
      Uterus Transplantation with Live Donors: Screening Candidates in One French Center.
      ). An alternative to directed living donation is altruistic, non-directed donation. Although currently offered by two teams (
      • Johannesson L.
      • Wallis K.
      • Koon E.C.
      • McKenna G.J.
      • Anthony T.
      • Leffingwell S.G.
      • Klintmalm G.B.
      • Gunby Jr., R.T.
      • Testa G.
      Living uterus donation and transplantation: experience of interest and screening in a single center in the United States.
      ;
      • Fronek J.
      • Kristek J.
      • Chlupac J.
      • Janousek L.
      • Olausson M.
      Human Uterus Transplantation from Living and Deceased Donors: The Interim Results of the First 10 Cases of the Czech Trial.
      ), this is considered controversial because of the potential risks of organ trading.
      Limited available experience suggests poorer outcomes when using a uterus from a post-menopausal compared with pre-menopausal living donor (
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ;
      • Brucker S.Y.
      • Brannstrom M.
      • Taran F.A.
      • Nadalin S.
      • Konigsrainer A.
      • Rall K.
      • Scholler D.
      • Henes M.
      • Bosmuller H.
      • Fend F.
      • Nikolaou K.
      • Notohamiprodjo M.
      • Rosenberger P.
      • Grasshoff C.
      • Heim E.
      • Kramer B.
      • Reisenauer C.
      • Hoopmann M.
      • Kagan K.O.
      • Dahm-Kahler P.
      • Kvarnstrom N.
      • Wallwiener D.
      Selecting living donors for uterus transplantation: lessons learned from two transplantations resulting in menstrual functionality and another attempt, aborted after organ retrieval.
      ), suggesting negative age-related changes in uterine vasculature. Although 60 years of age and/or 5 years after menopause are currently considered reasonable exclusion criteria, the oldest donor to date with a successful graft resulting in live birth was a 62-year-old mother (
      • Brannstrom M.
      • Dahm-Kahler P.
      • Kvarnstrom N.
      • Akouri R.
      • Rova K.
      • Olausson M.
      • Groth K.
      • Ekberg J.
      • Enskog A.
      • Sheikhi M.
      • Molne J.
      • Bokstrom H.
      Live birth after robotic-assisted live donor uterus transplantation.
      ). Other exclusion criteria for living donors typically include nulliparity, previous recurrent miscarriages, obesity and associated comorbidities, current or past long-term heavy smoking, and a history of uterine scar including one Caesarean section (
      • Carbonnel M.
      • Revaux A.
      • Menzhulina E.
      • Karpel L.
      • Snanoudj R.
      • Le Guen M.
      • De Ziegler D.
      • Ayoubi J.M.
      Uterus Transplantation with Live Donors: Screening Candidates in One French Center.
      ).

      Deceased donors

      UTx from deceased donors is a promising alternative to avoid potential living donor complications (
      • Ozkan O.
      • Akar M.E.
      • Erdogan O.
      • Ozkan O.
      • Hadimioglu N.
      Uterus transplantation from a deceased donor.
      ;
      • Ejzenberg D.
      • Andraus W.
      • Baratelli Carelli Mendes L.R.
      • Ducatti L.
      • Song A.
      • Tanigawa R.
      • Rocha-Santos V.
      • Macedo Arantes R.
      • Soares Jr., J.M.
      • Serafini P.C.
      • Bertocco de Paiva Haddad L.
      • Pulcinelli Francisco R.
      • Carneiro D'Albuquerque L.A.
      • Chada Baracat E.
      Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility.
      ;
      • Richards E.G.
      • Farrell R.M.
      • Ricci S.
      • Perni U.
      • Quintini C.
      • Tzakis A.
      • Falcone T.
      Uterus transplantation: state of the art in 2021.
      ). Five births have been reported (
      • Ejzenberg D.
      • Andraus W.
      • Baratelli Carelli Mendes L.R.
      • Ducatti L.
      • Song A.
      • Tanigawa R.
      • Rocha-Santos V.
      • Macedo Arantes R.
      • Soares Jr., J.M.
      • Serafini P.C.
      • Bertocco de Paiva Haddad L.
      • Pulcinelli Francisco R.
      • Carneiro D'Albuquerque L.A.
      • Chada Baracat E.
      Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility.
      ;
      • Flyckt R.
      • Falcone T.
      • Quintini C.
      • Perni U.
      • Eghtesad B.
      • Richards E.G.
      • Farrell R.M.
      • Hashimoto K.
      • Miller C.
      • Ricci S.
      • Ferrando C.
      • D'Amico G.
      • Maikhor S.
      • Priebe D.
      • Chiesa-Vottero A.
      • Heerema-McKenney A.
      • Mawhorter S.
      • Feldman M.
      • Tzakis A.
      First birth from a deceased donor uterus in the United States: from severe graft rejection to successful cesarean delivery.
      ;
      • Fronek J.
      • Janousek L.
      • Kristek J.
      • Chlupac J.
      • Pluta M.
      • Novotny R.
      • Maluskova J.
      • Olausson M.
      Live Birth Following Uterine Transplantation From a Nulliparous Deceased Donor.
      ;
      • Johannesson L.
      • Testa G.
      • Putman J.M.
      • McKenna G.J.
      • Koon E.C.
      • York J.R.
      • Bayer J.
      • Zhang L.
      • Rubeo Z.S.
      • Gunby R.T.
      • Gregg A.R.
      Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study.
      ;
      • Ozkan O.
      • Ozkan O.
      • Dogan N.U.
      • Bahceci M.
      • Mendilcioglu I.
      • Boynukalin K.
      • Ongun H.
      • Kantarci A.M.
      • Yaprak M.
      • Cengiz M.
      • Hadimioglu N.
      • Kafadar Y.T.
      • Celik K.
      Birth of a Healthy Baby 9 years after a Surgically Successful Deceased Donor Uterus Transplant.
      ), one of which was achieved after UTx from a nulliparous deceased donor. Despite the limited availability of this source of uterus, which poses a serious limitation to access (
      • Kristek J.
      • Johannesson L.
      • Testa G.
      • Chmel R.
      • Olausson M.
      • Kvarnstrom N.
      • Karydis N.
      • Fronek J.
      Limited Availability of Deceased Uterus Donors: A Transatlantic Perspective.
      ), some teams choose only to work with deceased donors (
      • Ozkan O.
      • Akar M.E.
      • Erdogan O.
      • Ozkan O.
      • Hadimioglu N.
      Uterus transplantation from a deceased donor.
      ;
      • Ejzenberg D.
      • Andraus W.
      • Baratelli Carelli Mendes L.R.
      • Ducatti L.
      • Song A.
      • Tanigawa R.
      • Rocha-Santos V.
      • Macedo Arantes R.
      • Soares Jr., J.M.
      • Serafini P.C.
      • Bertocco de Paiva Haddad L.
      • Pulcinelli Francisco R.
      • Carneiro D'Albuquerque L.A.
      • Chada Baracat E.
      Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility.
      ;
      • Richards E.G.
      • Farrell R.M.
      • Ricci S.
      • Perni U.
      • Quintini C.
      • Tzakis A.
      • Falcone T.
      Uterus transplantation: state of the art in 2021.
      ). Despite not being able to perform a pre-evaluation of the vessels in deceased donors, this may not present a problem as these women tend to be younger than living donors (current mean age 32.5 years versus 47.9 years) and so the age-related risk of sub-optimal arterial flow is reduced. Other constraints include less time to evaluate the uterus and to assess donor–recipient compatibility, infection risk including human papillomavirus (HPV) and the overall quality of the vessels.

      Recipient–donor mismatching issues

      As with other types of organ transplantation, ABO incompatibility and the presence of donor-specific antibodies (DSA) against the donor's human leukocyte antigens are the major, and absolute, reasons for donor exclusion (
      • Gentry S.E.
      • Segev D.L.
      • Montgomery R.A.
      A comparison of populations served by kidney paired donation and list paired donation.
      ). In addition, the risk of cytomegalovirus (CMV) and Epstein–Barr Virus (EBV) must also be considered in donor–recipient matching. Although donor-positive/recipient-negative mismatches for EBV and CMV have been permitted by some teams, the risk of severe complications in the case of infection cannot be excluded. The Swedish team experienced one serious and life-threatening complication in a deceased donor UTx procedure where the donor was EBV positive and the recipient was EBV negative (personal communication, J. Ekberg, Gothenburg, Sweden). The recipient acquired an EBV infection some months post-UTx and then developed post-transplantation lymphoproliferative disorder with multifocal, intestinal lymphoma, with multiple episodes of intestinal bleeding and perforation. Treatment was by hysterectomy with omission of immunosuppression and rituximab. The lymphoma regressed and the patient was in good physical health 2 years later, albeit with a considerable psychological burden.
      Considering the potential deleterious transfection of CMV to recipients and their subsequent pregnancies, some teams have avoided transplanting CMV-positive donor grafts into CMV-negative recipients. This mismatch is unfortunately frequent because 50% of adults are CMV positive. Living donors are often positive (older and mothers), while recipients are more likely to be negative (younger and without children) (
      • Carbonnel M.
      • Revaux A.
      • Menzhulina E.
      • Karpel L.
      • Snanoudj R.
      • Le Guen M.
      • De Ziegler D.
      • Ayoubi J.M.
      Uterus Transplantation with Live Donors: Screening Candidates in One French Center.
      ), which reduces the pool of potential living donors. Nevertheless, preventive and curative treatment is available for CMV. Furthermore, close monitoring for CMV infection during the post-UTx course, with treatment as indicated prior to the embryo transfer, has been reported, with the recipient successfully carrying a healthy child to term (
      • Rosenzweig M.
      • Wall A.
      • Spak C.W.
      • Testa G.
      • Johannesson L.
      Pregnancy after CMV infection following uterus transplantation: A case report from the Dallas Uterus Transplant Study.
      ).
      Another concern relating to the health of the recipient post-UTx is the risk of cervical dysplasia. Cervical intraepithelial neoplasia 2 has been reported in recipients after UTx with no previous dysplasia or HPV infection in the donor (
      • Johannesson L.
      • Kvarnstrom N.
      • Molne J.
      • Dahm-Kahler P.
      • Enskog A.
      • Diaz-Garcia C.
      • Olausson M.
      • Brannstrom M.
      Uterus transplantation trial: 1-year outcome.
      ). This observation indicates that HPV vaccination in the recipient and her partner should be encouraged before UTx, and if either the donor or recipient is HPV positive, transplantation should not proceed. This is a limitation on the use of deceased donors as the HPV status is often not known prior to UTx in such cases.

      Surgical considerations

      Recipients

      Surgery in the recipient is traditionally performed by laparotomy and begins in an adjacent operative room before graft retrieval is completed in the donor. Dissection of the vaginal vault from the bladder and rectum is performed first, followed by exposure of the external iliac vessels. In cases of MRKH, the midline rudimentary uterus, above the vaginal vault, must also be cleaved, followed by lateralization of the halves. The uterine graft is placed in the orthotopic position adjacent to the top of the vagina, and end-to-side vascular anastomoses are performed between the internal iliac segments of the graft and the external iliac vessels of recipient. The recipient's vaginal vault is then opened to allow end-to-end anastomosis to the vaginal rim of the graft. Fixation sutures are usually placed, at least between the stumps of the round ligaments of the graft and the sacro-uterine ligaments of the recipient. The average duration of surgery in the recipient is 4–5 h (
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ).
      To date, the risk of at least one complication of grade III or more in recipients according to the Clavien–Dindo classification is 32.4% (n = 22/68), with 23.5% (n = 16/68) resulting in graft removal (
      • Fageeh W.
      • Raffa H.
      • Jabbad H.
      • Marzouki A.
      Transplantation of the human uterus.
      ;
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ;
      • Testa G.
      • Koon E.C.
      • Johannesson L.
      • McKenna G.J.
      • Anthony T.
      • Klintmalm G.B.
      • Gunby R.T.
      • Warren A.M.
      • Putman J.M.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Olausson M.
      Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned From Early Setbacks to Technical Success.
      ). In all but four of the 16 uteri that required removal the cause was surgical complications, thrombosis of the donor uterine vessels or hypoperfusion caused by their small size or arteriosclerosis. The four remaining cases were related to bacterial, fungal or viral infection (
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ;
      • Flyckt R.
      • Kotlyar A.
      • Arian S.
      • Eghtesad B.
      • Falcone T.
      • Tzakis A.
      Deceased donor uterine transplantation.
      ;
      • Chmel R.
      • Novackova M.
      • Janousek L.
      • Matecha J.
      • Pastor Z.
      • Maluskova J.
      • Cekal M.
      • Kristek J.
      • Olausson M.
      • Fronek J.
      Revaluation and lessons learned from the first 9 cases of a Czech uterus transplantation trial: Four deceased donor and 5 living donor uterus transplantations.
      ).
      Other complications have included vaginal stenosis, vesico-vaginal fistula and haemorrhagic shock (
      • Testa G.
      • Koon E.C.
      • Johannesson L.
      • McKenna G.J.
      • Anthony T.
      • Klintmalm G.B.
      • Gunby R.T.
      • Warren A.M.
      • Putman J.M.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Olausson M.
      Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned From Early Setbacks to Technical Success.
      ;
      • Fronek J.
      • Kristek J.
      • Chlupac J.
      • Janousek L.
      • Olausson M.
      Human Uterus Transplantation from Living and Deceased Donors: The Interim Results of the First 10 Cases of the Czech Trial.
      ). Vaginal stenosis, probably caused by discrepancies in the vaginal diameters of the donor and recipient, or thermal sectioning of the vagina and/or circumferential anastomosis, has frequently occurred and has often required re-intervention or stenting (
      • Chmel R.
      • Novackova M.
      • Janousek L.
      • Matecha J.
      • Pastor Z.
      • Maluskova J.
      • Cekal M.
      • Kristek J.
      • Olausson M.
      • Fronek J.
      Revaluation and lessons learned from the first 9 cases of a Czech uterus transplantation trial: Four deceased donor and 5 living donor uterus transplantations.
      ).
      A sufficient vaginal length is necessary to perform a good anastomosis with the graft. Self-dilatation, if feasible, is recommended for all women with MRKH during the years to months before UTx, to create a minimal vaginal length of around 7 cm (
      • Kolle A.
      • Taran F.A.
      • Rall K.
      • Scholler D.
      • Wallwiener D.
      • Brucker S.Y.
      Neovagina creation methods and their potential impact on subsequent uterus transplantation: a review.
      ). Forced dilatation with Vecchietti surgery also appears beneficial (
      • Chmel R.
      • Cekal M.
      • Pastor Z.
      • Chmel Jr., R.
      • Paulasova P.
      • Havlovicova M.
      • Macek Jr., M.
      • Novackova M.
      Assisted reproductive techniques and pregnancy results in women with Mayer-Rokitansky-Kuster-Hauser syndrome undergoing uterus transplantation: the Czech experience.
      ). Both dilatation approaches lead to creation of a vagina with normal epithelium, and most likely a normal bacterial flora. The latter may be of importance for embryo implantation, since the uterine microbiome, in part, mimics the vaginal microbiome (
      • Jones B.P.
      • Saso S.
      • L'Heveder A.
      • Bracewell-Milnes T.
      • Thum M.Y.
      • Diaz-Garcia C.
      • MacIntyre D.A.
      • Quiroga I.
      • Ghaem-Maghami S.
      • Testa G.
      • Johannesson L.
      • Bennett P.R.
      • Yazbek J.
      • Smith J.R.
      The vaginal microbiome in uterine transplantation.
      ). Adequate vaginal access is important for allowing menstruation, cervical biopsies and embryo transfer.
      Appropriate preservation perfusions have to be used to reduce cold ischaemia damage in deceased donors (
      • Ozkan O.
      • Akar M.E.
      • Erdogan O.
      • Ozkan O.
      • Hadimioglu N.
      Uterus transplantation from a deceased donor.
      ). When the duration of cold ischaemia must be prolonged, an extended normothermic ex-vivo reperfusion model could be developed (
      • Padma A.M.
      • Truong M.
      • Jar-Allah T.
      • Song M.J.
      • Oltean M.
      • Brannstrom M.
      • Hellstrom M.
      The development of an extended normothermic ex vivo reperfusion model of the sheep uterus to evaluate organ quality after cold ischemia in relation to uterus transplantation.
      ). Revascularization of half of the uterus when the anastomoses are completed on one side may reduce warm ischaemia damage (
      • Testa G.
      • Koon E.C.
      • Johannesson L.
      • McKenna G.J.
      • Anthony T.
      • Klintmalm G.B.
      • Gunby R.T.
      • Warren A.M.
      • Putman J.M.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Olausson M.
      Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned From Early Setbacks to Technical Success.
      ).
      Robotic graft transplantation could improve postoperative follow-up and reduce scars in recipients. The first case of fully robotic uterus transplantation (including both graft harvest and graft transplantation) was performed in Sweden in October 2021 (unpublished), and that graft was successful (personal communication, Brännström, Gothenburg, Sweden ).
      Unfortunately, contrary to functional markers for other organs (such as creatinine for the kidney), no early biological or radiological marker of uterine function exists. Therefore, evaluation is performed using Doppler ultrasound monitoring of the uterine arteries, size of the uterus and growth of the endometrium, and by assessing the regularity of the menstrual periods.

      Donors

      Living donors

      Living donor surgery is associated with risks of major complications. It is far more complex than a simple hysterectomy because the uterine arteries and veins must be preserved and include segments of the internal iliac artery and vein. Dissection of the uterine veins is complex due to their proximity to the ureters, firm attachment to the paracervical tissue and number of venous branches. Complete ureterolysis is also necessary. Moreover, the preservation of substantial portions of the uterine ligaments, an extensive sheet of bladder peritoneum and part of the vagina is also beneficial for easy uterine fixation in the recipient (
      • Testa G.
      • McKenna G.J.
      • Gunby Jr., R.T.
      • Anthony T.
      • Koon E.C.
      • Warren A.M.
      • Putman J.M.
      • Zhang L.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Klintmalm G.B.
      • Olausson M.
      • Johannesson L.
      First live birth after uterus transplantation in the United States.
      ).
      The typically long duration of living donor surgery has been accompanied by risks including uretero-vaginal fistulae, ureter injury, pyelonephritis, faecal impaction, acute anaemia and vaginal cuff dehiscence (Table 1). Ten of 58 (17.2%) living donors to date have had grade III or higher complications by the Clavien–Dindo classification (
      • Clavien P.A.
      • Barkun J.
      • de Oliveira M.L.
      • Vauthey J.N.
      • Dindo D.
      • Schulick R.D.
      • de Santibanes E.
      • Pekolj J.
      • Slankamenac K.
      • Bassi C.
      • Graf R.
      • Vonlanthen R.
      • Padbury R.
      • Cameron J.L.
      • Makuuchi M.
      The Clavien-Dindo classification of surgical complications: five-year experience.
      ;
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ;
      • Ramani A.
      • Testa G.
      • Ghouri Y.
      • Koon E.C.
      • Di Salvo M.
      • McKenna G.J.
      • Bayer J.
      • Marie Warren A.
      • Wall A.
      • Johannesson L.
      DUETS (Dallas UtErus Transplant Study): Complete report of 6-month and initial 2-year outcomes following open donor hysterectomy.
      ;
      • Johannesson L.
      • Koon E.C.
      • Bayer J.
      • McKenna G.J.
      • Wall A.
      • Fernandez H.
      • Martinez E.J.
      • Gupta A.
      • Ruiz R.
      • Onaca N.
      • Testa G.
      Dallas UtErus Transplant Study: Early Outcomes and Complications of Robot-assisted Hysterectomy for Living Uterus Donors.
      ). Therefore, efforts have focused on simplifying the procedure and increasing safety. Decreased use of thermal energy near the ureter, systematic use of pre- and post-operative ureteric stents for 4–6 weeks, and use of indocyanine green to identify vessels by fluorescence imaging may reduce the risk of ureteral lesions in living donors (
      • Johannesson L.
      • Koon E.C.
      • Bayer J.
      • McKenna G.J.
      • Wall A.
      • Fernandez H.
      • Martinez E.J.
      • Gupta A.
      • Ruiz R.
      • Onaca N.
      • Testa G.
      Dallas UtErus Transplant Study: Early Outcomes and Complications of Robot-assisted Hysterectomy for Living Uterus Donors.
      ). With increasing experience, many teams have replaced laparotomy by laparoscopy, often with robotic assistance (
      • Wei L.
      • Xue T.
      • Tao K.S.
      • Zhang G.
      • Zhao G.Y.
      • Yu S.Q.
      • Cheng L.
      • Yang Z.X.
      • Zheng M.J.
      • Li F.
      • Wang Q.
      • Han Y.
      • Shi Y.Q.
      • Dong H.L.
      • Lu Z.H.
      • Wang Y.
      • Yang H.
      • Ma X.D.
      • Liu S.J.
      • Liu H.X.
      • Xiong L.Z.
      • Chen B.L.
      Modified human uterus transplantation using ovarian veins for venous drainage: the first report of surgically successful robotic-assisted uterus procurement and follow-up for 12 months.
      ;
      • Brannstrom M.
      • Dahm-Kahler P.
      • Kvarnstrom N.
      Robotic-assisted surgery in live-donor uterus transplantation.
      ;
      • Puntambekar S.
      • Puntambekar S.
      • Telang M.
      • Kulkarni P.
      • Date S.
      • Panse M.
      • Sathe R.
      • Agarkhedkar N.
      • Warty N.
      • Kade S.
      • Manchekar M.
      • Chitale M.
      • Parekh H.
      • Parikh K.
      • Mehta M.
      • Kinholkar B.
      • Jana J.S.
      • Pare A.
      • Kanade S.
      • Sadre A.
      • Hardikar S.
      • Jathar A.
      • Bakre T.
      • Chate M.
      • Tiruke R.
      Novel Anastomotic Technique for Uterine Transplant Using Utero-ovarian Veins for Venous Drainage and Internal Iliac Arteries for Perfusion in Two Laparoscopically Harvested Uteri.
      ;
      • Ayoubi J.M.
      • Carbonnel M.
      • Pirtea P.
      • Kvarnstrom N.
      • Brannstrom M.
      • Dahm-Kahler P.
      Laparotomy or minimal invasive surgery in uterus transplantation: a comparison.
      ;
      • Johannesson L.
      • Koon E.C.
      • Bayer J.
      • McKenna G.J.
      • Wall A.
      • Fernandez H.
      • Martinez E.J.
      • Gupta A.
      • Ruiz R.
      • Onaca N.
      • Testa G.
      Dallas UtErus Transplant Study: Early Outcomes and Complications of Robot-assisted Hysterectomy for Living Uterus Donors.
      ;
      • Vieira M.A.
      • Souza C.
      • Nobrega L.
      • Reis R.
      • Andrade C.
      • Schmidt R.
      • Carvalho L.
      Uterine Transplantation with Robot-assisted Uterus Retrieval from Living Donor: First Case in Brazil.
      ), and some have reported fully robotic removal (
      • Wei L.
      • Xue T.
      • Tao K.S.
      • Zhang G.
      • Zhao G.Y.
      • Yu S.Q.
      • Cheng L.
      • Yang Z.X.
      • Zheng M.J.
      • Li F.
      • Wang Q.
      • Han Y.
      • Shi Y.Q.
      • Dong H.L.
      • Lu Z.H.
      • Wang Y.
      • Yang H.
      • Ma X.D.
      • Liu S.J.
      • Liu H.X.
      • Xiong L.Z.
      • Chen B.L.
      Modified human uterus transplantation using ovarian veins for venous drainage: the first report of surgically successful robotic-assisted uterus procurement and follow-up for 12 months.
      ) with faster post-operative recovery times and the same early graft function. However, such comparisons may be confounded as laparotomy cases are typically performed in the initial cases when logistical and surgical competence may not have been fully acquired (
      • Testa G.
      • Koon E.C.
      • Johannesson L.
      • McKenna G.J.
      • Anthony T.
      • Klintmalm G.B.
      • Gunby R.T.
      • Warren A.M.
      • Putman J.M.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Olausson M.
      Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned From Early Setbacks to Technical Success.
      ).
      Additional efforts to simplify UTx and increase safety have included vascular reconstruction, although this has largely been unsuccessful due to the increased risk of thrombosis (
      • Fageeh W.
      • Raffa H.
      • Jabbad H.
      • Marzouki A.
      Transplantation of the human uterus.
      ;
      • Testa G.
      • Koon E.C.
      • Johannesson L.
      • McKenna G.J.
      • Anthony T.
      • Klintmalm G.B.
      • Gunby R.T.
      • Warren A.M.
      • Putman J.M.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Olausson M.
      Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned From Early Setbacks to Technical Success.
      ). Alternatively, the use of ovarian or utero-ovarian veins instead of uterine veins for the venous outflow has been attempted. This approach has since been found to reduce operative time and donor ureteral complications in humans (
      • Wei L.
      • Xue T.
      • Tao K.S.
      • Zhang G.
      • Zhao G.Y.
      • Yu S.Q.
      • Cheng L.
      • Yang Z.X.
      • Zheng M.J.
      • Li F.
      • Wang Q.
      • Han Y.
      • Shi Y.Q.
      • Dong H.L.
      • Lu Z.H.
      • Wang Y.
      • Yang H.
      • Ma X.D.
      • Liu S.J.
      • Liu H.X.
      • Xiong L.Z.
      • Chen B.L.
      Modified human uterus transplantation using ovarian veins for venous drainage: the first report of surgically successful robotic-assisted uterus procurement and follow-up for 12 months.
      ;
      • Puntambekar S.
      • Puntambekar S.
      • Telang M.
      • Kulkarni P.
      • Date S.
      • Panse M.
      • Sathe R.
      • Agarkhedkar N.
      • Warty N.
      • Kade S.
      • Manchekar M.
      • Chitale M.
      • Parekh H.
      • Parikh K.
      • Mehta M.
      • Kinholkar B.
      • Jana J.S.
      • Pare A.
      • Kanade S.
      • Sadre A.
      • Hardikar S.
      • Jathar A.
      • Bakre T.
      • Chate M.
      • Tiruke R.
      Novel Anastomotic Technique for Uterine Transplant Using Utero-ovarian Veins for Venous Drainage and Internal Iliac Arteries for Perfusion in Two Laparoscopically Harvested Uteri.
      ;
      • Testa G.
      • McKenna G.J.
      • Gunby Jr., R.T.
      • Anthony T.
      • Koon E.C.
      • Warren A.M.
      • Putman J.M.
      • Zhang L.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Klintmalm G.B.
      • Olausson M.
      • Johannesson L.
      First live birth after uterus transplantation in the United States.
      ). A team in China used only the ovarian vein in the first case of wholly robotic uterus harvest, completed in 6 h (
      • Wei L.
      • Xue T.
      • Tao K.S.
      • Zhang G.
      • Zhao G.Y.
      • Yu S.Q.
      • Cheng L.
      • Yang Z.X.
      • Zheng M.J.
      • Li F.
      • Wang Q.
      • Han Y.
      • Shi Y.Q.
      • Dong H.L.
      • Lu Z.H.
      • Wang Y.
      • Yang H.
      • Ma X.D.
      • Liu S.J.
      • Liu H.X.
      • Xiong L.Z.
      • Chen B.L.
      Modified human uterus transplantation using ovarian veins for venous drainage: the first report of surgically successful robotic-assisted uterus procurement and follow-up for 12 months.
      ); a team in India, also using the ovarian veins, reported surgical times of 3–4 h, with the donor undergoing laparoscopy (
      • Puntambekar S.
      • Puntambekar S.
      • Telang M.
      • Kulkarni P.
      • Date S.
      • Panse M.
      • Sathe R.
      • Agarkhedkar N.
      • Warty N.
      • Kade S.
      • Manchekar M.
      • Chitale M.
      • Parekh H.
      • Parikh K.
      • Mehta M.
      • Kinholkar B.
      • Jana J.S.
      • Pare A.
      • Kanade S.
      • Sadre A.
      • Hardikar S.
      • Jathar A.
      • Bakre T.
      • Chate M.
      • Tiruke R.
      Novel Anastomotic Technique for Uterine Transplant Using Utero-ovarian Veins for Venous Drainage and Internal Iliac Arteries for Perfusion in Two Laparoscopically Harvested Uteri.
      ,
      • Puntambekar S.
      • Telang M.
      • Kulkarni P.
      • Puntambekar S.
      • Jadhav S.
      • Panse M.
      • Sathe R.
      • Agarkhedkar N.
      • Warty N.
      • Kade S.
      • Manchekar M.
      • Parekh H.
      • Parikh K.
      • Desai R.
      • Mehta M.
      • Chitale M.
      • Kinholkar B.
      • Jana J.S.
      • Pare A.
      • Sadre A.
      • Karnik S.
      • Mane A.
      • Gandhi G.
      • Kanade S.
      • Phadke U.
      Laparoscopic-Assisted Uterus Retrieval From Live Organ Donors for Uterine Transplant: Our Experience of Two Patients.
      ); and an American team reported a live birth after the use of laparotomy and only ovarian veins following an 8 h operation for the donor (
      • Jarvholm S.
      • Warren A.M.
      • Jalmbrant M.
      • Kvarnstrom N.
      • Testa G.
      • Johannesson L.
      Preoperative psychological evaluation of uterus transplant recipients, partners, and living donors: Suggested framework.
      ;
      • Ramani A.
      • Testa G.
      • Ghouri Y.
      • Koon E.C.
      • Di Salvo M.
      • McKenna G.J.
      • Bayer J.
      • Marie Warren A.
      • Wall A.
      • Johannesson L.
      DUETS (Dallas UtErus Transplant Study): Complete report of 6-month and initial 2-year outcomes following open donor hysterectomy.
      ).
      These reported successes with ovarian veins require further investigation to confirm that adequate uterine drainage and support of implantation and pregnancy are provided without complications. If confirmed, this approach could significantly simplify and shorten the procedure in living donors. However, these advantages must be balanced against the risk of oophorectomy and early menopause for younger donors (a Clavien–Dindo grade II complication), although this may be reduced if only ovarian veins proximal to the ovaries are used (
      • Testa G.
      • Koon E.C.
      • Johannesson L.
      • McKenna G.J.
      • Anthony T.
      • Klintmalm G.B.
      • Gunby R.T.
      • Warren A.M.
      • Putman J.M.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Olausson M.
      Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned From Early Setbacks to Technical Success.
      ).

      Deceased donors

      In deceased donors, uterine removal is facilitated by larger vessels as the dissection can include major parts of the internal arteries and veins and the complicated ureterolysis is not necessary. The ureters can be transected above the ureteric tunnel and close to the bladder, to be included in the uterine vessel-containing parametrial tissue. However, other problems may be encountered, such as: increased cold ischaemia time due to transportation of the organ, which may affect the graft quality; increased risk of haemorrhage when transplantation is performed due to the presence of small, unsealed vessels around the uterus; increased potential for rejection (particularly in non-related donors); decreased functionality due to unknown uterine pathology; and organizational challenges due to any unplanned surgery.

      Immunosuppression therapy and monitoring for graft rejection

      Immunosuppression therapy

      No data currently exist regarding the long-term risk of immunosuppressive therapy in women undergoing UTx. However, a general recommendation is graft removal within 6–7 years to reduce the long-term risks, especially nephrotoxicity and immunosuppression.
      Immunosuppressive treatment is like that used with kidney grafts. Early experience in the Swedish trial involved treatment with methylprednisolone (500 mg i.v. on day 0), anti-thymoglobulins (2.5 mg/kg on day 0 and day 1), mycophenolate mofetil (MMF) for 8 months, continuous tacrolimus but with higher trough concentrations during the initial 2 months, and prednisone for 1 week after UTx or in cases of rejection (
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ). As MMF is fetotoxic, switching to azathioprine 2 months before the embryo transfer is recommended (
      • Hoeltzenbein M.
      • Elefant E.
      • Vial T.
      • Finkel-Pekarsky V.
      • Stephens S.
      • Clementi M.
      • Allignol A.
      • Weber-Schoendorfer C.
      • Schaefer C.
      Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services.
      ;
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ). Indeed, more recent protocols eliminate the use of MMF entirely by using azathioprine directly at the time of UTx and waiting only 4 months before embryo transfer (
      • Testa G.
      • McKenna G.J.
      • Gunby Jr., R.T.
      • Anthony T.
      • Koon E.C.
      • Warren A.M.
      • Putman J.M.
      • Zhang L.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Klintmalm G.B.
      • Olausson M.
      • Johannesson L.
      First live birth after uterus transplantation in the United States.
      ;
      • Johannesson L.
      • Wall A.
      • Putman J.M.
      • Zhang L.
      • Testa G.
      • Diaz-Garcia C.
      Rethinking the time interval to embryo transfer after uterus transplantation - DUETS (Dallas UtErus Transplant Study).
      ).

      Monitoring rejection

      Signs of rejection occur most commonly during the first 3–8 months after UTx (
      • Molne J.
      • Broecker V.
      • Ekberg J.
      • Nilsson O.
      • Dahm-Kahler P.
      • Brannstrom M.
      Monitoring of Human Uterus Transplantation With Cervical Biopsies: A Provisional Scoring System for Rejection.
      ). Rejections are almost invariably asymptomatic and so must be closely monitored by assessing the presence of DSA in the peripheral blood, and by regular cervical biopsies. Using the uterine graft primate model (
      • Johannesson L.
      • Enskog A.
      • Molne J.
      • Diaz-Garcia C.
      • Hanafy A.
      • Dahm-Kahler P.
      • Tekin A.
      • Tryphonopoulos P.
      • Morales P.
      • Rivas K.
      • Ruiz P.
      • Tzakis A.
      • Olausson M.
      • Brannstrom M.
      Preclinical report on allogeneic uterus transplantation in non-human primates.
      ), three grades of rejection have been established based on lymphocyte invasion. The overall risk of some degree of rejection following UTx is currently high, although none has resulted in graft removal, and the majority were resolved with additional corticoids (
      • Molne J.
      • Broecker V.
      • Ekberg J.
      • Nilsson O.
      • Dahm-Kahler P.
      • Brannstrom M.
      Monitoring of Human Uterus Transplantation With Cervical Biopsies: A Provisional Scoring System for Rejection.
      ).

      Risks of infection

      As with other solid organ transplantations, the risk of infection within the first 6 months after transplantation is high, but with UTx this risk also exists during pregnancy due to associated physiological immunomodulation. Removal of grafts for uterine abscess, herpes simplex virus and candida (
      • Brannstrom M.
      • Johannesson L.
      • Dahm-Kahler P.
      • Enskog A.
      • Molne J.
      • Kvarnstrom N.
      • Diaz-Garcia C.
      • Hanafy A.
      • Lundmark C.
      • Marcickiewicz J.
      • Gabel M.
      • Groth K.
      • Akouri R.
      • Eklind S.
      • Holgersson J.
      • Tzakis A.
      • Olausson M.
      First clinical uterus transplantation trial: a six-month report.
      ;
      • Flyckt R.
      • Kotlyar A.
      • Arian S.
      • Eghtesad B.
      • Falcone T.
      • Tzakis A.
      Deceased donor uterine transplantation.
      ;
      • Chmel R.
      • Novackova M.
      • Janousek L.
      • Matecha J.
      • Pastor Z.
      • Maluskova J.
      • Cekal M.
      • Kristek J.
      • Olausson M.
      • Fronek J.
      Revaluation and lessons learned from the first 9 cases of a Czech uterus transplantation trial: Four deceased donor and 5 living donor uterus transplantations.
      ), as well as for a septic abortion (Escherichia coli), has been reported (
      • Fronek J.
      • Kristek J.
      • Chlupac J.
      • Janousek L.
      • Olausson M.
      Human Uterus Transplantation from Living and Deceased Donors: The Interim Results of the First 10 Cases of the Czech Trial.
      ). CMV infections have also occurred both with and without pre-transplant mismatches (D+, R–), albeit with some favourable results following treatment (
      • Rosenzweig M.
      • Wall A.
      • Spak C.W.
      • Testa G.
      • Johannesson L.
      Pregnancy after CMV infection following uterus transplantation: A case report from the Dallas Uterus Transplant Study.
      ). Of note, most infections could be prevented by prophylactic antimicrobial therapy (e.g. 6 months of trimethoprim sulfamethoxazole to prevent Toxoplasma gondii, Nocardia, Pneumocystis and Listeria, aciclovir/valganciclovir prophylaxis for 3–6 months to prevent CMV, and antifungal prophylaxis). Although the uterus graft is transitory and so the life-time infection risk should be low, data to assess overall probability of this risk are currently lacking.

      Pregnancy

      Challenges relating to IVF

      Due to the absence of the oviducts, pregnancy cannot be achieved by intercourse and so must involve use of IVF embryos frozen for use in a subsequent cryopreservation–thaw cycle.
      In all cases to date, the first IVF cycle has been performed before UTx surgery because of the increased risks of infectious and haemorrhagic complications of oocyte harvesting, due to immunosuppressive therapy and the altered vascular anatomy of the pelvis, as well for the assurance of a sufficient number of frozen embryos to warrant a UTx. Many teams require a minimum of 8–10 frozen embryos, which typically requires two pre-UTx IVF cycles (
      • Brännström M.
      • Dahm-Kähler P.
      • Kvarnström N.
      • Enskog A.
      • Olofsson J.I.
      • Olausson M.
      • Mölne J.
      • Akouri R.
      • Järvholm S.
      • Nilsson L.
      • Stigson L.
      • Hagberg H.
      • Bokström H.
      Reproductive, obstetrical and long-term health outcome after uterus transplantation: results of the first clinical trial.
      ). Nevertheless, in a few cases additional IVF cycles have been performed after UTx without complications (
      • Brucker S.Y.
      • Strowitzki T.
      • Taran F.A.
      • Rall K.
      • Scholler D.
      • Hoopmann M.
      • Henes M.
      • Guthoff M.
      • Heyne N.
      • Zipfel S.
      • Schaffeler N.
      • Bosmuller H.
      • Fend F.
      • Rosenberger P.
      • Heim E.
      • Wiesing U.
      • Nikolaou K.
      • Fleischer S.
      • Bakchoul T.
      • Poets C.F.
      • Goelz R.
      • Wiechers C.
      • Kagan K.O.
      • Kramer B.
      • Reisenauer C.
      • Oberlechner E.
      • Hubner S.
      • Abele H.
      • Dahm-Kahler P.
      • Kvarnstrom N.
      • Brannstrom M.
      • Nadalin S.
      • Wallwiener D.
      • Konigsrainer A.
      Living-Donor Uterus Transplantation: Pre-, Intra-, and Postoperative Parameters Relevant to Surgical Success, Pregnancy, and Obstetrics with Live Births.
      ;
      • Brännström M.
      • Dahm-Kähler P.
      • Kvarnström N.
      • Enskog A.
      • Olofsson J.I.
      • Olausson M.
      • Mölne J.
      • Akouri R.
      • Järvholm S.
      • Nilsson L.
      • Stigson L.
      • Hagberg H.
      • Bokström H.
      Reproductive, obstetrical and long-term health outcome after uterus transplantation: results of the first clinical trial.
      ), either because no pre-UTx embryos remained or, in one case, because the couple separated within a year after transplantation. Although this has not yet been undertaken, it may be prudent for prospective UTx recipients to cryopreserve some oocytes in case of separation from their partner before embryo transfer. This could also be an option for single women.
      As in standard clinical IVF for fertility treatment, ovarian stimulation protocols have varied among teams and patients. However, trans-abdominal retrieval may be required in those women with MRKH who have a high localization of the ovaries. In the Swedish laparotomy (
      • Brännström M.
      • Dahm-Kähler P.
      • Kvarnström N.
      • Enskog A.
      • Olofsson J.I.
      • Olausson M.
      • Mölne J.
      • Akouri R.
      • Järvholm S.
      • Nilsson L.
      • Stigson L.
      • Hagberg H.
      • Bokström H.
      Reproductive, obstetrical and long-term health outcome after uterus transplantation: results of the first clinical trial.
      ) and robotic (
      • Brannstrom M.
      • Dahm-Kahler P.
      • Ekberg J.
      • Akouri R.
      • Groth K.
      • Enskog A.
      • Broecker V.
      • Molne J.
      • Ayoubi J.M.
      • Kvarnstrom N.
      Outcome of Recipient Surgery and 6-Month Follow-Up of the Swedish Live Donor Robotic Uterus Transplantation Trial.
      ) trials, 4 out of 9 and 1 of 8 patients, respectively, underwent oocyte retrieval transabdominally.
      The original recommendation of 1 year between UTx and embryo transfer is now being questioned (
      • Johannesson L.
      • Wall A.
      • Putman J.M.
      • Zhang L.
      • Testa G.
      • Diaz-Garcia C.
      Rethinking the time interval to embryo transfer after uterus transplantation - DUETS (Dallas UtErus Transplant Study).
      ). The Dallas team shortened the interval to 6 months, and then reduced this further to 4 months (
      • Testa G.
      • McKenna G.J.
      • Gunby Jr., R.T.
      • Anthony T.
      • Koon E.C.
      • Warren A.M.
      • Putman J.M.
      • Zhang L.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Klintmalm G.B.
      • Olausson M.
      • Johannesson L.
      First live birth after uterus transplantation in the United States.
      ;
      • Johannesson L.
      • Wall A.
      • Putman J.M.
      • Zhang L.
      • Testa G.
      • Diaz-Garcia C.
      Rethinking the time interval to embryo transfer after uterus transplantation - DUETS (Dallas UtErus Transplant Study).
      ) with no complications to either mother or fetus. Hence, the timing of embryo transfers may reasonably be standardized to 6 months post-UTx providing the recipient has good post-operative recovery, resumption of uterine function with a return of menstrual cyclicity within 2–3 months and no sign of rejection or infection, and is on immunosuppressive treatment compatible with pregnancy (
      • Johannesson L.
      • Kvarnstrom N.
      • Molne J.
      • Dahm-Kahler P.
      • Enskog A.
      • Diaz-Garcia C.
      • Olausson M.
      • Brannstrom M.
      Uterus transplantation trial: 1-year outcome.
      ;
      • Chmel R.
      • Novackova M.
      • Janousek L.
      • Matecha J.
      • Pastor Z.
      • Maluskova J.
      • Cekal M.
      • Kristek J.
      • Olausson M.
      • Fronek J.
      Revaluation and lessons learned from the first 9 cases of a Czech uterus transplantation trial: Four deceased donor and 5 living donor uterus transplantations.
      ). This standardization could provide the emotional benefit of a shorter time to pregnancy, and reduce the time with the graft and any potential long-term risks of immunosuppressive therapy.
      The embryo transfer procedure per se has typically not varied among UTx recipients, except when there is vaginal stricture, in which case dilatation and stent insertion may be necessary. Transfer of a single embryo is mandatory to avoid multiple pregnancies and the associated increased risks of obstetric complications. In the first Swedish trial, the mean number of transfers was six per patient, the pregnancy rate per embryo transfer was 32% and the live birth rate per transfer was 19.6% in the seven women with viable grafts (
      • Brännström M.
      • Dahm-Kähler P.
      • Kvarnström N.
      • Enskog A.
      • Olofsson J.I.
      • Olausson M.
      • Mölne J.
      • Akouri R.
      • Järvholm S.
      • Nilsson L.
      • Stigson L.
      • Hagberg H.
      • Bokström H.
      Reproductive, obstetrical and long-term health outcome after uterus transplantation: results of the first clinical trial.
      ). The transfers involved cleavage-stage embryos, which probably contributed to the overall lower implantation rate per embryo. The cumulative live birth rate for successful transplants ranged from 71% to 85.7% and for the attempted UTx procedures it ranged from 50% to 55% in the biggest series to date (
      • Fronek J.
      • Kristek J.
      • Chlupac J.
      • Janousek L.
      • Olausson M.
      Human Uterus Transplantation from Living and Deceased Donors: The Interim Results of the First 10 Cases of the Czech Trial.
      ;
      • Johannesson L.
      • Testa G.
      • Putman J.M.
      • McKenna G.J.
      • Koon E.C.
      • York J.R.
      • Bayer J.
      • Zhang L.
      • Rubeo Z.S.
      • Gunby R.T.
      • Gregg A.R.
      Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study.
      ;
      • Brännström M.
      • Dahm-Kähler P.
      • Kvarnström N.
      • Enskog A.
      • Olofsson J.I.
      • Olausson M.
      • Mölne J.
      • Akouri R.
      • Järvholm S.
      • Nilsson L.
      • Stigson L.
      • Hagberg H.
      • Bokström H.
      Reproductive, obstetrical and long-term health outcome after uterus transplantation: results of the first clinical trial.
      ). Despite these promising statistics, repeated implantation failures or miscarriages were observed in some women (
      • Ozkan O.
      • Dogan N.U.
      • Ozkan O.
      • Mendilcioglu I.
      • Dogan S.
      • Aydinuraz B.
      • Simsek M.
      Uterus transplantation: From animal models through the first heart beating pregnancy to the first human live birth.
      ;
      • Fronek J.
      • Kristek J.
      • Chlupac J.
      • Janousek L.
      • Olausson M.
      Human Uterus Transplantation from Living and Deceased Donors: The Interim Results of the First 10 Cases of the Czech Trial.
      ;
      • Ozkan O.
      • Ozkan O.
      • Dogan N.U.
      • Bahceci M.
      • Mendilcioglu I.
      • Boynukalin K.
      • Ongun H.
      • Kantarci A.M.
      • Yaprak M.
      • Cengiz M.
      • Hadimioglu N.
      • Kafadar Y.T.
      • Celik K.
      Birth of a Healthy Baby 9 years after a Surgically Successful Deceased Donor Uterus Transplant.
      ;
      • Brännström M.
      • Dahm-Kähler P.
      • Kvarnström N.
      • Enskog A.
      • Olofsson J.I.
      • Olausson M.
      • Mölne J.
      • Akouri R.
      • Järvholm S.
      • Nilsson L.
      • Stigson L.
      • Hagberg H.
      • Bokström H.
      Reproductive, obstetrical and long-term health outcome after uterus transplantation: results of the first clinical trial.
      ), indicating that research is needed to investigate and prevent them.

      Gestational complications

      Forty-six pregnancies have led to 34 healthy children. Of the 12 miscarriages, six were experienced by one patient in the Swedish laparotomy trial of 2013 (
      • Brännström M.
      • Dahm-Kähler P.
      • Kvarnström N.
      • Enskog A.
      • Olofsson J.I.
      • Olausson M.
      • Mölne J.
      • Akouri R.
      • Järvholm S.
      • Nilsson L.
      • Stigson L.
      • Hagberg H.
      • Bokström H.
      Reproductive, obstetrical and long-term health outcome after uterus transplantation: results of the first clinical trial.
      ). There have been no reported stillbirths, and no neonates of low birthweight for gestational age. There is one reported case of a congenital malformation, which was an anteriorly/caudally displaced urethra, with urethral reimplantation undertaken at the age of 11 months (
      • Johannesson L.
      • Testa G.
      • Putman J.M.
      • McKenna G.J.
      • Koon E.C.
      • York J.R.
      • Bayer J.
      • Zhang L.
      • Rubeo Z.S.
      • Gunby R.T.
      • Gregg A.R.
      Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study.
      ). There have been complications including pre-eclampsia (n = 6, including our French patient who had a single kidney), gestational hypertension (n = 2), placenta praevia (n = 3), placenta accreta with impaired renal function (n = 1), premature rupture of membranes (n = 3), gestational diabetes (n = 3), cholestasis (n = 2), preterm labour (n = 5), subchorionic hematomas (n = 2), oligohydramnios (n = 1), polyhydramnios (n = 2) and pyelonephritis (n = 1) (
      • Brannstrom M.
      • Belfort M.A.
      • Ayoubi J.M.
      Uterus transplantation worldwide: clinical activities and outcomes.
      ;
      • Ozkan O.
      • Ozkan O.
      • Dogan N.U.
      • Bahceci M.
      • Mendilcioglu I.
      • Boynukalin K.
      • Ongun H.
      • Kantarci A.M.
      • Yaprak M.
      • Cengiz M.
      • Hadimioglu N.
      • Kafadar Y.T.
      • Celik K.
      Birth of a Healthy Baby 9 years after a Surgically Successful Deceased Donor Uterus Transplant.
      ;
      • Richards E.G.
      • Farrell R.M.
      • Ricci S.
      • Perni U.
      • Quintini C.
      • Tzakis A.
      • Falcone T.
      Uterus transplantation: state of the art in 2021.
      ). The risks of such varied complications require the involvement of a multidisciplinary team, including nephrologists. Moreover, careful monitoring and adaptation of immunosuppressive therapy is necessary because of variations in the immune response during pregnancy. Particular attention must also be given to risk of infection, with regular vaginal swabs included in the routine care.

      Delivery

      Because UTx recipients do not feel contractions due to the absence of uterine innervation (
      • Chmel R.
      • Cekal M.
      • Pastor Z.
      • Chmel Jr., R.
      • Paulasova P.
      • Havlovicova M.
      • Macek Jr., M.
      • Novackova M.
      Assisted reproductive techniques and pregnancy results in women with Mayer-Rokitansky-Kuster-Hauser syndrome undergoing uterus transplantation: the Czech experience.
      ), the risk of premature delivery must be monitored with special attention. However, even with such monitoring, the incidence of prematurity is high. Overall mean gestational age among all the reported deliveries was 34 + 3 weeks (
      • Richards E.G.
      • Farrell R.M.
      • Ricci S.
      • Perni U.
      • Quintini C.
      • Tzakis A.
      • Falcone T.
      Uterus transplantation: state of the art in 2021.
      ). In the largest series of 12 births, the mean gestational age at birth was 36 + 6 (range 30 + 6 to 38 + 0) weeks (
      • Johannesson L.
      • Testa G.
      • Putman J.M.
      • McKenna G.J.
      • Koon E.C.
      • York J.R.
      • Bayer J.
      • Zhang L.
      • Rubeo Z.S.
      • Gunby R.T.
      • Gregg A.R.
      Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study.
      ). Deliveries are performed by Caesarean section due to the risk of uterine rupture and have been mainly uneventful, although one case of placenta accreta has been described (
      • Flyckt R.
      • Falcone T.
      • Quintini C.
      • Perni U.
      • Eghtesad B.
      • Richards E.G.
      • Farrell R.M.
      • Hashimoto K.
      • Miller C.
      • Ricci S.
      • Ferrando C.
      • D'Amico G.
      • Maikhor S.
      • Priebe D.
      • Chiesa-Vottero A.
      • Heerema-McKenney A.
      • Mawhorter S.
      • Feldman M.
      • Tzakis A.
      First birth from a deceased donor uterus in the United States: from severe graft rejection to successful cesarean delivery.
      ). Delivery can be combined with hysterectomy if the woman does not desire more children. Of note, although a maximum of two pregnancies is currently considered the upper limit allowable, only four recipients have delivered two children to date, so the safety of two or more deliveries from one transplant is currently uncertain.
      It is ideal for maternal-fetal medicine specialists to be part of the team from the outset and be available to follow the pregnancy and perform the Caesarean section with the UTx surgeons.

      Psychological considerations

      Extensive psychological evaluation must be part of the screening process. As with all medical procedures, informed consent is required. However, three people must consent when using a live donor: the recipient, her partner and the donor. In cases involving a relative, potential complicated feelings of obligation and pressure must be carefully considered using counselling. Live donors and recipients must also be resilient in case of failure of the UTx or complications.
      Aside from the emotional aspects surrounding donation, all involved parties must understand the intense nature of the surgical and medical treatments involved. Strict adherence to medical follow-up must be agreed to for at least 6 months by live donors, and for the duration of graft retention and for at least a year post-hysterectomy by recipients. Recipients must take daily immunosuppressive medications for years with regular medical appointments and blood tests, and be careful to avoid infections. Regular psychological support is therefore essential throughout the process and most likely for some years after hysterectomy.
      The Swedish team developed a psychological pre-transplantation assessment programme (
      • Jarvholm S.
      • Johannesson L.
      • Brannstrom M.
      Psychological aspects in pre-transplantation assessments of patients prior to entering the first uterus transplantation trial.
      ) and evaluated the psychological state of live donors and recipients after transplantation. Compared with baseline, the recipients and their partners showed similar or better scores up to 3 years after UTx. Understandably, recipients with graft failure and failure to achieve parenthood had worse scores (
      • Jarvholm S.
      • Dahm-Kahler P.
      • Kvarnstrom N.
      • Brannstrom M.
      Psychosocial outcomes of uterine transplant recipients and partners up to 3 years after transplantation: results from the Swedish trial.
      ), and donors with unsuccessful outcomes had worse scores for health-related, quality of life, mood and relationship issues (
      • Jarvholm S.
      • Kvarnstrom N.
      • Dahm-Kahler P.
      • Brannstrom M.
      Donors' health-related quality-of-life and psychosocial outcomes 3 years after uterus donation for transplantation.
      ).

      Ethical questions

      From the outset of UTx, ethical questions have been raised regarding the need for this transplant surgery, the most common being that the uterus is not a vital organ, its sole raison d’être being to enable women to gestate. Indeed, UTx incurs real risks for live donors and the recipients, as well as a risk of prematurity for the offspring. However, childbearing is considered central to maternal, paternal and even extended family bonding to the baby to be born.
      Alternatives to UTx are childlessness, adoption or gestational surrogacy. A survey in Japan indicated that the lay public would choose UTx (34.4%), gestational surrogacy (31.9%) or adoption (40.3%) if there were AUFI (
      • Nakazawa A.
      • Hirata T.
      • Arakawa T.
      • Nagashima N.
      • Fukuda S.
      • Neriishi K.
      • Harada M.
      • Hirota Y.
      • Koga K.
      • Wada-Hiraike O.
      • Koizumi Y.
      • Fujii T.
      • Irahara M.
      • Osuga Y.
      A survey of public attitudes toward uterus transplantation, surrogacy, and adoption in Japan.
      ). Adoption is a long and difficult process. Although gestational surrogacy is perhaps the most common alternative to UTx, it is considered ethically problematic, and is unregulated in most countries and banned in many others (
      • Kisu I.
      • Banno K.
      • Mihara M.
      • Iida T.
      • Yoshimura Y.
      Current status of surrogacy in Japan and uterine transplantation research.
      ). Even in the USA, where gestational surrogacy is widely practised in most states, public acceptance of UTx appears to be high. A survey published 4 years after the first UTx birth revealed that 78% of respondents would support the practice, while only 4% would oppose it. Quite surprisingly, a full 45% of respondents believe that UTx should be covered by health insurance (
      • Hariton E.
      • Bortoletto P.
      • Goldman R.H.
      • Farland L.V.
      • Ginsburg E.S.
      • Gargiulo A.R.
      A Survey of Public Opinion in the United States Regarding Uterine Transplantation.
      ).
      Similarly, a survey among healthcare professionals in the UK revealed that a great majority support UTx medically and consider it ethically appropriate (
      • Saso S.
      • Clarke A.
      • Bracewell-Milnes T.
      • Al-Memar M.
      • Hamed A.H.
      • Thum M.Y.
      • Ghaem-Maghami S.
      • Del Priore G.
      • Smith J.R.
      Survey of perceptions of health care professionals in the United Kingdom toward uterine transplant.
      ). A more recent survey of US fertility specialists and gynaecological surgeons confirmed majority support of UTx (58%), with the most common ethical concerns relating to medical/surgical complications for the recipient (
      • Hariton E.
      • Bortoletto P.
      • Goldman R.H.
      • Farland L.V.
      • Ginsburg E.S.
      • Gargiulo A.R.
      A Survey of Public Opinion in the United States Regarding Uterine Transplantation.
      ).
      The removal of ethical barriers for the advancement of UTx from experimental status to current clinical practice includes decreasing risks to live donors by further optimizing uterine removal. Nevertheless, the potential for abuse involving trading and financial reward for donation exists and must be fought. An extension of UTx for men transitioning to women raises other complex ethical questions and is being discussed although not yet performed (
      • Jones B.P.
      • Williams N.J.
      • Saso S.
      • Thum M.Y.
      • Quiroga I.
      • Yazbek J.
      • Wilkinson S.
      • Ghaem-Maghami S.
      • Thomas P.
      • Smith J.R.
      Uterine transplantation in transgender women.
      ). The Montreal criteria, updated in 2013, have been published to try to define the indications and limits of UTx candidates (
      • Lefkowitz A.
      • Edwards M.
      • Balayla J.
      Ethical considerations in the era of the uterine transplant: an update of the Montreal Criteria for the Ethical Feasibility of Uterine Transplantation.
      ). As limitations, coupled with advances, may evolve, an ethical reflection will be mandatory in parallel to technical progress (
      • Farrell R.M.
      • Johannesson L.
      • Flyckt R.
      • Richards E.G.
      • Testa G.
      • Tzakis A.
      • Falcone T.
      Evolving ethical issues with advances in uterus transplantation.
      ).
      High overall costs of UTx may seriously limit its development and application. In Sweden, an estimated $69,000 are needed to cover the pre-surgical work-up of a live donor and the recipient, the IVF, UTx and 2 months of post-operative follow-up for the two patients (
      • Davidson T.
      • Ekberg J.
      • Sandman L.
      • Brannstrom M.
      The costs of human uterus transplantation: a study based on the nine cases of the initial Swedish live donor trial.
      ). However, the actual cost is higher due to the costs of long-term medication and medical follow-up, which may involve high-risk obstetric care and Caesarean section. Some centres in the USA are offering the procedure outside experimental protocols for a cost of around $250,000. The cost of surrogacy in the USA is within the range $75,000–$120,000 (
      • Blake V.K.
      Financing uterus transplants: The United States context.
      ).
      When UTx becomes a mainstream clinical practice, it remains to be seen whether the costs will be covered by public health, national/private health insurance systems or directly by the patient (
      • Polk H.
      • Johannesson L.
      • Testa G.
      • Wall A.E.
      The Future of Uterus Transplantation: Cost, Regulations, and Outcomes.
      ). The question must be asked of whether it is justified to divert funding from healthcare systems to support the high costs of this non-vital transplantation procedure, particularly in settings of limited medical financial resources. On the other hand, in countries that widely cover assisted reproductive technology, UFI patients may have clear claims of a right to access UTx: relative to other patients with infertility, patients with UFI were left without clinical treatments until UTx was introduced and have had to either forego reproduction or pay out of pocket for surrogacy or adoption (
      • Blake V.K.
      Financing uterus transplants: The United States context.
      ).

      Increasing access to UTx and standardizing care

      Increasing the donor pool

      A central challenge to translating UTx into mainstream clinical practice concerns the availability of donors. Several possible ways in which the donor pool could be expanded include the following.
      The first group is women with a normal uterus who require a hysterectomy for an unrelated reason. For example, in cases of female-to-male transitioning, 84% of individuals reported that they would volunteer for donation (
      • Api M.
      • Boza A.
      • Ceyhan M.
      Could the female-to-male transgender population be donor candidates for uterus transplantation?.
      ). This is a particularly interesting possibility in view of advances in minimally invasive UTx surgery resulting in reductions in the duration, complications and post-operative recovery. However, this group are often treated with high doses of androgens for prolonged periods before surgery, which may affect the functionality of the uterus.
      The second possibility is altruistic donation by women who otherwise do not require a hysterectomy. A US survey found that 70% of US women were willing to donate their uterus in 2016, only 2 years after the first birth following UTx (
      • Rodrigue J.R.
      • Tomich D.
      • Fleishman A.
      • Glazier A.K.
      Vascularized Composite Allograft Donation and Transplantation: A Survey of Public Attitudes in the United States.
      ). However, the willingness for such altruistic donation must be weighed against the risks of a complex donor hysterectomy, which hopefully will be minimized in the future with the introduction of robotics.
      Third, there could be reuse of a uterus from another recipient. However, the risks of rejection by the new recipient are currently unknown (
      • Yeo S.M.
      • Kim Y.
      • Kang S.S.
      • Park W.Y.
      • Jin K.
      • Park S.B.
      • Park U.J.
      • Kim H.T.
      • Cho W.H.
      • Han S.
      Long-term Clinical Outcomes of Kidney Re-transplantation.
      ).
      Fourth, live donors aged over 60 years or at 5 years after menopause could be accepted if a pre-surgery evaluation of their uterine vessels deemed them appropriate. Magnetic resonance imaging, including magnetic resonance angiography (MRA), is the initial modality to examine potential UTx donors to acquire valuable details regarding the uterine anatomy, and if the uterine arteries are fully visualized, there is no need for further angiographic methods involving radiation. However, in about 50% of cases the uterine arteries are not well visualized by MRA, and so computed tomography angiography should be performed to evaluate uterine arteriosclerotic lesions. In selected cases, digital subtraction angiography with the addition of an invasive modality may be required (
      • Leonhardt H.
      • Thilander-Klang A.
      • Bath J.
      • Johannesson M.
      • Kvarnstrom N.
      • Dahm-Kahler P.
      • Brannstrom M.
      Imaging evaluation of uterine arteries in potential living donors for uterus transplantation: a comparative study of MRA, CTA, and DSA.
      ).
      Fifth, the administration of oestrogen treatment for a few months before UTx might improve graft quality even years after menopause.
      Sixth, the donor age could be lowered. A precedent for this has already been set in the Dallas trial (
      • Testa G.
      • Koon E.C.
      • Johannesson L.
      • McKenna G.J.
      • Anthony T.
      • Klintmalm G.B.
      • Gunby R.T.
      • Warren A.M.
      • Putman J.M.
      • dePrisco G.
      • Mitchell J.M.
      • Wallis K.
      • Olausson M.
      Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned From Early Setbacks to Technical Success.
      ), which included 17 pre-menopausal altruistic donors. However, in such cases, extensive psychological evaluation regarding an irreversible loss of infertility is mandatory to be certain that donors would not later regret their loss of childbearing.
      Finally, women with two or more Caesarean sections could be included, although to date, only one team has allowed this approach (
      • Johannesson L.
      • Testa G.
      • Putman J.M.
      • McKenna G.J.
      • Koon E.C.
      • York J.R.
      • Bayer J.
      • Zhang L.
      • Rubeo Z.S.
      • Gunby R.T.
      • Gregg A.R.
      Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study.
      ). Screening would need to include evaluation of the thickness of the lower uterine segment to exclude those with a thin niche after Caesarean section.

      Developing a new UTx centre

      Starting a new UTx programme is complex. An optimal setting and meticulous preparation are necessary for the responsible introduction of UTx (
      • Moore F.D.
      Ethical problems special to surgery: surgical teaching, surgical innovation, and the surgeon in managed care.
      ;
      • McCulloch P.
      • Altman D.G.
      • Campbell W.B.
      • Flum D.R.
      • Glasziou P.
      • Marshall J.C.
      • Nicholl J.
      • Balliol C.
      • Aronson J.K.
      • Barkun J.S.
      • Blazeby J.M.
      • Boutron I.C.
      • Campbell W.B.
      • Clavien P.A.
      • Cook J.A.
      • Ergina P.L.
      • Feldman L.S.
      • Flum D.R.
      • Maddern G.J.
      • Nicholl J.
      • Reeves B.C.
      • Seiler C.M.
      • Strasberg S.M.
      • Meakins J.L.
      • Ashby D.
      • Black N.
      • Bunker J.
      • Burton M.
      • Campbell M.
      • Chalkidou K.
      • Chalmers I.
      • de Leval M.
      • Deeks J.
      • Ergina P.L.
      • Grant A.
      • Gray M.
      • Greenhalgh R.
      • Jenicek M.
      • Kehoe S.
      • Lilford R.
      • Littlejohns P.
      • Loke Y.
      • Madhock R.
      • McPherson K.
      • Meakins J.
      • Rothwell P.
      • Summerskill B.
      • Taggart D.
      • Tekkis P.
      • Thompson M.
      • Treasure T.
      • Trohler U.
      • Vandenbroucke J.
      No surgical innovation without evaluation: the IDEAL recommendations.
      ). Much advanced preparation is needed, including surgical training on large animal models (
      • Favre-Inhofer A.
      • Carbonnel M.
      • Revaux A.
      • Sandra O.
      • Mougenot V.
      • Bosc R.
      • Gelin V.
      • Rafii A.
      • Hersant B.
      • Vialard F.
      • Chavatte-Palmer P.
      • Richard C.
      • Ayoubi J.M.
      Critical steps for initiating an animal uterine transplantation model in sheep: Experience from a case series.
      ). Indeed, prior to performing the first UTx procedure in a woman, the Swedish team worked on rodents (
      • Racho El-Akouri R.
      • Kurlberg G.
      • Brannstrom M.
      Successful uterine transplantation in the mouse: pregnancy and post-natal development of offspring.
      ) and then pigs (
      • Wranning C.A.
      • El-Akouri R.R.
      • Lundmark C.
      • Dahm-Kahler P.
      • Molne J.
      • Enskog A.
      • Brannstrom M.
      Auto-transplantation of the uterus in the domestic pig (Sus scrofa): Surgical technique and early reperfusion events.
      ), sheep (
      • Wranning C.A.
      • Dahm-Kahler P.
      • Molne J.
      • Nilsson U.A.
      • Enskog A.
      • Brannstrom M.
      Transplantation of the uterus in the sheep: oxidative stress and reperfusion injury after short-time cold storage.
      ) and baboons (
      • Enskog A.
      • Johannesson L.
      • Chai D.C.
      • Dahm-Kahler P.
      • Marcickiewicz J.
      • Nyachieo A.
      • Mwenda J.M.
      • Brannstrom M.
      Uterus transplantation in the baboon: methodology and long-term function after auto-transplantation.
      ) for over a decade. This team has continued with regular training on sheep, the closest model to humans for UTx.
      Aside from surgical training, developing a new UTx centre requires a multidisciplinary team, which is only available at a tertiary care hospital, typically a university hospital, with a large division of transplantation surgery (
      • Brannstrom M.
      Uterus transplantation in a Nordic perspective: A proposition for clinical introduction with centralization.
      ). The surgical team should involve not only transplant surgeons, but also gynaecological surgeons with skills of extraperitoneal pelvic surgery. Other team members should include the following: specialists in reproductive medicine who perform the IVF and prepare the endometrium for embryo transfer; maternal-fetal medicine specialists, particularly those with experience in managing high-risk pregnancies; physicians who routinely follow patients with MRKH syndrome; and specialists in anaesthesiology, internal medicine, nephrology, pathology, psychology and radiology. Furthermore, in centres using deceased donors, organization is further complicated by the need to coordinate with a procurement team and a surgical team available 24 h a day.
      An institution with a UTx programme should provide long-term support, including resources and commitment to care for the recipient, her partner, the donor and the children. A centralization of UTx procedures is necessary to provide enough volume for the approach to be efficient and reproducible, as for pancreas or live liver donor transplantations (
      • Brannstrom M.
      Uterus transplantation in a Nordic perspective: A proposition for clinical introduction with centralization.
      ). Finally, given the complexities, it is highly recommended that centres are developed in collaboration with a UTx team with considerable experience and repeated surgical successes.

      International guidelines

      The USUTC has recently proposed guidelines for nomenclature related to the operative technique, vascular anatomy and donor, recipient and offspring outcomes to improve the quality of evidence available on the efficacy and value of the procedure (
      • Johannesson L.
      • Testa G.
      • Flyckt R.
      • Farrell R.
      • Quintini C.
      • Wall A.
      • O'Neill K.
      • Tzakis A.
      • Richards E.G.
      • Gordon S.M.
      • Porrett P.M.
      Guidelines for standardized nomenclature and reporting in uterus transplantation: An opinion from the United States Uterus Transplant Consortium.
      ). However, it is still an experimental procedure, and guidelines for UTx have not yet been established. The International Society of Uterus Transplantation (ISUTx), which was created in 2016 and recently incorporated into the Transplantation Society, holds an international registry for data collection. Annual reports on activities and with group data on donors, recipients, operations, complications, immunosuppression, pregnancies and live births will be published and all cases will be followed until hysterectomy. In the future, the registry could be used to extract data for purely scientific questions. It is essential that all teams continue to report their experience and outcomes so that the procedure can be further optimized to increase the safety and efficacy, and to develop reasonable international guidelines.

      Meeting the challenges

      With 34 healthy children born, the feasibility of UTx has been proven. However, as highlighted in this review, there are several challenges currently preventing the translation of this emerging area of medicine into mainstream clinical practice. As discussed, possible advancements are underway including widening the criteria for the acceptance of donors and recipients, freezing oocytes as well as embryos, improving surgery, shortening the time to pregnancy and improving post-UTx management such as developing non-invasive biomarkers for rejection (Table 2). As these collective advancements continue, UTx will represent a realistic and accessible alternative to gestational surrogacy for the treatment of UFI and should become part of the armamentarium of reproductive specialists worldwide.
      Table 2Typical current limitations and possible advancements for uterus transplantation.
      ProcedurePatientTypical current limitations/practicePossible advancements
      Evaluation and screeningDeceased donor<40 yearsExtend age beyond 40 years providing vessels are suitable
      Parous with at least one live-born babyNulliparous
      Live donorMainly limited to relativesExpand use of altruistic donation to hysterectomy patients with a normal uterus
      Age limited to <60 years or 5 years post-menopauseIncrease age to >60 years + HRT, regardless of the interval between menopause and donation, providing the vessels are suitable
      Parous with at least one live-born babyNulliparous
      Angio-MRIIf the uterine arteries are not well visualized, use CT angiography or digital subtraction angiography: exclude patient if uterine artery is <1.5 mm in diameter and arteriosclerosis is present
      RecipientMainly limited to women with MRKHExpand to all cases of AUFI and RUFI
      Donor and recipientMatching: typically no CMV, EBV, HPV (D+, R–)Allow mismatching of CMV, EBV and HPV
      IVFRecipientEmbryos frozenOocytes as well as embryos frozen
      Possible use of PGT-A/blastocysts
      SurgeryLive donorMidline laparotomyRobotic surgery with laparoscopy rather than midline laparotomy
      Use of deep uterine veinUse of utero-ovarian vein
      Risks to urethral integrityNo thermal use near ureter
      Ureteric stent for 4–6 weeks
      Long surgical time: up to 10 hReduce surgical time to 5 h
      RecipientMidline laparotomyRobotic surgery with laparoscopy
      Risk of graft failureImprove warm/cold ischaemia (hemi-uterus vascularization and use of a perfusion machine for deceased donors)
      Risk of vaginal stenosisImprove sectioning, suturing of vagina
      ETRecipientMMF/azathioprine started 2 months before ETNo MMF and start azathioprine immediately after UTx
      ET after a minimum of 1 yearET after 4–6 months
      Post-UTxRecipient1 or 2 pregnanciesMore than 2 pregnancies
      Life of transplant no more than 6 yearsIncrease life of the transplant beyond 6 years
      Regular cervical biopsies for signs of rejectionNon-invasive biomarkers for signs of rejection
      AUFI, absolute uterine factor infertility; CMV, cytomegalovirus; CT, computed tomography; EBV, Epstein–Barr virus; ET, embryo transfer; HPV, human papillomavirus; HRT, hormone replacement therapy; MMF, mycophenolate mofetil; MRI, magnetic resonance imaging; MRKH, Mayer–Rokitansky–Küster–Hauser syndrome; PGT-A, preimplantation genetic testing for aneuploidies; RUFI, relative uterine factor infertility; UTx, uterus transplantation.

      Acknowledgements

      The authors thank the Department of Clinical Research at Foch Hospital.

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      Biography

      Jean-Marc Ayoubi is a Professor at the Simone Veil Health Sciences UFR of the University of Versailles Saint-Quentin-en-Yvelines, and head of the Obstetric Gynecology and Reproductive Medicine department at Foch Hospital, France. He is mainly renowned for being the person who performed the first French uterus transplantation.
      Key message
      This review considers the challenges of uterus transplantation and ways to overcome them so that the procedure could become part of the reproductive specialist's armamentarium when counselling patients with uterine factor infertility.