Uterine Transplantation for the Treatment of Uterine Factor Infertility

Uterine factor infertility (UFI) is one of the few irreversible causes of female infertility.
Until recently, no medical or surgical options have been available for women with this
diagnosis. UFI is defined by the lack of a functional uterus; this condition can either be
congenital (e.g. Rokitansky syndrome, where a woman is born without an intact uterus) or
acquired (e.g. resulting from hysterectomy or damage to the uterus from procedures or
infections).

Uterine infertility affects 3-5% of the female population. It is estimated that there are at
least 50,000 women of reproductive age with uterine infertility in the United States.
Existing options for women affected by UFI are limited to adoption or maternal surrogacy.
Surrogacy involves harvesting eggs from the UFI patient and fertilizing these eggs in a lab
with the intention of implanting fertilized embryos into a third party who will carry the
pregnancy. Adoption and surrogacy are considered acceptable options for many women with UFI.
For others, due to social, ethical, cultural and/or religious reasons, these options are not
permissible. In many countries around the world, maternal surrogacy is illegal, leaving no
option for UFI patients to conceive a biological child.

Recently, uterine transplantation has been proposed as an alternative method of treating UFI.
Uterine transplantation is intended as a life enhancing procedure, not a life saving
procedure, and is considered to be similar to transplants of the face, extremities and
pancreas. Interestingly, uterine transplantation is considered an "ephemeral" transplant, and
is not intended to last for the duration of the life of the recipient. The transplant is
maintained for only as long as is necessary to produce one or two offspring for the patient.

The need for novel approaches to UFI is clear and exciting work from a team of investigators
in Sweden has finally demonstrated this year that uterine transplantation can result in the
successful delivery of healthy infants with minimal risk to the mother. After careful
collaboration with this Swedish group, we now aim to bring the first uterine transplantation
protocol to the United States using a multidisciplinary team of investigators from within the
Cleveland Clinic.

There have been 11 uterine transplants performed in humans worldwide. The first uterine
transplant was performed in Saudi Arabia in 2000. The living-donor graft survived for 3
months and was subsequently removed due to graft failure. The failure of the graft was
attributed to thrombosis (blood clots affecting the circulation to the organ). Pregnancy was
never attempted using the transplanted uterus prior to it being removed.

This year, Brännström M. et al. published their experience with the first clinical trial of
human uterine transplantation in a series of 9 women. The clinical trial, based in Sweden,
began in 2012 under Institutional Review Board (IRB) approval from the University of
Gothenburg. The nine women in the study group received uteri from living donors and the
report, published in Fertility and Sterility in May 2014, described that seven out of the
nine transplants were viable after six months of follow up. Nonviability of the two grafts
was reportedly due to uterine artery thrombosis. In most cases, donors were the recipient's
mother. Eight of the recipients had Rokitansky syndrome. One recipient had undergone a
hysterectomy for cervical cancer. There were no immediate perioperative complications and all
patients with successful grafts began to have spontaneous menstrual periods within a few
months of transplantation. Mild rejection appeared to be treatable with steroids. All
recipients had 10 viable embryos produced by in vitro fertilization performed prior to
uterine transplantation. Those embryos were then transferred into the transplanted uterus to
achieve pregnancy. This research has now resulted in the first published report of a human
live birth from uterine transplantation.

In the Gothenburg experience, the donor operation consisted of a hysterectomy including the
uterine arteries and veins with the branches of the internal iliac artery and vein and vault
of vagina. The first segment of the ovarian veins caudad to the ovaries (in order to protect
their outflow) was also included. The explanted uterus was perfused with chilled University
of Wisconsin (UW) solution and prepared for implantation. The implantation was achieved by
anastomosis into the iliac vessels bilaterally, in some cases the donor ovarian veins where
included. The vault of the donor vagina was anastomosed into the existing vagina or
neovagina. Immunosuppression following uterine transplantation included induction with
thymoglobulin and maintenance with tacrolimus, mycophenolate mofetil and oral steroids.
Mycophenolate mofetil was discontinued before pregnancy attempts as it is contraindicated in
pregnancy. This immunosuppression regimen is similar to the regimen proven effective in
kidney transplantation, another solid organ graft.

Dr. Andreas Tzakis has been working closely with the Gothenburg group through both early
animal models as well as the recent clinical trial in humans. Below is a summary of this
group's published relevant findings:

1. Two grafts were lost (one soon after transplant and the other 4 months later) due to
uterine artery thrombosis.

2. One donor had a surgical complication, her ureter was injured during removal of the
uterus, and she required a late ureteral reimplantation due to ischemic damage of her
ureter

3. Five recipients developed mild rejection of the graft. This was detected by cervical
biopsy and was treated successfully with steroids in all cases.

4. Menstruation occurred regularly in all seven subjects with a successful transplant
within a few months of transplantation.

5. One documented subject had one live birth by Cesarean section; this pregnancy was
complicated by preeclampsia (high blood pressure of pregnancy) at 31.5 weeks gestation

4. Pregnancy after Solid Organ Transplantation

Since only one live birth in human uterine transplant recipients has been reported, the
pregnancy risks are not firmly established; however pregnancies and deliveries after uterine
transplantation of healthy offspring have been accomplished in small and large animals (mice,
rats, sheep, nonhuman primates). In addition, pregnancy after other solid organ transplants
in humans is well documented.

The use of immunosuppressive medication is well studied in pregnancy after solid organ
transplantation as well as in women with certain rheumatologic conditions and inflammatory
bowel disease. Tacrolimus and cyclosporine are among the most widely used in pregnancy. Birth
defects with cyclosporine or tacrolimus occur at an incidence of 4-5% which is no different
than the general population. Cyclosporine is associated with low birth weight but does not
appear to impact long term outcomes including intelligence quotient (IQ). Mycophenolate
mofetil (MMF) is associated with a specific pattern of birth defects including facial
malformations, finger abnormalities and heart defects. This medication should not be used in
the first trimester of pregnancy. Azathioprine does not cause birth defects. Corticosteroids
are considered safe however high doses can increase the risk of premature rupture of
membranes. Immunosuppression is also noticed in infants exposed to these medications during
pregnancy including low immunoglobulin levels and lymphocyte counts. Most of these deficits
seem to normalize by the sixth month of life, with no noted impact on the infants' health.

Renal transplant is the most common solid organ transplant after which pregnancy has been
reported. In these women over 90% achieve successful pregnancy outcomes after the first
trimester. Pregnancy risks include low birth weight, preterm delivery and preeclampsia. It
has consistently been shown that pregnancy does not adversely affect the graft function or
survival.

The most frequent maternal complication in this patient population is pregnancy induced
hypertension. Management of such pregnancy complications uterine transplant recipients should
follow standard obstetric guidelines.

Prematurity is the main fetal complication, which affects nearly 40% of live births. The mean
reported gestational age at delivery is 36.5 weeks, while the mean birth weight is
approximately 14% less than general population (6 lb 5 oz vs 7 lb 4 oz). Other fetal
complications that have been observed include intrauterine growth restriction (approximately
20%), prenatal infections, and birth defects.

Over 400 pregnancies after liver transplantation have been reported. Similar risks are
reported in these women including preeclampsia preterm birth and low birth weight. Less data
is available from women who have undergone less common transplants. Kidney-pancreas
transplant is associated with a higher complication rates. Hypertension is reported and 75%
in addition there is a 55% risk of infection and 68% risk of low birth weight. These studies
are limited by lack of consideration of the original disease of the organ recipient or the
functional status of the transplanted organ. Women undergoing uterine transplantation will
have no significant preexisting medical conditions unlike women undergoing other solid organ
transplantations. Both these elements are likely to have an influence on the incidence of
complications of the pregnancy and have not been included in previous large analyses.

According to The American Society of Transplantation, pregnancy is allowable in renal organ
transplantation one year after transplantation if there has been no signs of rejection, the
transplanted organ has adequate function, there is no active infection (particularly
cytomegalovirus infection) and the immunosuppression dose has been stable.

Waiting one year after the transplantation prior to conception decreases the risk of acute
rejection and infection. During the pregnancy it is important to monitor blood pressure and
treat hypertension diligently, maintain strict glycemic control, monitor for signs of
infection, and assess maternal levels of immunosuppressive medications more frequently.

Inclusion Criteria:

1. Must meet criteria for uterine factor infertility

1. Prior hysterectomy

2. Congenital absence or malformation of the uterus preventing pregnancy c,
Infertility due to uterine damage from prior injury or infection

2. Must be between the ages of 21-45 and the embryos must have been produced between the
age of 21-39. (age at the time the embryos are produced, not current age)

3. Must be willing to undergo a psychiatric and social work pre-transplant evaluation

4. Must be willing to undergo general anesthesia, in vitro fertilization, major
gynecologic surgery, pregnancy with potential high risk complications, cesarean
delivery and eventual hysterectomy to remove the graft

5. Must be willing and able to receive potent immunosuppressive medications and must be
able to follow standard infection prophylaxis protocols

6. Must be willing to receive standard vaccinations such as influenza, pneumococcus,
human papillomavirus (HPV) and hepatitis B

7. Must be willing and able to sign informed consent and follow all outlined procedures
and recommendations in the protocol

Exclusion Criteria:

1. History of hypertension, diabetes, or significant heart, liver, kidney or central
nervous system disease

2. Any medical diagnosis placing the subject at high risk of surgical complications based
on the transplant team's review of medical history.

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

4. History of prior malignancy except for cervical cancer in stage 1a or 1b after 3
years.

5. Human immunodeficiency virus, mycobacteria, hepatitis B (Hepatitis risk is for those
with hepatitis B (HB) surface and/or core antigen and/or hepatitis B virus (HBV) DNA
positive. Thos that are HB core antibody positive are at minimal risk and everyone
else is not at risk), or hepatitis C.

6. Presence of active documented systemic infection or recent systemic infection within
the past three months

7. Chemical and/or alcohol dependency or abuse

8. Presence of low lying pelvic kidney(s). Pelvic and horse shoe kidneys are common in
the Rokitansky syndrome, and occur with a frequency as high as 30-40%. These
abnormalities are usually known to subjects as part of their Mullerian agenesis
diagnosis. If the patient is unsure about the status of their kidneys, the performance
of a renal ultrasound is considered standard of care. These patients need to be
informed of any kidney abnormalities, as they are frequently associated with kidney
stones or obstructive kidney disease.

9. BMI greater than 30 kg/m2