Uterus Transplantation for Absolute Uterine Factor Infertility Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 10|01|2022 POLICY LAST REVIEWED: 09|03|2025 OVERVIEW 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. MEDICAL CRITERIA Not applicable PRIOR AUTHORIZATION Not applicable POLICY STATEMENT Medicare Advantage Plans Uterus transplantation for absolute uterine factor infertility is not covered as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Commercial Products Uterus transplantation for absolute uterine factor infertility is not medically necessary as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome. MEDICAL CRITERIA Not applicable 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. 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. 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 (eg, 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 Medical Coverage Policy | Uterus Transplantation for Absolute Uterine Factor Infertility

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

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.
As of May 2024, 48 uterus transplants resulting in 33 live births have occurred in the United States.

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 pelvis.

For individuals with absolute uterine factor infertility (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. Surgical success rates have ranged from 64% to 78% for deceased donor procedures. 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.

COVERAGE Benefits may vary between groups/contracts. Please refer to the Evidence of Coverage or Subscriber Agreement for applicable not medically necessary/not covered benefits/coverage

CODING The following codes are not covered for Medicare Advantage Plans and not medically necessary for Commercial Products:
0664T Donor hysterectomy (including cold preservation); open, from cadaver donor 0665T Donor hysterectomy (including cold preservation); open, from living donor 0666T Donor hysterectomy (including cold preservation); laparoscopic or robotic, from living donor 0667T Recipient uterus allograft transplantation from cadaver or living donor 0668T Backbench standard preparation of cadaver or living donor uterine allograft prior to transplantation, including dissection and removal of surrounding soft tissues and preparation of uterine vein(s) and uterine artery(ies), as necessary 0669T Backbench reconstruction of cadaver or living donor uterus allograft prior to transplantation; venous anastomosis, each 0670T Backbench reconstruction of cadaver or living donor uterus allograft prior to transplantation; arterial

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM

anastomosis, each

RELATED POLICIES None

PUBLISHED Provider Update, November 2025 Provider Update, November 2024 Provider Update, November 2023 Provider Update, August 2022

REFERENCES

1. Brännström 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. Hellström 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. 2001; 7(2): 161-74. PMID 11284660
4. Folch M, Pigem I, Konje JC. Müllerian 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 preeclampsia 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. Järvholm 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. Mölne 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

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 4 (401) 274-4848 WWW.BCBSRI.COM

17. Brännström M, Johannesson L, Bokström 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. Testa G, McKenna GJ, Wall A, et al. Uterus Transplant in Women With Absolute Uterine-Factor Infertility. JAMA. Sep 10 2024; 332(10): 817-824. PMID 39145955
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 June 16, 2025.
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. 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. PMID 34535036
25. 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. PMID 35951434
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. 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. PMID 35697530
28. 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
29. 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
30. 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. PMID 35793102
31. Walter JR, Johannesson L, Falcone T, et al. In vitro fertilization practice in patients with absolute uterine factor undergoing uterus transplant in the United States. Fertil Steril. Sep 2024; 122(3): 397-
32. PMID 38631504
33. 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. PMID 36445981
34. 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. PMID 37995381
35. Amies Oelschlager AE. ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment. Obstet Gynecol. Jan 2018; 131(1): e35-e42. PMID 29266078
36. 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

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 5 (401) 274-4848 WWW.BCBSRI.COM

i

ii

This medical policy is made available to you for informational purposes only. It is not a guarantee of payment or a substitute for your medical judgment in the treatment of your patients. Benefits and eligibility are determined by the member's subscriber agreement or member certificate and/or the employer agreement, and those documents will supersede the provisions of this medical policy. For information on member-specific benefits, call the provider call center. If you provide services to a member which are determined to not be medically necessary (or in some cases medically necessary services which are non-covered benefits), you may not charge the member for the services unless you have informed the member and they have agreed in writing in advance to continue with the treatment at their own expense. Please refer to your participation agreement(s) for the applicable provisions. This policy is current at the time of publication; however, medical practices, technology, and knowledge are constantly changing. BCBSRI reserves the right to review and revise this policy for any reason and at any time, with or without notice. Blue Cross & Blue Shield of Rhode Island is an independent licensee of the Blue Cross and Blue Shield Association.

CLICK THE ENVELOPE ICON BELOW TO SUBMIT COMMENTS