DNA aneuploidy screening. Because the cell-free DNA that is analyzed is maternal and placental, results may not relect the fetal DNA complement but rather may indicate con ined placental mosaicism, early demise of an aneuploid co twin, maternal mosaicism, or even occult maternal malignancy (Bianchi, 2015; Curnow, 2015; Grati, 2014; Wang, 2014). In addition, if a twin pregnancy is identiied sonographically, cell free DNA screening is not currently recommended because of limited evidence regarding eicacy.
Another limitation is that cell-free DNA testing does not yield a result in approximately 4 to 8 percent of screened pregnancies, due to assay failure, high assay variance, or low fetal fraction (Norton, 2012; Pergament, 2014; Quezada, 2015). Most cell-free DNA is maternal. he fetal fraction is the proportion derived from the placenta and generally is about 10 percent of the total. A low fetal fraction is usually defined as <4 percent of the total and confers signiicantly higher risk for fetal aneuploidy (Ashoor, 2013; Norton, 2015; Pergament, 2014). Women with a low fetal fraction or "no-call" results have fetal aneuploidy rates as high as 4 percent, a percentage comparable to the average predictive value conferred by a positive irst-trimester screening test result (see Table 14-4). The fetal fraction is not related to maternal age or analyte-based screening test results. However, it is lower earlier in pregnancy and appears to be reduced in women of greater weight (Ashoor, 2013).
Because of the increased risk for fetal aneuploidy in cases not generating a cell-free DNA screening result (no-call result), genetic counseling is indicated, and amniocentesis should be ofered. If the patient elects repeat screening, the risk for screen failure may exceed 40 percent (Dar, 2014; Quezada, 2015). Targeted sonography is recommended but is not a substitute for amniocentesis, because it is unclear what the residual risk would be with normal sonogram indings. (American College of Obstetricians and Gynecologists, 2016b, 2017 c). Pretest counseling should include the possibility of a low fetal fraction or no-call result and its clinical signiicance.
Comparison with Analyte-Based Screening
Cell-free DNA screening has obvious advantages, but it is not simply a "better" test-because no screening test is superior for all test characteristics (American College of Obstetricians and Gynecologists, 20 16c). Compared with analyte-based tests, beneits of cell-free DNA screening in women 35 years and older include the lower likelihood of a false-positive result, its higher positive-predictive value, and the fact that isolated minor aneuploidy markers are generally not a concern (p. 286).
But, analyte-based tests are frequently positive with a large range of chromosomal abnormalities, whereas cell-free DNA
TABLE 14-7. Aneuploidy Risk Associated with Selected Major Fetal Anomalies
Cystic hygroma 1/5000 50-70 45,X; 21; 18; 13; triploidy
Nonimmune hydrops 1/1500-4000 10-20 21, 18, 13, 45X, triploidy
Ventricu Iomega Iy 1/1000-2000 5-25 13, 18,21/ triploidy
Holoprosencephaly 1/10,000-15,000 30-40 13, 18, 22, triploidy