Cell-free DNA screening for women at low risk for fetal aneuploidy
A high sensitivity and specificity and low false-positive rate make cell-free DNA screening an appealing draw for clinicians and patients, even for those who are at low risk for chromosome abnormalities. But a clear understanding of this test’s nuances and proper pretest and ongoing counseling are needed to answer our patients' tough questions.
In this Article
- Pros and cons of cfDNA in low-risk patients
- Optimal and less optimal candidates for cfDNA screening
- Checklist for pretest counseling for cfDNA
CASE Continued
Your patient’s results are positive for trisomy 13. Her understanding is that the test is more than 99% accurate, and she interprets this to mean that the chance of trisomy 13 in her fetus is more than 99%. She is distraught and asks about pregnancy termination.
What are the limitations of cfDNA screening?
Similar to other noninvasive screening tests, cfDNA screening does not carry direct risk to the pregnancy. However, there are limitations to this testing. As a result, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recently have stated that traditional screening is the most appropriate option for most women.11,12
One reason that cfDNA screening may not be the best choice for low-risk women is that Down syndrome is quite uncommon in this group, so cfDNA screening is a very precise test for a rare condition. Traditional multiple marker screening, on the other hand, is more effective at signaling risk for the broad range of adverse perinatal outcomes that can affect a pregnancy, including other structural birth defects, as well as such obstetric complications as preterm birth, preeclampsia, and fetal growth restriction.13,14
Many women who undergo cfDNA screening are under the impression that they have had a definitive test for all birth defects when, in fact, the coverage of cfDNA for all possible birth defects in a low-risk woman is very limited; her residual risk for a birth defect is little changed by a normal cfDNA result.
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 cfDNA28
- 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.
ACOG recommends that diagnostic testing should be available to all pregnant women, regardless of age.15 In prenatal series, trisomies 13, 18, and 21 make up approximately two-thirds of all clinically significant aneuploidies.16,17 Given that cfDNA detects only these aneuploidies, the other third will not be identified prenatally in patients who choose cfDNA. Traditional aneuploidy screening has been demonstrated to detect a broader range of these less common but clinically important chromosomal abnormalities.18
