A recent California study examining cell-free DNA (cfDNA) testing suggests that the test generally performs well as a second-line screen for fetal aneuploidy. However, while the test itself is reliable, some physicians say gaps in patient education, limited availability of genetic counseling, and a lack of coordinated research and data collection are all standing in the way of its optimal utilization.

In some of the most recent data presented on cfDNA test performance, researchers in California found that the test had few false positives and was best at predicting Down syndrome, with a positive predictive value of 98.6%.

In a presentation at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine, Robert Currier, PhD , reported on California’s experience with cfDNA testing. The procedure was authorized by the state as a follow-up service in November 2013, so researchers at the California Department of Public Health examined state-level data from that point through October 2015.

California offers prenatal screening as a public health program, with a structured system of screening tests and follow-up services, according to Dr. Currier, who is chief of the evaluation section of the state’s Genetic Disease Screening Program. First trimester screening includes screens for trisomies 18 and 21. During the second trimester, the screening adds on checks for neural tube defects and Smith-Lemli-Opitz syndrome, also known as 7-dehydrocholesterol reductase deficiency.

Patients who have positive first-trimester screens are seen at a prenatal diagnosis center and offered genetic counseling, chorionic villus sampling, and cfDNA testing. During the second trimester, patients with a positive screening result may also receive a fetal anatomic survey by ultrasound, as well as an amniocentesis.

Overall, 20,852 patients were offered cfDNA screening during this period, and 63% (n = 12,960) went on to have the screen. Dr. Currier and his colleagues found that about a third of patients with a first- or second-trimester positive cfDNA test opted for diagnostic testing with either chorionic villus sampling or amniocentesis. If patients had a known karyotype, most were in agreement with the trisomy or sex-chromosome aneuploidies that had been picked up by cfDNA testing.

There were a small number of false-positive cfDNA results seen in the California data, Dr. Currier noted. Performance was best for Down syndrome, where cfDNA had a positive predictive value of 98.6%. Here, 214 of the 611 cfDNA positive results received diagnostic confirmation. Of those, 197 were true positives and 3 were false positives, while a karyotype other than trisomy 21 was revealed in 14 cases. Positive predictive values were lower in the less-common aneuploidies, he said.

A small number of test failures also occurred. Of the 148 failures reported, just 40 were followed by successful repeat tests.

“Cell-free DNA is a good second-tier screening test, but it does have false-positive and false-negative results, so pre- and post-test counseling addressing these limitations are essential,” Dr. Currier said.

Nancy Rose, MD , agrees with that assessment of the limitations of the cfDNA test. She helped write the American College of Obstetricians and Gynecologists 2015 opinion on cell-free DNA screening for aneuploidy, which states that conventional screening methods “remain the most appropriate choice for first-line screening for most women in the general obstetric population.”

While it is “perfectly reasonable” for general ob.gyns. to offer cfDNA screening, in her practice, “genetic counselors call out all the results for general providers because patients don’t really understand what a screen negative result is,” Dr. Rose said in an interview. “Certainly, screen positive results should go to a genetic counselor for sure.”

However, that level of follow-up may be hard to implement. “One issue that we’re all facing right now is that genetic counselors are a scarce commodity because of the competition with them working for labs or insurance companies,” said Dr. Rose, a maternal-fetal medicine specialist in Salt Lake City.

If the lack of appropriate counseling is an issue, are patients sometimes jumping the gun? The immediate past president of the Society for Maternal-Fetal Medicine, Mary Norton, MD , said maybe so.

When asked whether she thinks pregnancies are being terminated on the basis of cfDNA results alone, Dr. Norton said, “I absolutely think that is happening. How many is hard to know. I do know that we have many patients that we see who say, ‘My result here says that the chance of Down syndrome is greater than 99%,’ but that is not what that number means, and people don’t understand that.”

She added, “In some cases there are also ultrasound abnormalities, but there is no question that there is misunderstanding leading to the loss of normal fetuses.”

Patient misunderstandings about what’s entailed in first- and second-line screening tests persist, said Dr. Norton, professor of obstetrics and gynecology and reproductive sciences at the University of California, San Francisco. One example is ongoing hesitancy about amniocentesis. “Amnio has become very, very safe,” she said. “It’s much safer than it used to be. The miscarriage rate is nearly nonexistent.”

The care team needs to work to find time to educate patients about both older technologies and noninvasive prenatal testing (NIPT), Dr. Rose and Dr. Norton stressed.

“Even though ‘NIPT’ is easy to say – it rolls off the tongue – we really shouldn’t call it that. It’s misleading, because all of the other screening tests are noninvasive too,” Dr. Norton said. “I’ve had many patients who declined diagnostic testing, even though they want as much information as possible about what they should do.”

Dr. Rose added, “It’s a screening test; it’s not perfect. But screening tests are really what obstetricians do. They do pap smears; they do breast exams. So I think that isn’t the issue so much as that there is no time in an obstetrician’s office to really educate women about what they are accepting.”

Additional ethical issues revolving around the mother may arise in rare cases. Only about 10% of the DNA sampled is fetal, meaning that the rest is maternal DNA, Dr. Norton explained. “And they’re not separated,” she said. “So, the issue that is coming up is that they are finding things in the mother that are unanticipated, and women aren’t told that ahead of time.”

Some of these thorny – and still evolving – legal and ethical questions were addressed during a workshop at the 2017 Pregnancy Meeting. A working group that met there is developing a summary of their discussion for future publication.

For Dr. Rose, the larger issue is the lack of coordinated data collection and quality initiatives. She pointed out that the California outcomes study may not be generalizable to most of the rest of the country because most states don’t have such a coordinated public health approach to prenatal testing and data collection.

This reality is hampering knowledge advancement in the field, she said. When she was asked about terminations on the basis of cfDNA alone, Dr. Rose said, “Because there’s no outcome data on these patients, because there are no unbiased studies that cross through these companies, we actually don’t really know that on a national level. There are no unbiased outcome data. There may be small studies, but I think there are no national data to answer that question at the moment.”

Overall, Dr. Rose said that cfDNA screening is fairly reliable. “This is no different than what has been done before with serum analyte screening, and it’s probably a little bit better,” she said. “My feeling is the tragedy is really in the lack of companies either being able to work together or to have some unbiased funding so you could really actually know what test performance means.”

Dr. Norton reported receiving research funding from Natera and Ultragenyx. Dr. Rose reported no relevant disclosures. Dr. Currier’s study was funded by the California Department of Public Health, where he is employed.

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