Low-risk prenatal testing gives 12 times more false positives than cell-free DNA testing

The current prenatal screening standard of care for Down syndrome and other trisomies in low-risk pregnancies is more than three times as likely to return a false positive, compared with false positive rates from noninvasive, cell-free DNA testing, according to a new study.

The findings likely will strengthen public demand for the novel testing to become routine, according to Dr. Diana W. Bianchi, lead author of the CARE (Comparison of Aneuploidy Risk Evaluation) study.

"The pregnant women social media groups are very aware of the false positives. I think everybody knows somebody who has had one, since there’s 1 in 20 chance of that [happening]," Dr. Bianchi said in an interview.

Surprising results

Also revealed in the study was cell-free DNA testing’s essentially 100% negative predictive value for aneuploidies in low-risk populations.

The results are "very impressive," said Dr. Michael F. Greene, associate editor of the New England Journal of Medicine, in an interview. "I do think this is going to sweep the table in terms of what is offered to pregnant women," particularly if other studies demonstrate the same level of efficacy, he said. The study was published online (N. Engl. J. Med. 2014;370:799-808).

©iStock/thinkstockphotos.com

To compare false positive rates in the two methods of screening, Dr. Bianchi and her team analyzed test results from 1,914 women (average age, 30 years) enrolled from the general obstetrical population across 21 centers in 14 states. Participants either had or planned to have standard aneuploidy serum screening. All women were risk classified according to standard screening and had a singleton fetus without aneuploidy and a gestational age of at least 8 weeks. A second serum sample was taken from each woman, and massively parallel sequencing was used by laboratory personnel blinded to fetal karyotype to determine the chromosome dosage. Birth outcomes or karyotypes were used as the reference standard.

For trisomies 21 and 18, the false positive rates returned by cell-free DNA testing were significantly lower than those returned by standard screening: 6 patients vs. 69 out of 1,909 for trisomy 21 (0.3% vs. 3.6%; P less than .001), and 3 vs. 11 out of 1,905 for trisomy 18 (0.2% vs. 0.6%, P = .03).

The positive detection rate for cell-free DNA testing of all aneuploidies (5 for trisomy 21, 2 for trisomy 18, and 1 for trisomy 13) was 100% (95% confidence interval, 99.8-100). The positive predictive values for the cell-free DNA testing, compared with standard screening, were 45.5% vs. 4.2% for trisomy 21, and 40.0% vs. 8.3% for trisomy 18.

These positive predictive values, Dr. Greene and Dr. Elizabeth G. Phimister wrote in an accompanying editorial, "underscore the conclusion that assaying fetal DNA is a screening tool and not a diagnostic intervention." However, they concluded, "the observed negative predictive values of 100% with 95% confidence limits down to 99.8%, combined with the significantly and substantively lower false positive rates with cell-free DNA screening than with standard screening, augur well for pregnant women and their fetuses" (N. Engl. J. Med. 2014;370:874-5).

"I think it is going to surprise people when they see that the current standard of care has such a low positive predictive value in a general obstetrical population," said Dr. Bianchi, who also directs the Mother Infant Research Institute at Tufts Medical Center, Boston.

The primary outcome was determined by newborn physical examination in 1,857 patients (97.0%) and by karyotype in 57 patients (3.0%). Of these, chorionic villus sampling was performed in 10 patients, amniocentesis in 38, testing of the products of conception in 3, and postnatal evaluation in 6. The women whose cell-free DNA tests came back with false positive readings all had live births with normal physical examinations.

The secondary endpoint was a similar comparison of detection rates for trisomy 13 (Patau syndrome). There was one false positive result for trisomy 13 with cell-free DNA testing, as compared with six false positive results on standard screening, thus showing a trend toward significance (P = .059) in the 899 patients who underwent standard screening for trisomy 13.

Fetal fraction not maternal age–related

The researchers found that cell-free DNA testing had the same high-sensitivity detection rates in low-risk obstetrical populations as has been previously established in high-risk ones. Generally considered at higher risk for trisomy 21, women 35 years and older who were tested in either the first or second trimesters had results that were nearly identical to results from women under age 35 in terms of both their mean percentage of free fetal DNA and their standard screening results and/or cell-free DNA results (11.3% and 11.6%, respectively). For women tested in the third trimester, the fetal fraction was higher (mean, 24.6%).

This finding further strengthens the argument that the technology should be available to the general obstetric population. "The amount of the DNA was the same when we stratified the relatively high risk from the relatively low risk," said Dr. Bianchi. "That will be a surprise to some people who postulated that the high-risk women would have more DNA circulating. They don’t."

The consistent fetal fraction also lends itself to greater flexibility when prenatal screening occurs, allowing women to be screened anytime between 10 and 40 weeks gestational age. This could mean better prenatal care for women who do not have their first prenatal visit until late in the second trimester, for example. Because the current screening methods are specific to certain gestational times, if a woman is erratic with her prenatal visits, testing may be impossible.

Regarding its utility in women carrying multiple fetuses, Dr. Bianchi said that about 10% of the time, the fetal fraction per fetus tends to be too low to get an accurate reading.

‘Throwing down the gauntlet’

The test’s unparalleled accuracy could give greater peace of mind to women who might have had difficulty getting pregnant and so are wary of the miscarriage risks posed by invasive diagnostic testing, according to Dr. Bianchi. Fewer invasive diagnostic tests could also lower costs across the system.

When all results for trisomies 21 and 18 were combined, the researchers found that the false positive rates for standard screening were 4.2%, compared with 0.5% for cell-free DNA testing. "If all pregnant women had undergone cell-free DNA testing as a primary screening method and if all women with positive results had undergone post-test counseling and had decided to undergo an invasive procedure," wrote the authors, "there would have been a relative reduction of 89% in the number of diagnostic invasive procedures required to confirm a positive screening result."

The data should move professional societies to take action, according to Dr. Bianchi. "That’s kind of the gauntlet that we’re throwing down." More data are on the way, she said, which will "enable the professional societies to take a cumulative look and decide what their recommendations are going to be."

As it stands, the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists state that the testing be used only in women at higher risk for giving birth to children with aneuploidies, such as women aged 35 years or older or those with a history of pregnancy with trisomy, and that positive cell-free DNA results should be confirmed by invasive diagnostic testing.

For now, because the tests are not considered routine prenatal care, low-risk patients usually pay out of pocket for these tests, which Dr. Bianchi said many women are willing to do. The cost of the test ranges anywhere from $1,200 to upward of $2,700, although some careful Internet searching for deals can net tests at substantially lower prices, she said.

Market pressures

For some physicians in the field, this public demand for a screening test not subject to Food and Drug Administration (FDA) regulation has not outweighed the level of proof it offers in the clinical setting. One of these critics was, until recently, Dr. Greene.

"Companies have been free to build consumer demand for cell-free DNA testing by aggressively marketing the tests, emphasizing data that do not answer key questions," wrote Dr. Greene in July 2013, in an editorial he coauthored (N. Engl. J. Med. 2013;369:499-501). "As a result, cell-free DNA testing seems to be drifting into routine practice ahead of the evidence," stated Dr. Greene, who is also chief of obstetrics at Massachusetts General Hospital in Boston, and who wrote with his colleagues that the test’s positive predictive value, largely unreported by manufacturers, was still in question.

"The problem is that the proof-of-principle studies that all these companies have published to date have been with ratios of ‘Down’s’ to ‘normals’ ranging from 1 to 7, 1 to 13, or 1 to 20," said Dr. Greene in an interview. "All were done in retrospective populations at extraordinarily high risk."

However, with the CARE study, "what’s impressive is the positive predictive value in a low-incidence group of patients," he said.

Sponsored by Illumina/Verinata, the study puts pressure on other companies to publish their own data in peer-reviewed journals, said Dr. Greene. "Once this paper appears in print, [Verinata] will get a leg up, and the other companies won’t want to let them get too far ahead of them."

According to Dr. Bianchi, Verinata is now seeking FDA approval to market the testing as an in vitro diagnostic product. She expects demand for the testing to be led not by physicians but by patients. "People often ask me why the DNA testing took off so quickly," said Dr. Bianchi. "I think a factor is social media. I find there is a discrepancy between what the average patient knows and the general obstetrician knows because of the discussions [online]. "

Although some women will still need an invasive procedure to resolve a screen positive test, Dr. Bianchi said most pregnant women, including older women, are going to be reassured with the 100% negative predictive value.

"The younger woman’s benefit will primarily be the reduced false positive rate, because overwhelmingly, she is going to have a normal fetus, so her major benefit is not being made anxious and being sent for all the subsequent testing."

Dr. Bianchi and her coauthors disclosed relationships with Verinata/Illumina, maker of the Verifi cell-free DNA prenatal test. Dr. Bianchi is also on the clinical advisory board of Verinata. Dr. Greene stated that he had no conflict of interest disclosures. The study was sponsored by Illumina, ClinicalTrials.gov number NCT01663350.

[email protected]

The current prenatal screening standard of care for Down syndrome and other trisomies in low-risk pregnancies is more than three times as likely to return a false positive, compared with false positive rates from noninvasive, cell-free DNA testing, according to a new study.

The findings likely will strengthen public demand for the novel testing to become routine, according to Dr. Diana W. Bianchi, lead author of the CARE (Comparison of Aneuploidy Risk Evaluation) study.

"The pregnant women social media groups are very aware of the false positives. I think everybody knows somebody who has had one, since there’s 1 in 20 chance of that [happening]," Dr. Bianchi said in an interview.

Surprising results

Also revealed in the study was cell-free DNA testing’s essentially 100% negative predictive value for aneuploidies in low-risk populations.

The results are "very impressive," said Dr. Michael F. Greene, associate editor of the New England Journal of Medicine, in an interview. "I do think this is going to sweep the table in terms of what is offered to pregnant women," particularly if other studies demonstrate the same level of efficacy, he said. The study was published online (N. Engl. J. Med. 2014;370:799-808).

©iStock/thinkstockphotos.com

To compare false positive rates in the two methods of screening, Dr. Bianchi and her team analyzed test results from 1,914 women (average age, 30 years) enrolled from the general obstetrical population across 21 centers in 14 states. Participants either had or planned to have standard aneuploidy serum screening. All women were risk classified according to standard screening and had a singleton fetus without aneuploidy and a gestational age of at least 8 weeks. A second serum sample was taken from each woman, and massively parallel sequencing was used by laboratory personnel blinded to fetal karyotype to determine the chromosome dosage. Birth outcomes or karyotypes were used as the reference standard.

For trisomies 21 and 18, the false positive rates returned by cell-free DNA testing were significantly lower than those returned by standard screening: 6 patients vs. 69 out of 1,909 for trisomy 21 (0.3% vs. 3.6%; P less than .001), and 3 vs. 11 out of 1,905 for trisomy 18 (0.2% vs. 0.6%, P = .03).

The positive detection rate for cell-free DNA testing of all aneuploidies (5 for trisomy 21, 2 for trisomy 18, and 1 for trisomy 13) was 100% (95% confidence interval, 99.8-100). The positive predictive values for the cell-free DNA testing, compared with standard screening, were 45.5% vs. 4.2% for trisomy 21, and 40.0% vs. 8.3% for trisomy 18.

These positive predictive values, Dr. Greene and Dr. Elizabeth G. Phimister wrote in an accompanying editorial, "underscore the conclusion that assaying fetal DNA is a screening tool and not a diagnostic intervention." However, they concluded, "the observed negative predictive values of 100% with 95% confidence limits down to 99.8%, combined with the significantly and substantively lower false positive rates with cell-free DNA screening than with standard screening, augur well for pregnant women and their fetuses" (N. Engl. J. Med. 2014;370:874-5).

"I think it is going to surprise people when they see that the current standard of care has such a low positive predictive value in a general obstetrical population," said Dr. Bianchi, who also directs the Mother Infant Research Institute at Tufts Medical Center, Boston.

The primary outcome was determined by newborn physical examination in 1,857 patients (97.0%) and by karyotype in 57 patients (3.0%). Of these, chorionic villus sampling was performed in 10 patients, amniocentesis in 38, testing of the products of conception in 3, and postnatal evaluation in 6. The women whose cell-free DNA tests came back with false positive readings all had live births with normal physical examinations.

The secondary endpoint was a similar comparison of detection rates for trisomy 13 (Patau syndrome). There was one false positive result for trisomy 13 with cell-free DNA testing, as compared with six false positive results on standard screening, thus showing a trend toward significance (P = .059) in the 899 patients who underwent standard screening for trisomy 13.

Fetal fraction not maternal age–related

The researchers found that cell-free DNA testing had the same high-sensitivity detection rates in low-risk obstetrical populations as has been previously established in high-risk ones. Generally considered at higher risk for trisomy 21, women 35 years and older who were tested in either the first or second trimesters had results that were nearly identical to results from women under age 35 in terms of both their mean percentage of free fetal DNA and their standard screening results and/or cell-free DNA results (11.3% and 11.6%, respectively). For women tested in the third trimester, the fetal fraction was higher (mean, 24.6%).

This finding further strengthens the argument that the technology should be available to the general obstetric population. "The amount of the DNA was the same when we stratified the relatively high risk from the relatively low risk," said Dr. Bianchi. "That will be a surprise to some people who postulated that the high-risk women would have more DNA circulating. They don’t."

The consistent fetal fraction also lends itself to greater flexibility when prenatal screening occurs, allowing women to be screened anytime between 10 and 40 weeks gestational age. This could mean better prenatal care for women who do not have their first prenatal visit until late in the second trimester, for example. Because the current screening methods are specific to certain gestational times, if a woman is erratic with her prenatal visits, testing may be impossible.

Regarding its utility in women carrying multiple fetuses, Dr. Bianchi said that about 10% of the time, the fetal fraction per fetus tends to be too low to get an accurate reading.

‘Throwing down the gauntlet’

The test’s unparalleled accuracy could give greater peace of mind to women who might have had difficulty getting pregnant and so are wary of the miscarriage risks posed by invasive diagnostic testing, according to Dr. Bianchi. Fewer invasive diagnostic tests could also lower costs across the system.

When all results for trisomies 21 and 18 were combined, the researchers found that the false positive rates for standard screening were 4.2%, compared with 0.5% for cell-free DNA testing. "If all pregnant women had undergone cell-free DNA testing as a primary screening method and if all women with positive results had undergone post-test counseling and had decided to undergo an invasive procedure," wrote the authors, "there would have been a relative reduction of 89% in the number of diagnostic invasive procedures required to confirm a positive screening result."

The data should move professional societies to take action, according to Dr. Bianchi. "That’s kind of the gauntlet that we’re throwing down." More data are on the way, she said, which will "enable the professional societies to take a cumulative look and decide what their recommendations are going to be."

As it stands, the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists state that the testing be used only in women at higher risk for giving birth to children with aneuploidies, such as women aged 35 years or older or those with a history of pregnancy with trisomy, and that positive cell-free DNA results should be confirmed by invasive diagnostic testing.

For now, because the tests are not considered routine prenatal care, low-risk patients usually pay out of pocket for these tests, which Dr. Bianchi said many women are willing to do. The cost of the test ranges anywhere from $1,200 to upward of $2,700, although some careful Internet searching for deals can net tests at substantially lower prices, she said.

Market pressures

For some physicians in the field, this public demand for a screening test not subject to Food and Drug Administration (FDA) regulation has not outweighed the level of proof it offers in the clinical setting. One of these critics was, until recently, Dr. Greene.

"Companies have been free to build consumer demand for cell-free DNA testing by aggressively marketing the tests, emphasizing data that do not answer key questions," wrote Dr. Greene in July 2013, in an editorial he coauthored (N. Engl. J. Med. 2013;369:499-501). "As a result, cell-free DNA testing seems to be drifting into routine practice ahead of the evidence," stated Dr. Greene, who is also chief of obstetrics at Massachusetts General Hospital in Boston, and who wrote with his colleagues that the test’s positive predictive value, largely unreported by manufacturers, was still in question.

"The problem is that the proof-of-principle studies that all these companies have published to date have been with ratios of ‘Down’s’ to ‘normals’ ranging from 1 to 7, 1 to 13, or 1 to 20," said Dr. Greene in an interview. "All were done in retrospective populations at extraordinarily high risk."

However, with the CARE study, "what’s impressive is the positive predictive value in a low-incidence group of patients," he said.

Sponsored by Illumina/Verinata, the study puts pressure on other companies to publish their own data in peer-reviewed journals, said Dr. Greene. "Once this paper appears in print, [Verinata] will get a leg up, and the other companies won’t want to let them get too far ahead of them."

According to Dr. Bianchi, Verinata is now seeking FDA approval to market the testing as an in vitro diagnostic product. She expects demand for the testing to be led not by physicians but by patients. "People often ask me why the DNA testing took off so quickly," said Dr. Bianchi. "I think a factor is social media. I find there is a discrepancy between what the average patient knows and the general obstetrician knows because of the discussions [online]. "

Although some women will still need an invasive procedure to resolve a screen positive test, Dr. Bianchi said most pregnant women, including older women, are going to be reassured with the 100% negative predictive value.

"The younger woman’s benefit will primarily be the reduced false positive rate, because overwhelmingly, she is going to have a normal fetus, so her major benefit is not being made anxious and being sent for all the subsequent testing."

Dr. Bianchi and her coauthors disclosed relationships with Verinata/Illumina, maker of the Verifi cell-free DNA prenatal test. Dr. Bianchi is also on the clinical advisory board of Verinata. Dr. Greene stated that he had no conflict of interest disclosures. The study was sponsored by Illumina, ClinicalTrials.gov number NCT01663350.

[email protected]

The current prenatal screening standard of care for Down syndrome and other trisomies in low-risk pregnancies is more than three times as likely to return a false positive, compared with false positive rates from noninvasive, cell-free DNA testing, according to a new study.

The findings likely will strengthen public demand for the novel testing to become routine, according to Dr. Diana W. Bianchi, lead author of the CARE (Comparison of Aneuploidy Risk Evaluation) study.

"The pregnant women social media groups are very aware of the false positives. I think everybody knows somebody who has had one, since there’s 1 in 20 chance of that [happening]," Dr. Bianchi said in an interview.

Surprising results

Also revealed in the study was cell-free DNA testing’s essentially 100% negative predictive value for aneuploidies in low-risk populations.

The results are "very impressive," said Dr. Michael F. Greene, associate editor of the New England Journal of Medicine, in an interview. "I do think this is going to sweep the table in terms of what is offered to pregnant women," particularly if other studies demonstrate the same level of efficacy, he said. The study was published online (N. Engl. J. Med. 2014;370:799-808).

©iStock/thinkstockphotos.com

To compare false positive rates in the two methods of screening, Dr. Bianchi and her team analyzed test results from 1,914 women (average age, 30 years) enrolled from the general obstetrical population across 21 centers in 14 states. Participants either had or planned to have standard aneuploidy serum screening. All women were risk classified according to standard screening and had a singleton fetus without aneuploidy and a gestational age of at least 8 weeks. A second serum sample was taken from each woman, and massively parallel sequencing was used by laboratory personnel blinded to fetal karyotype to determine the chromosome dosage. Birth outcomes or karyotypes were used as the reference standard.

For trisomies 21 and 18, the false positive rates returned by cell-free DNA testing were significantly lower than those returned by standard screening: 6 patients vs. 69 out of 1,909 for trisomy 21 (0.3% vs. 3.6%; P less than .001), and 3 vs. 11 out of 1,905 for trisomy 18 (0.2% vs. 0.6%, P = .03).

The positive detection rate for cell-free DNA testing of all aneuploidies (5 for trisomy 21, 2 for trisomy 18, and 1 for trisomy 13) was 100% (95% confidence interval, 99.8-100). The positive predictive values for the cell-free DNA testing, compared with standard screening, were 45.5% vs. 4.2% for trisomy 21, and 40.0% vs. 8.3% for trisomy 18.

These positive predictive values, Dr. Greene and Dr. Elizabeth G. Phimister wrote in an accompanying editorial, "underscore the conclusion that assaying fetal DNA is a screening tool and not a diagnostic intervention." However, they concluded, "the observed negative predictive values of 100% with 95% confidence limits down to 99.8%, combined with the significantly and substantively lower false positive rates with cell-free DNA screening than with standard screening, augur well for pregnant women and their fetuses" (N. Engl. J. Med. 2014;370:874-5).

"I think it is going to surprise people when they see that the current standard of care has such a low positive predictive value in a general obstetrical population," said Dr. Bianchi, who also directs the Mother Infant Research Institute at Tufts Medical Center, Boston.

The primary outcome was determined by newborn physical examination in 1,857 patients (97.0%) and by karyotype in 57 patients (3.0%). Of these, chorionic villus sampling was performed in 10 patients, amniocentesis in 38, testing of the products of conception in 3, and postnatal evaluation in 6. The women whose cell-free DNA tests came back with false positive readings all had live births with normal physical examinations.

The secondary endpoint was a similar comparison of detection rates for trisomy 13 (Patau syndrome). There was one false positive result for trisomy 13 with cell-free DNA testing, as compared with six false positive results on standard screening, thus showing a trend toward significance (P = .059) in the 899 patients who underwent standard screening for trisomy 13.

Fetal fraction not maternal age–related

The researchers found that cell-free DNA testing had the same high-sensitivity detection rates in low-risk obstetrical populations as has been previously established in high-risk ones. Generally considered at higher risk for trisomy 21, women 35 years and older who were tested in either the first or second trimesters had results that were nearly identical to results from women under age 35 in terms of both their mean percentage of free fetal DNA and their standard screening results and/or cell-free DNA results (11.3% and 11.6%, respectively). For women tested in the third trimester, the fetal fraction was higher (mean, 24.6%).

This finding further strengthens the argument that the technology should be available to the general obstetric population. "The amount of the DNA was the same when we stratified the relatively high risk from the relatively low risk," said Dr. Bianchi. "That will be a surprise to some people who postulated that the high-risk women would have more DNA circulating. They don’t."

The consistent fetal fraction also lends itself to greater flexibility when prenatal screening occurs, allowing women to be screened anytime between 10 and 40 weeks gestational age. This could mean better prenatal care for women who do not have their first prenatal visit until late in the second trimester, for example. Because the current screening methods are specific to certain gestational times, if a woman is erratic with her prenatal visits, testing may be impossible.

Regarding its utility in women carrying multiple fetuses, Dr. Bianchi said that about 10% of the time, the fetal fraction per fetus tends to be too low to get an accurate reading.

‘Throwing down the gauntlet’

The test’s unparalleled accuracy could give greater peace of mind to women who might have had difficulty getting pregnant and so are wary of the miscarriage risks posed by invasive diagnostic testing, according to Dr. Bianchi. Fewer invasive diagnostic tests could also lower costs across the system.

When all results for trisomies 21 and 18 were combined, the researchers found that the false positive rates for standard screening were 4.2%, compared with 0.5% for cell-free DNA testing. "If all pregnant women had undergone cell-free DNA testing as a primary screening method and if all women with positive results had undergone post-test counseling and had decided to undergo an invasive procedure," wrote the authors, "there would have been a relative reduction of 89% in the number of diagnostic invasive procedures required to confirm a positive screening result."

The data should move professional societies to take action, according to Dr. Bianchi. "That’s kind of the gauntlet that we’re throwing down." More data are on the way, she said, which will "enable the professional societies to take a cumulative look and decide what their recommendations are going to be."

As it stands, the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists state that the testing be used only in women at higher risk for giving birth to children with aneuploidies, such as women aged 35 years or older or those with a history of pregnancy with trisomy, and that positive cell-free DNA results should be confirmed by invasive diagnostic testing.

For now, because the tests are not considered routine prenatal care, low-risk patients usually pay out of pocket for these tests, which Dr. Bianchi said many women are willing to do. The cost of the test ranges anywhere from $1,200 to upward of $2,700, although some careful Internet searching for deals can net tests at substantially lower prices, she said.

Market pressures

For some physicians in the field, this public demand for a screening test not subject to Food and Drug Administration (FDA) regulation has not outweighed the level of proof it offers in the clinical setting. One of these critics was, until recently, Dr. Greene.

"Companies have been free to build consumer demand for cell-free DNA testing by aggressively marketing the tests, emphasizing data that do not answer key questions," wrote Dr. Greene in July 2013, in an editorial he coauthored (N. Engl. J. Med. 2013;369:499-501). "As a result, cell-free DNA testing seems to be drifting into routine practice ahead of the evidence," stated Dr. Greene, who is also chief of obstetrics at Massachusetts General Hospital in Boston, and who wrote with his colleagues that the test’s positive predictive value, largely unreported by manufacturers, was still in question.

"The problem is that the proof-of-principle studies that all these companies have published to date have been with ratios of ‘Down’s’ to ‘normals’ ranging from 1 to 7, 1 to 13, or 1 to 20," said Dr. Greene in an interview. "All were done in retrospective populations at extraordinarily high risk."

However, with the CARE study, "what’s impressive is the positive predictive value in a low-incidence group of patients," he said.

Sponsored by Illumina/Verinata, the study puts pressure on other companies to publish their own data in peer-reviewed journals, said Dr. Greene. "Once this paper appears in print, [Verinata] will get a leg up, and the other companies won’t want to let them get too far ahead of them."

According to Dr. Bianchi, Verinata is now seeking FDA approval to market the testing as an in vitro diagnostic product. She expects demand for the testing to be led not by physicians but by patients. "People often ask me why the DNA testing took off so quickly," said Dr. Bianchi. "I think a factor is social media. I find there is a discrepancy between what the average patient knows and the general obstetrician knows because of the discussions [online]. "

Although some women will still need an invasive procedure to resolve a screen positive test, Dr. Bianchi said most pregnant women, including older women, are going to be reassured with the 100% negative predictive value.

"The younger woman’s benefit will primarily be the reduced false positive rate, because overwhelmingly, she is going to have a normal fetus, so her major benefit is not being made anxious and being sent for all the subsequent testing."

Dr. Bianchi and her coauthors disclosed relationships with Verinata/Illumina, maker of the Verifi cell-free DNA prenatal test. Dr. Bianchi is also on the clinical advisory board of Verinata. Dr. Greene stated that he had no conflict of interest disclosures. The study was sponsored by Illumina, ClinicalTrials.gov number NCT01663350.

[email protected]