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    The promise and peril of new prenatal diagnostic technologies


    Reading between the lines of cfDNA testing 'failures'

    The study by Norton and colleagues also provided other crucial insights that may alter our approach to aneuploidy screening. For example, they noted that 488 of 16,329 (3%) women otherwise eligible for cfDNA testing had to be excluded because of a lack of results due to low or undetectable fetal cfDNA fractions, high assay variance, or assay failure. Interestingly, 13 (1/38 or 2.7%) of these women were found to carry an aneuploid fetus: 4 with triploidy, 3 with trisomy 21, 2 with trisomy 13, and 1 each with trisomy 18, trisomy 16 mosaic, deletion 11p, and a structurally abnormal chromosome. For the subset of these pregnancies with a fetal cfDNA fraction less than the required cutoff of 4%, 9 in 192, or nearly 5%, had aneuploidy. Thus, inability to assay for cfDNA is a major risk factor by itself for fetal aneuploidy, the magnitude of which would seem to justify invasive fetal testing with chromosomal microarray studies. However, it should be noted that among the pregnancies in which cfDNA results were not available and in which the fetuses had 1 of the 6 most common aneuploides, all were detected by standard testing. Moreover, amongst the technologies used by the 5 companies currently providing cfDNA screening, there are differing threshold requirements for the fetal fraction.

    Many false-positive cfDNA results are known to have clinically important causes, including a vanishing aneuploid twin, confined placental mosaicism, maternal mosaicism for aneuploidy, and even maternal cancers. Thus, in my opinion, “false-positive” cfDNA results require follow-up obstetric ultrasounds and a careful maternal history and physical examination to rule out maternal pathology.

    Related: Discordant NIPT and ultrasound results from vanishing twin pregnancy 


    Charles J. Lockwood, MD, MHCM
    Dr. Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South ...


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