A test that analyzes fetal DNA found in a pregnant woman's blood proved much more accurate in screening for Down syndrome and another chromosomal disorder than the now-standard blood test, a new study has found. The promising results may change how prenatal screening for genetic diseases is done, though the test is costly and generally not yet covered by insurance for women at low risk.
The study, published on Wednesday in The New England Journal of Medicine, found that the fetal DNA test was 10 times better in predicting cases of Down syndrome than the standard blood test and ultrasound screening, and five times better in predicting the other disorder, Trisomy 18. It also greatly reduced the number of false-positive results.
It could prevent many women who would otherwise get the standard blood test from needing to confirm positive results with invasive tests like amniocentesis or chorionic villus sampling, which can be stressful, much more costly and carry small risks of miscarriage. "Nine out of 10 women who are currently being referred for further testing would not need invasive tests," said the lead author of the study, Dr. Diana Bianchi, the executive director of the Mother Infant Research Institute at Tufts Medical Center's Floating Hospital for Children.
A positive result on the DNA screening would still need to be confirmed with invasive tests, because in more than half the cases in which the newer test predicted a disorder, there was no chromosomal abnormality. But a negative result would provide confidence that these two major chromosomal disorders are absent.
"It's a better mousetrap, there's no doubt about that," said Dr. Michael Greene, director of obstetrics at Massachusetts General Hospital and co-author of an editorial about the study. "If the test is normal, the overwhelming probability is that your fetus is normal. There will be far fewer women who will be encouraged to have invasive testing, and, as a result, far fewer miscarriages."
The screen analyzes blood from women who are at least 10 weeks pregnant. At that point, about 10 percent of DNA in the blood will be fetal DNA from the placenta, Dr. Bianchi said.
Dr. Bianchi is a paid advisory board member for Illumina, one of the laboratories that performs the test, which is known as the cell-free DNA test because the fetal DNA floats freely in the mother's blood, not inside a cell. Illumina, which is based in San Diego, financed the study.
Dr. Greene, an associate editor at The New England Journal of Medicine, said that the study "would sort of be purer from an academic perspective if somebody else pays for it," but that companies are "the ones that are going to finance the research to get it to where it's marketable."
He added, "We can't have our cake and eat it too." He said the journal had rejected other cell-free DNA studies, but considered this one well done.
Experts said they expected the test would ultimately be offered to all pregnant women, but noted limitations. The test, costing $500 to $2,000, is not now typically covered by insurance for women at low risk for having babies with chromosomal abnormalities. Nor is it regulated by the Food and Drug Administration, because it is considered "laboratory developed," to be used by the lab that created them and not sold to other labs or companies, Dr. Greene said.
The test also appears to work inconsistently in very obese women. And it screens only for major chromosomal disorders and some sex-linked diseases.
"This is a very good screening test for what it's designed to screen for," said Dr. Ignatia B. Van den Veyver, a prenatal geneticist at Baylor College of Medicine. But, she added, "we're concerned that if women stop there, they miss the opportunity to have a diagnostic test like amnio that can detect other chromosomal abnormalities."
For now, this new technology, which became available in 2011, is primarily used for women deemed more likely to have babies with abnormalities because they are age 35 or older or have other risk factors. At least four companies offer the tests. Medical organizations have not recommended them for other women because of a lack of data showing they work in the general population.
The new study, which involved 1,914 pregnant women from diverse backgrounds at 21 medical sites around the country, is the first large study to evaluate the cell-free DNA screen in average American women. Most women in the study were younger than 30, had conceived naturally, and were pregnant with their first child.
Dr. Deborah A. Driscoll, a professor of obstetrics and gynecology at the University of Pennsylvania, who was not involved in the research, said that given this new evidence, "this should be a test that we can offer women universally."
The women received standard screening from their doctors, a blood test that identifies proteins or other biological markers associated with chromosomal disorders. Some also got ultrasounds examining the fetus's neck for fluid associated with Down syndrome.
Separately, and without knowing the results of the standard tests, technicians at the Illumina lab screened samples of the women's blood for three copies of chromosomes instead of the normal two, seeking to identify chromosomes for Down syndrome, and for Trisomies 18 and 13, often fatal disorders.
Researchers later checked whether babies were born with or without these conditions.
In the study, the rate of false positives for Down syndrome was 0.3 percent with the cell-free DNA screening, while the rate for standard screening was 3.6 percent, 12 times higher. The false-positive rate for Trisomy 18 was 0.2 percent with the DNA screening; the rate with standard screening was three times that. Not everyone received standard screens for Trisomy 13, so complete comparisons could not be made.
The DNA screen was correct in predicting Down syndrome 45.5 percent of the time, while the rate for standard screens was 4.2 percent. The DNA screen accurately predicted babies with Trisomy 18 almost 41 percent of the time, five times better than standard screening, whose rate was 8 percent.
The cell-free DNA screen worked equally well in first, second or third trimesters, and in high- and low-risk women." Since positive tests are often wrong, women should get positive findings verified with amniocentesis or C.V.S., experts aid.
"The greatest risk is that the test will be oversold or over-interpreted and that women won't take the step of an invasive diagnostic procedure before they do something irreversible like terminate a pregnancy," Dr. Greene said.
In the study, one of the five fetuses with Down syndrome was aborted, one of two with Trisomy 18 was stillborn, and the sole fetus with Trisomy 13 died in utero. The other five chromosomally abnormal babies were born alive.
Jennifer Fontaine, 29, of Groveland, Mass., was not in the study, but chose cell-free DNA screening last year after standard screening showed an elevated risk of Trisomy 18 in her fetus. She was offered amniocentesis, but she said, "I wanted the noninvasive procedure." Her DNA screen was negative for Trisomy 18, and her daughter, Morgan, was born healthy.
Andrew Pollack contributed reporting.
This post has been revised to reflect the following correction:
Correction: February 27, 2014
An earlier version of this post misspelled the surname of a prenatal geneticist at Baylor College of Medicine. She is Dr. Ignatia B. Van den Veyver, not van der Veyver.
