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...
A repeat cfDNA test will be successful in some cases. Whether the patient chooses to attempt cfDNA again may depend in part on maternal body mass index (BMI), as well as gestational age—a patient at a more advanced gestation may not wish to delay obtaining definitive information given the high risk.
cfDNA screening has a low false-positive rate
One of the greatest benefits of cfDNA screening is a lower false-positive rate than is reported with traditional screening. However, when “no results” cases are also considered, the percentage of patients who require follow-up after cfDNA is close to that of traditional screening.
The chance of test failure is reported to be 0.9% to 8.1%, 7,9,10 and varies in part by whether the laboratory measures fetal fraction and requires a minimum concentration.
A recent meta-analysis estimated the overall test failure rate at 3%. 10 When comparing cfDNA to traditional screening, if “no results” cases are included with the “screen positive” group, the benefits of cfDNA over traditional screening are much less clear, particularly in a low-risk population.
ACOG: Offer traditional multiple-marker screening first
While multiple marker and cfDNA screening have differing performance characteristics, there are no data to support doing both tests concurrently. In fact, in a recent survey of nearly 200 women presented with different testing scenarios, women found it preferable and more reassuring to have a positive traditional screen followed by normal cfDNA results, rather that discrepant results of the 2 tests done concurrently. 20
For many reasons, the approach recommended by ACOG and SMFM is to offer traditional multiple-marker screening first, and cfDNA screening or diagnostic testing as a follow-up for patients that screen positive. In that scenario, the benefits and limitations of diagnostic testing versus follow-up with cfDNA screening should be explained carefully.
In all patients who have a positive cfDNA result, diagnostic testing for confirmation should be offered and strongly recommended prior to pregnancy termination if that is considered. Even if a structural abnormality is present and a true positive result is highly likely, karyotyping is important to determine if there may be an inherited translocation putting subsequent pregnancies at higher risk.
Components of pretest counseling
A woman of any age can have a fetus with trisomy or another chromosomal abnormality, and some women prefer diagnostic testing or no testing regardless of age. It is therefore appropriate to offer diagnostic testing, screening, or the option of no testing to all women.
Recent studies have demonstrated that providing well-informed access to all prenatal tests results in more informed choices and no increase in uptake of invasive testing. 22 However, the offer of prenatal testing requires discussion of the pros and cons of all test options, including the detection rates of all significant abnormalities, the screen positive rates, and recommended follow-up if an abnormal result is obtained. See TABLE 4.
Cost-effectiveness
Although the detection rate of cfDNA for trisomy 21 is higher than that of traditional screening, the detection rate of traditional screening is also quite high at lower cost. For low-risk women, therefore, traditional screening provides a less expensive alternative to cfDNA. Because aneuploidy is rare in low-risk patients, the residual chance of aneuploidy after a normal traditional screen is very low, and the cost per additional case of Down syndrome detected by cfDNA is very high.
