A trailblazing genetic scan could bring the tools of precision medicine to a woefully understudied field.
“The first time I got pregnant, I had a gut feeling that something was wrong. I just didn’t see it working out,” Lisa, a 37-year-old New Yorker who asked to keep her last name private, told me over the phone. Her premonition came true: 10 weeks into her first pregnancy, she miscarried. And then she miscarried again, and again, and again — seven times in total over two years.
Even as recently as a year ago, her physician might have told Lisa to just give up on having a baby. But a new genetic test is beginning to alter the possibilities surrounding fertility and women’s health.
The Fertilome test, developed by Celmatix Clinical Laboratories in New York, scans for 49 variants across 32 genes that indicate the risk for endometriosis, recurrent pregnancy loss, early menopause, polycystic ovarian syndrome, and other disorders that make it harder to get or stay pregnant. These risks still aren’t easily quantified, which means that Fertilome isn’t exactly an oracle. But “it’s helping us see around corners,” says Celmatix’s founder and CEO, Piraye Beim. “For a lot of women and a lot of physicians there are no other tools in the tool box [like this].”
In Lisa’s case, it helped her doctor find a way to halt her miscarriages, some of which appeared to have no cause.
After her fourth miscarriage, Lisa turned to Tanmoy Mukherjee at Reproductive Medicine Associates in New York and tried in vitro fertilization (IVF). That would rule out unhealthy embryos as the culprit of her miscarriages, because IVF allows doctors to select only healthy-appearing embryos for implantation. But, in time, Lisa endured her fifth, sixth, and seventh miscarriages — even though Mukherjee could see she had normal embryos, normal hormone levels, and a structurally sound uterus. “There has to be something else going on here,” he told her.
That’s when he ordered the nascent Fertilome test (which, incongruously, shares its name with a line of lawn fertilizers) and found that Lisa has a genetic variant that makes it likelier for estrogen to cause the lining of her uterus to be inhospitable. Mukherjee put her on an estrogen-reducing drug, tried another round of IVF, and soon Lisa was pregnant an eighth time. Now at 19 weeks, it’s her longest pregnancy yet.
Things are working out for Lisa not because the Fertilome test told her doctor exactly what was wrong with her and what to do about it. It worked because a peek inside Lisa’s genetics gave Mukherjee a useful hint at what might be wrong, leading him to try a treatment that he would’ve otherwise forgone.
“In reproductive health, we’ve been lacking movement toward personalized medicine and targeted therapies, like those you see in oncology,” says Amber Cooper, the medical director of Vios Fertility Institute St. Louis, and a member of Celmatix’s scientific advisory board. “I look at this test as a big step forward.”
But even with the new insight that Fertilome can offer, tackling reproductive issues like Lisa’s is still very much a guessing game. It requires a doctor willing to think outside the box, a patient willing to follow her doctor’s educated guess, and still, to be honest, a little luck.
In 1994, when a mutation in the BRCA1 gene was first found to increase a woman’s risk of developing breast cancer, not much information was yet available about the specific increase in risk it caused. More than two decades later, enough women have been screened and their disease outcomes tracked that a doctor can tell a woman that a BRCA1 mutation gives her a 55 to 65 percent chance of developing breast cancer, compared with 7 percent for the general population.
With the Fertilome test, it’s basically still 1994. Physicians like Mukherjee have enough information to know that certain genetic variations may generally increase a woman’s risk of certain reproductive disorders, but the extent of the risk is still hard to pinpoint.
For example, given the studies that have been done so far, we know that a variant in one of the genes in Fertilome’s test, BMP15, correlates with a four-fold increased risk of early menopause, which generally affects one in 100 women. But just as our understanding of breast cancer risk improved over the years, the numbers associated with this risk factor could change as more studies are done on early menopause and other reproductive conditions.
Part of what’s causing this knowledge gap in women’s health overall is inequity in research funding. In 2016, for example, the National Institutes of Health spent $51 million studying anthrax, which affected zero Americans that year. By contrast, it spent $10 million studying endometriosis, a painful disease that affects at least one in 10 American women; the rate is probably higher because endometriosis often goes undiagnosed. About $18 million was spent on research related to polycystic ovarian syndrome, or PCOS, the most common endocrine disorder affecting American women.
When Beim talks about this, the incredulity in her voice is palpable.
“There’s an infertility crisis coming,” she says. She’s referring both to the lack of detailed knowledge that we have about women’s health and to the rising age of first-time mothers, a factor that increases the riskiness of pregnancy. The Centers for Disease Control and Prevention announced in 2017 that American women in their 30s were having more babies than their twentysomething counterparts for the first time ever. “We’re spending very little to try to understand these things,” Beim says.
Her exasperation inspired her to ditch the academic route after she completed postdoctoral work in embryology at the University of Cambridge. Instead she went into the private sector, founding Celmatix in 2009 to buoy this kind of research.
To get where Fertilome is now, a year out from its launch, Beim and her team started by manually combing through 25,000 peer-reviewed studies on the health conditions that interested them and any related genetic information they could find. After whittling the information down, they picked the 49 genetic variants that are in the Fertilome test today. Before that, all the individual pieces of information were like little islands floating alone in the broad field of women’s health. Beim’s team appears to be the first to look at the whole picture and bring some of this information together in one test.
“Why should a woman only be able to know she’s at risk for something by earning it through multiple miscarriages, or a stillbirth, or infertility for 12 months?” she says. “That’s a pretty high bar.”
Give women more credit
For the Fertilome test to make much of a difference, however, the average physician will need to see it as a go-to tool. That’s one of the biggest barriers to success right now, says Cooper, one of Celmatix’s advisors.
Unlike, say, 23andMe’s direct-to-consumer genetic tests, Fertilome can be ordered only through a physician. Celmatix’s in-house technicians provide a report with some contextual detail to help physicians walk through the results with their patients, but the ultimate task of deciding how to interpret genetic risk factors and translate them into treatment options still lies with doctors, not Celmatix. That’s something many doctors feel unequipped to do.
“If you take physicians who are 20 years out of medical school, they didn’t get a lot of genetic training,” says Cooper. “The more advanced genetics gets, the more we need to train patients and doctors. This is not a test that you look at the same way you’d look at a test for diabetes.”
Beim has also heard it argued that since a genetic risk does not a disease make, giving patients all this information about potential health risks and fertility issues could cause them undue anxiety. She disagrees, resolutely. “I actually think we should give women more credit,” Beim says. “When people share this concern of, ‘Oh, you’re going to worry women,’ well, we worry women all the time. Let’s at least put the choice in their hands about whether they want this [genetic information].”
“Why should a woman only be able to know she’s at risk for something by earning it through multiple miscarriages, or a stillbirth, or infertility for 12 months?”
Beim wants Fertilome to be a more definitive tool. The key will be collecting data and tracking how many women actually develop the reproductive disorders that the gene variants in the test identify. That would let physicians and patients deal with more concrete disease diagnoses, not just vague risk factors. To move toward this goal, Celmatix partnered with 23andMe last February on a study that will track the DNA and reproductive health outcomes of 4,500 women.
Fertilome could eventually help women understand more than their potential fertility issues. It could help better diagnose polycystic ovarian syndrome, which encompasses a spectrum of symptoms and is often hard to pin down; it could help formally diagnose endometriosis, which is often brushed off as overly sensitive women experiencing regular period cramps and, on average, takes a painful decade to diagnose; and it could help screen for blood clotting risk factors that might affect what birth control method a woman chooses. For the record, the American Congress of Obstetricians and Gynecologists and the CDC both recommend that women not be screened for variants that appear to increase the risk of developing blood clots, which some birth control pills exacerbate. Instead, they recommend a wait-and-see approach. Beim feels strongly that it’s unsafe and untenable for women to fly blind on this until something terrible happens.
So far there are about 80 physicians in the U.S. ordering Fertilome for a few hundred patients who are mostly clustered at fertility clinics in New York and San Francisco. The test costs $950 out of pocket and is not covered by any insurance companies, but that’s already down from the $1,900 price tag it launched with in January 2017. Beim knows the cost is prohibitive for many women and hopes to lower it further. The general decrease in the cost of DNA analysis will help.
And yet Lisa says that even at its original price, the Fertilome test would have been worth paying. It would have saved her tens of thousands of dollars on IVF and other fertility treatments, which were all in vain until she and her doctor got a bit of genetic insight that allowed her to finally hold onto a pregnancy. On May 23, 2018, she gave birth to a healthy baby boy.
This story was updated on January 29, 2018, to correct the amount of money spent by the NIH on PCOS research in 2016.
It was updated again on June 1 with Lisa’s baby news.