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Commentaries

The Value of a Nulliparous Uterus

Testa, Giuliano MD, MBA1; Johannesson, Liza MD, PhD1

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doi: 10.1097/TP.0000000000003347
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Uterus transplantation (UTx), with <100 transplants performed worldwide, is a fertility treatment that has the potential to help thousands of women affected by absolute uterine-factor infertility experience gestation and childbirth.1,2 The article by Fronek et al in Transplantation reports a live birth from a mother who had received a uterus from a nulliparous deceased donor. The report provides valuable information that may change the previous praxis of not using uterine grafts from nulliparous donors in UTx and thereby may increase organ availability. Among the 20 reported live births after UTx, only 3, including the 1 reported in this issue, have occurred from deceased donors,3,4 and, in the 2 preceding cases, the deceased donor had at least 1 proven pregnancy and delivery.

One of the recommendations for both deceased and living uterus donors has been previous completion of an uncomplicated pregnancy.2 The reason for being cautious is the risk that the uterus might have undiagnosed pathologies that might impede a successful pregnancy. In the available literature, the prevalence of primary female infertility is calculated as 1.9% of women aged 20–44 y.5 If normal uterine anatomy is verified, the likelihood of transplanting a uterus unable to implant an embryo and carry a pregnancy is slim.

In UTx, as in any other organ transplant, the age of the donor and clinical history are important variables. In the first live birth after UTx in 2014, the uterus was obtained from a living 61-y-old postmenopausal woman.6 Before donation, the donor received hormonal stimulation to assess the uterus’s ability for endometrial response.6 Clearly, the same proof of functionality cannot be replicated with the time constraints of brain death. In the context of the deceased organ supply, age becomes an important issue; although demand for UTx still needs to be assessed, eliminating all nulliparous brain death donors may further reduce what could be an already limited supply. According to data from the United Network for Organ Sharing, the yearly number of female deceased donors of gestational age (18–49 y) in the United States is approximately 2400.7 Since not all of these donors may qualify for uterus donation for many other clinical reasons, the inclusion of nulliparous donors becomes even more important.

The paper by Fronek et al also provides valuable information regarding uterus tolerance to ischemia that might have significance in the developing field of UTx. Small animal studies have shown that the uterus is fairly resistant to ischemia, and pregnancies have been reported to occur after 24 h of cold ischemia.8 In women, the average cold ischemia time in births from uteri obtained from live donors has been 2 h 47 min.8 In previous reports of successful deceased-donor UTx, the ischemia times were 1 h 50 min4 and 6 h 20 min.3 Uterine tolerance to longer cold ischemia times may mean less constraints for donor acceptance, especially in a large country like the United States, and greater flexibility in timing the UTx when the same surgical team has to prioritize other organ transplants from the same donor.

In the report by Fronek et al, both the donor and recipient were cytomegalovirus (CMV) IgG positive. In organ transplantation, CMV prophylaxis is the norm when an organ is given to a CMV-positive recipient or to a CME-negative recipient from a CMV-positive donor. The risk of developing CMV disease may differ among recipients of solid organ transplants, based both on their serology status at the time of transplantation and on the organ they receive.9 For UTx recipients, the implications of CMV infection are more severe than for other organ recipients, since infection may affect not only the health of the mother but also the development of the child. CMV infection is a leading cause of birth defects and childhood disorders, specifically affecting the central nervous system.10 The risk of transplacental transmission of CMV is higher in CMV-seronegative women with primary infection during pregnancy (with a vertical transmission risk as high as 30%–40%).10 CMV infection also adds the risk of placental insufficiency leading to fetal pathologies or termination of pregnancy. To further complicate the matter, it remains unproven whether the therapy that needs to be initiated for treating CMV in pregnancy is potentially teratogenic to the fetus and whether its efficacy is universal.10 Clearly, more data are needed on this matter. Since some pathological manifestations of CMV infection may appear later in life, the children born from mothers with CMV-positive serology during pregnancy will need long-term follow-up.

Strictures at the level of the vaginal anastomosis are common after UTx (personal communication, Cleveland Clinic, University of Pennsylvania, Baylor University Medical Center, Sahlgrenska University Hospital). These strictures are problematic because they may trigger infectious complications, prevent menstruation, and complicate embryo transfer. The strictures have previously been treated with self-dilation or surgical intervention (stricturoplasties). Fronek et al propose the innovative solution of using a self-expanding metallic stent to keep the anastomosis open. Importantly, the successful utilization of the stent described in this unique case was not associated with an increased incidence of infections or modifications of lifestyle. If these findings are confirmed in a larger number of recipients, the utilization of stents may become routine in UTx recipients with cervical strictures.

In summary, at this time when there is no question of the feasibility of UTx, the report by Fronek et al provides valuable information on several important issues in the field. It should be pointed out that conclusions cannot be made from case reports and that efforts should be directed toward collaborative research to optimize the success rate of UTx while minimizing risks for all involved parties.

REFERENCES

1. Jones BP, Saso S, Quiroga I, et al. Re: UK criteria for uterus transplantation: a review. BJOG. 2019;126:1507–1508. doi:10.1111/1471-0528.15912
2. Practice Committee of the American Society for Reproductive Medicine. American Society for Reproductive Medicine position statement on uterus transplantation: a committee opinion. Fertil Steril. 2018;110:605–610. doi:10.1016/j.fertnstert.2018.06.017
3. Ejzenberg D, Andraus W, Baratelli Carelli Mendes LR, et al. Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility. Lancet. 2019;392:2697–2704. doi:10.1016/S0140-6736(18)31766-5
4. Flyckt R, Falcone T, Quintini C, et al. First birth from a deceased donor uterus in the United States: from severe graft rejection to successful cesarean delivery. Am J Obstet Gynecol. 2020;223:143–151.
5. Mascarenhas MN, Flaxman SR, Boerma T, et al. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med. 2012;9:e1001356doi:10.1371/journal.pmed.1001356
6. Brännström M, Johannesson L, Bokström H, et al. Livebirth after uterus transplantation. Lancet. 2015;385:607–616. doi:10.1016/S0140-6736(14)61728-1
7. Organ Procurement and Transplantation Network. Data reports. Available at https://optn.transplant.hrsa.gov/data/view-data-reports/build-advanced/?v=18616.63324901264. Accessed April 29, 2020.
8. Tardieu A, Dion L, Lavoué V, et al. The key role of warm and cold ischemia in uterus transplantation: a review. J Clin Med. 2019;8:760doi:10.3390/jcm8060760
9. Humar A, Snydman D; AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S78–S86. doi:10.1111/j.1600-6143.2009.02897.x
10. Carlson A, Norwitz ER, Stiller RJ. Cytomegalovirus infection in pregnancy: should all women be screened? Rev Obstet Gynecol. 2010;3:172–179.
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