Story by Emma Kenfield
Video by Matilda Marshall
Graphic by Valentina Arismendi
Kris S. threw an apple at her husband across the room.
She was angry. She was tired. For two years they’d been trying to have children. Her husband had just shown her someone else’s baby announcement on Facebook. She knew she should be happy for this woman, for her pregnancy deserved celebration.
But when Kris looked at that ultrasound, all she felt was bitterness.
“It just felt like someone had punched me in the stomach,” she said.
It had been two years of failed pregnancy tests. She endured multiple trials of In Vitro Fertilization, which never took. She visited dozens of clinics across the East Coast, which never helped. She was tired of hearing about other people’s pregnancies, tired of coping with another negative test. Tired of feeling broken.
Kris had a uterine septum and uterine adhesions due to endometriosis surgery. Given she was almost 40 years old, she also had low progesterone levels, which is the hormone that prepares the endometrium for possible pregnancy. Having a child was near impossible.
“Every month was another ‘not pregnant,’” she said. “I was just like, there isn’t an answer.”
But at Wake Forest School of Medicine, Dr. Koudy Williams and the Institute for Regenerative Medicine are developing a procedure that could give women struggling with uterine fertility a child after all. The procedure, which has been tested successfully on rabbits, would basically supply an inhospitable uterus with nutrients required to conceive and carry a baby to term.
One in eight couples struggle with infertility in the United States. For those whose infertility is due to complications of the uterus, Williams and his team may finally have an answer.
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Having children wasn’t part of her plan until Kris S. met her second husband. It was only then that she knew she wanted to be a mother, with him by her side.
Never having tried to conceive, she hadn’t ever worried about infertility. They got married, Kris went off of birth control, and after two months, she was pregnant.
Six weeks later, she miscarried.
Kris was sad, but not hopeless. She thought it was normal, especially for someone who was 37 years old. They’d try again, and it would work out. Her father had some doubts, though, and advised her to see a reproductive endocrinologist, just in case.
Kris and her husband took some tests at a local clinic where they were living in Pennsylvania, and to her surprise, she was told she was infertile, the reason unexplained.
She went to a bigger clinic in Maryland to get a better diagnosis. Again, unexplained.
“It’s upsetting to me that the first large clinic in Maryland had called my infertility unexplained, which a lot of people get told,” she said. “Maybe there are some few cases where it’s truly unexplained, but too much of the time it’s that they didn’t bother to fully investigate.”
Around the same time, she began feeling pains in her lower stomach. At first, she credited those pains to the pregnancy. But they didn’t go away after her miscarriage.
She saw multiple doctors at multiple clinics, each failing to diagnose her pain. After so much frustration, she researched and sought out a pelvic pain specialist in Virginia. He diagnosed her with endometriosis, in which tissues similar to tissue that lines the inside of the uterus grows outside the uterus. Surgery to remove the tissue eventually left her with uterine adhesions and a uterine septum, making conceiving a child even more unlikely.
But Kris wouldn’t discover this herself for two years. It wasn’t until she visited The Colorado Center for Reproductive Medicine (CCRM) that she was told her endometriosis surgery left her uterus inhospitable.
According to Path Fertility, up to 5 percent of the population has uterine factor infertility (UFI). It is also tied to an increase in miscarriage rates, as an impaired uterus lacks nutrients needed to carry a baby to full term.
The most common causes are leiomyoma, or uterine fibroids, which are benign tumors that arise from the overgrowth of smooth muscle and connective tissues in the uterus, and congenital uterine problems, which occur when a woman is born with a malformed uterus.
Treatment options are limited, however. If a woman’s UFI is caused by fibroids or polyps, surgery to remove the adhesions is often her best bet. Following surgery, she would need to pursue IVF to conceive, which costs an average of $13,000 and is not covered by most North Carolina insurers.
If a woman’s UFI is absolute, that is, she either does not have a uterus, she was born with a malfunctioned uterus, or it no longer functions correctly, treatment options are scarce. In 2014, the first successful live birth following a uterine transplant was reported. However, this surgery poses major health risks for the mother and child, and would require a hysterectomy in the future — as it is not meant to be a permanent transplant.
Dr. Williams said that his team’s research could offer one umbrella solution. Almost 20 years in the making, the study for a tissue-engineered uterus began in 2002, in Boston, Mass. In a small pilot study at Harvard University in 2003, one rabbit delivered the first successful birth with a tissue-engineered uterus. The study was moved to Wake Forest shortly after, and has now been published in Nature Biotechnology.
“Usually what happens when women have uterine infertility is either there was a congenital problem, or sometimes women have to have a good part of their uterus removed. If it’s fibroids, it significantly reduces the size of the uterus, therefore making it harder for implantation of an embryo and full term growth of the baby,” Williams said. “We’re hoping to restore the size of the uterus with functional tissue, to permit full-term growth of the baby.”
Basically, a polymer mesh, which resembles a spider web, is created — leaving holes to fit functioning cells which are common in a healthy uterus. The goal is that the patch would mature with time, the uterus would receive its nutrients, and natural mating would eventually lead to successful fertilization and full-term pregnancy.
The study has only been tested on rabbits. Though they are not primates, and do not have the same uterine structure as humans, they are commonly used in reproductive biology research. Rabbits have a relatively large uterus, allowing one to easily see clinically-relevant outcomes.
In the trials, some rabbits received the polymer mesh, or “scaffold,” with cells, and some without. At six months post-implantation, only those whose mesh included cells developed tissue-like structures found in healthy uteri. Many of those rabbits also had normal pregnancies with the tissue-engineered uteri, carrying the fetus to term for a live, natural birth.
“With our bioengineered segments with the cells in it, about 70% of them (got pregnant). That’s very good,” Williams said. “We also, as a control put in that scaffold, but without seeded cells in it, and none of those get pregnant. So the cells were really necessary to this implant to make it work.”
Now, researchers take what they’ve learned from trials with rabbits and adjust the procedure to accommodate a woman’s uterus.
A rabbit’s uterus has a thinner wall, and two uterine horns, each with the potential to carry a pregnancy. A woman’s uterus is a single structure with a much thicker wall, more closely resembling that of a primate.
“The idea is OK, we were able to replace a thinner wall uterus, how would it do with a thicker uterus where the blood and everything has to get into that graph?” Williams said. “We’re thinking of it for humans right now as a big patch, and we’re trying to think of different ways to make the patch integrate quicker.”
Before this procedure can be performed on humans, the next step is to test it on monkeys, whose uteri are single structures with a thicker wall — very similar to a human uterus. If successful, as history has proven likely, the FDA must approve the procedure for clinical trials.
According to Harvard Health Publishing, a study of 200 couples seen consecutively at a fertility clinic found that half of the women said that infertility was the most upsetting experience of their lives. Another study of 488 women concluded that women with infertility felt as anxious or depressed as those diagnosed with cancer, hypertension or recovering from a heart attack.
Dr. Martine Jones, owner of Hazel Tree Counseling in Asheville, N.C., runs a virtual infertility support group for women struggling to cope and trying to conceive. She was diagnosed with unexplained infertility in 2018. After a year-and-a-half of IVF, she finally had her son, Jules, in 2020.
Though she did not have UFI, she knows the emotional impact infertility poses on a woman, and said this procedure could bring hope to a very gray area of medicine.
“It’s a lot of throwing stuff at the wall, a lot of ‘we don’t know why this worked,’” she said. “It would make it a concrete process for women which would help with the uncertainty, and that would help so much with anxiety and hope.”
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Finally.
After two years of seemingly unexplained infertility, two years of bitterness and two years of negative tests, Kris was given hope. Doctors at CCRM diagnosed her cause of UFI, and she eventually underwent surgery to remove the adhesions and septum.
After surgery, she took progesterone to regulate hormone levels, flew countless times from Pennsylvania to Colorado for appointments, until she was finally ready for IVF. She knew it was her last chance, as one round of IVF would cost her $25,000, on top of expensive medical bills, prescriptions and travel fees.
Kris did everything she could to make this work. She kept up with all her shots, sticking her belly with a needle multiple times a day. She ate pineapple religiously, for it’s supposed to make the embryos stick. On the way home from implantation, she only listened to funny tapes, because she heard feeling happy helps implantation.
This was it for her. And if it didn’t work, she may feel the bitterness forever.
Kris was at home in Pennsylvania when she got the call.
She picked up the phone, bracing herself for bad news.
“You’re pregnant,” said the nurse. “I knew it would be positive, I knew this was going to work for you.”
Dr. Williams predicts a timeline of three to five years until clinical trials. Once those go into effect, the timeline is a bit longer. This patch would need to be inserted prior to pregnancy, including time for healing and cell growth. Then, women would need to successfully conceive and carry the fetus until live delivery. Williams estimates at least a decade before enough successful trials bring the procedure into practice.
“We try to go from bench to bedside as quickly as we can, but as safely as we can,” Williams said. “We’re all set up here to basically go from cell work, to animal work to human work all within our building and to do clinical trials here.”
Today, Kris and her husband live in Raleigh, N.C., with their twin daughters, who are now 9 years old. When the girls were babies, Kris and her husband slept in 10-minute increments, for one of the children was always crying. Some nights, they skipped dinner, because they couldn’t leave the girls’ room long enough to eat.
“And it was more worth it than I ever could have imagined,” she said. “I care so much more about them than anything else in life. And I would do anything for them. My life is just totally centered around them.”
For the first time, the struggle wasn’t bitter.
It was sweet.
