Noninvasive Prenatal DNA Test Detects Trisomy 18 and 21

Major Finding: A noninvasive DNA test for fetal abnormalities had a sensitivity of 100% for trisomy 21 and 97% for trisomy 18.

Data Source: The data come from 3,228 pregnant women in a multicenter, prospective cohort study.

Disclosures: Dr. Norton said she had no relevant financial disclosures. The study was funded by Ariosa Diagnostics, which makes the test used in the study. Several of her coauthors are employees, consultants, or board members of Ariosa Diagnostics.

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Not Yet Ready for Prime Time

Current methods of screening for common chromosomal abnormalities require multiple steps with ultrasound and blood work. This complex algorithm gives a risk for trisomy 21 that provides a sensitivity of only 88%-95%, with a 5% false-positive rate for Down syndrome. As families face the decision to choose invasive testing and the risk of fetal loss associated with these procedures, a screening test that provides more reliable results might allow parents to feel more comfortable with their decision to choose or not choose invasive testing.

Dr. Norton and her colleagues present their multicenter trial for the detection of fetal chromosomal abnormalities using analysis of cell-free DNA within maternal serum. They report a sensitivity for detection of Down syndrome of 100% for high-risk cases and 99.97% in the low risk group (with a false positive rate of 0.03%). The prediction of trisomy 18 was less sensitive, with a sensitivity of 97.4%. These tests, however, are done on women already undergoing amniocentesis for a specific reason.

Effective, low-cost screening methods are ideal in screening for chromosomal abnormalities. And this type of testing may be promising for the detection of chromosomal abnormalities other than trisomy 21 and trisomy 18. We must be reminded that this testing remains a screening test. The only way to definitively determine the karyotype is through invasive prenatal diagnosis. And is another screening test the right answer?

As we consider this testing modality, it must be studied in routine populations for low-risk patients who are not undergoing invasive testing – the clinical setting in which most of our patients would be. Although cell-free DNA testing modalities offer promise for screening, they are not yet ready to replace invasive testing for definitive diagnosis of karyotypic abnormalities.

Kristin Atkins, M.D., is in the department of obstetrics, gynecology, and reproductive sciences, and the division of maternal/fetal medicine, at the University of Maryland, Baltimore. She said she had no relevant financial disclosures.



A noninvasive DNA screening test effectively detected chromosome abnormalities in fetuses of women with singleton pregnancies, based on data from approximately 3,000 women published online in June in the American Journal of Obstetrics and Gynecology.

Data from previous case-control studies have shown that the Digital Analysis of Selected Regions (DANSR) assay can identify chromosome abnormalities by evaluating specific fragments of maternal cell-free DNA (cfDNA), said Dr. Mary E. Norton of Stanford (Calif.) University and her colleagues.

In this multicenter, prospective cohort study, the researchers included pregnant women aged 18-50 years with singleton pregnancies who were planning to undergo invasive prenatal diagnostic testing for any reason. Women with multiples, those with known chromosome abnormalities, or those who had already undergone an invasive prenatal test in the current pregnancy were excluded. The final analysis included samples from 3,228 women with a mean maternal age of 34 years and a mean gestational age of 17 weeks (Am. J. Obstet. Gynecol. 2012 [doi:10.1016/j.ajog.2012.05.021]).

The sensitivity of the test was 100% for trisomy 21 malformations. A total of 81 cases of trisomy 21 were identified and all were classified as high risk, with one false positive out of 2,888 normal cases, for a false positive rate of 0.3% (specificity 99.97%). Similarly, the sensitivity was 97% for trisomy 18. A total of 38 cases of trisomy 18 were identified, and 37 were classified as high-risk, with 2 false positives for a false positive rate of 0.07% (specificity 99.93%).

The positive predictive values for trisomy 21 and trisomy 18 were 98.8% and 94.9%, respectively. The negative predictive values for trisomy 21 and trisomy 18 were 100% and 99.96%, respectively.

Another 73 cases of other chromosomal abnormalities were identified, but they did not affect the analysis of risk for trisomy 18 or 21, Dr. Norton and her associates noted.

The test involved collecting 20 mL of blood from each patient before she underwent any invasive diagnostic testing procedure. DNA samples were classified as high risk or low risk based on a predefined cutoff value of 1% based on previous analyses. Results from the DANSR assay were compared with results from invasive tests as a reference.

"With the methods reported here, the higher throughput and lower cost make this technique potentially scalable for population screening," Dr. Norton and her associates wrote. However, even the high detection rates achieved in the study do not compare with those obtained with invasive diagnoses and may not provide much in the way of additional information for women who then have invasive tests, they noted.

"Further experience in larger populations of average-risk women is needed to clarify the role and utility of cfDNA in clinical practice," they said.

Dr. Norton said she had no relevant financial disclosures. The study was funded by Ariosa Diagnostics, which makes the test used in the study. Several of her coauthors are employees, consultants, or board members of Ariosa Diagnostics.

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