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
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.
In one study, this was estimated at $3.6 million.23 These authors suggested that, at present, cfDNA is optimally used as a secondary screen for high-risk women. Other cost analyses also have demonstrated that the most cost-effective strategy is a model in which cfDNA is used as a follow-up test in patients found to be screen positive by traditional screening.15,24 A recent cost utility analysis compared outcomes of 6 approaches to prenatal screening, including sequential screening, cfDNA screening, nuchal translucency only, and diagnostic testing with microarray (alone, in combination, or in sequence).
The clinical outcomes included fetal abnormalities detected, taking into account all chromosomal abnormalities, as well as failed cfDNA tests. For younger women (<40 yr), traditional sequential screening provided the highest detection of all abnormalities and was the optimal testing strategy, while cfDNA was preferable for women aged 40 or older, given the higher prevalence of trisomy 21.20
Incidental findings
Given that the cfDNA in maternal serum is a mixture of maternal and placental DNA, a number of biologic phenomena can cause a false-positive cfDNA result. In many cases, these false-positives reveal unanticipated or unexpected maternal conditions and information that the woman may have preferred not to know. A few cases of maternal malignancies with chromosomal abnormalities within the tumor have been reported in patients with false-positive cfDNA results.26
These case reports have raised the question about the need for further evaluation for maternal malignancy in women with false-positive results. Maternal genetic disorders also can cause false-positive results, and may lead to unanticipated detection of adult-onset conditions. In some cases, positive results for sex chromosomal aneuploidy can occur in pregnant women who themselves have a sex chromosomal abnormality, often in mosaic form and previously undiagnosed.27
Again, this has led to discussion of the possible health benefit of karyotyping women who have a false-positive cfDNA result to rule out a mosaic chromosomal abnormality in the mother.
At this time, the clinical utility of such investigations is unknown and there are no recommendations regarding appropriate follow-up for such cases.
CASE Resolved
Given the results of her cfDNA screening, your patient opts to undergo diagnostic testing. In that testing, trisomy 13 is ruled out and she goes on to have a healthy daughter.
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