Fetal DNA Testing for Low-Risk Women Gets Mixed Reviews

Ricki Lewis, PhD

March 08, 2014

Two professional societies have released comments on the use of cell-free fetal (cff) DNA noninvasive prenatal testing (NIPT) to detect trisomies in low-risk pregnant women.

The statements follow publication in the February 27 issue of the New England Journal of Medicine of a report on the feasibility of such expanded testing. At this time, the test is used in high-risk pregnancies, but the authors of the recent study conclude that it is also useful in low-risk pregnancies.

The Royal College of Obstetricians & Gynaecologists (RCOG) concludes that, "In time, this technology is likely to become the primary screen for chromosomal abnormalities in pregnancy."

In contrast, the Society for Maternal Fetal Medicine (SMFM) statement is more cautious: "SMFM has reviewed the evidence, including this recent paper, and feels that while NIPT is a promising new technology, and this new report is important and excellent news, it is not enough to change current [American College of Obstetricians and Gynecologists] and SMFM recommendations."

NIPT detects fetal DNA that enters the maternal circulation from the placenta. It is detectable from the first trimester on, diminishing rapidly after delivery. Massively parallel sequencing, also known as next-generation DNA sequencing, can reconstruct entire fetal genomes. Targeting sequencing detects specific DNA sequences. cffDNA testing detects trisomies based on excess DNA from a specific chromosome, relative to all other chromosome pairs.

RCOG Statement Favors NIPT

The RCOG's report begins with a recap of early applications of the technology. The first tests were for DNA sequences known not to be in the pregnant woman, such as Y chromosome sequences to detect male fetuses in families with X-linked disorders and fetal blood grouping for a RhesusD-positive fetus in a RhesusD-negative pregnant woman. These indications have UK Genetic Testing Network approval. Exclusion of known paternal alleles has allowed testing of a few dominant and recessive conditions on a case-by-case basis. cffDNA NIPT lowers the need for more invasive testing for these conditions, none of which is at the chromosomal level.

After citing 8 studies indicating that the sensitivity and specificity of cffDNA testing approaches 100% for trisomies 21 and 18, the RCOG statement lists sources of potential error:

  • early gestational age leading to false-negatives because of too-low concentrations of cffDNA;

  • maternal obesity associated with a lower cffDNA fraction;

  • testing for dichorionic twins is not well understood, nor is the effect of in utero demise of 1 dizygotic twin;

  • confined placental mosaicism can yield discordant results, as happens in 1% of chorionic villus samples, and a pregnant woman may also have mosaicism, confounding conclusions; and

  • maternal conditions can cause confusion (eg, 1 woman in the series had a malignancy that was not diagnosed until after the pregnancy, and the prenatal test inadvertently sampled tumor DNA).

The statement also mentions the challenging clinical situations of a serendipitous finding and discovery of a genetic variant of uncertain significance.

Perhaps the greatest effect of more widespread use of cffDNA NIPT will be on the prenatal testing marketplace, which will shift away from maternal serum markers, with amniocentesis and chorionic villus sampling largely reserved for diagnostic confirmation. Ultrasound will remain an important tool to detect malformations that indicate a possible trisomy, genetic anomalies that are not specifically tested for, and noninherited anomalies, as well as to provide information on phenotypes.

The RCOG envisions 3 models for implementing cffDNA NIPT within the National Health Service:

  • as a contingency (step-wise) after screening with the combined test of nuchal translucency on ultrasound and serum markers (20% of screened pregnancies estimated to go on for cffDNA NIPT);

  • as part of combined testing; and

  • as primary testing.

The RCOG report favors the primary testing approach, pointing out that resources from biochemical marker testing might be shifted toward implementing the new testing method, which many women already use in the private sector. In addition, the cost is likely to fall as DNA sequencing costs plummet.

Overall, replacing biochemical markers that reveal elevated risk with the more definitive cffDNA-based testing will improve accuracy. "The major, and probably decisive, advantage of this implementation approach is that the false-negative rate will be very low and so, in women who want to know about Down syndrome, few affected pregnancies would not be detected," the report concludes. In addition, the new testing will decrease the exposure of healthy fetuses to invasive diagnostic procedures.

SMFM Emphasizes Need for More Data

The SMFM emphasizes the need for more data in low-risk populations and the limitations of the recently reported study. For example, Vincenzo Berghella, MD, president of SMFM, points out that the rate of a trisomy 21 detected in the recent study is substantially higher than what would be seen in a "truly 'average' or 'low-risk' cohort," which is important if this study serves as the basis for expanding testing into low-risk women.

Other limitations highlighted by SMFM include:

  • Data should be evaluated beyond trisomies 21 and 18, especially as commercially available tests include trisomy 13 and the sex chromosomes, which have higher false-positive rates.

  • Some samples in the study were from third trimester pregnancies, which yield more fetal DNA, perhaps inflating estimation of the accuracy of the test.

  • The "standard prenatal screening" tests to which cffDNA was compared come in many varieties.

  • For some women, cffDNA testing will not yield a result.

  • The study detected only 8 aneuploid fetuses, which is too few to accurately judge test performance.

The 2 documents, although differing in their conclusions, clearly sum up both the promises and shortcomings of cffDNA NIPT, providing a resource clinicians can consult until guidelines become available.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.