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...
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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