Barnes-Jewish Hospital | Washington University Physicians
  History | breakthroughs from the lab

PAST, PRESENT AND FUTURE OF FERTILITY CARE

BY ANDRREA MONGLER

The first baby conceived by in vitro fertilization, or IVF, was born in 1978 in Manchester, England. In 1985, a couple from Creve Coeur gave birth to Missouri’s first baby conceived by IVF at what was then called Jewish Hospital. The technology was controversial in its early days. The idea of “creating” a baby in a lab felt strange to some and raised ethical concerns in others.

Because of this perceived controversy, if you were grappling with infertility you likely were reluctant to talk about it. Your partner would know, of course, and maybe your doctor. But infertility was typically considered a hush-hush topic—embarrassing to discuss and better kept private. If you decided to try IVF, you certainly weren’t going to shout it from the rooftops. “When I first started in this field 25 years ago, there were many patients who didn’t want anyone to know they were going through IVF,” says Valerie Ratts, MD, Washington University reproductive endocrinologist at the Women & Infants Center, a collaboration by Barnes-Jewish Hospital, Washington University Physicians and St. Louis Children’s Hospital.

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MISSOURI’S FIRST—AND SECOND—”IN VITRO” BABIES WERE CONCEIVED AND DELIVERED AT JEWISH HOSPITAL, NOW BARNES-JEWISH HOSPITAL. IN THIS PHOTO: PHYLLIS AND MATHEW LIBRACH, FRONT ROW LEFT, WITH THEIR NEWBORN SON; KERRY AND SANDY KLARFELD, FRONT ROW RIGHT, WITH THEIR DAUGHTER. THE HOSPITAL’S IVF TEAM IS IN THE BACKGROUND.
Photo courtesy of Washington University School of Medicine Bernard Becker Medical Library

But much has changed in the last four decades. IVF technology has improved dramatically, and many would argue that attitudes have too. People are much more likely to talk openly about their infertility, and IVF is widely viewed as positive rather than ethically questionable. “People are definitely more likely to talk about infertility today than they were 20 years ago,” says Kenan Omurtag, MD, Washington University reproductive endocrinologist at the Women & Infants Center. “Part of that is because values change over time. In addition, the ability to crowdsource information on the internet and share conversations over social media has provided greater exposure to fertility treatments.”

This willingness to openly discuss infertility has led to an important realization for many people: If you’re struggling with infertility, you’re not alone. In fact, about one in eight people of reproductive age have infertility. Many of the people in this group don’t need IVF. Depending on the cause of infertility, medications to stimulate ovulation might be enough to result in a pregnancy. Intrauterine insemination, or IUI—in which sperm is injected directly into the uterus—is often effective, too. And some people have anatomical issues that can be corrected with surgery. But for people who do need IVF, the experience is much different today than in decades past.

Advances and successes

Randall Odem, MD, chief of the School of Medicine’s Division of Reproductive Endocrinology and Infertility, has seen many changes in the fertility field since he started a fellowship at the School of Medicine in 1985. Back then, for instance, retrieving a woman’s eggs so she could undergo IVF required general anesthesia and an incision in the abdomen. Today, the process is ultrasound-guided and less invasive. And the medicines used to stimulate ovulation before the egg-retrieval process are easier for women to use and much less likely to cause serious complications. In addition, the large majority of women who underwent IVF in the early days didn’t end up pregnant.

“Our success rate was 4%, meaning 1 in 25 IVF cycles would lead to pregnancy, and that was pretty typical of the few IVF programs in the country at that time,” says Odem. “Fortunately, our success rate has dramatically increased. For patients younger than 35, it’s been 50% or higher for quite a few years.”

Rising success rates are due in part to what’s known as extended culture. Put simply, extended culture means that embryos are grown in the lab for five or six days rather than two or three days like they used to be. On day 3, embryos consist of about six to 10 cells. By day 5, they’re made up of more than 100 cells. Extended culture is important in part because it helps doctors more reliably predict the likelihood of success. As Omurtag says, “The holy grail of IVF is: How do you know which embryo is likely to implant?” Doctors can glean a lot more information about how well an embryo is developing when it’s five days old, and called a blastocyst, than when it’s three days old and in what’s called the cleavage stage.

Although the process of extended culture has been possible for a couple of decades, it’s gotten better in the last one. This is partly because embryos used to be grown in atmospheric oxygen—meaning an oxygen level of about 20%. That’s far higher than the oxygen level an embryo is exposed to in the fallopian tube or uterus. “Eventually it was discovered that the higher oxygen concentration was detrimental to embryo development,” says Joan Riley, PhD, HCLD, director of the IVF Laboratory at the School of Medicine. “Today we use low-oxygen incubators with an oxygen level of 5%, which is much more physiologic. This has significantly improved the number of cleavage-stage embryos that develop into blastocysts.”

Extended culture not only increases the chance that a woman who undergoes IVF will become pregnant but also reduces the likelihood that she’ll have a multiple birth. Since extended culture makes it easier to predict which embryos will successfully implant, there’s less of a drive to use more than one at a time.

“It used to be very common for IVF programs to put more than one embryo in the uterus to increase the chance that at least one would implant,” Odem says. “That’s why it was fairly common for women who underwent IVF to give birth to twins or triplets. But as labs have improved and standards have changed, most programs now put just one embryo in the uterus.”

Another major advance in the fertility field is the ability to reliably cryopreserve, or freeze, eggs. Though cryopreservation of sperm and embryos was possible in the early days of IVF, it was frequently unsuccessful. Cryopreservation of eggs wasn’t possible until much later. Today it’s common.

The ability to freeze eggs or sperm and store them for years makes IVF possible for a wide range of people. For example, people who may become infertile because of certain cancer treatments can have their eggs or sperm frozen before their treatment begins. Women who don’t have partners or aren’t ready to have children but are concerned about declining fertility as they age can also have their eggs frozen for future use. “Thanks in part to cryopreservation, IVF isn’t one-sizefits- all anymore,” Odem says.

Declining stigma, increasing inclusivity

Ideas about who should have access to IVF have come a long way since the field started. “In the early days, a lot of programs would only treat couples that literally had to prove they were legally married,” Odem says. “IVF was a service done for a husband and wife.” These days, neither marriage nor heterosexuality are requirements for IVF if a sperm donor is used. Some same-sex female partners choose a process called co-maternity, or reciprocal IVF, in which one partner provides eggs and the other carries the pregnancy in her uterus. Same-sex male couples with an egg donor and a gestational carrier have access to IVF, too. And some transgender men and women choose to have their eggs or sperm frozen before they undergo surgical or hormonal treatment that could cause infertility. This gives them the possibility of using IVF later.

As IVF has become available to more and more people, the language used to describe fertility treatment has evolved too. “Instead of talking about infertility, we talk about fertility,’” Omurtag says. “Same-sex couples who undergo IVF don’t always have infertility. We talk about ‘fertility treatment’ because it’s more inclusive.” Omurtag says it’s critical for fertility clinics and specialists to have an inclusive approach to care and to be open about that inclusivity instead of secretive, as in the past.

“So much of fertility care is making sure people are comfortable from the minute they arrive for consultation and throughout the duration of the relationship,” he says. “It’s important to share with them through verbal and nonverbal cues that we are here to help them build their family.”

Preventing disease

Though IVF is associated with an inability to conceive the “old-fashioned” way, some people use it for an entirely different reason: the ability to prevent certain rare and serious genetic diseases in their future children. Through a process called PGT-M, or preimplantation genetic testing for monogenic disorders, embryos are screened to determine whether they’re carrying particular mutations. PGT-M is often used to screen for diseases such as cystic fibrosis and sickle cell disease. Though these diseases are serious, people who have them often live long into adulthood. But PGT-M is also used to screen for very rare, lethal diseases.

Those interested in PGT-M are often parents who previously had a baby with a genetic disease. As a result, the parents know they’re carriers of a mutation that causes the disease and want to make sure they don’t pass it on to another child. So they begin the IVF process. Once embryos have formed, cells are removed and sent to a lab, where they’re screened for the mutation.

The decision on which embryo or embryos to implant—if any—likely depends on the results. “PGT-M is somewhat controversial, but it’s a major advancement. It allows couples to make sure they’re only using embryos that won’t be affected by a lethal disease,” Odem says. “Without PGT-M, it takes a lot of careful thought to try to get pregnant knowing you could have a child that’s likely to die.”

Embryos can also be screened for chromosomal abnormality, like the one that causes Down syndrome. This process is called PGT-A, or preimplantation genetic testing for aneuploidy. Though some fertility clinics perform PGT-A on all embryos, others, including the Fertility & Reproductive Medicine Center at Washington University, offer it but don’t require it.

The ability to reliably grow embryos for five to six days rather than two or three before implantation has had a direct impact on the genetic-testing process. Screening an embryo requires taking a biopsy from it. These biopsies used to be done at day 3, when embryos are made up of just six to 10 cells. An embryologist would take one of those cells for the biopsy. “When you take one out of six cells, that’s a significant fraction of the total embryo,” Riley says. “Researchers found that it negatively affected implantation.”

Today, biopsies are performed on day 5 or 6. Embryologists remove about five cells from the 100 to 150 that make up the embryo, a significantly smaller percentage of the whole. In addition, the cells are removed from the portion of the embryo that will form the placenta rather than the fetus. These later-stage biopsies appear to have no effect on an embryo’s developmental competence.

Riley says this advance in the field of fertility treatment, and other developments, have been inspiring to witness. “Even though I’m trained as a scientist, the work we do in the lab still amazes me,” she says. “The fact that we can use technology and science to help people create families—it’s incredibly rewarding.”

Looking ahead

Though IVF has improved tremendously since it began, researchers and practitioners in the field continue to look for ways to make it even safer and more effective. Genetic screening, for example, is certain to improve with time as the field of genetics itself advances. Riley hopes to see noninvasive testing methods become feasible.

Like any invasive procedure, the biopsy that’s required to perform genetic testing on an embryo involves some risk to the embryo. But there might be another way. When embryos are removed from the media they’re grown in, they leave behind something called cell-free DNA. Researchers have been able to “amplify” this DNA and use it for genetic testing in lieu of biopsy. Although the accuracy of this method is still being studied, early results are promising.

Artificial intelligence, or AI, may also begin to play a bigger role. The current standard for determining which embryos are most likely to implant is called embryo morphology. It’s a somewhat subjective process that involves looking at embryos under a microscope and “grading” them based on their structural features. Embryos with higher scores are more likely to implant and therefore more likely to be transferred to the uterus.

But several research groups are developing AI tools to improve the embryo-selection process. In these studies, scientists train algorithms on large datasets that contain images of embryos, patient-specific information and pregnancy-outcome data. Then, when an image of a new embryo is presented, the algorithm gives the embryo a score that predicts the likelihood of successful implantation. These algorithms are still in the early phases of development, but initial results suggest they can improve an embryologist’s ability to choose the most viable embryo for transfer. As AI improves and becomes more commonly used across disciplines, its applications to IVF may grow.

Another change that many fertility specialists hope to see has nothing to do with technology: They’d like access to IVF expanded so that everyone who needs it gets the chance. As of January 2020, just 16 states (including Illinois but not Missouri) have laws requiring insurers to cover or offer coverage for fertility treatment. If these types of laws were in place nationwide, they potentially could have a huge impact on the number of pregnancies conceived by IVF.

“We’ve demonstrated that people who have the ability to complete multiple cycles of IVF because it’s covered by their employers have a better chance of success because they’re less likely to drop out of treatment due to cost,” Omurtag says.

And although most companies nationwide don’t offer their employees insurance plans that cover IVF, some are changing that policy. “Access to IVF has dramatically improved,” Ratts says. “But we’re still not where we want to be, and that’s why we continue to push for insurers to cover IVF.”

Omurtag is hopeful that as attitudes about IVF continue to shift, more and more people will gain access to it. “With time, people filling leadership positions with power to make policy changes may have struggled with infertility themselves, had IVF, or know someone who had IVF,” Omurtag says. “As a result, they will be more intimately familiar with the struggle of infertility, and they may be more interested in providing the benefit to their employees. And that likelihood will only increase over time.”


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