Expert Commentary
When is cell-free DNA best used as a primary screen?
At age 38 years, cell-free DNA screening as the first-line test becomes the optimal strategy; at age 40 years, cell-free DNA as a primary screen...
The ease of obtaining a blood sample for cfDNA screening is an advantage of the test. However, because it is simple to perform, it often is done with inadequate pretest counseling or consideration. Just because the test is easily obtained does not negate the need for adequate discussion to assure that each woman understands what the test can and cannot measure, and the possible outcomes of testing.
Another perceived benefit of cfDNA screening is the simple presentation of results. While reports vary, they generally provide very dichotomized results. Aneuploidy risk is reported as “Positive” or “Negative,” or as “Detected” or “Not detected.”
Some laboratories report the chance of aneuploidy; this is almost always stated to be more than 99% in patients at increased risk, and less than 1 in 10,000 in patients at low risk.
All of these results suggest a near diagnostic certainty. However, this reporting is oversimplified and misleading, as it does not account for each patient’s prior or background risk. The chance that a positive result is a true positive is very different in a 20-year-old versus a 35-year-old woman, yet the reports do not reflect this difference in positive predictive value (PPV). See TABLE 1.
Accurate interpretation of risk for the individual patient, therefore, requires calculation by the provider; this can be done through an online calculator available through the Perinatal Quality Foundation ( www.perina talquality.org ).
CASE Continued
You explain to your patient that the chance her fetus has trisomy 13 is far lower than 99%, based in part on the very low prior risk given her age. You calculate the PPV using an online calculator, which estimates that there is only a 7% chance that this is a true positive result.
As mentioned earlier, there has been a tremendously rapid uptake of cfDNA screening. Given wider use by practitioners not as familiar with the complexities of genetic testing and statistical analysis, misunderstanding of the test characteristics carries risks if inappropriate recommendations or decisions are made or actions taken.
Most low-risk patients do not request or desire diagnostic testing. It is important during pretest counseling to explain that cfDNA cannot detect all significant chromosomal aneuploidies. Some serious abnormalities will be undetected; therefore, some women may prefer more comprehensive prenatal testing ( TABLE 3 ).
TABLE 3 Checklist for pretest counseling for cfDNA 28
- cfDNA screening is the most accurate screening test for trisomy 21
- cfDNA is a screening test, and false-positive and false-negative results can and do occur
- Diagnostic confirmation with chorionic villus sampling or amniocentesis is recommended for women with abnormal cfDNA results
- A negative cfDNA result decreases risk but does not rule out trisomy 21 and other chromosomal conditions
- cfDNA does not test for all chromosomal conditions
- Women who desire definitive information about chromosome conditions in the pregnancy should consider diagnostic testing with chorionic villus sampling or amniocentesis
- All genetic testing is optional. Whether a woman chooses to have a screening test, a diagnostic test, or no testing is a personal decision; any are reasonable options for any pregnant woman.
