New Prenatal Tests Called Into Question
Stacie Chapman’s heart skipped when she answered the phone at home and her doctor — rather than a nurse — was on the line. More worrisome was the doctor’s gentle tone as she asked, “Where are you?”
On that spring day in 2013, Dr. Jayme Sloan had bad news for Chapman, who was nearly three months pregnant. Her unborn child had tested positive for Edwards syndrome, a genetic condition associated with severe birth defects. If her baby — a boy, the screening test had shown — was born alive, he probably would not live long.
Sloan explained that the test — MaterniT21 PLUS — has a 99 percent detection rate. Though Sloan offered additional testing to confirm the result, a distraught Chapman said she wanted to terminate the pregnancy immediately.
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What she — and the doctor — did not understand, Chapman’s medical records indicate, was that there was a good chance her screening result was wrong. There is, it turns out, a huge and crucial difference between a test that can detect a potential problem and one reliable enough to diagnose a life-threatening condition for certain. The screening test only does the first.
Sparked by the sequencing of the human genome a decade ago, a new generation of prenatal screening tests, including MaterniT21, has exploded onto the market in the past three years. The unregulated screens claim to detect with near-perfect accuracy the risk that a fetus may have Down or Edwards syndromes, and a growing list of other chromosomal abnormalities.
Hundreds of thousands of women in early pregnancy have taken these tests — through a simple blood draw in the doctor’s office — and studies show them to perform far better than traditional blood tests and ultrasound screening.
But a three-month examination by the New England Center for Investigative Reporting has found that companies are overselling the accuracy of their tests and doing little to educate expecting parents or their doctors about the significant risks of false alarms.
Two recent industry-funded studies show that test results indicating a fetus is at high risk for a chromosomal condition can be a false alarm half of the time. And the rate of false alarms goes up the more rare the condition, such as Trisomy 13, which almost always causes death.
Companies selling the most popular of these screens do not make it clear enough to patients and doctors that the results of their tests are not reliable enough to make a diagnosis.
California-based Sequenom Inc., for instance, promises on its web page that its MaterniT21 blood test provides “simple, clear results.” Only far down below does Sequenom disclose that “no test is perfect” and that theirs can produce erroneous results “in rare cases.”
Now, evidence is building that some women are terminating pregnancies based on the screening tests alone. A recent study by another California-based testing company, Natera Inc., which offers a screen called Panorama, found that 6.2 percent of women who received test results showing their fetus at high risk for a chromosomal condition terminated pregnancies without getting a diagnostic test such as an amniocentesis.
And at Stanford University, there have been at least three cases of women aborting healthy fetuses that had received a high-risk screen result.
“The worry is women are terminating without really knowing if [the initial test result] is true or not,” said Athena Cherry, professor of pathology at the Stanford University School of Medicine, whose lab examined the cells of the healthy aborted fetuses.
In one of the three Stanford cases, the woman actually obtained a confirmatory test and was told the fetus was fine, but aborted anyway because of her faith in the screening company’s accuracy claims. “She felt it couldn’t be wrong,” Cherry said.
Companies that sell the screens stand behind their tests, saying they provide much more reliable assurance for expecting mothers than earlier screens. Some say their research focused first on how to accurately identify fetuses with potential genetic defects and only recently have they been able to get enough data to understand how often positive tests are wrong.
“The clinical performance of [noninvasive prenatal tests] has been extremely robust,” Dr. Vance Vanier, vice president of marketing for reproductive and genetic health for San Diego-based Illumina Inc., which offers the Verifi prenatal screen, wrote in an email statement.
The screens are not subject to approval by the Food and Drug Administration. Because of a regulatory loophole, the companies operate free of agency oversight and the kind of independent analysis that would validate their accuracy claims. Doctors often get that information from salespeople, according to doctors themselves.
And there are other emerging concerns about the new generation of prenatal tests. Two Boston-area obstetricians, with funding from a testing company, recently sent samples from two nonpregnant women to five testing companies for analysis. Three companies returned samples indicating they came from a woman who was carrying a healthy female fetus.
Meanwhile, there are a growing number of cases emerging of women told their screen shows virtually no chance of a fetus having a problem but who then deliver a child with a genetic condition.
“My son lived for four days,” said Belinda Boydston, a web/graphic designer in Chandler, Ariz., whose son was born with Edwards syndrome despite a screening test showing that he was extremely unlikely to carry the condition.
But Stacie Chapman knew nothing about these uncertainties when Dr. Sloan told her that her unborn son had screened positive for a genetic condition that was largely incompatible with life.
Hysterical with grief when she hung up, Chapman phoned her husband at a Las Vegas airport on his way home from a business trip. Together, sobbing, they concluded that their son would only suffer if he survived birth. So, that afternoon, Sloan put her in touch with a nurse who found a doctor who could do the termination the next morning.
Chapman spent the afternoon Googling the horrors of Edwards syndrome, with its heart defects, development delays and extraordinarily high mortality. She was steeling herself for the termination when Sloan called back, urging her to wait, according to Chapman’s medical record.
Chapman had a diagnostic test and learned her son did not have Edwards syndrome. A healthy Lincoln Samuel just turned 1 and has a wide smile that reminds Chapman of her recently deceased father.
However briefly considered, their decision to abort — informed by the MaterniT21’s advertised 99 percent detection statistic — haunts them to this day.
“He is so perfect,” Chapman, 43, said, choking up as she watched her son play with a toy lamb. “I almost terminated him.”
Overselling a Screen
Advertisements for these new prenatal screens are filled with bright skies, serene, full-bellied women, and, most of all, assurances that the tests can be trusted.
“Never maybe” promises MaterniT21 in pamphlets. Panorama states its test is “99% Accurate, Simple & Trusted” on a web page.
The screens, conducted as early as nine weeks into a pregnancy, detect placental DNA in a mother’s blood and test it for chromosomal abnormalities as well as gender.
Originally designed for older women and others at higher risk for having a problematic fetus, some of the screens are now marketed to all pregnant women. Company and analyst data indicate there have probably been between 450,000 to 800,000 tests performed in the United States since 2011 and several companies are racing to corner what one market research firm predicts will be a $3.6 billion global industry by 2019.
Independent medical experts say the new screens are far better able to rule out the possibility of certain fetal conditions, especially Down syndrome, than traditional ultrasounds and blood screenings.
That dramatically cuts down on the number of women who are incorrectly told their fetus may have a problem, and helps them avoid a more invasive follow-up test, such as amniocentesis, which carries a small risk of miscarriage.
But the new screens are not perfect, and can indicate fetuses may have serious genetic abnormalities when they do not, the industry’s own research shows.
For example, among older pregnant women such as Chapman, for whom chromosomal abnormalities are more common, a positive test result for Edwards syndrome is accurate around 64 percent of the time, according to a recent study by Quest Diagnostics, a large provider of medical tests and other services. That means baby Lincoln had about a 36 percent chance of not having the condition.
Among younger women who are at lower risk for fetal abnormalities, the error rate is even higher. Only about 40 percent of the positive tests showing high risk for Edwards syndrome turned out to be accurate, according to a recent well-regarded Illumina study of its Verifi screen.
The testing companies do recommend that women who get a positive screen result should seek additional tests to confirm it — much the way a woman whose mammogram showed potential breast cancer would undergo a biopsy to determine whether the dark spots actually are cancerous.
But some companies blur the distinction between the results of their screening tests and a true diagnosis, potentially confusing patients and doctors about the trustworthiness and meaning of their test results. Illumina, for example, claims its Verifi screen has “near-diagnostic accuracy,” a term medical experts say has no meaning.
“The companies have done a very poor job of education [and] advertising this new technology, failing to make clear that it is screening testing with very good but inevitably not perfect test performance . . . and that doctors are recommending, offering, ordering a test they do not fully understand,” said Dr. Michael Greene, director of obstetrics at Massachusetts General Hospital and a professor at Harvard Medical School.
Company officials say they are now focusing on the accuracy of all test results, including false positives, carrying out research on their frequency and looking for ways to reduce the stress of these events.
Getting patients to understand limits on the accuracy of positive test results can be “extremely challenging,” said Juan-Sebastian Saldivar, vice president of clinical services and medical affairs at Sequenom, which offers the screen that Chapman used. He said the company works with doctors on how to best explain it to patients.
Officials at Natera, which offers the Panorama test, insist their screens are highly accurate and produce relatively few false alarms. A company-funded study found that positive test results are correct 83 percent of the time, which is more accurate than studies of other tests have shown.
Melissa Stosic, Natera’s director of medical education and clinical affairs, stresses that the company doesn’t oversell the test, working to educate doctors “to be very clear it’s a screening and not diagnostic.”
However, the same Natera study found that some women are ignoring that advice and having abortions without getting a confirmatory diagnostic test. In its study, 22 women out of 356 who were told their fetuses were at high risk for some abnormality terminated the pregnancy without getting an invasive test to confirm the results.
“It’s troubling,” said Katie Stoll, a genetic counselor in Washington state who has written extensively on the marketing of noninvasive prenatal screens. “Women are getting the wrong message.”
A Short Life
The field of this prenatal testing is so new, and the research so dominated by the companies selling the tests, that basic questions about their reliability and testing methods remain unresolved.
For instance, screening companies say they have had exceedingly few cases of women whose screen shows little problem, but then deliver a baby with a genetic condition. Yet such cases are popping up across the country.
It is not clear how large a problem it is, but critics say the troubling anecdotes are another example of quality control concerns that are not being independently vetted.
Belinda Boydston, 43, of Arizona, was stunned to give birth to a baby with Edwards syndrome after a Harmony screen result in October 2013 showed her fetus had only a 0.01 percent chance of having Edwards syndrome, also known as Trisomy 18.
“I delivered prematurely, and they knew right away he had Trisomy 18,” Boydston said, recounting the scene in the delivery room. “I could hear them talking, ‘Didn’t she have that test?’ ”
This year alone, at the Emory Healthcare Department of Human Genetics in Georgia, officials have seen five newborns with Down syndrome whose prenatal noninvasive screens indicated that there was little risk of the condition.
And a couple in Belmont, Calif., sued Ariosa Diagnostics Inc. last year, alleging its Harmony screen falsely indicated their child would not have Down syndrome and that the company’s marketing material misled patients about the screen’s accuracy. The lawsuit is still pending. Ariosa declined to comment, as did Roche, which is acquiring it.
“There needs to be more transparency and accuracy from the companies about what their results mean,” said Mary Norton, vice chair of genetics in the department of obstetrics, gynecology and reproductive sciences at the University of California San Francisco. Norton, who has received funding from Ariosa and Natera, said research in the field is almost all being funded by industry. “There isn’t a lot of independent research going on.”
FDA regulatory loophole
The loophole that allows unregulated tests in the marketplace dates back to the mid-1970s, when the FDA began overseeing diagnostic tests. The FDA exempted what was then a small group of relatively simple tests developed, manufactured and performed all in a single lab — for example, in a hospital.
In the past decade, for-profit companies have used that regulatory running room to develop complex tests to diagnose or screen for conditions ranging from cancer to Lyme disease and now, fetal chromosomal conditions. Not all of the tests undergo robust independent review and it is challenging for the public to distinguish good and bad tests, according to medical experts.
In late September, the FDA stepped in, publishing draft regulations for the industry expected to take nine years to be fully phased in. Officials there said that the new prenatal tests would probably be among the first few groups to be regulated. Already, the industry is expected to challenge the legality of those rules and a trade group, the American Clinical Laboratory Association, has retained Harvard Law professor Laurence Tribe to help represent them.
However, the FDA has made it clear that the companies don’t have to wait for regulations to act.
We “have told the [prenatal] companies . . . they really should bring their test into the agency,” said Alberto Gutierrez, director of the FDA’s office of in vitro diagnostics in the Center for Devices and Radiological Health. He indicated they could voluntarily submit to regulation, as other types of diagnostic testing companies have done.
While the regulatory fight goes on, doctors say one immediate way to limit potential misuse of possibly inaccurate prenatal screening results is for women to receive genetic counseling before they get the screens — and after. Several women, including Chapman, told the New England Center they were offered the prenatal screens without any clear understanding of what their fetus would be tested for other than Down syndrome and to learn the sex of the baby.
Lincoln Chapman, Stacie’s husband, said he will be forever grateful to Dr. Sloan, of Harvard Vanguard Medical Associates in Boston, for calling Stacie Chapman back to more strongly recommend further tests.
But Stacie Chapman remains conflicted about the doctor’s first call that set in motion the near termination of her pregnancy. Sloan did not stress that the test was just a screen that could be wrong, she recalled.
“I didn’t seek this test out — this test was offered to me by the doctor’s office. They should know how it performs,” Chapman said, adding that she would never have considered a pregnancy termination if she had better understood the odds that her result could be wrong.
A health professional involved in Chapman’s case who was not authorized by her employer to comment said Sloan initially was unaware that the screen could be wrong a significant amount of the time.
Sloan did not return calls to discuss her understanding of the statistics, but a statement from Harvard Vanguard noted its policy recommends genetic counseling and confirmatory testing for women whose fetuses test positive for a genetic abnormality.
Chapman said enormous heartache could have been avoided in her family if companies advertised more scrupulously, and if her doctor had understood the limitations of the screen.
As millions of women in the United States and elsewhere expect babies this year, some inevitably will be in the same situation as Chapman.
“You know when I found out [the baby] was fine, my midwife said, ‘You are one in a million, you are so lucky,’ ” Chapman recalls. “But you know? I really wasn’t.”
The New England Center for Investigative Reporting is a nonprofit investigative reporting newsroom based at Boston University and WGBH News and supported in part by New England news outlets. NECIR interns Samantha Costanzo, John Hilliard, Shan Wang and Andrea Keklak contributed to this report.