Latest Review Date: August 2024

Category: Surgery                                                      

POLICY:

Uterus transplantation for absolute uterine factor infertility is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

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.

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 one in 4500 females. Individuals with MRKH syndrome type I present with two 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 preeclampsia).

Hysterectomy is the most common cause of acquired AUFI, with 240,000 procedures taking place in females under age 44 in the United States. 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.

Uterus Transplantation

Uterus transplantation may provide a unique fertility restoration option for individuals desiring to carry and birth a child. 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. The transplantation surgery involves radical hysterectomy in the donor to ensure long vascular pedicles for transplantation; however, several cases of robot-assisted laparoscopic approaches have been reported. 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. 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. 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.

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. 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 preeclampsia at 31 weeks, and a healthy male child was born 5 days later via cesarean delivery. 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. According to the Organ Procurement and Transplantation Network (OPTN), 35 uterus transplants have been performed in the United States via 17 deceased and 24 living donors as of March 2022.

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 non-gynecoid uterus.

KEY POINTS:

The most recent literature update was performed through June 12, 2024.

Summary of Evidence:

For individuals with absolute uterine factor infertility (AUFI) who receive uterus transplantation, the evidence includes of two systematic reviews and five case series. Relevant outcomes are health status measures, perinatal outcomes, quality of life, treatment-related morbidity, and treatment-related mortality.  Two systematic reviews found similar surgical success rates of 64% for deceased donor procedures and 78% for living donor procedures. These reviews reported 24 to 29 live births, and it was estimated that the overall live birth success rate exceeded 80% among surgically successful transplants. 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 newborns 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.

Practice Guidelines and Position Statements

American College of Obstetricians and Gynecologists

In 2018 (reaffirmed in 2024), 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. 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. 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.

KEY WORDS:

Absolute Uterine Factor Infertility, (AUFI), uterus transplantation, Mayer-Rokitansky-Küster-Hauser syndrome; (MRKH); infertility; pregnancy; transplantation; uterus; Asherman syndrome; müllerian agenesis; UTx, womb transplant

APPROVED BY GOVERNING BODIES:

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).

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply.  Refer to member’s benefit plan. 

CURRENT CODING: 

CPT codes:   

REFERENCES:

1. 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.
2. Amies Oelschlager AE. ACOG Committee Opinion No. 728: Mullerian Agenesis: Diagnosis, Management, And Treatment. Obstet Gynecol. Jan 2018; 131(1): e35-e42.
3. 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.
4. 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.
5. 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.
6. Brannstrom M, Belfort MA, Ayoubi JM. Uterus transplantation worldwide: clinical activities and outcomes. Curr Opin Organ Transplant. Dec 01 2021; 26(6): 616-626.
7. Brännström M, Dahm-Kähler P, Kvarnström N, et al. Reproductive, obstetric, and long-term health outcome after uterus transplantation: results of the first clinical trial. Fertil Steril. Sep 2022; 118(3): 576-585. 
8. Brannstrom M, Johannesson L, Bokstrom H, et al. Livebirth after uterus transplantation. Lancet. Feb 14 2015; 385(9968): 607-616. 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.
9. Brännström M, Tullius SG, Brucker S, et al. Registry of the International Society of Uterus Transplantation: First Report. Transplantation. Jan 01 2023; 107(1): 10-17.
10. Brett KM, Higgins JA. Hysterectomy prevalence by Hispanic ethnicity: evidence from a national survey. Am J Public Health. Feb 2003; 93(2): 307-12.
11. Escandón JM, Bustos VP, Santamaría E, et al. Evolution and Transformation of Uterine Transplantation: A Systematic Review of Surgical Techniques and Outcomes. J Reconstr Microsurg. Jul 2022; 38(6): 429-440. 
12. Fageeh W, Raffa H, Jabbad H, et al. Transplantation of the human uterus. Int J Gynaecol Obstet. Mar 2002; 76(3): 245-51.
13. Folch M, Pigem I, Konje JC. Mullerian agenesis: etiology, diagnosis, and management. Obstet Gynecol Surv. Oct 2000; 55(10): 644-9.
14. 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).
15. Garg AX, Nevis IF, McArthur E, et al. Gestational hypertension and preeclampsia in living kidney donors. N Engl J Med. Jan 08 2015; 372(2): 124-33.
16. Gauthier T, Piver P, Pichon N, et al. Uterus retrieval process from brain dead donors. Fertil Steril. Aug 2014; 102(2): 476-82.
17. 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.
18. 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. 
19. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
20. 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. 
21. Järvholm S, Kättström A, Kvarnström N, et al. Long-term health-related quality-of-life and psychosocial outcomes after uterus transplantation: a 5-year follow-up of donors and recipients. Hum Reprod. Feb 01 2024; 39(2): 374-381.
22. 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.
23. Johannesson L, Richards E, Reddy V, et al. The First 5 Years of Uterus Transplant in the US: A Report From the United States Uterus Transplant Consortium. JAMA Surg. Sep 01 2022; 157(9): 790-797.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. Organ Procurement and Transplantation Network (OPTN). National data: Transplants by Donor Type [GU: Uterus]. March 2022; optn.transplant.hrsa.gov/data/view-data-reports/national-data/#.
31. Organ Procurement and Transplantation Network (OPTN). Vascular composite allograft. n.d.; optn.transplant.hrsa.gov/professionals/by-organ/vascular-composite-allograft.
32. 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. 
33. 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. 
34. 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.
35. Wilson NK, Schulz P, Wall A, et al. Immunosuppression in Uterus Transplantation: Experience From the Dallas Uterus Transplant Study. Transplantation. Mar 01 2023; 107(3): 729-736. 

POLICY HISTORY:

Medical Policy Panel, April 2022

Medical Policy Group, April 2022 (3): New medical policy. Available for comment May 1, 2022 through June 15, 2022.

Medical Policy Administration Committee, May 2022

Medical Policy Panel, August 2023

Medical Policy Group, August 2023 (3): 2023 Updates Key Points, Benefit Applications, and References. No changes to policy statement or intent.

Medical Policy Panel, August 2024

Medical Policy Group, August 2024 (3): Updates Description, Key Points, and References. No changes to policy statement or intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.