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).
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The current prenatal screening standard for low-risk pregnancies is more than three times as likely to return a false positive for Down syndrome and other trisomies than noninvasive, cell-free DNA testing.
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.
Dr. Diana W. Bianchi
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%).