Uterus Transplants Hit the Clinic

ABOVE: MODIFIED FROM © SHUTTERSTOCK.COM, HAPPY_FOX_ART

Learning at age 14 that she had a developmental abnormality that left her with no uterus, Jennifer Dingle didn’t immediately understand or share the devastation that she could see in her mom’s eyes. But years later, after she got married and her friends began getting pregnant, she fell into a depression thinking about how she would be able to have a family of her own. The options, gestational surrogacy and adoption, didn’t appeal to her. She wanted to carry her own child.

She first heard about a more palatable solution to her predicament in her mid-20s, when her gynecologist mentioned that uterus transplantation was beginning to enter clinical trials. The doctor told her not to count on the experimental procedure, which was only just beginning to be tested in humans, but Dingle began looking into it. She found an ongoing clinical trial in Sweden and another in the UK that was just getting off the ground, “and then I had my hopes and dreams set on it.” 

Unfortunately, the Swedish trial was fully recruited, and the UK program hadn’t yet begun enrolling participants—she’d hit a dead end. Then one day in early 2016, in her two-bedroom apartment on a US military base in Naples, Italy, where her husband was on assignment for the Navy, she got a call from her mom back home in Texas. “She says, ‘You’re never going to believe what I seen on the news here,’” Dingle recalls. “‘Baylor Dallas is starting a uterine transplant trial for women like you.’”

A MIRACLE IS BORN: Jennifer Dingle and her husband Jason welcome their daughter Jiavannah on February 19, 2018.

SHANNON FAULK FOR BAYLOR SCOTT & WHITE

Dingle quickly tracked down the uterine transplant nurse at Baylor University Medical Center and asked to be considered for the trial. By the end of the year, she was headed to the hospital for the study’s fifth transplant surgery—and she did it knowing that three of the first four had failed. Even facing those odds, “there was nothing in me that wanted to cancel my uterus transplant,” she recalls.

On December 8, 2016, the Baylor team made an incision in Dingle’s abdominal wall, identified the top of her vagina, and placed the donated uterus, which less than an hour earlier had been removed from an anonymous living donor, into the cavity where Dingle’s own uterus should have been. The surgeons then sewed the organ’s veins and arteries to blood vessels that extended down Dingle’s legs and watched as it began to circulate her oxygenated blood. Finally, they connected the cervix and small piece of the vagina that had come with the donor organ to the top of Dingle’s own vagina.

With the help of immunosuppressant drugs, Dingle’s body accepted the uterus, and six months later, her doctors placed an embryo made from her egg and her husband’s sperm into her new womb. It worked. For nearly 37 weeks she experienced an anxiety-ridden but uneventful pregnancy, and on February 19, 2018, she underwent a Cesarean section to welcome her daughter Jiavannah—the second baby born to a woman with a transplanted uterus at Baylor, and among the first dozen such babies in the world.

The idea of uterus transplantation to treat infertility caused by the lack of a functional uterus is less than 25 years old. Clinical trials testing the procedure in humans all started within the past decade, primarily for the condition that Dingle has: Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), in which XX-carrying individuals are born with ovaries but no uterus. Despite its short history, uterus transplant is now becoming clinically available. This past April, Baylor surgeons performed the country’s, and possibly the world’s, first uterus transplant outside the context of a clinical trial, and the University of Alabama at Birmingham (UAB) is beginning to screen patients for its brand-new uterus transplant program. “It has been very fast,” says transplant surgeon Paige Porrett, who is spearheading the UAB program. “This is a tempo that we don’t usually see in medical innovation.”

It’s going to be a transformative transplant. It’s a life-creating, life-enabling type of transplant.

—Cristiano Quintini,  Cleveland Clinic

Some doctors urge caution in recommending uterus transplantation to patients when gestational surrogacy is legal in many countries and most US states, providing people lacking a uterus the means to have children who are biologically their own. Meanwhile, ethicists are actively discussing factors such as the use of living donors, who are putting themselves at risk, and the value people place on carrying the pregnancy themselves. Patients must also consider the price tag—just under $300,000 for the donor’s and recipient’s surgeries and care—and the fact that uterus transplantation is not currently covered by health insurance companies. 

The transplant surgeons and obstetrician-gynecologists involved in developing and trialing the procedure express passionate beliefs that uterus transplant is safe, effective, and addresses a need felt by hundreds of thousands of people. In addition to MRKH, which affects roughly 1 in 4,500 XX individuals worldwide, more than 600,000 people undergo hysterectomies each year in the US alone, and many of them are still of reproductive age. Uterus transplant could provide a way for those people to carry their own children even after having their own wombs removed. Some in the uterus transplant field even envision a future in which transgender women will be able to carry their own children.

“It’s going to be a transformative transplant,” says surgeon Cristiano Quintini, who runs the Cleveland Clinic’s uterus transplant trial, the first of three clinical studies to be launched in the US. “It’s a life-creating, life-enabling type of transplant.”

The Uterus Transplantation Process THE SCIENTIST STAFF; © istock.com, anttohoho

Mice to humans in a decade

One Friday afternoon in 1998, during a stint as a gynecological oncology surgery fellow at Royal Adelaide Hospital in Australia, Mats Brännström spoke with a cervical cancer patient who was about to have her uterus removed. Wanting to one day carry her own child, the patient asked Brännström if she could get a replacement womb. 

He’d never thought about transplanting a uterus before, and at first blush it seemed a bit crazy, he admits. But after discussing the idea with a colleague over beers at a pub after his shift that day, Brännström began to consider it more seriously. With his background in treating infertility, he was intimately aware of the needs that uterus transplantation could meet, and having just learned the complexities of hysterectomies and other uterine surgeries, “I could see that this was possible.” And so, returning to his home country of Sweden the following year, Brännström started an animal research program at the University of Gothenburg to investigate the feasibility of the procedure, and the ability of a transplanted womb to gestate a fetus to term.

Brännström had never thought about transplanting a uterus before, and at first blush it seemed a bit crazy, he admits.

He started in rodents, publishing on the first successful births from transplanted uteruses in mice in 2003. Around this time, other physicians and researchers independently began to consider the concept. The year before, a research group in Saudi Arabia had published a case study of the first uterus transplant in a human being, completed in April 2000. Unfortunately, doctors had to remove that uterus within a few months due to major blood clots in the uterine vessels. “Of course, I was a little worried because it had failed,” Brännström says, but he adds that he felt confident that the procedure was possible; it just needed some basic research to support it. Over the next several years, he and his colleagues began transplanting uteruses in larger and larger animals—first rats, then pigs, sheep, and baboons.

In May 2013, the team was ready to move the technology into human patients and launched the world’s first uterus transplant clinical trial, based at Gothenburg’s Sahlgrenska University Hospital. Nine women, eight of whom were born without a uterus and one who’d had a hysterectomy, had their eggs extracted for in vitro fertilization (IVF) and underwent the transplantation procedure. In most cases the living donors were family members, but in one case, a close friend. Two of the transplanted uteruses had to be removed after an artery in one became blocked and the other developed an antibiotic-resistant bacterial infection, but the other seven were accepted by their hosts, and in September 2014, the first baby was born. Several other births followed, with six participants from the trial having at least one child each; three of those individuals had two each before having the organs removed to allow them to discontinue immunosuppressant drugs, which increase risk of infection, among other side effects.

Although some of these infants had to be delivered up to eight weeks before their due date due to the risks of preeclampsia, all of the babies were healthy. Overall, Brännström and his colleagues reported no red flags for a procedure that was allowing XX individuals once missing a uterus to carry their own children. Other institutions around the world were beginning to take notice. 

Trials to the clinic within another decade

When Kate O’Neill, then a fellow at the University of Pennsylvania (UPenn), heard Brännström give a talk at the American Society for Reproductive Medicine (ASRM) about uterus transplants in October 2014, she thought the approach “was a little fringe,” she says. Outside of the Gothenburg trial, very few sites in the world, and none in the US, had attempted uterus transplantation in humans, and investing time and resources into the procedure was controversial, she says. But O’Neill was drawn to the idea. “You have transplants used to save and extend lives, and here was an application of transplant to generate new life.” Just a few years later, she would launch a uterus transplantation trial at UPenn, on the heels of two other programs in the US. 

The Cleveland Clinic was the first to launch, in October 2015. After conducting his own animal work and traveling to Sweden to observe Brännström’s team complete a uterus transplantation, Cleveland Clinic transplant surgeon Andreas Tzakis, who collaborated with the Swedish group, helped launch a trial of 10 people seeking the procedure. The trial would be the first in the US to use uteruses from deceased donors, which eliminates the risks involved with harvesting uteruses from living donors (see also “Bioengineering a Uterus” below) and allows for a shorter organ retrieval surgery that could also give surgeons the opportunity to harvest more, larger blood vessels that might reduce the risk of blockage after transplantation. “We do see this as the future in the field,” says Quintini. But the Cleveland Clinic program got off to a rocky start, with the first transplanted uterus having to be removed within a couple weeks after the recipient developed a severe yeast infection that was transferred from the donor. Additional transplantations were then delayed as the team reworked the protocol to reduce the time the donated organ was in cold storage and take other measures to minimize the risk of complications.

Baylor Scott & White Research Institute (BSWRI) in Dallas launched its 10-patient trial at Baylor University Medical Center in January 2016, headed by transplant surgeon Giuliano Testa and gynecologist Liza Johannesson, a former member of Brännström’s transplant team in Sweden. The Baylor group chose to use both deceased and living donors, though in contrast to the Swedish trial, living donors and recipients didn’t typically know each other. As it planned its trial, BSWRI launched a registry that was quickly filled with hundreds of volunteer donors. But like the ongoing study at the Cleveland Clinic, the Baylor trial also had a rough start: as Dingle learned just a few months before she underwent her own surgery in December 2016, three of first four transplanted uteruses had to be removed before the women were able to attempt pregnancy. 

There comes a transition point where this is no longer research.

—­Paige Porrett, University of Alabama at Birmingham

O’Neill, by this time an assistant professor of obstetrics and gynecology at UPenn, had been following these events closely. When Baylor announced its early failures, she was already working with other faculty and administrators at the university, including Porrett, then lead surgeon at UPenn, to start its own program. The trial officially launched in the fall of 2017, just a few months before Baylor’s first successful birth. More births followed, including several more from Baylor using living donors and a report from Brazil of the first baby born from a uterus transplanted from deceased donor, something the Cleveland Clinic then achieved twice over. And in between those two births, UPenn celebrated the delivery of its first baby from a transplanted uterus (from a deceased donor). Ongoing trials in Europe have been sharing similar news. 

Now, several physicians and researchers tell The Scientist, it is time to widely offer the procedure to women with uterine factor infertility. Earlier this year, Baylor moved toward doing just that, completing its first uterus transplant outside the context of a clinical trial. And a similar program, launched last October at UAB, is close on its heels. Officially launched in October 2020, the university has committed to covering the costs of 25 uterus transplantations from deceased donors over the next five years, with its first transplants expected in the next few months, Porrett says.

“There comes a transition point where this is no longer research,” she argues. “We, as medical professionals and scientists, need to make this jump: label it clinical care and to have the expectation that it will be paid for by the patient or hopefully by insurance companies.”

Exploring Uterine and Transplant Biology Thanks to more than two decades of animal and clinical research, dozens of women who lacked a uterus have received the organ via donation and transplant surgery, and many of these patients have had successful pregnancies. While the procedure was developed explicitly for the purpose of rescuing a woman’s reproductive capacity, scientists are taking advantage of the unique model to ask some basic research questions about endometrial turnover and other aspects of uterine biology, as well as questions about transplantation, and specifically, immune rejection of an organ. After every uterus transplant, recipients undergo regular blood draws and cervical biopsies—samples that clinical trial researchers are actively interrogating and banking for future studies. A few of those research directions are illustrated below.	© lucy reading-ikkanda
© lucy reading-ikkanda Immune rejection of organ Immunosuppressant drugs designed to help recipients accept the transplanted uterus can be discontinued prior to having the organ removed. From cervical biopsies and other samples, researchers can watch for signs of rejection and look for biomarkers that could provide a less invasive way to test for rejection following transplant surgeries involving uteruses or other organs.
© lucy reading-ikkanda See full infographic: WEB | PDF	Source of uterine cells Researchers have long wondered about the origin of the various cells that make up the internal lining, or endometrium, of the uterus, which is shed and regenerated monthly as part of a normal menstrual cycle. With uterus transplantion, researchers can look at the genetics of the cells in the uterus and determine if they came from the organ itself, with genetic signatures of the donor, or from outside the organ, with genetic signatures of the recipient.
	Source of immune cells in uterus Immune cells called natural killer (NK) cells are important for the establishment of pregnancy and, specifically, the development of the vasculature in the placenta. As with cells that replenish the endometrium, researchers can determine whether these and other immune cells come from within the uterus or from elsewhere in the body by testing to see if they have donor or recipient genes.

On the cusp of a transition

Performing uterus transplants in the clinic is not without its dissenters. And unlike new drugs and medical devices, surgical interventions don’t require approval from the US Food and Drug Administration (FDA), so there are no hard-and-fast rules about when it is acceptable to go from doing clinical trials with the oversight of institutional review boards to offering a surgical intervention widely to patients in need. “Surgical research is known as the wild West of medicine for a reason, and that’s because there is so little ethical guidance,” says Lancaster University bioethicist Nicola Williams.

We are at the stage now where we’re thinking about clinical translation of uterine transplantation.

—Laura O’Donovan, Lancaster University

As a result, some physicians are hesitant to recommend uterus transplant to patients at this stage, with the technique being so new and with so much research ongoing. “My concern is about the safety of this approach,” says Eric Forman, a reproductive endocrinologist at the Columbia University Fertility Center. “I’m not saying [uterus transplantation] shouldn’t be explored or shouldn’t be done. . . . This is an exciting area, and it’s pretty amazing that some women who could not have delivered otherwise were able to. But again, I think there should be transparency about the unknowns, the potential risks, and the alternatives.” The ASRM, for now, seems to agree. In June 2018, the society put out a position statement recommending that uterus transplant remain an area of research, not clinical practice. 

Undeterred, the researchers and clinicians involved in uterus transplant are moving forward with this transition. Porrett notes that there have been 32 uterus transplants performed to date at three independent centers in the US—enough, she argues, to give doctors have a good sense of the procedure’s safety, efficacy, and reproducibility. “That to me is grounds to move out of the research realm.” 

In support of this, surgeons from UPenn, Baylor, and the Cleveland Clinic traveled to Washington, DC, to speak with members of Congress about the importance of the procedure, as some of the researchers made the case for creating Current Procedural Terminology (CPT) codes for the surgeries involved in uterus transplantation. These codes would allow the procedure to one day be filed with insurance companies for coverage. “It’s the code that’s attached to a price you can claim,” says Johannesson, who was involved in these processes. “It’s a big step.”

But at what point patients can reasonably expect the procedure to be covered by insurers remains an open question. In countries such as the UK with public healthcare, there is already political hostility over the idea of government funding for infertility treatments in general, including IVF, notes Williams’s Lancaster colleague, bioethicist Stephen Wilkinson. “As long as it’s safe and effective, and as long as it’s sufficiently cost-effective . . . then absolutely it’s a candidate for being funded and should be funded,” he says. But “if it were funded,” he adds, “it would be extremely controversial.” 

Uterus transplants also raise additional ethical concerns, such as challenges in evaluating the intangible value of pregnancy itself, notes Williams, who has published on the ethics of live versus deceased donation in uterus transplantation. “There’s a really important balance to strike between exploring . . . social norms and values that we think might valorize biological parenthood [and devalue its alternatives] yet also recognizing the harm that women with [absolute uterine factor infertility] experience” as a result of not being able to carry a child. Laura O’Donovan, who is finalizing her PhD at Lancaster on the legal and ethical analysis of uterine transplant, adds that racial and social inequalities must also be considered as the medical community considers offering the procedure to the general population. “We are at the stage now where we’re thinking about clinical translation of uterine transplantation. . . . It’s probably about time that researchers came together to develop a concrete framework.”

However widely the procedure is offered, experts who spoke with The Scientist agree that research must continue. (See “A New Data Stream to Tackle Many Questions” and illustration above.) This will involve tracking not just the success of the procedure itself, but medical and psychological outcomes for the children born from transplanted wombs and for the people undergoing these procedures. Last year, Brännström’s group published on two- and three-year follow ups with uterus transplant recipients in Sweden. “This is a new chapter in the literature that has already been written about the psychological trauma of infertility.”

Such evaluations are a key part of any new medical innovation, but Testa notes that this particular surgery is especially charged. “I was completely blown away about the emotional response [to] this transplantation—much more so than any other transplant I’ve done in my life,” he says. He notes that when it comes time to remove the organ, recipients in the Baylor trial were often upset, and some even initially refused to schedule the hysterectomy. “We have to go through several conversations to make sure they understand the value of doing what we’re doing,” Testa says. “This was one of the things that was unexpected for me.”

Two years after Jennifer Dingle and her husband Jason welcomed their first daughter Jiavannah (pictured here), they had their second little girl, Jade.

SHANNON FAULK FOR BAYLOR SCOTT & WHITE

Dingle can personally attest to the emotions of the process. Following the high of giving birth to her daughter Jiavannah, Dingle suffered a series of miscarriages when she and her husband tried for a second child. They were down to their last embryo frozen as part of the initial IVF process when a pregnancy finally took. In February 2020, just two days after Jiavannah’s second birthday, Dingle gave birth to a second daughter, Jade. Then, for the final drop in the emotional rollercoaster, Dingle had her uterus removed. 

“As time goes on, I’m starting to mourn the loss of the uterus,” she says. “Because even though I had a uterus transplant and it allowed me to carry my two miracle girls, it didn’t fix me.” She adds that, if given the opportunity, she’d continue to grow her family in this way. “I definitely would love to have another chance to have another baby, and I would do it over and over again.” 

Bioengineering a Uterus Women who receive a transplanted uterus must take immunosuppressive drugs to lower the risk that the foreign organ will be attacked by their immune systems. And in the case of transplants from living individuals, the procedure holds significant risks to donors, who are undergoing major abdominal surgery that makes them vulnerable to various complications, including bleeding, infection, and damage to the urinary tract. Paige Porrett, a transplant surgeon at the University of Alabama at Birmingham (UAB) who is running a new uterus transplant program there, notes that such issues are not all that uncommon. The Baylor group and European centers have observed complication rates of approximately 12 percent—five- to tenfold higher than rates of complications seen in living kidney or liver donors, Porrett notes. A rat uterus that has been decellularized and then recellularized with mesechymal stem cells Mats Hellström “Every program who has performed a living donor uterus transplant has had major complications occur in the living donor,” she says. “And while there’s been no living donor deaths, thank god, there has been significant morbidity for the patients,” including requiring additional surgery to correct the problems that were caused by the donation. To sidestep these issues, researchers are now working to bioengineer a uterus in the lab. Mats Brännström and colleagues at the University of Gothenburg in Sweden first started working on the challenge in animal models about 10 years ago. The researchers use detergents and other reagents to decellularize uteruses taken from dead animals, then seed those organs with endometrial and mesenchymal stem cells to generate tissue that can be transplanted into a living animal. So far, they’ve had success engineering and transplanting patches of uterine tissue in rodents, and the group has begun to try out the same approach in sheep. But the “efficiency of recellularization is not as great as we hoped,” Brännström says. “We are not able to make a whole copy of a uterus.”  Regenerative medicine researcher Mats Hellström, the preclinical lab manager in Mats Brännström’s group, says the team is now testing out different culture systems, modern perfusion bioreactors for supporting the organs prior to transplantation, and various protocols for seeding the scaffold, including introducing various cell types in different orders. “There are obviously a lot of different cell types in the uterus: endothelial cells for the vasculature, muscle cells for the muscular layer, glandular cells for the endometrium, and we also need a lot of stroma cells for the endometrium as well. Then there is another type of cell that lines the inner side of the lumen: epithelial cells,” Hellström says. “It’s challenging [to determine] in what sequence should we add all these cells.” Recellularization of sheep uterus scaffolds in a bioreactor MATS HELLSTRÖM While the Swedish group has not yet tried to establish pregnancy in animals that have received uterine grafts, another team has. In June 2020, a group led by Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine, took the field a step closer to reality with live birth from cell-seeded uterine constructs in rabbits. “He’s got the best results so far in terms of using bioengineered uterus graft,” Hellström says. In this case, the researchers used a synthetic scaffold composed of more than three dozen biomaterials that will get resorbed by the body, and seeded it with the recipient rabbits’ own cells. The researchers didn’t replace the entire organ, but more than 80 percent of it, explains Atala, noting that the benefits will be huge if he and others can achieve a clinically viable approach. “Because the organ is your own, once it’s implanted it just stays there, and you don’t need antirejection medicine,” says Atala, who is an inventor on two patents covering uterus bioengineering technology. Now there are four or five groups working on bioengineering uteruses, including one in Spain and one in Japan, but it’ll still be some time before the technology has been scaled up and is ready to be tried in humans, says Brännström. “To create the whole uterus will at least take 20 years.”