Uterine Factor Infertility (UFI) is a devastating and prevalent condition that affects five percent of women worldwide and 50,000 women in the United States. Whether congenital or acquired, women with UFI are unable to carry and deliver babies. But, advancements in women’s health and transplant surgery are helping to create new solutions for these women and their families. In 2014, a team of researchers from Sweden published a paper in The Lancet on the first successful uterine transplantation with a subsequent pregnancy and live birth. Quickly, several institutions in the United States – including experts at Penn Medicine – began exploring the feasibility of uterine transplantation (UTx).
Women with the congenital form of UFI are born without a uterus. Acquired UFI occurs when women have had the uterus removed surgically (a procedure called a hysterectomy), or it can be the result of dysfunction (generally due to adhesions or lesions in the uterus which would inhibit a woman’s ability to conceive). While there are alternative options like adoption and surrogacy, many women aspire to carry a child. At the same time, surrogacy is not an option in some parts of the world. In fact, it’s illegal in places like Sweden, where the world’s first live birth after uterus transplant occurred. Importantly, compensated surrogacy is also illegal in several states in the United States, including New York.
“Uterine transplantation is an experimental therapy that gives women with uterine factor infertility the opportunity to have a genetic child outside of surrogacy,” said Kate O’Neill, MD, MTR, an assistant professor of Obstetrics and Gynecology in the Perelman School of Medicine at the University of Pennsylvania. “Uterine transplantation has the potential to provide women suffering from UFI with a real treatment, not just an alternative, but a true opportunity for them to conceive, carry, and deliver children.”
Since the 1950’s, physicians and surgeons have been perfecting the field of transplantation — beginning with the first successful kidney transplant in 1954, the first successful lung transplant in the early 1980’s, and eventually standardizing heart, liver, and intestinal transplants. Today, these procedures are commonplace and have saved the lives of tens of thousands of patients who would otherwise not survive their illnesses.
Recent progress in the field of transplantation has been expanding beyond lifesaving solid organ transplants to Vascularized Composite Allograft (VCA) transplants — the transplantation of multiple tissues including muscle, bone, nerve and skin, as a functional unit, such as a hand or face. VCA transplants, which include UTx, are the way of the future, providing patients with a significantly better quality of life.
L. Scott Levin, MD, FACS, director of Penn’s Hand Transplant Program and chair of Orthopaedic Surgery, said in a 2016 interview with the Philadelphia Inquirer, "If you don't have a functioning heart, we know you're going to die. We know you can live without hands, a face…but your quality of life is extremely compromised. Some would say, 'Without them, 'I'm not living.'”
However, improving quality of life through UTx does not come without a myriad of questions, considerations, and potential surgical, obstetric, and medical risks: Are the immunosuppressant medicines moms-to-be must take safe for their babies? Should these women put themselves at risk by undergoing such a complicated elective procedure? Is there a possibility for organ rejection while the patient is pregnant and if so, could that lead to complications with the fetus? If UTx with deceased donor organs is a viable avenue, what are the cost implications if the procedure becomes widespread? While some of these questions will remain unanswered until more is known about the procedure, as is the case with any pioneering medical breakthrough, first comes a leap of faith, coupled with a tremendous amount of rigorous research and planning in preparation for any and all possible outcomes. And so far, things have been progressing positively in the field over the last six decades.
“We are at a pivotal point in the field where we need to determine whether VCA transplantation is going to become the standard of care,” said Levin, who pioneered the Hand Transplant Program alongside Abraham Shaked, MD, PhD, director of the Penn Transplant Institute. Levin was lead surgeon on the Philadelphia region’s first bilateral hand transplant in 2014, the world’s first pediatric bilateral hand transplant in 2015, the world’s first bilateral hand transplant on an international patient in the United States in 2016, all of which have contributed to making Penn Medicine a preeminent domestic and international VCA center. “We are moving past transplant exclusively in a lifesaving capacity and toward a future where we can give patients, those who are devastated by limb loss, uterine infertility, or severe facial injury, a significantly improved quality of life,” Levin said.
To date, more than 30 uterine transplants have been completed across the world including Brazil, China, the Czech Republic, Germany, Sweden, and at two centers in the United States (the Cleveland Clinic and Baylor Medical Center). The transplanted uterus can come from either a deceased or a living donor. In the world, the majority of the transplants have come from living donors. With living donors, a woman who has had children and does not plan to have any more can donate her uterus to another woman who has UFI. In trials across the world, this has happened for mother-to-daughter or sister-to-sister donors, and in one case, one woman’s friend donated her uterus so she could conceive.
While the field is still in its earliest stages, uterine transplantation has already proven successful for some women. Eight babies have been born in Sweden, following seven successful uterine transplants, with two of the women delivering two healthy babies. Emelie Eriksson, the first woman to have a baby following UTx – a son, named Albin, who is now two years old – said in an interview, “it was a pretty tough journey over the years, but we now have the most amazing baby. He's no different from any other child, but he will have a good story to tell.” This milestone came as a result of a living donation: Emelie’s mother, Marie, donated her uterus to her daughter. In another interview, Marie said, “I thought this was something that could only happen (far) in the future. But then I said to Emelie, ‘I’m so old, I don’t need my womb and I don’t want any more children. This is your only chance to have a child and you should take it.”
“Uterine transplants are at the forefront of women’s health advancements,” said Deborah Driscoll, MD, chair of Obstetrics and Gynecology at Penn Medicine. “There was a time when we had no answers for these women who couldn’t have children, many of whom had heartbreaking stories, and lifelong struggles. But, advancements over the years have made IVF a standard practice, and now we’re able to see uterine transplants as a promising avenue for these women who otherwise have no option to carry children. We’re thrilled to be part of these breakthrough efforts.”
While the only babies born following UTx in the world so far have been born following transplants from living donors, Penn Medicine’s newly launched UTx clinical trial — known as The Uterine Transplantation for Uterine Factor Infertility (UNTIL) trial, and led by O’Neill and a team of colleagues across Transplant Surgery, Obstetrics and Gynecology, and Maternal Fetal Medicine — is moving forward with uterine transplantation only from deceased donors; donors who have delivered babies of their own (i.e. proven fertility).
“We’ve elected to move this trial forward using organs from deceased donors for a variety of reasons,” said Paige Porrett, MD, PhD, a transplant surgeon and a co-principal investigator on the UNTIL trial. “However, one of the challenges with this approach is the timing. Once we retrieve the organ, we aim to transplant the donor uterus within six to eight hours into the recipient. Although it may be possible to extend this time further, rapid transplantation will help us best attain our goal of a viable and healthy uterine transplant”
The UNTIL trial will occur in a two-phased approach—the first phase is a feasibility phase, which will encompass the patient evaluation, embryo harvesting, and the transplant itself. Importantly, following the transplant the woman will need to be on immunosuppressive medications that prevent her body from rejecting the donor uterus. The second phase, which will occur approximately one year after successful transplantation, will include the embryo transfer, pregnancy, and delivery. The team also plans to study pregnancy and the maternal immune system in this unique setting which has the potential to advance their understanding of these processes and benefit all women.
“After one year of clinical stability following uterine transplantation, the woman’s frozen embryos will be placed directly back into the uterus one at a time. Once pregnancy is achieved the woman and her baby will be monitored closely by a team Maternal Fetal Medicine (MFM) physicians that specialize in high-risk obstetrics,” said Eileen Wang, MD, an associate professor of Obstetrics and Gynecology and lead Maternal Fetal Medicine physician on the UNTIL trial. “People take for granted the complexity of normal pregnancy. If you layer the issues of transplantation and immunosuppressive medications on top of pregnancy, the pregnancy inherently becomes more complicated. MFMs have experience managing pregnancies in women with transplanted organs such as kidney, heart, and pancreas and therefore are well equipped to provide care for women and pregnancies following uterine transplantation.”
The women in the trial will undergo cesarean delivery at 37 to 39 weeks unless medically indicated to deliver sooner. Cesarean delivery is required since women cannot labor and deliver children vaginally following uterine transplantation. While the birth of a healthy baby may be the ultimate goal for these women, it’s not the end of their road in the trial. Once the woman has had one or two live born children, the uterus will be surgically removed, thus eliminating the need for the women in the trial to be on life-long immunosuppression medications.
O’Neill added, “We believe this procedure has the potential to provide women with the ability to choose the best option for them—whether it is carrying their children through uterine transplant or another alternative way to become a parent.”