a screening option in those at greater risk for fetal autosomal trisomy (American College of Obstetricians and Gynecologists, 2017b; Society for Maternal-Fetal Medicine, 2015).
Unfortunately, cell-free DNA screens do not yield a result in 4 to 8 percent of cases. This may be due to assay failure, high assay variance, or low fetal fraction (Norton, 2012; Pergame nt, 2014; Quezada, 2015). Such pregnancies carry a greater risk for fetal aneuploidy. In addition, results may not relect the fetal DNA complement but rather may indicate conined placental mosaicism, early demise of an aneuploid cotwin, maternal mosaicism, or rarely occult maternal malignancy (Bianchi, 2015; Curnow, 2015; Grati, 2014b; Wang, 2014). Recommendations for counseling are discussed in Chapter 14 (p. 285).
Fetal Sex Determination. From the standpoint of genetic disease, fetal sex determination may be clinically useful if the fetus is at risk for an X-linked disorder. It may also be beneficial if the fetus is at risk for congenital adrenal hyperplasia because maternal corticosteroid therapy may be avoided if the fetus is male (Chap. 16, p. 317). In a metaanalysis of more than 6000 pregnancies by Devaney and associates (201i1), the sensitivity of cell-free DNA testing for fetal sex determination approximated 95 percent between 7 and 12 weeks' gestation and improved to 99 percent after 20 weeks. The test speciicity was 99 percent at both time periods, suggesting that cellfree fetal DNA is a reasonable alternative to invasive testing in selected cases.
Rh D Genotype In a predominantly white population, nearly 40 percent of fetuses of h D-negative women are themselves h D negative. Fetal h D genotype assessment from maternal blood can eliminate administration of anti-D immune globulin in these pregnancies, thereby reducing cost and potential risk. With h D alloimmunization, early identification of an h D-negative fetus might avoid unnecessary middle cerebral artery Doppler assessment or amniocentesis. Evaluation using cell-free DNA is done using real-time PCR to target several exons of the HD gene. These are typically exons 4,i5, and 7.
h D-genotyping is performed routinely with cell-free DNA in Denmark and the Netherlands (Clausen, 2012; de Haas, 2016). In a population-based study of more than 25,000 h D-negative women screened at 27 weeks, the false-negative rate-in which h D-negative status was missed-was only 0.03 percent. The false-positive rate-in which h immune globulin would be given unnecessarily-was less than 1 percent (de Haas, 2016). Similar results were reported from the United Kingdom, although the false-negative rate was higher in the irst trimester (Chitty, 2014). Investigators concluded that false-negative screening results might increase the alloimmunization risk, but by less than 1 case per million births (Chitty, 2014). h D alloimmunization is discussed in Chapter 15 (p. 301).
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