Blood Test May Trump Standard for Early Down Syndrome Screening

A new multicenter study provides landmark evidence that a blood test undertaken between 10 to 14 weeks of pregnancy may be more accurate in diagnosing Down syndrome (DS), and two less common chromosomal abnormalities, than standard noninvasive screening techniques.

The research team, led by first author Mary Norton, MD, professor of clinical obstetrics and gynecology at University of California San Francisco (UCSF; San Francisco, CA, USA), followed pregnancy outcomes in close to 16,000 women (average age 30, with approximately 25% over 35). The cell-free DNA (cfDNA) blood test resulted in correctly identifying all 38 fetuses with DS, confirmed by newborn exam, prenatal or postnatal genetic analysis. The test focuses on the small percentage of fetal DNA in a pregnant woman’s blood. DNA from the targeted genes is molecularly “photocopied” and amplified by PCR, products are sequenced, and comparisons are made between relative amounts of the chromosomal DNA.

With standard screening, only 30 of the 38 fetuses with DS were identified. The standard screening comprises a blood sample in which hormones and proteins associated with chromosomal defects are identified, together with an ultrasound of the nuchal fold fluid in the back of the neck, an excess of which is suggestive of DS.

A second compelling advantage of cfDNA analysis was the relatively low incidence of DS misdiagnoses. While standard testing is acknowledged to result in a large number of false-positives, these were significantly less likely with the cfDNA test, which resulted in 9 false-positives vs. 854 with standard screening.

While far fewer cases of trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome) were found in the study population, the accuracy of cfDNA screening still surpassed standard screening.

The researchers emphasized areas of caution. Standard screening “can identify risk for a broad array of abnormalities that are not detectable on cfDNA testing,” they said. Additionally, a surprisingly high number of aneuploidies were present in the 488 pregnant women whose blood samples were disqualified (due to inadequate or immeasurable quantity of fetal DNA, or assay failure, or high sequencing-variance that could lead to misinterpreting results). Had this disqualified cohort been included in the findings, detection rates of the cfDNA test would have been lower.

cfDNA tests will result in far fewer false-positives than current screening, and so can reduce the number of invasive tests and of miscarriages wrongly attributed to positives. However, patients should be made aware of its limitations. “Providers need to be attuned to patients’ preferences and counsel them about the differences in prenatal screening options. Women who opt for cfDNA testing should be informed that it is highly accurate for DS, but it focuses on a small number of chromosomal abnormalities and does not provide the comprehensive assessment available with other approaches,” said Prof. Norton, “Counseling should also include information about the risks associated with failed tests and the pros and cons of pursuing invasive testing if no results are obtained.”

The study, by Norton M et al., was published April 1, 2015, in the New England Journal of Medicine.

Related Links:
University of California San Francisco 
Ariosa Diagnostics’s Harmony prenatal blood test for trisomy 21, 18, & 13
Perinatal Quality Foundation