Mats Brännström, MD, PhD, was beyond skeptical when a patient undergoing a hysterectomy for cervical cancer in 1998 asked him for a uterus transplant to restore her fertility.
“I thought she was crazy,” said the professor of obstetrics and gynecology at the University of Gothenburg in Sweden.
But the request set off a more than decade-long effort by Brännström, a fertility researcher and gynecologic surgeon, and his colleagues to determine whether transplanting a uterus was feasible. Meanwhile, groups in Saudi Arabia and Turkey sought to answer the same question. Even though they performed the first 2 human transplants, neither resulted in a successful pregnancy.
By 2013, the Swedish team was close to its goal. A 9-patient trial of uterine transplants launched that year produced the first successful delivery in 2014. Since then, 7 of the 9 women have become pregnant, resulting in 5 successful deliveries.
“We were well prepared as a group because we had done the surgery for many years together in animals,” Brännström said.
The team’s success has inspired others around the globe to attempt the transplants. Two US institutions, the Cleveland Clinic and Baylor University Medical Center in Dallas, have launched their own clinical trials with 5 transplants between them at press time. So far, 4 of the 5 transplanted uteruses have been removed because of complications. The trials have thrust the experimental procedure into the spotlight and sparked debates about the ethics of the procedure, which involves living or deceased donors.
The Brännström trial is scheduled to wrap up in a year and a half when all 7 of the women who retained their transplants will have given birth. Three women are currently pregnant, including one with her second pregnancy with the transplanted uterus.
The trial enrolled 8 women who were born without a uterus and 1 who had undergone a hysterectomy. All of the donors were living; most were relatives of the recipient. One was a mother-in-law and another a family friend. All donors had at least one normal pregnancy and delivery.
The donors underwent an 11- to 13-hour surgery to retrieve their uterus and “long vascular trees with arteries and veins,” he said. The length of the procedure surprised Brännström and his team, who initially thought it could be done in 5 to 6 hours.
“It’s an extremely difficult surgery,” Brännström said. By comparison, a hysterectomy typically takes 1 to 3 hours.
The transplant itself takes about 4 hours, but it is complex requiring microsurgical connections of the veins and arteries on both sides of the uterus as well as connecting the uterus and securing the uterus itself in place.
“This is one of the most complicated types of transplants because the vessels are small and we are so deep in the pelvis,” he said.
Two of the transplanted uteruses had to be removed shortly after the procedure. One women developed thrombotic occlusion of the uterine artery and the other developed a bacterial infection that did not respond to antibiotic treatment.
“We learned mostly from the failures,” Brännström said. For example, he said some postmenopausal donors older than 60 years might have had uterine blood vessels that were too thin to keep the transplanted organ well nourished.
All recipients underwent in vitro fertilization procedures prior to the transplant. A year after surgery, recipients with successful transplants had individual embryo transfers to try to become pregnant. The trial has begun to reveal risks associated with the procedure. Some of the women who were born without a uterus also have one kidney, which increases the likelihood of preeclampsia, and some of the recipients have developed the condition during their pregnancies, Brännström noted. Some of the neonates have also been delivered several weeks early because of concerns about the risks of continuing the pregnancy. For example, preeclampsia can lead to a stroke in the mother or fetal growth restriction.
Recipients require immunosuppressive therapy for as long as they retain the uterus, although Brännström and his colleagues hope the women will agree to surgical removal after 1 or 2 pregnancies to spare them lifelong immune suppression.
Data on the risks to the fetuses gestated in a transplanted uterus are limited. However, a higher risk of early delivery and low birth weight has been documented in infants of mothers who have undergone kidney transplants relative to those whose mothers had not undergone transplant. Registries that have tracked the rate of major malformations in infants born to kidney transplant recipients on immunosuppressive medications during pregnancy haven’t found higher rates than in the general population. So far, the babies delivered after uterine transplant are healthy and doing well after delivery, Brännström and his colleagues have reported.
As far as the donors, one suffered a ureter injury during surgery that later had to be repaired, he noted. Brännström and his colleagues have followed up with donors for 3 years and plan to follow them for another 2 years. “All are in good health psychologically and physically,” he said.
In the United States, uterine transplants have gotten off to a rockier start.
The Cleveland Clinic conducted the first US uterine transplant last year in a 9-hour procedure using a deceased donor as part of a 10-patient trial. The team, which included a transplant surgeon from the Swedish team, chose to use a deceased donor to avoid subjecting a living donor to the risks of surgery.
“We felt in this country, there had to be almost no risk to the donor,” said Tommaso Falcone, MD, a professor and chair of the department of obstetrics and gynecology at the Cleveland Clinic.
Using a deceased donor also allowed for a shorter 2-hour organ retrieval surgery, which was performed after potentially life-saving organs were removed. Another advantage is that the surgeons were able to retrieve larger blood vessels from the donor without risking bleeding, said Falcone. It was hoped the larger vessels would reduce the risk of thrombosis in the recipient.
Unfortunately, the recipient developed a yeast infection and surgeons later removed the uterus.
“We had a complication that was not foreseen,” said Falcone. “Since then, we’ve been working diligently on how to prevent it next time.”
The team sent protocol revisions to its institutional review board and plans to schedule the next transplant later this year. The revisions aim to reduce cold ischemia time for the donated organ and to avoid thrombosis and infection in the recipient.
The Baylor Scott & White Research Institute in conjunction with the Baylor University Medical Center, both in Dallas, also embarked on a 10-patient clinical trial in 2016 that will use both living and deceased donors.
“We felt that this clinical trial was a natural next step in the evolution of transplantation and fertility treatment,” said Giuliano Testa, MD, the principle investigator and chief of abdominal transplantation at Baylor. The Baylor team announced the planned trial in January 2016 and received inquiries from both potential recipients and donors, said Testa.
“The response of the donors has been one of the most uplifting experiences and has positively charged the whole team,” Testa said.
The Baylor team performed 4 transplants—each transplant took about 5 to 6 hours—between September 14 and 22, 2016, using organs from the living donors and modifying the procedure along the way, said Testa. A gynecologist and a transplant surgeon from the Swedish team participated, according to Brännström. Within 3 weeks of the transplants, 3 of the organs had to be removed because of inadequate blood flow. The fourth recipient was still doing well late last year.
Reviews of the 3 failed transplants by the Baylor team and their Swedish colleagues have yielded valuable insights that may change “operative and postoperative management of uterine transplant patients,” said Testa. In particular, he said that the thickness of uterine veins in the donors must be carefully assessed.
“We have learned that additional radiology imaging can assist in determining the quality of uterine veins when in the evaluation phase and that the status of the arteries within the uterus can be a major factor in assuring a good outcome,” Testa said.
Brännström and his colleagues plan to launch a second trial of uterine transplants with robot-assisted surgery, which he thinks will help improve retrieval of the blood vessels.
Meanwhile, Nebraska Medicine is in the early stages of planning its own trial using deceased donors, and Brigham and Women’s Hospital is exploring the possibility of starting a trial.
As a non-lifesaving transplant, uterine transplants, which may involve risks to the donor, recipient, and fetus, exist in complicated ethical territory.
Women have a long history of taking on serious risks to become pregnant, noted Ana Iltis, PhD, director of the Center for Bioethics, Health, and Society at Wake Forest University in Winston-Salem, North Carolina.
“These women are saying this is worth it to me,” she said. But it also raises “larger societal questions about the value we place on having biological children and the experience of pregnancy.” Recipients must be informed about the potential risks and alternatives to the procedure, such as adoption or use of a gestational surrogate, Iltis emphasized.
But she also noted that it’s important participants know that many risks to uterine transplant recipients, their donors, and their children are unknown.
“We don’t know enough about what it means to gestate in a uterus that was transplanted,” Iltis said.
In Sweden and much of Europe, however, gestational surrogacy is prohibited, Brännström said. He suggested that exploring the feasibility of uterine transplants as a treatment “is a matter of justice,” because it provides a fertility option for women born without a uterus.
Fertility treatments are covered for free in the Swedish health system, he noted. He estimated the cost in the Swedish system to be about $60 000. In the United States, he noted, the cost would be much higher.
The use of living donors has also proved controversial. It is hoped living donors might offer a better quality organ and easier scheduling of surgery, but living donors are exposed to serious risks, noted Iltis.
“The first thing is people need to be incredibly clear that this is not a hysterectomy,” Iltis said. “It’s a much more complicated and involved surgery.”
She said at minimum donors must be fully informed about the known and potential risks and the experience level of the surgeons doing the procedure.
With fewer deceased donor uterine transplants to date, there isn’t yet enough information to decide whether they might provide a viable alternative.
“It’s way too soon to give up on using deceased donors,” Iltis said.
Brännström agreed and suggested that it is important for trials involving both living and deceased donors to continue to allow surgeons to optimize the procedure and to gather information for patients.
Falcone predicted that uterine transplants are here to stay.
“It’s driven by patients, not gynecologists and transplant surgeons,” Falcone said. “As long as patients want it, there will be people trying to figure out how to make it safe and effective.”
read more at JAMA