Description
Absolute uterine factor infertility is a condition in which an individual is unable to achieve pregnancy due to an absent or non-functioning uterus. Uterus transplantation may present a childbearing option that is an alternative to existing family planning pathways, including adoption, foster parenting, and gestational carrier pregnancy. Uterus transplantation is a complex, multi-stage process involving a living or deceased donor, recipient, and genetic partner.

Background 
Absolute Uterine Factor Infertility
Absolute uterine factor infertility (AUFI) refers to infertility that is attributable to an absent or non-functional uterus due to congenital, surgical, anatomical, or acquired factors that prevent embryo implantation and term pregnancy. AUFI is estimated to impact 1 in 500 females of childbearing age.^1,2

Uterine agenesis or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome results in the congenital absence of the uterus or presence of a rudimentary solid bipartite uterus. MRKH syndrome accounts for less than 3% of all müllerian malformations with an estimated prevalence of 1 in 4500 females.^3,4 Individuals with MRKH syndrome type I present with 2 kidneys and are considered ideal candidates for uterine transplantation. Individuals with MRKH syndrome type II presenting with a single kidney have a higher risk of medication-induced nephrotoxicity and associated obstetric complications (e.g., severe pre-eclampsia).⁵

Hysterectomy is the most common cause of acquired AUFI, with 240,000 procedures taking place in females under age 44 in the United States.⁶ In one clinical trial screening study of 239 individuals at the Cleveland Clinic, indications for uterus transplantation included prior hysterectomy (64%) and congenital anomalies (32%). Among individuals with prior hysterectomy, 50% were performed for benign indications, 25% for malignancy, and 25% for obstetric complications.⁷

Uterus Transplantation
Uterus transplantation may provide a unique fertility restoration option for individuals desiring to carry and birth a child.⁸ Uterus transplantation is a complex, multi-stage process involving a living or deceased donor, recipient, and genetic partner. Once screening and consent is established for all involved parties, in-vitro fertilization is performed prior to transplantation to ensure fertilization and normal embryo development.⁹ The transplantation surgery involves radical hysterectomy in the donor to ensure long vascular pedicles for transplantation;¹⁰ however, several cases of robot-assisted laparoscopic approaches have been reported.^11,12 An advantage of uterus procurement in a deceased donor involves freedom to transect ureters, but this convenience is balanced by the potential for prolonged uterus ischemic time.¹³ The surgical approach in the recipient is dictated by underlying pelvic anatomy which may be impacted by AUFI etiology. For example, in individuals with Asherman syndrome, a traditional total hysterectomy must first be performed in the recipient. Immunosuppression is initiated at the time of transplantation and protocol and for-cause cervical biopsies enable monitoring for organ rejection.^14,15 After 6 to 12 months of immunosuppression, embryo transfer, pregnancy, and cesarean delivery may follow. When childbearing has been deemed complete, the transplanted uterus is removed to avoid lifelong immunosuppression. Thus, uterus transplantation is the first form of organ transplantation intended to be temporary.^1,9

The first human uterus transplant was performed in 2000 in Saudi Arabia with a 46 year old living donor and 26 year old recipient with acquired AUFI due to hysterectomy for prior post-partum hemorrhage. Due to the development of acute vascular thrombosis at 3 months post-transplant, graft hysterectomy was required.¹⁶ The first successful live birth occurred in 2014 in Sweden in a 35 year old recipient with MRKH syndrome via a living, 61 year old, two-parous donor. The recipient was admitted with pre-eclampsia at 31 weeks, and a healthy male child was born 5 days later via cesarean delivery.¹⁷ The first live birth in the United States occurred in 2017 in a 29 year old recipient with MRKH syndrome via a living, 32 year old, two-parous donor.¹⁸ According to the Organ Procurement and Transplantation Network (OPTN), 35 uterus transplants have been performed in the United States via 13 deceased and 22 living donors as of March 2022.¹⁹

Literature has explored the implications of uterus transplantation in transgender women, identifying several theoretical medical issues in genetic males meriting further investigation. These include creation of adequate de novo uterine vascularization, administration of appropriate hormone replacement therapy, and placement of the donor uterus in a nongynecoid uterus.^20,21

Regulatory Status
Solid organ transplants are a surgical procedure and, as such, are not subject to regulation by the U.S. Food and Drug Administration (FDA).

The FDA regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation Title 21, parts 1270 and 1271. Solid organs used for transplantation are subject to these regulations.

Restorative or life-enhancing uterine vascularized composite allograft (VCA) procurement and transplantation falls under the oversight of the Organ Procurement and Transplantation Network (OPTN).²²

Policy 
Uterus transplantation for absolute uterine factor infertility is considered investigational/unproven therefore NOT MEDICALLY NECESSARY. 

Policy Guidelines 
Coding
See the Codes table for details.

Benefit Application
BlueCard/National Account Issues
If and when uterus transplant might be considered for coverage, more than one benefit or contractual consideration may be applicable: traditional organ transplant benefits and/or assisted reproductive technology services. 

Rationale 
This evidence review was created in April 2022 with a search of the PubMed database. The most recent literature update was performed through March 14, 2022.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Due to the nature of absolute uterine factor infertility (AUFI), there are no RCTs directly comparing uterus transplant with alternatives. Systematic reviews are based on case series. Studies comparing surgical technique, infection prophylaxis, and immunosuppressive regimens are not germane to this evidence review.

Uterus Transplantation
Clinical Context and Therapy Purpose
The purpose of uterus transplantation in individuals who have AUFI is to provide a unique childbearing option that is an alternative to or a desired improvement on existing family planning pathways.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with AUFI due to an absent or non-functioning uterus. Most congenital cases of uterine agenesis are due to Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Individuals with uterine factors contributing to, but not exclusively causing, infertility are generally not considered candidates for uterus transplantation unless established medical or surgical therapeutic options (eg, hysteroscopic adhesiolysis, myomectomy) have failed. These factors may include müllerian malformations, intrauterine adhesions or Asherman syndrome, radiation injury, poor endometrial receptivity, or uterine leiomyoma(s) of submucosal or intramural type. Most acquired cases of AUFI are due to prior hysterectomy for malignancy, obstetric complications, or uterine fibroids.

Interventions
The therapy being considered is uterus transplantation. Uterus transplantation is a complex, multi-stage process involving a living or deceased donor, recipient, and genetic partner. Uterus transplantation is the first organ transplantation procedure intended to be temporary, concluding with graft hysterectomy to avoid the need for lifelong immunosuppression once childbearing is deemed complete. Pregnancy in the transplanted uterus is achieved through in-vitro fertilization (IVF) and embryo transfer.

Comparators
The relevant comparators are alternative family planning pathways, such as adoption, foster parenting, or gestational carrier pregnancy.

Outcomes
The general outcomes of interest are health status measures, perinatal outcomes, quality of life, treatment-related morbidity, and treatment-related mortality. Benefits and harms should be considered for the donor, recipient, developing fetus, and newborn. Several years of follow-up may be required to fully observe outcomes through all stages of the procedure from procurement through graft removal.

In 2020, the United States Uterus Transplant Consortium issued guidelines for standardized nomenclature and reporting in uterus transplantation trials, identifying 7 progressive stages with milestones of success: (1) technical, (2) menstruation, (3) embryo implantation, (4) pregnancy, (5) delivery, (6) graft removal, and (7) long-term follow-up.²³ Primary outcomes of interest include recipient posttransplant survival, graft survival, and the transplant success rate, defined as the delivery of a child per transplanted recipient reported at 2-year intervals for the duration of the transplant. Secondary outcomes of interest for recipients include onset of menstruation or withdrawal bleeding, clinical pregnancy, failed embryo transfer, miscarriage, rejection episode(s), stricture, acute kidney injury, adjusted live birth rate, pre-eclampsia, malignancy, metabolic wellness, health of the newborn, and health of the child. The primary outcome of interest for living uterus donors is patient survival at 1 and 2 years after donation. Secondary outcomes for the living donor include complications (e.g., ureteral complications), hospitalizations, and adverse renal events.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;
• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought;
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Brannstrom etl al. (2021) published a systematic review of all published clinical uterus transplantation data and major interim results from 2000 through 2019.¹ Of 62 uterus transplants identified for the review, the overall technical success rate defined as subsequent regular menstruation, was 76%. Technical success rates for living and deceased donor procedures were 78% and 64%, respectively. Rates of serious postsurgical complications were 18% for living donors and 19% for recipients. Most uterus transplantation procedures to date have involved living donors (51/62; 82%). Complications in living donors have included ureteric laceration, urinary bladder hypotonia, unplanned bilateral oophorectomy, vaginal dehiscence, fecal impaction, and unilateral pyelonephritis and hydronephrosis. Postoperative complications in recipients have included vaginal anastomotic stenosis and treatable episodes of minor to severe graft rejection.

The cumulative live birth rate per transplant attempt, and per surgically successful uterus transplant is estimated to be > 60% and > 80%, respectively, as based on 24 published live birth accounts from interim data. High rates of preterm birth (19/24; 80%) and respiratory distress syndrome in the newborn (9/24; 38%) have been observed across cases. Obstetric complications have included pre-eclampsia, gestational hypertension, and several cases of placenta previa and gestational diabetes. Newborns had an Apgar score of 8 or higher at 5 minutes. One minor malformation in a female newborn involving an anteriorly caudally displaced urethra was reported, which was surgically corrected at 11 months. The reviewers concluded that "the modest success rate and the fairly high complication rate among (living donors), indicate that further research and development under strict governance are needed before this option should be widely offered."

Case Series
Characteristics and interim results from select case series are summarized in Tables 1 and 2.

Table 1. Summary of Key Case Series Characteristics

AUFI: absolute uterine factor infertility; DD: deceased donor; HPV: human papillomavirus; LD: living donor; MRKH: Mayer-Rokitansky-Küster-Hauser syndrome; NR: not reported; UTx: uterus transplant.

Table 2. Summary of Key Case Series Results

CKD: chronic kidney disease; CMV: cytomegalovirus; DD: deceased donor; HLA: human leukocyte antigen; HSV: herpes simplex virus; LD: living donor; MRKH: Mayer-Rokitansky-Küster-Hauser syndrome; UTI: urinary tract infection.

Section Summary: Uterus Transplantation
Case series of uterus transplantation for AUFI have predominantly enrolled individuals with MRKH syndrome type I. A systematic review of interim trial data has reported live birth success estimates exceeding 60% overall and 80% among transplant attempts with surgical success. Slightly higher technical success rates have been reported for living donor compared to deceased donor procedures (78% vs. 64%, respectively). Rates of serious complications are high among both recipients (19%) and living donors (18%). High rates of preterm birth (80%) and episodes of acute respiratory distress syndrome in the newborn have been reported. Long-term health outcomes in children born via uterus transplantation and recipients following graft hysterectomy continue to accumulate in ongoing trials.

Summary of Evidence
For individuals with AUFI who receive uterus transplantation, the evidence includes a systematic review and case series. Relevant outcomes are health status measures, perinatal outcomes, quality of life, treatment-related morbidity, and treatment-related mortality. One systematic review of 62 uterus transplants has reported 24 published live birth accounts, with an estimated overall live birth success rate exceeding 80% among surgically successful transplants. Surgical success rates have ranged from 64% to 78% for deceased and living donor procedures, respectively. Complications have been reported in 19% of recipients and 18% of living donors. High rates of preterm birth (80%) and episodes of acute respiratory distress syndrome in the newborn have been reported. Data for individuals with acquired AUFI are lacking. Further study is necessary to increase success rates, decrease complications and preterm births, and assess long-term outcomes in recipients and their children. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Obstetricians and Gynecologists
In 2018 (reaffirmed 2020), the American College of Obstetricians and Gynecologists (ACOG) Committee on Adolescent Health Care issued a Committee Opinion (Number 728) on the diagnosis, management, and treatment of müllerian agenesis.²⁷ Regarding future fertility options, the opinion states that while live births have resulted from uterine transplantation, "given limited data, this procedure currently is considered experimental and is not widely available."

American Society for Reproductive Medicine
In 2018, the American Society for Reproductive Medicine (ASRM) issued a position statement recognizing uterus transplantation as the first successful medical treatment for absolute uterine factor infertility, emphasizing its experimental nature.²⁸ The statement recommends that the procedure should be performed within an Institutional Review Board-approved research protocol, with recommendations for the composition of "well-coordinated and multidisciplinary" uterus transplantation teams and suggested recipient inclusion and exclusion criteria.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

NCT: national clinical trial

References

1. Brannstrom M, Belfort MA, Ayoubi JM. Uterus transplantation worldwide: clinical activities and outcomes. Curr Opin Organ Transplant. Dec 01 2021; 26(6): 616-626. PMID 34636769
2. Hellstrom M, El-Akouri RR, Sihlbom C, et al. Towards the development of a bioengineered uterus: comparison of different protocols for rat uterus decellularization. Acta Biomater. Dec 2014; 10(12): 5034-5042. PMID 25169258
3. Grimbizis GF, Camus M, Tarlatzis BC, et al. Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update. Mar-Apr 2001; 7(2): 161-74. PMID 11284660
4. Folch M, Pigem I, Konje JC. Mullerian agenesis: etiology, diagnosis, and management. Obstet Gynecol Surv. Oct 2000; 55(10): 644-9. PMID 11023205
5. Garg AX, Nevis IF, McArthur E, et al. Gestational hypertension and pre-eclampsia in living kidney donors. N Engl J Med. Jan 08 2015; 372(2): 124-33. PMID 25397608
6. Brett KM, Higgins JA. Hysterectomy prevalence by Hispanic ethnicity: evidence from a national survey. Am J Public Health. Feb 2003; 93(2): 307-12. PMID 12554591
7. Arian SE, Flyckt RL, Farrell RM, et al. Characterizing women with interest in uterine transplant clinical trials in the United States: who seeks information on this experimental treatment?. Am J Obstet Gynecol. Feb 2017; 216(2): 190-191. PMID 27865979
8. Jarvholm S, Enskog A, Hammarling C, et al. Uterus transplantation: joys and frustrations of becoming a 'complete' woman-a qualitative study regarding self-image in the 5-year period after transplantation. Hum Reprod. Aug 01 2020; 35(8): 1855-1863. PMID 32619006
9. Malasevskaia I, Al-Awadhi AA. A New Approach for Treatment of Woman With Absolute Uterine Factor Infertility: A Traditional Review of Safety and Efficacy Outcomes in the First 65 Recipients of Uterus Transplantation. Cureus. Jan 18 2021; 13(1): e12772. PMID 33614361
10. Johannesson L, Diaz-Garcia C, Leonhardt H, et al. Vascular pedicle lengths after hysterectomy: toward future human uterus transplantation. Obstet Gynecol. Jun 2012; 119(6): 1219-25. PMID 22617587
11. Wei L, Xue T, Tao KS, et al. 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. Fertil Steril. Aug 2017; 108(2): 346-356.e1. PMID 28778283
12. Ayoubi JM, Carbonnel M, Pirtea P, et al. Laparotomy or minimal invasive surgery in uterus transplantation: a comparison. Fertil Steril. Jul 2019; 112(1): 11-18. PMID 31277761
13. Gauthier T, Piver P, Pichon N, et al. Uterus retrieval process from brain dead donors. Fertil Steril. Aug 2014; 102(2): 476-82. PMID 24837613
14. Molne J, Broecker V, Ekberg J, et al. Monitoring of Human Uterus Transplantation With Cervical Biopsies: A Provisional Scoring System for Rejection. Am J Transplant. Jun 2017; 17(6): 1628-1636. PMID 27868389
15. Balko J, Novackova M, Skapa P, et al. Histopathological examination of the ectocervical biopsy in non-transplanted uteri: A study contributing to the provisional scoring system of subclinical graft rejection after uterus transplantation. Acta Obstet Gynecol Scand. Jan 2022; 101(1): 37-45. PMID 34693986
16. Fageeh W, Raffa H, Jabbad H, et al. Transplantation of the human uterus. Int J Gynaecol Obstet. Mar 2002; 76(3): 245-51. PMID 11880127
17. Brannstrom M, Johannesson L, Bokstrom H, et al. Livebirth after uterus transplantation. Lancet. Feb 14 2015; 385(9968): 607-616. PMID 25301505
18. Testa G, McKenna GJ, Gunby RT, et al. First live birth after uterus transplantation in the United States. Am J Transplant. May 2018; 18(5): 1270-1274. PMID 29575738
19. Organ Procurement and Transplantation Network (OPTN). National data: Transplants by Donor Type [GU: Uterus]. March 2022; https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/#. Accessed March 14, 2022.
20. 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. Fertil Steril. Oct 2013; 100(4): 924-6. PMID 23768985
21. Jones BP, Rajamanoharan A, Vali S, et al. Perceptions and Motivations for Uterus Transplant in Transgender Women. JAMA Netw Open. Jan 04 2021; 4(1): e2034561. PMID 33471119
22. Organ Procurement and Transplantation Network (OPTN). Vascular composite allograft. n.d.; https://optn.transplant.hrsa.gov/professionals/by-organ/vascular-composite-allograft. Accessed March 14, 2022.
23. Johannesson L, Testa G, Flyckt R, et al. Guidelines for standardized nomenclature and reporting in uterus transplantation: An opinion from the United States Uterus Transplant Consortium. Am J Transplant. Dec 2020; 20(12): 3319-3325. PMID 32379930
24. Johannesson L, Testa G, Putman JM, et al. Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study. Obstet Gynecol. Feb 01 2021; 137(2): 241-249. PMID 33416285
25. Putman JM, Zhang L, Gregg AR, et al. Clinical pregnancy rates and experience with in vitro fertilization after uterus transplantation: Dallas Uterus Transplant Study. Am J Obstet Gynecol. Aug 2021; 225(2): 155.e1-155.e11. PMID 33716072
26. Fronek J, Kristek J, Chlupac J, et al. Human Uterus Transplantation from Living and Deceased Donors: The Interim Results of the First 10 Cases of the Czech Trial. J Clin Med. Feb 04 2021; 10(4). PMID 33557282
27. Amies Oelschlager AE. ACOG Committee Opinion No. 728: Mullerian Agenesis: Diagnosis, Management, And Treatment. Obstet Gynecol. Jan 2018; 131(1): e35-e42. PMID 29266078
28. Allyse M, Amer H, Coutifaris C, et al. American Society for Reproductive Medicine position statement on uterus transplantation: a committee opinion. Fertil Steril. Sep 2018; 110(4): 605-610. PMID 30196945

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2022 Forward     

APPENDIX 

Brannstrom M, Belfort MA, Ayoubi JM. Uterus transplantation worldwide: clinical activities and outcomes. Curr Opin Organ Transplant. Dec 01 2021; 26(6): 616-626. PMID 34636769

Women with absolute uterine factor infertility, because of uterine absence, or the presence of a nonfunctional uterus, were regarded as being untreatable until 2014 when the first birth following uterus transplantation (UTx) took place in Sweden. This proof-of-concept occurred in a woman with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHs) with congenital uterine absence, who received a uterus from a 61-year-old live donor (LD). Since then, several births after UTx have occurred in Sweden and subsequently in other countries, including both LD and deceased donor (DD) transplants. A great majority of the recipients were women with MRKHs. The efficiency and safety of UTx can be determined only when a complete study cohort of transplanted women have reached the definitive endpoint of graft hysterectomy. The different outcomes of transplanted women include graft failure, as well as graft survival with failure to achieve livebirth, or livebirth(s). Published data from a completed trial are not yet available. The results that we have to rely on are reports of completed surgeries and interim outcomes that may be as early as a few months after surgery and up to several years after UTx. The purpose of this review is to give an update on all published clinical UTx data and major results, including live births up to mid 2021. The interim results of a number of UTx studies have been published. LD UTx procedures have been reported from four European countries (Sweden, the Czech Republic, Germany, Spain), four Asian nations (Saudi Arabia, India, China, Lebanon), as well as some from the USA. DD UTx procedures have been reported from Turkey, the Czech Republic, the USA and Brazil. To our knowledge, there also exist unpublished UTx cases from some of the countries mentioned above and from at least four other countries (Serbia, France, Mexico, Italy). We estimate that at least 80 UTx procedures have been performed, resulting in more than 40 births. The present study includes only data from published, peer-reviewed, research papers. The results of 62 UTx cases show an overall surgical success rate, as defined by a technically successful transplantation with a subsequent regular menstrual pattern, of 76%. The success rates for LD and DD UTx procedures were 78% and 64%, respectively. The rate of serious postsurgical complications requiring invasive or radiological intervention was 18% for LDs and 19% for recipients. The cumulative live birth rate in successful UTx procedures is estimated to be above 80%. Twenty-four births after UTx have been reported and the results show a high rate of preterm birth, with an associated high proportion of respiratory distress syndrome. UTx has proven to be a successful treatment for uterine factor infertility at several centers around the world. The modest success rate and the fairly high complication rate among LDs, indicate that further research and development under strict governance are needed before this option should be widely offered.

Brannstrom M, Johannesson L, Bokstrom H, et al. Livebirth after uterus transplantation. Lancet. Feb 14 2015; 385(9968): 607-616. PMID 25301505

Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus. Eleven human uterus transplantation attempts have been done worldwide but no livebirth has yet been reported. In 2013, a 35-year-old woman with congenital absence of the uterus (Rokitansky syndrome) underwent transplantation of the uterus in Sahlgrenska University Hospital, Gothenburg, Sweden. The uterus was donated from a living, 61-year-old, two-parous woman. In-vitro fertilisation treatment of the recipient and her partner had been done before transplantation, from which 11 embryos were cryopreserved. The recipient and the donor had essentially uneventful postoperative recoveries. The recipient's first menstruation occurred 43 days after transplantation and she continued to menstruate at regular intervals of between 26 and 36 days (median 32 days). 1 year after transplantation, the recipient underwent her first single embryo transfer, which resulted in pregnancy. She was then given triple immunosuppression (tacrolimus, azathioprine, and corticosteroids), which was continued throughout pregnancy. She had three episodes of mild rejection, one of which occurred during pregnancy. These episodes were all reversed by corticosteroid treatment. Fetal growth parameters and blood flows of the uterine arteries and umbilical cord were normal throughout pregnancy. The patient was admitted with pre-eclampsia at 31 full weeks and 5 days, and 16 h later a caesarean section was done because of abnormal cardiotocography. A male baby with a normal birthweight for gestational age (1775 g) and with APGAR scores 9, 9, 10 was born. We describe the first livebirth after uterus transplantation. This report is a proof-of-concept for uterus transplantation as a treatment for uterine factor infertility. Furthermore, the results show the feasibility of live uterus donation, even from a postmenopausal donor. Jane and Dan Olsson Foundation for Science.

Brannstrom M, Johannesson L, Dahm-Kahler P, et al. First clinical uterus transplantation trial: a six-month report. Fertil Steril. May 2014; 101(5): 1228-36. PMID 24582522

To report the 6-month results of the first clinical uterus transplantation (UTx) trial. This type of transplantation may become a treatment of absolute uterine-factor infertility (AUFI). Prospective observational study. University hospital. Nine AUFI women and their live uterine donors, the majority being mothers. Live-donor UTx and low-dose induction immunosuppression. Data from preoperative investigations, surgery and follow-up for 6 months. Durations of donor and recipient surgery ranged from 10 to 13 hours and from 4 to 6 hours, respectively. No immediate perioperative complications occurred in any of the recipients. After 6 months, seven uteri remained viable with regular menses. Mild rejection episodes occurred in four of these patients. These rejection episodes were effectively reversed by corticosteroid boluses. The two graft losses were because of acute bilateral thrombotic uterine artery occlusions and persistent intrauterine infection. The results demonstrate the feasibility of live-donor UTx with a low-dose immunosuppressive protocol. NCT01844362.

Fageeh W, Raffa H, Jabbad H, et al. Transplantation of the human uterus. Int J Gynaecol Obstet. Mar 2002; 76(3): 245-51. PMID 11880127

Human uterine transplantation was performed on 6 April 2000 on a 26-year-old female who lost her uterus 6 years earlier due to post-partum hemorrhage. The donor, a 46-year-old patient with multiloculated ovarian cysts, underwent a hysterectomy modified to preserve tissue and vascular integrity. The donor uterus was connected in the orthotopic position to the recipient's vaginal vault and additional fixation was achieved by shortening the uterosacral ligament. The uterine arteries and veins were extended using reversed segments of the great saphenous vein, then connected to the external iliac arteries and veins, respectively. Immunosuppression was maintained by oral cyclosporine A (4 mg/kg/body wt.), azathioprine (1 mg/kg/body wt.) and prednisolone (0.2 mg/kg/body wt.). Allograft rejection was monitored by Echo-Doppler studies, magnetic resonance imaging (MRI), and measurement of the CD4/CD8 ratio in peripheral blood by fluorescence activated cell sorter (FACS scan). An episode of acute rejection was treated and controlled on the ninth day with anti-thymocytic globulin (ATG). The transplanted uterus responded well to combined estrogen--progesterone therapy, with endometrial proliferation up to 18 mm. The patient had two episodes of withdrawal bleeding upon cessation of the hormonal therapy. Unfortunately, she developed acute vascular thrombosis 99 days after transplantation, and hysterectomy was necessary. Macro- and microscopic histopathological examination revealed acute thrombosis in the vessels of the uterine body, with resulting infarction. Both fallopian tubes remained viable, however, with no evidence of rejection. The acute vascular occlusion appeared to be caused by inadequate uterine structure support, which led to probable tension, torsion, or kinking of the connected vascular uterine grafts.

Fronek J, Kristek J, Chlupac J, et al. Human Uterus Transplantation from Living and Deceased Donors: The Interim Results of the First 10 Cases of the Czech Trial. J Clin Med. Feb 04 2021; 10(4). PMID 33557282

Uterus transplantation (UTx) is a rapidly evolving treatment of uterine-factor infertility. We report the results of the first 10 UTx procedures performed at our institution. The program started in April 2016 as a two-arm study comparing the efficacy of UTx from live donors (LD) and deceased donors (DD). Between April 2016 and April 2018, we performed five DD UTx and five LD UTx. Two grafts had to be removed early due to thrombosis. One graft was removed due to chronic rejection and previous herpes simplex infection at month 7. Graft survival is 70% at one year. Recipient survival is 100% at two years. Live donor survival is 100% at three years. Three live-births have been achieved, two from a LD and one from a graft from a nulliparous DD. Vaginal anastomotic stenosis occurred in 63% (5/8) of grafts. Self-expanding stents have shown preliminary suitability for the treatment of vaginal stenosis. Three recipients developed severe acute rejection. The interim results of our study demonstrate mid-term viability in 70% of grafts. The LD UTx produced two live births and the DD UTx produced one live birth. Nulliparous donors should be considered for donation.

Jarvholm S, Kvarnstrom N, Dahm-Kahler P, et al. Donors' health-related quality-of-life and psychosocial outcomes 3 years after uterus donation for transplantation. Hum Reprod. Jul 08 2019; 34(7): 1270-1277. PMID 31241745

What are the effects on donors' health-related quality-of-life, mood and marital relationship 2 and 3 years after uterus donation for transplantation? Overall, uterus donors were relatively stable regarding health-related quality-of-life, mood and marital relationship after donation, although slight negative deviations existed in a few participants, presumably associated with older age or with continued non-pregnancy outcomes from the donation. Uterus transplantation has recently proved to be a successful treatment for absolute uterine factor infertility. However, there is no previous research on health-related quality-of-life and long-term psychosocial outcomes of donors. The present cohort of nine donors represents the cases of the first clinical uterus transplantation study, which took place in Sweden. Long-term follow-up studies of health-related quality-of-life in other living donors, such as of kidneys and livers, suggest that donors have above average quality-of-life prior to donation and that this typically continues during the years after donation. In our previous 1-year report on psychosocial and quality-of-life outcomes, we found that two out of nine donors showed decreased health-related quality-of-life at 6 and 12 months post donation. This complete, prospective cohort study included the nine donors of the first uterus transplantation trial, which took place in Sweden in 2013. Donors were assessed by questionnaires 2 and 3 years after surgery for uterus donation. The nine donors (aged 39 to 62 years) were all a close relative or friend of their recipient. Physical and mental component summaries of health-related quality-of-life were measured with the SF-36 questionnaire. Mood was assessed by the Hospital Anxiety Depression Scale. Relationship with partner was measured with the Dyadic Adjustment Scale. The physical and mental components of the SF-36 were generally above the mean scores for a normative population. At Year 3, the two oldest donors (above 60 years of age at surgery) showed clear negative deviations in the physical component. The mental component summary of SF-36 was essentially unaltered overall at Year 2, but slight negative deviations were seen in three donors at Year 3. These three donors were among the four with unsuccessful pregnancy outcomes for the recipients following donation. Scores of anxiety and depression (mood) were within normative values for all donors at Year 2, but one donor presented with increased (worse) values for both variables at Year 3. Two donors showed signs of relationship distress during the follow-up period and another had divorced during this period. The small sample size is a limitation. The present study suggests that live uterus donation does not in general negatively influence health-related quality-of-life, mood and relationship in a 2 to 3-year perspective follow-up. Longer follow-up studies, including larger number of donors and in different cultural settings, are needed. The Jane and Dan Olsson Foundation for Science; the Wallenberg Foundation; an ALF grant from the Swedish state under an agreement between the government and the county councils; the Swedish Research Council; a Ferring Pharmaceuticals scholarship in memory of Robert Edwards; and the Iris Jonzén-Sandbloms and Greta Jonzéns Foundation. The authors have no competing interests. NCT01844362.

Johannesson L, Testa G, Flyckt R, et al. Guidelines for standardized nomenclature and reporting in uterus transplantation: An opinion from the United States Uterus Transplant Consortium. Am J Transplant. Dec 2020; 20(12): 3319-3325. PMID 32379930

Uterus transplantation is a nascent but growing field. To support this growth, the United States Uterus Transplant Consortium proposes guidelines for nomenclature related to operative technique, vascular anatomy, and donor, recipient, and offspring outcomes. In terms of anatomy, the group recommends reporting donor arterial inflow and recipient anastomotic site delivering inflow to the graft and offers standardization of the names for the 4 veins originating from the uterus because of current inconsistency in this particular nomenclature. Seven progressive stages with milestones of success are defined for reporting on uterus transplantation outcomes: (1) technical, (2) menstruation, (3) embryo implantation, (4) pregnancy, (5) delivery, (6) graft removal, and (7) long-term follow-up. The 3 primary metrics for success are recipient survival (as reported for other organ transplant recipients), graft survival, and uterus transplant live birth rate (defined as live birth per transplanted recipient). A number of secondary outcomes should also be reported, most of which capture stage-specific milestones, as well as data on graft failure. Outcome metrics for living donors include patient survival, survival free of operative intervention, and data on complications and hospitalizations. Finally, we make specific recommendations on follow-up for offspring born from uterine grafts, which includes specialty surveillance as well as collection and reporting of routine pediatric outcomes. The goal of standardization in reporting is to create consistency and improve the quality of evidence available on the efficacy and value of the procedure.

Johannesson L, Testa G, Putman JM, et al. Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study. Obstet Gynecol. Feb 01 2021; 137(2): 241-249. PMID 33416285

To describe aggregated pregnancy outcomes after uterus transplantation from a single, experienced center. This prospective study reports on live births among 20 women who received a uterus transplant from 2016 to 2019 at Baylor University Medical Center at Dallas. These live births occurred between November 2017 and September 2020. The main measures were live birth, maternal complications, and fetal and newborn outcomes. There were six graft failures (four surgical complications and two with poor perfusion postoperatively). Of the 14 technically successful transplants, at least one live birth occurred in 11 patients. Thus far, the live birth rate per attempted transplant is 55%, and the live-birth rate per technically successful transplant is 79%. Ten uteri were from nondirected living donors and one uterus was from a deceased donor. In vitro fertilization was performed to achieve pregnancy. Ten recipients delivered one neonate, and one recipient delivered two neonates. One organ rejection episode was detected during pregnancy and was resolved with steroids. The median birth weight was 2,890 g (range 1,770-3,140 g [median 68th percentile]). Maternal weight gain was higher than Institute of Medicine recommendations. Maternal medical complications were observed in five recipients (elevated creatinine level, gestational diabetes, gestational hypertension (n = 2), and pre-eclampsia). In five recipients, maternal medical or obstetric complications led to an unplanned preterm delivery (elevated creatinine level, pre-eclampsia; preterm labor [n = 3]). The median gestational age at delivery was 36 6/7 weeks (range 30 6/7 – 38 weeks). All neonates were liveborn, with Apgar scores of 8 or higher at 5 minutes. Over the first 3 years, our program experienced a live-birth rate per attempted transplant of 55% and a live-birth rate per technically successful transplant of 79%. In our experience, uterus transplantation resulted in a third-trimester live birth in all cases in which pregnancies reached 20 weeks of gestation. Maternal medical and obstetric complications can occur; however, these were manageable by applying principles of generally accepted obstetric practice. ClinicalTrials.gov, NCT02656550.

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. Fertil Steril. Oct 2013; 100(4): 924-6. PMID 23768985

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Malasevskaia I, Al-Awadhi AA. A New Approach for Treatment of Woman With Absolute Uterine Factor Infertility: A Traditional Review of Safety and Efficacy Outcomes in the First 65 Recipients of Uterus Transplantation. Cureus. Jan 18 2021; 13(1): e12772. PMID 33614361

Uterine transplantation restores fertility in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The number of cases being performed is increasing dramatically, with detailed outcomes from 65 cases now available. Pregnancies achieved through uterus transplantation and following in vitro fertilization (IVF) are associated with an increased risk for further mother and newborn babies. This traditional review is focused on the safety and efficacy features of the treatment. However, it is associated with significant risk, with approximately one-quarter of grafts are removed because of complications. Uterine transplantation is realizable in women with uterine factor infertility but is associated with a significant complication risk. The risk of the procedure and gestational and delivery complications deserve important consideration before receiving such treatments. Nevertheless, these observations are preliminary and should be revised after a larger series of data are published.

Putman JM, Zhang L, Gregg AR, et al. Clinical pregnancy rates and experience with in vitro fertilization after uterus transplantation: Dallas Uterus Transplant Study. Am J Obstet Gynecol. Aug 2021; 225(2): 155.e1-155.e11. PMID 33716072

The clinical pregnancy rates among patients with uterus transplantation have been reported by only a limited number of centers, and those centers have not used preimplantation genetic testing for aneuploidy in their protocol. This study examined clinical pregnancy rates among women with absolute uterine-factor infertility undergoing in vitro fertilization using good-quality, expanded-blastocyst-stage, euploid embryos after uterus transplantation. This cohort observational study involved 20 women who underwent uterus transplantation over 3 years. Notably, 14 of these patients had successful transplants and were followed prospectively for a median of 14.1 months (range, 11-34.8 months). In vitro fertilization was performed before subjects underwent uterus transplantation, and good-quality expanded-blastocyst-stage euploid embryos were obtained and frozen for future embryo transfer. Interventions consisted of in vitro fertilization, preimplantation genetic testing for aneuploidy, uterus transplantation, and frozen embryo transfer. All 14 subjects with successful transplants underwent single embryo transfer of a warmed, good-quality, euploid, expanded blastocyst and had at least 1 documented clinical pregnancy within the uterus. In 71.4%, the first embryo transfer resulted in clinical pregnancy. The median time from successful uterus transplantation to first embryo transfer was 4.5 months; from successful uterus transplantation to first clinical pregnancy, 7.3 months; and from successful uterus transplantation to first live birth, 14.1 months. A total of 13 live births have occurred in 12 subjects. Women with absolute uterine-factor infertility who have surgically successful uterus transplantation and in vitro fertilization using preimplantation genetic testing for aneuploidy can achieve high clinical pregnancy rates. We have reduced the time interval from uterus transplantation to embryo transfer by at least 50% and the interval from uterus transplantation to clinical pregnancy by > 6 months compared with previous studies. We believe our approach may shorten the time from transplant to clinical pregnancy and therefore decrease patient exposure to immunosuppressant therapies.

Testa G, McKenna GJ, Gunby RT, et al. First live birth after uterus transplantation in the United States. Am J Transplant. May 2018; 18(5): 1270-1274. PMID 29575738

Uterus transplantation has proven to be a successful treatment for women with absolute uterine infertility, caused either by the absence of a uterus or the presence of a nonfunctioning uterus. We report the first birth of a healthy child following uterus transplantation in the United States, from a recipient of a uterus allograft procured from an altruistic living donor. Two major modifications from the previously reported live births characterized this uterus transplant. First, the transplanted uterus relied upon and sustained the pregnancy while having only the utero-ovarian vein as venous outflow. The implication is a significantly simplified living donor surgery that paves the way for minimally invasive laparoscopic or robot-assisted techniques for the donor hysterectomy. Second, the time from transplantation to embryo transfer was significantly shortened from prior protocols, allowing for an overall shorter exposure to immunosuppression by the recipient and lowering the risk for potential adverse effects from these medications.