The University of Pennsylvania Uterus Transplant for Uterine Factor Infertility Trial

BACKGROUND The inability to conceive children can be one of the most devastating and traumatic situations to arise in the life of an individual or couple. While assisted reproductive technologies have been developed that help overcome many causes of infertility, uterine factor infertility has remained an intractable condition. Absolute uterine factor infertility (AUFI) occurs when the uterus is either not present (congenitally absent or surgically removed) or is present but is not capable of sustaining a pregnancy. AUFI can result from either congenital absence of a uterus (Mayer-Rokitansky-Kuster-Hauser [MRKH] syndrome) or other Müllerian anomalies. MRKH occurs in 1:4000 of females. It is difficult to determine the exact number of women that suffer from AUFI, however estimates are as high as 7 million women between the ages of 15-34 may suffer from this condition in the United States.

Existing options for individuals with AUFI to achieve parenthood are adoption and the use of a gestational carrier. Use of a gestational carrier is the only alternative that allows an individual or couple to have a child genetically related to the intended parent(s). These options are considered acceptable to many women with AUFI; however, there are a number of significant limitations to these alternatives. The use of a gestational carrier is fraught with ethical, legal, and social controversy because it shifts the burden of gestation from one woman to another, usually for payment. Additionally, adoption and/or surrogacy may not be permissible to a couple due to social, ethical, moral or religious considerations. If these alternatives are acceptable to a couple, they may not be affordable. Finally, these alternatives may not be accessible as barriers to domestic and international adoption have increased and the use of a compensated gestational carrier is not legally protected in most states (and is illegal in some states). The limitations of these alternatives may account for the extraordinary interest in UTx by women with AUFI, as 92% of women with AUFI would undergo UTx as first line management for their AUFI, above adoption and surrogacy.

Understanding the limitations of these alternatives, uterine transplantation (UTx) began to be explored as a concept in animal studies in the 1970s. In 2012, a Swedish team led by Dr. Mats Brannstrom started the first human uterine transplantation trial. The first live birth after successful UTx occurred in Sweden in 2014. As of September 2021, the investigators estimate 33 uterus transplants have been performed in the United States and >10 babies have been born to these women.

Unlike all other transplants, uterine transplantation is "ephemeral". This means that a uterine transplant is only maintained during the individual's child-bearing period which, in the case of uterine transplantation, will be the time necessary to produce one or two children (<10 years). Although pregnancy after transplant is considered high risk, more than 15,000 babies have been born to female recipients of solid organ transplants that were immunosuppressed with no reported increased risk of fetal malformations.

STUDY DESIGN Recognizing that the University of Pennsylvania has been a leader in all of the domains required to build a successful uterus transplant program, planning for the Penn UNTIL trial began in October 2016. The UNTIL trial is is a nonrandomized, interventional human study whose goal is to achieve live birth after donor uterus transplantation. The investigators plan to perform approximately five uterus transplants in this pilot trial. Prior to being listed for transplant, the participants will need to create embryos through ovarian stimulation, oocyte retrieval and in vitro fertilization that will be cryopreserved. After undergoing donor uterus transplantation, participants will be monitored for rejection, infection and other complications for twelve months.

If the graft is clinically stable and any complications that arise are successfully treated 6 months after transplantation, the embryos created prior to transplantation will be directly placed into the uterus in order for the women to achieve pregnancy. If pregnancy is achieved the participant will be monitored by a Maternal Fetal Medicine specialist (high-risk obstetrician) with goal to deliver at 37-39 weeks unless otherwise indicated. All deliveries will occur via cesarean delivery. If the participant and partner wish to attempt an additional pregnancy and the medical team feel it is safe to proceed, attempts at a second pregnancy will be undertaken. Again, if pregnancy is achieved following embryo transfer the participant will be monitored for the duration of her pregnancy by a Maternal Fetal Medicine specialist with goal to deliver at 37-39 weeks through repeat cesarean delivery unless otherwise indicated. Hysterectomy will either be performed at the time of cesarean delivery or shortly following the final cesarean delivery.

The transplanted uteri will be from either living or deceased donors. Interested potential donors will be screened and evaluated and if eligible with continued interest in participation, will undergo radical hysterectomy for the purpose of uterus transplant into a woman with AUFI. Deceased donors will be considered and screened with the organ procurement organization Gift of Life Donation Program.

For more information please visit: https://clinicalresearch.itmat.upenn.edu/clinicaltrial/4821/congenital-abnormalitiesfemale-infertility-penn-ut/