New prenatal blood tests for genetic abnormalities such as Down syndrome are reshaping care for expectant mothers, but their rapid rollout has raised fears that poorly understood results could lead to confusion among patients and doctors managing high-risk pregnancies.
Four companies, including
Sequenom Inc.
SQNM -4.91% and a unit of gene-sequencing firm
Illumina Inc.,
ILMN -0.46% are vying for the new market for the tests, which examine traces of fetal DNA in the mother's bloodstream. The market has grown rapidly since the tests were first introduced in late 2011—with Sequenom alone topping 61,000 tests in 2012. The industry expects that at current rates it will run hundreds of thousands of tests this year, and many doctors believe they could fast become the standard of care for pregnant women.
Agence France-Presse/Getty Images
Ultrasound can be used to help screen for Down syndrome.
At the same time, case reports of inaccurate results—though rare—are turning up more frequently than expected, medical specialists say. They worry that in the worst-case scenario, inaccurate test results could contribute to the abortion of healthy babies.
Members of the American College of Medical Genetics and Genomics question whether the products should be called "tests" at all. The group plans to release a statement renaming them "screenings," to indicate they predict risk rather than give definitive results, according to Anthony Gregg, a board member at the college and a specialist in treating high-risk pregnancies.
As physicians begin deploying the tests more routinely, experts worry they are being used in lieu of more invasive—but more definitive—diagnostic measures such as amniocentesis, in which a needle as long as 6 inches is inserted into the womb to extract fluid. That test carries a slight risk—generally estimated at well below 1%—of inducing miscarriage. Some clinics have promoted the new tests as a safer alternative.
Test makers and experts say positive results in a blood test should be confirmed with invasive procedures. Negative results may help rule out the need for such procedures.
But there is a risk that aggressive marketing based on test performance from the early clinical trials could confuse physicians and patients with complex information, said Girish Putcha, a practicing molecular-genetics pathologist and former laboratory director for Ariosa Diagnostics Inc., one of the test makers.
In translating clinical trials—focused on high-risk women and carried out in controlled environments—"to the actual practice of medicine, the numbers usually tend to be not quite as good," Dr. Putcha said, speaking broadly about the industry. "The question is, how not-quite-as-good?"
Test Race
- Ultrasound screening: Doctors can predict Down syndrome by seeing a thicker-than-normal layer of fluid behind the neck of a fetus. Up to 70% accurate
- Serum tests: Combining ultrasound with blood tests seeking certain proteins can improve detection rates. Alone, the blood tests are less precise. Up to 87% accurate
- Noninvasive prenatal testing:Fetal DNA in a mother's blood is scanned for genetic signs of Down syndrome. More than 99% accurate
- Amniocentesis: Using a needle, doctors extract amniotic fluid from the uterus for testing. Nearly 100% accurate
Commercial performance so far tracks with clinical studies based on physician feedback, said Ken Song, chief executive of Ariosa. The company has "always been trying to position this as a screen," he said. Still, Dr. Song said, "you've got confusion because you have multiple competing interests," including competitive companies, medical societies with varying guidelines, and an array of doctors in the field with different views about the tests.
The debate shows the challenges of pushing the predictive power of genomic science from the lab into the world of work-a-day medicine. Studies funded by the companies show the blood tests accurately predict roughly 99% of positive results for Down syndrome, though some are less accurate for two other abnormalities.
The largest studies are limited to a few hundred positive results, and some exclude patients whose conditions may result in inconclusive findings, such as those with samples that lack sufficient DNA fragments related to the pregnancy or have irregularities that confuse results.
That has left women and their doctors to sort out the value and limitations of the tests in real-world clinical settings, where many patients have a strong incentive to favor a test that might help avoid amniocentesis.
"Women and physicians will do almost anything to reduce their need for invasive testing. That is why it is taking off," said Lee Shulman, chief of clinical genetics for Northwestern Medicine's obstetrics unit in Chicago. But while the tests are "a profound improvement over the tarot cards we used to use" to screen for risk, they don't replace amniocentesis, he said.
In one case, Dr. Shulman, who consults for Sequenom and Natera Inc., another test maker, said one patient who had received a positive Sequenom test result for a chromosomal abnormality arrived at his clinic seeking to terminate her pregnancy, but amniocentesis showed the fetus was normal.
The Companies Behind the Tests
Four companies have introduced new prenatal tests for Down syndrome and two other chromosomal abnormalities since late 2011. They are on track to do hundreds of thousands of tests this year.
Sequenom Inc.
The publicly traded pioneer of the industry launched its test, MaterniT21 PLUS, in the fall of 2012. Weekly sales soared last year from a few hundred per week to more than 2,500 showing the expotential curve of adoption in medical practices.
Ariosa Diagnostics Inc.
The venture-capital backed firm arrived on the market second, in May, 2012. An agreement with Laboratory Corp. of America to market the test helped pave the way for quick catch up.
Verinata Health Inc.
Just over six-months after launching a test in late May of 2012, Illumina Inc., the sequencing giant, acquired the firm in a bid to move from the business of selling genomics equipment to providing direct services in the industry.
Natera Inc.
The late-comer formally launched its version of the test last month, ahead of a forthcoming publication of a study validating its approach. The nine-year-old firm makes other prenatal tests, too.
Source: The companies, WSJ reporting
"I'm doing everything I can do to promote the message" that positive results should be confirmed with invasive testing, said Allan Bombard, chief medical officer at Sequenom. "False positives are not unexpected," he said, "and there are other things that can confound us."
The tests aren't approved by the U.S. Food and Drug Administration. So-called laboratory-developed tests, performed at a single facility with proven technical expertise, historically haven't required clearance, a policy the agency is reviewing in light of the new wave of complex genomic tests. These tests are done at the makers' own labs. Generally, test kits sold to other laboratories do require approval.
The tests have quickly changed care. At the Cleveland Clinic, doctors perform 50% fewer invasive procedures, thanks to the testing advances, said Jeff Chapa, section head of obstetrics and maternal-fetal medicine.
"This is my first child, and I'm 43. I'm not sure I want to risk this miracle that I have," said Jennifer Turcotte of Redwood, Calif., who is 14 weeks into her pregnancy and at risk of abnormalities because of her age. After learning about the miscarriage rates associated with invasive testing, she opted to receive one of the new tests at Lucile Packard Children's Hospital. The results tentatively ruled out problems. It "took a lot of that stress and anxiety away," she said.
In addition to reducing the risks of complications, the tests appeal to women because they can be performed earlier in a pregnancy—beginning at about 10 weeks, offering a head start on potentially difficult decisions.
But false-positive results raise the specter that women could choose to terminate healthy pregnancies if they don't receive appropriate follow-up care. False-negative results, which are rarer, also present a quandary for women and doctors who may not find out until much later that a fetus has an abnormality.
Some medical practices advertise the tests as a way to avoid amniocentesis. New Jersey Perinatal Associates in Livingston, N.J., describes Sequenom's MaterniT21 test in a promotional page of its website as "an alternative to traditional" methods, and notes that unlike invasive tests, it "is a simple blood test that is noninvasive to you and your baby."
"All patients want to hear that you don't need to have something invasive," said Laura Limone, genetic-counseling supervisor at the perinatal group and a member of Sequenom's speakers bureau. "Those who understand the technology find it very promising, but we also know it isn't perfect yet," and patients with positive results are advised to undergo follow-up invasive testing, she said.
In one case published online by the American Journal of Obstetrics & Gynecology, a positive result from one of the new tests—together with preliminary results from another less-precise invasive measure—prompted a patient to terminate her pregnancy without undergoing a confirmatory amniocentesis. Testing of tissue from the aborted fetus showed the pregnancy was normal, the report said.
Though companies say patients should confirm positive results with invasive procedures, such case studies show "that message isn't driven home enough," said Athena Cherry, director of Stanford University Medical Center's cytogenetics laboratory. In her lab, Dr. Cherry said she had found four out of six positive results for Trisomy 18, or Edwards syndrome, which the tests also detect, appeared to be false alarms after follow-up testing.
Sometimes, the reasons for these rare errors aren't fully understood, doctors say. Obese mothers, twin fetuses, and a phenomenon called mosaicism, in which placenta DNA differs from fetal DNA, among other things, could confuse results. In one recently reported case, researchers believe inaccurate test results were linked to a previously undiagnosed cancer in the mother.
At least one case of a false-negative report also raised questions. Verinata, Illumina's testing unit, incorrectly cleared a New York woman's fetus of Down syndrome, according to the case report presented at a medical society meeting last month. Further testing prompted by unusual ultrasound readings later determined that the fetus did, in fact, have Down syndrome, and the patient opted to terminate the pregnancy.
"I didn't know what to expect when I was told to see these specialists for this prenatal testing," said the 35-year-old woman, who asked not to be named because she hadn't discussed her abortion last fall with family members. "It was my first pregnancy so we really wanted to avoid [invasive testing] at all cost if we could. But we were getting no answers."
At the time, Verinata's testing materials claimed 100% sensitivity in detecting Down syndrome. The firm has since revised the assertion to ">99.9%."
Rachel Allen, a genetic counselor at the Poughkeepsie, N.Y., medical practice that caught the error, said she was puzzled by the test's failure. "Before we all get caught up in the hype, we really need to pay attention to how we can best utilize it," she said.
Verinata will soon publish a review of its field performance over its first nine months on the market, said Richard Rava, chief scientific officer for the testing firm. He expects the results to be "completely consistent" with the high detection rates shown in clinical trials, though he acknowledged the test had missed the New York case.
Dr. Rava said Verinata changed the statistics in its testing materials because "doctors were uncomfortable with anything on a report that said it was going to be 100% accurate."
Verinata's test reports include information about limitations, such as confidence intervals—a measure of the precision of an estimate—for such statistics, and fine print advises that patients receive additional testing "if a definitive diagnosis is desired."
The FDA has asked some of the companies for information about whether their products should be more closely regulated. A proposal to regulate certain "high-risk" laboratory tests, including the new prenatal screenings, has been in the works for two years and is under "administrative review," the agency said.
"We have been trying to plug some of the regulatory gaps," said Alberto Gutierrez, who leads the FDA's in vitro diagnostics group. "We want to make sure the performance of the test is good so people can make the decisions that they're going to make."
Sequenom recently released data suggesting its real-world performance tracked with trial results, based on physician feedback. "It's not the same type quality control as a controlled trial," Sequenom's Dr. Bombard said, though he expects doctors to proactively report unusual results. He said the company had sought to be conservative in its rollout by limiting the test to women with risk factors and recommending that it be administered in conjunction with genetic counseling.
Physicians and test makers are split over whether the test should be distributed more widely, with some test makers beginning to sell to the broader market. There is also a hope the tests could eventually be used to gather more definitive diagnoses.
"Noninvasive prenatal [testing] as a whole has the potential to someday replace invasive procedures," said Jonathan Sheena, chief technology officer at Natera, the latest company to enter the fray. "The field has taken a giant leap forward," he said, "but we believe it is important to understand they don't replace invasive tests yet."
Karyotype of 21 trisomy (Down syndrome).Down syndrome, the most common genetic form of intellectual disability, results from an extra copy of one chromosome. Although people with Down syndrome experience intellectual difficulties and other problems, scientists have had trouble identifying why that extra chromosome causes such widespread effects. 
