BY ANDREA MONGLER PHOTOS BY JAY FRAM
A little girl has just been diagnosed with cancer, and her parents are facing a new and terrifying reality. Whys and what-ifs dominate their thoughts, and a feeling of helplessness threatens to overwhelm them. They would suffer the disease for her if they could, but they can’t. They would do anything for this to be over, for her to be OK.
Year after year, thousands of parents in the United States experience this kind of despair. But because of important treatment advances in recent decades, most of their children will be OK. In fact, the five-year survival rate for children with cancer is now greater than 80 percent.
Survivors of childhood cancer usually grow up to lead normal, healthy lives. Even so, the disease — and the treatments used to eradicate it — can have permanent adverse effects. For some survivors, that includes fertility problems.
Radiation, chemotherapy and bone marrow transplants all increase the risk of infertility. Though it’s possible to cover a girl’s ovaries during radiation treatment that targets the pelvic area and to move the ovaries out of the radiation field, those methods simply minimize the effects of radiation but can’t actually preserve fertility. In fact, until recent years, true fertility preservation wasn’t possible for prepubertal girls at all.
Now, however, there is a way to preserve future fertility in girls with cancer or other diseases that put them at risk for infertility. It’s called ovarian tissue cryopreservation, or ovarian tissue freezing. Early research is promising, and the procedure is becoming more widespread.
“There is a wide variety of patients who can benefit from fertility preservation,” says Holly Hoefgen, MD, co-director and co-founder of the Integrated Care & Fertility Preservation Program at Washington University School of Medicine. “We used to use the term ‘onco-fertility’ — combining the oncology and fertility fields — but we’ve steered away from that to ‘fertility preservation’ instead because there are so many different diseases and diagnoses and treatments that can cause harm to future fertility. We want all of these patients to have access to ovarian tissue cryopreservation.”
The first step in the ovarian tissue cryopreservation process is to remove part or all of one ovary. This is typically done laparoscopically and involves an incision in the navel and one to three small incisions along the underwear line.
For older pediatric patients and adult women, the surgeon may remove just part of the ovary through one of those incisions; all of the eggs are found in the cortex — the ovary’s outer layer — so it is all that’s necessary to remove. In younger girls, though, the entire ovary is often removed.
"The pediatric ovary is very small,” says Hoefgen, who performed the procedure more than 40 times at Cincinnati Children’s Hospital before coming to Washington University and St. Louis Children’s Hospital. “Separating it would be technically very difficult. The increased time and difficulty and expense are not worth the risk. Also, removing the entire ovary ensures that we will get the maximum amount of eggs.” The procedure is performed on just one ovary; the other is left intact inside the patient.
If just the cortex is removed, it is then cut into small strips and cryopreserved, or stored at very low temperatures. A removed ovary is stored in the same manner. This preserves the tissue indefinitely.
Eventually, if the patient decides she would like to bear children, she can undergo orthotopic transplantation, in which the surgeon implants the ovary or the strips of ovarian tissue either in the area they were removed from or on the ovary that was left in place.
Women may someday have an alternative to this ovarian tissue re-implantation: in vitro maturation, in which pre-ovulatory eggs from the removed tissue or ovary can be matured, stimulated and combined with sperm via in vitro fertilization. There have been no pregnancies from this technique yet, but researchers are working on it — important because it would allow patients to avoid any potential risks associated with re-implantation.
“The real hope is that in the future we won’t have to put that tissue back in the patient,” Hoefgen says. “We want patients, especially those at risk for a recurrence of the original malignancy, to have the option of in vitro maturation. This growing technology will open options of fertility preservation to them that are otherwise unavailable.”
The fact that a young girl’s eggs are immature is the reason why she had no fertility preservation options before ovarian tissue cryopreservation became available. Post-pubertal patients could have their individual eggs frozen — it’s been the standard of care since 2012 — but that wasn’t feasible for prepubertal girls.
HOLLY HOEFGEN, MD, CO-DIRECTOR, CO-FOUNDER, INTEGRATED CARE & FERTILITY PRESERVATION PROGRAM
Instead, a diagnosis requiring radiation, chemotherapy or a bone marrow transplant meant a young girl’s future fertility was at risk and nothing could be done about it. Girls with a non-cancer diagnosis whose disease process or treatment could affect ovarian function were in the same situation. But ovarian tissue cryopreservation might just be a game-changer for them.
The procedure also has a major advantage over egg freezing for post-pubertal patients: Ovarian tissue cryopreservation is a much faster process. In fact, it can be completed within days of a diagnosis.
Removing eggs from a patient, on the other hand, typically takes about six weeks. It involves stimulating the ovaries, waiting for them to mature eggs and then extracting the eggs before they emerge from the follicles. It is possible to accelerate the process, completing it in just two weeks or so, but for certain patients with cancer, that might not be fast enough. “In some patients, delaying cancer therapy even two weeks is not suggested,” says Hoefgen. “With ovarian tissue cryopreservation, though, we can be finished in one to three days, and the patient can start therapy right away.”
Every type of fertility preservation comes with ethical concerns. For every positive, someone will see a negative. This effect is magnified when children are involved.
Think about that little girl who was diagnosed with cancer. Maybe she’s only 2 years old. The recommended age range for ovarian tissue cryopreservation is 1 month to 41 years, so she might very well be quite young. That little girl doesn’t understand what’s happening. She doesn’t know what “fertility” and “cryopreservation” mean. She might know what cancer is, but only in the way a 2-year-old can understand it: It’s in her body, and it makes her feel bad.
The point is that she doesn’t have the mental capacity or reasoning skills to make decisions about her future fertility. She’s far too young to give her informed consent. The decision is up to her parents alone.
“We definitely want children to have access to fertility preservation,” Hoefgen says. “If parents couldn’t make that decision for them, these patients might lose that option altogether. That said, when girls are old enough and cognizant enough to be part of the conversation, we include them in it, and we get their assent — even consent from older adolescent patients.” Likewise, Hoefgen says, when parents decide to have their daughter’s ovarian tissue cryopreserved, they are asked to make a second decision: what will happen to the tissue if she doesn’t survive. Legally, they have two choices: The tissue can be used for research or it can be discarded. Adult patients have a third option: to donate the tissue — to a partner, perhaps. Another big decision for certain patients has to do with whether the tissue should even be re-implanted. Those with certain types of malignancies — such as ovarian cancer, leukemia and lymphoma — are at high risk for having cancerous cells in the ovary, which means implanting the removed tissue could re-introduce the cancer.
Hoefgen says institutions that offer re-implantation in these cases perform extensive testing on the tissue to ensure no cancer cells are present. For most pediatric patients in this situation, though, the tissue is often simply removed and cryopreserved with the hope that in vitro maturation will be possible in the future.
Worldwide, there have been more than 130 live births resulting from ovarian tissue cryopreservation and transplantation. That number might sound small, but governing bodies like the American Society for Reproductive Medicine and the American College of Obstetricians and Gynecologists still consider the procedure experimental, and it’s performed at relatively few institutions.
Just two of those live births were in women who were prepubertal when their tissue was frozen, but Hoefgen expects that number to grow soon, as more and more of those patients reach childbearing age. At this point, not many of them have.
The first live birth resulting from ovarian tissue cryopreservation and transplantation was reported by Belgian researchers in 2004, and much of the existing data — some dating back two decades — comes from Europe. Only in the last five to 10 years has the procedure really become available for people in the United States.
More important than the number of live births though, is the rate of births. In other words, of women who attempted to become pregnant and give birth after ovarian transplantation, how many actually did? A recent meta-analysis of 19 studies found a clinical pregnancy rate of 57.5 percent and a live birth rate of 37 percent, very similar to the rates associated with egg freezing. Researchers concluded that “the efficacy of orthotopic transplantation with cryopreserved ovarian tissue has reached acceptable levels.” In addition, the rate of fetal anomalies is low — 1 to 2 percent, similar to the rate seen in the general population.
So why is this treatment still considered experimental?
“The governing bodies of our medical societies are still holding on for more data to consider this procedure as standard of care,” Hoefgen says. “They would like to see higher numbers of patients with successful pregnancies that continue to prove the safety and efficacy of ovarian tissue cryopreservation.”
There’s one big limitation for some patients, however: cost. As is common with experimental procedures, insurance often doesn’t cover ovarian tissue cryopreservation. Plans may offer coverage for infertility treatment without covering fertility preservation.
If more states pass laws requiring coverage for fertility preservation and as the data continue to mount, more and more families will be able to choose ovarian tissue cryopreservation. Hoefgen expects to have approval from the Institutional Review Board to begin performing the procedure — as well as the more novel testicular tissue cryopreservation for boys — at St. Louis Children’s and Barnes-Jewish hospitals by year-end, and she is eager for her patients to have the option.
“Right now, when I explain ovarian tissue cryopreservation to patients, I tell them they’ll have to travel. But it will be a much more realistic option for them when they can stay here,” she says. “Having this option available will open a lot more doors for our younger patients.”
Ultimately, Hoefgen is working toward a future when tissue cryopreservation is a feasible fertility preservation option for any patient who faces the possibility of infertility. In that future, when the little girl with cancer gets better, grows up and has children of her own, tissue cryopreservation will no longer be experimental or — for some patients and their families — unrealistic.
“That’s the goal,” Hoefgen says. “And as more and more patients undergo successful pregnancies and we make advances in the lab, I’m very hopeful that we’ll get there.” Here’s the difference: Someone who is trying to preserve her future fertility isn’t infertile — yet. Until she is, she may not be covered. Only five states — Illinois, Connecticut, Delaware, Maryland and Rhode Island — have laws specifically requiring coverage for fertility preservation.
If that little girl with cancer doesn’t live in one of those five states and her parents can’t afford the procedure, then she’s out of options. No matter how much they want her to have her own chance at parenthood someday, it’s not a gift they can give her.
“It’s so hard when we discuss fertility preservation with parents and explain that their child is a great candidate but the one thing that keeps them from choosing it is the cost,” Hoefgen says. “Even families that may otherwise be financially stable — once they find out their child has a chronic illness such as cancer, they’re already looking ahead and wondering how they will make it through financially as well as emotionally. We are looking for any sort of philanthropic assistance to help families cover the cost.”