| Coverage Policy Manual | |
| Policy #: | 2022021 |
| Category: | Surgery |
| Initiated: | August 2022 |
| Last Review: | September 2024 |
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| Uterus Transplantation for Absolute Uterine Factor Infertility | |
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| 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
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 (Brannstrom, 2021; Hellstrom, 2014).
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 (Grimbizis, 2001; Folch, 2000). 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) (Garg, 2015).
Hysterectomy is the most common cause of acquired AUFI, with 240,000 procedures taking place in females under age 44 in the United States (Brett, 2003). 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 (Arian, 2017).
Uterus Transplantation
Uterus transplantation may provide a unique fertility restoration option for individuals desiring to carry and birth a child (Jarvholm, 2020). 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 (Malasevskaia, 2021). 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 (Johannesson, 2012; Wei, 2017; Ayoubi, 2019). 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 (Gauthier, 2014). 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 (Molne, 2017; Balko, 2022). 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 (Brannstrom, 2021; Malasevskaia, 2021).
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 (Fageeh, 2002). 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 (Brannstrom, 2015). 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 (Testa, 2018). 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 (OPTN, 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 nongynecoid pelvis (Lefkowitz, 2013; Jones, 2021).
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) (OPTN, 2022).
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Policy/ Coverage: |
Effective August 15, 2022
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Uterus transplantation for absolute uterine factor infertility does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, uterus transplantation for absolute uterine factor infertility is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| 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.
Systematic Reviews
Brannstrom etl al published a systematic review of all published clinical uterus transplantation data and major interim results from 2000 through 2019 (Brannstrom, 2021). 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 preeclampsia, 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
A case series conducted in the United States between 2016-2019 included women with absolute uterine factor infertility and intact native ovaries in women of childbearing age between 20-35 years of age with a negative history of HPV or prior vaccination for HPV who meets physiological criteria (Johannesson, 2021; Putman, 2021). The result was 12 live births (11 from living donors and 1 from deceased donor). The overall success rate was 60%. Complications included acute rejection, gestational hypertension, preeclampsia, gestational diabetes mellitus, placenta previa, and preterm delivery.
Another case series conducted in the Czech Republic between 2016-2018 included females between the ages of 18-40 years of age with absolute uterine factor infertility due to congenital or acquired uterus absence who have the desire for a child, a male partner, and good general health (Fronek, 2021). The result was 3 live births (2 from living donors and 1 from deceased donor). The overall success rate was 30%. Complications included vaginal stenosis, leukopenia, UTI, acute rejection, CMV replication, graft HSV infection, C difficile infection, HLA mismatch, and CKD.
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.
Practice Guidelines and Position Statements
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 (Amies Oelschalager, 2018). 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 (Allyse, 2018). 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.
Ongoing and Unpublished Clinical Trials:
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A case series conducted in the United States between 2016-2019 included women with absolute uterine factor infertility (AUFI) and intact native ovaries in women of childbearing age between 20-35 years of age with a negative history of HPV or prior vaccination for HPV who meets physiological criteria (Johannesson, 2021; Putman, 2021: Johannesson, 2022). Participants had a median age of 31 plus or minus 4.7 years; 31 (94%) MRKH type I or II; 2 (6%) prior hysterectomy for leiomyoma(s); Mean donor age of 35 plus or minus 7.3 years; 21 (64%) live donor uterine transplants; 12 (36%) deceased donor uterine transplants. Survival: Graft: 23/31 (74% at 1 year). There was a total of 59 (1 to 4 plus) embryo transfers. The result was 21 (19) live births. 12 from living donors and 7 from deceased donors. The overall success rate was 61% with surgical success of 83%. Complications included acute rejection, gestational hypertension, preeclampsia, gestational diabetes mellitus, placenta previa, and preterm delivery.
Escandon et al published a systematic review summarizing data on uterine transplantation from 1995 through November 2020 from PubMed, Cochrane Evidence-Based Medicine Reviews, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) (Escandon, 2022). A total of 64 uterus transplants were included in the review across 40 publications including 16 case reports, 5 case reports which were part of an observational study, 2 commentaries, 13 prospective observational studies, and 4 reviews. The quality of included studies was assessed by dual reviewers using the Newcastle-Ottawa Scale (NOS) for nonrandomized cohort studies and the Oxford Center for Evidence-Based Medicine (OCEBM) levels of evidence. Sixteen total studies were graded 2b (individual cohort study or low-quality RCT, n=7) or 4 (case series or poor-quality cohort and case-control studies, n=9) on the OCEBM and scores of 2 (n=1), 4 (n=2), 5 (n=11) or 6 (n=2) on the NOS with higher scores indicating better quality reporting of patient selection, comparability, and exposure. No overall assessment of the quality of evidence was provided.
Brannstrom et al reported on a study that took place in Sweden from 2016-2021 (Brannstrom, 2022). The study consisted of females with AUFI who were younger than 38 years of age, had a BMI less than 30, who were without systemic or psychiatric illness. The mean recipient age, 31.5 plus or minus 3.9 years. 8 (89%) had MRKH type I or II. Mean donor age was 53 plus or minus 7. 9 living donor uterine transfers. Survival included: Graft: 7/9 (78% at 4 years); Recipient: 9/9 (100% at 4 years). 46 (1 to 11) embryo transfers occurred. There was a total of 15 (7) clinical pregnancies. 9 (6) live births. The overall birth success rate was 66.7% with surgical success of 86%. Complications included acute rejection, anxiety, depression preeclampsia, and respiratory distress syndrome.
Brannstrom et al reported on a study with International Registry (Sweden, China [2 centers), Czech Republic, Brazil, Germany, Serbia, France, Belgium, Lebanon, Mexico, Spain, and Italy) (Brannstrom, 2023). The study took place from 2012-2020. The living donor criteria was female with at least 1 normal pregnancy, BMI of less than 28, no serious systemic psychiatric illness, and completion of childbearing. Recipient criteria requirements included female of fertile age (generally younger than 39 years of age), BMI less than 28, who is absent of overt systemic or psychiatric illness. Participants had a mean recipient age of 29 years (range 22 to 38); 44 (98%) MKRH type I or II; 1 (2%) prior hysterectomy; Mean donor age was not reported; 33 live donor uterine transplants (all related); 10 deceased donor uterine transplants. Survival included Graft:26/39 (67% at 7 mos). 32 (71%) underwent embryo transfer. There were 19 (16) live births (14 from living donor and 2 from deceased donor). Surgical success was 40%. Complications included acute rejection, arterial hypertension, cholestasis, elevated creatine, gestational diabetes, gestational hypertension, hematologic cytopenia, opportunistic infection, premature rupture of membranes, and subchorionic hematoma.
Wilson et al reported on a study that occurred in the United States from 2016-2019 (Wilson, 2023). Recipients were females 20 to 35 years of age, with a diagnosis of AUFI with intact native ovaries, a BMI less than or equal to 30, with systemic or active infection, history of cancer in previous 5 years, history of solid organ or bone marrow transplant, history of or prior vaccination for HPV, no history of smoking or drug abuse in previous year, who meets physiological criteria. Participants had a mean recipient age of 31 years (range 20 to 35); 13 (93%) MRKH; 1 (7%) prior hysterectomy. Survival: Graft: 14/21 (67% at 1 mo); 13 living donors and 1 deceased donor. Total clinical pregnancy of 23 (14). There were 14 (12) live births. The overall live births success rate was 57% with surgical success of 86%. Complications included acute rejection, CMV viremia, gestational diabetes, gestational hypertension, nausea, opportunistic infection, preeclampsia, prepregnancy hypertension, renal toxicity, UTI, and vomiting.
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| References: |
Allyse M, Amer H, Coutifaris C, et al.(2018) American Society for Reproductive Medicine position statement on uterus transplantation: a committee opinion. Fertil Steril. Sep 2018; 110(4): 605-610. PMID 30196945 Amies Oelschlager AE.(2018) ACOG Committee Opinion No. 728: Mullerian Agenesis: Diagnosis, Management, And Treatment. Obstet Gynecol. Jan 2018; 131(1): e35-e42. PMID 29266078 Arian SE, Flyckt RL, Farrell RM, et al.(2019) 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 Ayoubi JM, Carbonnel M, Pirtea P, et al.(2019) Laparotomy or minimal invasive surgery in uterus transplantation: a comparison. Fertil Steril. Jul 2019; 112(1): 11-18. PMID 31277761 Balko J, Novackova M, Skapa P, et al.(2022) 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 Brannstrom M, Belfort MA, Ayoubi JM.(2021) Uterus transplantation worldwide: clinical activities and outcomes. Curr Opin Organ Transplant. Dec 01 2021; 26(6): 616-626. PMID 34636769 Brannstrom M, Johannesson L, Bokstrom H, et al.(2015) Livebirth after uterus transplantation. Lancet. Feb 14 2015; 385(9968): 607-616. PMID 25301505 Brett KM, Higgins JA.(2003) Hysterectomy prevalence by Hispanic ethnicity: evidence from a national survey. Am J Public Health. Feb 2003; 93(2): 307-12. PMID 12554591 Fageeh W, Raffa H, Jabbad H, et al.(2002) Transplantation of the human uterus. Int J Gynaecol Obstet. Mar 2002; 76(3): 245-51. PMID 11880127 Folch M, Pigem I, Konje JC.(2000) Mullerian agenesis: etiology, diagnosis, and management. Obstet Gynecol Surv. Oct 2000; 55(10): 644-9. PMID 11023205 Fronek J, Kristek J, Chlupac J, et al.(2021) 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 Garg AX, Nevis IF, McArthur E, et al.(2015) Gestational hypertension and preeclampsia in living kidney donors. N Engl J Med. Jan 08 2015; 372(2): 124-33. PMID 25397608 Gauthier T, Piver P, Pichon N, et al.(2014) Uterus retrieval process from brain dead donors. Fertil Steril. Aug 2014; 102(2): 476-82. PMID 24837613 Grimbizis GF, Camus M, Tarlatzis BC, et al.(2001) Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update. Mar-Apr 2001; 7(2): 161-74. PMID 11284660 Hellstrom M, El-Akouri RR, Sihlbom C, et al.(2014) 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 Jarvholm S, Enskog A, Hammarling C, et al.(2020) 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 Johannesson L, Diaz-Garcia C, Leonhardt H, et al.(2012) Vascular pedicle lengths after hysterectomy: toward future human uterus transplantation. Obstet Gynecol. Jun 2012; 119(6): 1219-25. PMID 22617587 Johannesson L, Testa G, Putman JM, et al.(2021) Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study. Obstet Gynecol. Feb 01 2021; 137(2): 241-249. PMID 33416285 Jones BP, Rajamanoharan A, Vali S, et al.(2021) Perceptions and Motivations for Uterus Transplant in Transgender Women. JAMA Netw Open. Jan 04 2021; 4(1): e2034561. PMID 33471119 Lefkowitz A, Edwards M, Balayla J.(2013) 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 Malasevskaia I, Al-Awadhi AA.(2021) 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 Molne J, Broecker V, Ekberg J, et al.(2017) 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 Organ Procurement and Transplantation Network (OPTN).(2022) 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. Organ Procurement and Transplantation Network (OPTN).(2022) Vascular composite allograft. https://optn.transplant.hrsa.gov/professionals/by-organ/vascular-composite-allograft. Accessed March 14, 2022. Putman JM, Zhang L, Gregg AR, et al.(2021) 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 Testa G, McKenna GJ, Gunby RT, et al.(2018) First live birth after uterus transplantation in the United States. Am J Transplant. May 2018; 18(5): 1270-1274. PMID 29575738 Wei L, Xue T, Tao KS, et al.(2017) 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 |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2025 American Medical Association. |
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