Uterine infertility, the last frontier

Originally developed for bypassing tubal infertility, assisted reproductive technology has progressively broadened the scope of its indications to now include nearly all known forms of infertility. However, uterine infertility remains poorly managed. The availability of assisted reproductive technology-derived embryos has outlined three distinct options and/or research paths when the issue is uterine infertility. The active nature of research and clinical care in these areas justifies an update of each of these pathways. The emblematic form of absolute uterine infertility is the Mayer-Rokitansky-Küster-Hauser syndrome, which is characterized by a congenital absence of the uterus. This syndrome is not transmitted to the offspring. Children obtained through surrogate carriers remain unaffected, and the Mayer-Rokitansky-Küster-Hauser syndrome accounts for <3% of all müllerian malformations, which present in 1 per 4,500 women (1Brannstrom M. Dahm Kahler P. Greite R. Molne J. Diaz-Garcia C. Tullius S.G. Uterus transplantation: a rapidly expanding field.Transplantation. 2018; 102: 569-577Google Scholar). The uterus can also be surgically removed because of hysterectomy performed for either hemostasis, generally after peripartum complications, gynecological cancers, or benign uterine defects incompatible with gestation. Emergency peripartum hysterectomies for uterine rupture, atony, or placenta accreta and percreta are performed in approximately 1 per 5,000 deliveries (1Brannstrom M. Dahm Kahler P. Greite R. Molne J. Diaz-Garcia C. Tullius S.G. Uterus transplantation: a rapidly expanding field.Transplantation. 2018; 102: 569-577Google Scholar). Moreover, 3.5% of women have had a hysterectomy for large and/or unmanageable fibroid(s) before the age of 39 years (1Brannstrom M. Dahm Kahler P. Greite R. Molne J. Diaz-Garcia C. Tullius S.G. Uterus transplantation: a rapidly expanding field.Transplantation. 2018; 102: 569-577Google Scholar). Finally, there are women whose endometrium has been damaged beyond any reasonable chance of repair and/or proper functioning through multiple surgeries for Asherman syndrome and/or submucosal fibroids. Together, all women suffering from absolute uterine infertility are candidates for the following three experimental treatments. The first successful uterine transplantation (UTx) reported by Brannstrom et al. (1Brannstrom M. Dahm Kahler P. Greite R. Molne J. Diaz-Garcia C. Tullius S.G. Uterus transplantation: a rapidly expanding field.Transplantation. 2018; 102: 569-577Google Scholar) was part of a series of 9 UTx procedures. All used live donors who most often (7/9) were genetically related to the recipient and whose age ranged from 32 to 62 years. Eight of the first 9 recipients suffered from Mayer-Rokitansky-Küster-Hauser syndrome, and one underwent a hysterectomy for cervical cancer 7 years prior (2Brannstrom M. Enskog A. Kvarnstrom N. Ayoubi J.M. Dahm-Kahler P. Global results of human uterus transplantation and strategies for pre-transplantation screening of donors.Fertil Steril. 2019; 112: 3-10Google Scholar). Since then, several other UTx programs have been initiated throughout the world, using living or deceased donors. Although UTx using deceased donors is theoretically preferable because it does not impose any risk on a living donor, the approach suffers from a lack of suitable donors and potentially insufficient testing of these donors (3Kvarnstrom N. Enskog A. Dahm-Kahler P. Brannstrom M. Live versus deceased donor in uterus transplantation.Fertil Steril. 2019; 112: 24-27Google Scholar). Surgery for uterine removal in live donors is a complex process, which carries significant risks to the donor. At this time, the procedure, which typically lasts for 10–13 hours, is more invasive than a radical hysterectomy and involves the dissection of uterine arteries and veins and ovarian veins. The latter, which are easier to identify and dissect, may be sufficient for assuring a properly functional uterine graft in the recipient according to the data reported from China (1Brannstrom M. Dahm Kahler P. Greite R. Molne J. Diaz-Garcia C. Tullius S.G. Uterus transplantation: a rapidly expanding field.Transplantation. 2018; 102: 569-577Google Scholar). Recipient surgery is shorter than that required for removal of the uterine graft, lasting approximately 4 to 6 hours (1Brannstrom M. Dahm Kahler P. Greite R. Molne J. Diaz-Garcia C. Tullius S.G. Uterus transplantation: a rapidly expanding field.Transplantation. 2018; 102: 569-577Google Scholar). To date, over 30 UTx procedures have been performed worldwide (1Brannstrom M. Dahm Kahler P. Greite R. Molne J. Diaz-Garcia C. Tullius S.G. Uterus transplantation: a rapidly expanding field.Transplantation. 2018; 102: 569-577Google Scholar). Although its efficacy has been proven, UTx—using live or deceased donors—remains an experimental procedure that is currently still in its infancy. First, the following are the concerns among the limitations of UTx:•Live donors are exposed to significant surgical risk and are almost exclusively family members. Progress is expected in the technical aspects of surgery for graft removal, especially if preliminary data suggest that the sole drainage by ovarian vein(s) is sufficient for the vascular integrity of the graft. The use of robot-assisted surgery may also reduce the operative time for graft removal (2Brannstrom M. Enskog A. Kvarnstrom N. Ayoubi J.M. Dahm-Kahler P. Global results of human uterus transplantation and strategies for pre-transplantation screening of donors.Fertil Steril. 2019; 112: 3-10Google Scholar). Moreover, recipients need to be immunosuppressed for a nonvital condition, such as uterine infertility, for 2–4 years depending on whether 1 or 2 pregnancies are sought.•Currently, most UTx procedures have been performed and financed by research grants. The actual cost of UTx, similar to the published cases that were performed, would be outrageously expensive and beyond the reach of most who suffer from uterine infertility.•Ethical differences around the world regarding reproductive issues will likely lead to different rules and regulations overseeing UTx, which will probably vary from country to country. Further research is warranted, which might permit simplifying the surgical procedure for uterine graft removal in live donors and/or improved fast screaming procedures for diseased donors. Bulletti et al. (4Bulletti C. Palagiano A. Pace C. Cerni A. Borini A. de Ziegler D. The artificial womb.Ann N Y Acad Sci. 2011; 1221: 124-128Google Scholar) first reported the implantation of a human embryo outside the human body, using an ex -vivo uterine perfusion model. The reported data suggest that this approach, using an artificial womb, could allow for the possibility to continue fetal development outside the mother’s body (4Bulletti C. Palagiano A. Pace C. Cerni A. Borini A. de Ziegler D. The artificial womb.Ann N Y Acad Sci. 2011; 1221: 124-128Google Scholar) possibly until a novel artificial placenta could take over further development (4Bulletti C. Palagiano A. Pace C. Cerni A. Borini A. de Ziegler D. The artificial womb.Ann N Y Acad Sci. 2011; 1221: 124-128Google Scholar). Vociferous political and ethical reactions led to the interruption of further studies. In parallel with this effort, the development of an artificial endometrium using stromal and epithelial endometrial cells is also underway. However, for the time being, the most permissive ethical regulation—in the UK (http://www.progress.org.uk/the-14-day-rule-for-human-embryonic-research-in-the-uk/)—only allows the study of embryo development for up to 14 days (13 days after conception). Changes in these dispositions might one day allow the study of the in vitro development of embryos up until artificial placentas may take over the control of embryo development. A different line of research is directed toward the development of an artificial placenta to permit the maturation of extremely premature infants. In this area, the development of the bio-bag project deserves mention. It consists of a sealed bag designed to contain the developing fetus, a pumpless oxygenator circuit, and umbilical cord access. This promising approach has been tested in lambs starting at a developmental stage equivalent to that of a 24-week human fetus. After incubation, all lambs were delivered at term and survived. The bio-bag enables the constant exchange of amniotic fluid and provides all the necessary water and nutrients. The umbilical cord is cannulated with an artificial circulation mimicking the function of a normal placenta (4Bulletti C. Palagiano A. Pace C. Cerni A. Borini A. de Ziegler D. The artificial womb.Ann N Y Acad Sci. 2011; 1221: 124-128Google Scholar). Finally, the first pig-to-human heart transplantation offers a new possible avenue for helping women with absolute uterine infertility through xenograft models (5Reardon S. First pig-to-human heart transplant: what can scientists learn?.Nature. 2022; 601: 305-306Google Scholar). Alone or in combination with artificial placenta, systems such as the bio-bag could be developed one day. The artificial uterus pathway toward treating cases of absolute uterine infertility is still in preclinical stages. Yet the work accomplished to date assures that this approach may one day be feasible as a real clinical option in the near future. Surrogacy per se has its roots in antiquity and is notably found in biblical tales. The story of Sarah and Abraham, who conceived their heir with the help of their handmaiden, Hagar, who carried the child, Ishmael, is an early description of traditional surrogacy. Today, we refer to traditional surrogacy as a situation wherein a woman becomes pregnant through insemination with the sperm of the intended father while contributing her own oocyte and carrying the pregnancy. Alternatively, a gestational surrogate, or gestational carrier, is a woman who becomes pregnant through the transfer of an embryo obtained in vitro from the gametes of the two intended parents with or without the use of donor gametes as needed. Hence, the gestational carrier has no genetic relationship with the offspring she carries. The use of gestational carriers is authorized in some states in the United States with sets of guidelines overseeing this practice regarding the requirements for the surrogate carrier and the intended parents. Unlike the United States, gestational surrogacy is forbidden in many other countries. For example, surrogacy is considered criminal in France. However, gestational surrogacy is authorized and unrestricted—for natives and foreigners— in certain countries, such as Russia, Georgia, and Ukraine. In the latter country, a hub of international gestational surrogacy, approximately 2,500 cases were performed annually because of the relatively low costs and minimal regulations. Some have argued that surrogacy is an example of “first-world” countries taking advantage of “third-world” countries. According to these views, women from relatively poor countries are being used to satisfy the desires of Western couples. In fact, many countries—including India, Thailand, and Cambodia—have passed laws to limit surrogacy in their nation or to use only an altruistic model that limits payments to medical costs. The recent unfolding of the war in Ukraine has led to dramatic consequences for some gestational carriers and Western intended parents as well. Some infants delivered by surrogate mothers have been seen in the media, parked in the basements of bombarded buildings. Some surrogate mothers have been forced by agencies to flee Ukraine, often leaving their own families behind. The war in Ukraine and its dreadful consequences have highlighted the limitations of the international transborder gestational surrogacy business in a most dramatic way (https://www.nytimes.com/2022/05/03/magazine/surrogates-ukraine.html). Absolute uterine infertility stands as the last frontier for developing adequate treatments. Uterine transplantation has had a series of successes and represents the current most promising option, but it remains experimental and engenders serious surgical risk for the live donor and screening difficulties in the case of deceased donors. The artificial uterus option is still far from being clinically viable, but hopes exist that remaining technical problems may be solved in the future. At first glance, gestational surrogacy appears to be an ideal option in countries, such as the United States, where it is authorized and accompanied by guidelines. Yet the costs and ethical issues raised by gestational surrogacy, especially when carried out in international settings, continue to give the reproductive medicine community pause for thought. A recent article on surrogate mothers and infants in times of war in Ukraine eloquently speaks about these issues: The nightmare of being a surrogate mother in the Ukraine war, The New York Times (https://www.nytimes.com/2022/03/12/world/europe/ukraine-surrogate-mothers-babies.html?searchResultPosition=1).