Penn Uterine Transplantation 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 gestational
surrogacy. Gestational surrogacy 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. Gestational surrogacy 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 compensated surrogacy 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. Since 2014, in total eight children have
been born to women who underwent uterine transplantation in Sweden.

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.

Several centers in the world are either embarking on or are considering the development of
uterine transplantation protocols. Although multiple centers have had successful organ
engraftment occur following uterine transplants from both living and deceased donors, as of
September 2017, no live births have occurred outside of Sweden.

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 deceased donor uterus transplantation
(DDUTx). There are two phases to the trial. In Phase 1, the investigators plan to evaluate
approximately 40 women with AUFI. From this cohort, the investigators will select five
candidates who fulfill the inclusion criteria and are deemed the most suitable candidates for
uterine transplant. Prior to being listed for transplant, the women will need to create
embryos through ovarian stimulation, oocyte retrieval and in vitro fertilization that will be
cryopreserved. After undergoing deceased 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
12 months after transplantation, the women will enter Phase 2 of the trial. In Phase 2, 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. Two months after the second cesarean
delivery when the uterus has returned to its normal size, a hysterectomy will be performed
and immunosuppression withdrawn.

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

Participant Inclusion Criteria:

1. XX-bearing individual diagnosed with Absolute Uterine Factor Infertility (AUFI) as a
result of: A) prior hysterectomy or B) congenital absence or malformation of the
uterus preventing pregnancy

2. Age 21-40

3. Received counseling regarding alternatives to uterine transplant such as adoption or
surrogacy

4. Intact ovaries and normal ovarian reserve (defined as anti-Müllerian hormone level ≥2
ng/mL and/or follicle-stimulating hormone level ≥10 IU/L)

5. Vaginal length >6 cm (average vaginal length established with dilators)

6. Body mass index <30 kg/m2

7. Fluent in the English Language

8. If cervix present/previously present, human papillomavirus (HPV)) negative or received
vaccination for HPV

9. Willing to comply with screening, protocol and all required procedures

10. In stable committed relationship for ≥3 years

11. Has undergone controlled ovarian hyperstimulation, egg retrieval, in vitro
fertilization, preimplantation genetic screening and embryo freezing and has frozen
embryos of sufficient embryo quality/quantity (minimum 4 blastocysts ≥3BB grade or ≥2
chromosomally normal embryos)

Participant Exclusion Criteria:

1. Previous multiple major abdominal/pelvic surgery

2. Severe endometriosis

3. History of hypertension, diabetes mellitus, thrombophilia or other clotting or
bleeding disorders, significant heart, liver, kidney or central nervous system disease

4. History of prior malignancy except for cervical cancer in stage 1a or 1b (must be in
remission for 3 years)

5. History of significant psychiatric illness

6. Allergy, hypersensitivity, or intolerance of expected immunosuppressive agents (i.e.
Thymoglobulin®, tacrolimus, etc.)

7. Allergy, hypersensitivity, or intolerance of heparin or aspirin

8. Presence of active documented systemic infection or recent systemic infection within
the past 3 months

9. Seropositivity for HIV, HBV, HCV, HTLV-1

10. Current smoker (smoking cessation must have occurred 3 months prior to enrollment)

11. Chemical and/or alcohol dependency or abuse

12. Psychosocial problems (including alcoholism, drug abuse, documented behavioral
disorders)

13. Renal abnormalities, specifically single kidney or pelvic kidneys

14. Contraindications to pregnancy

15. Unwilling to receive a transfusion of blood or blood products

Women interested in being a live donor of their uterus are also being accepted.