Expanding the indications for cell-free DNA in the maternal circulation: clinical considerations and implications

Noninvasive prenatal testing for fetal aneuploidy using cell-free DNA has been widely integrated into routine obstetrical care. The scope of cell-free DNA testing has expanded from trisomies 21, 18, and 13 to include sex chromosome conditions, panels of specific microdeletions, and more recently genome-wide copy number variants and rare autosomal trisomies. Because the technical ability to test for a condition does not necessarily correspond with a clinical benefit to a population or to individual pregnant women, the benefits and harms of screening programs must be carefully weighed before implementation. Application of the World Health Organization criteria to cell-free DNA screening is informative when considering implementation of expanded cell-free DNA test menus. Most microdeletions and duplications are rare to the point that the prevalence has not even been defined and their natural history cannot be reliably predicted in the prenatal period. At the current time, scientific evidence regarding clinical performance of expanded cell-free DNA panels is lacking. Expanded cell-free DNA menus therefore create a dilemma for diagnosis, treatment, and counseling of patients. The clinical utility of expanding cell-free DNA testing to include panels of microdeletions and genome-wide assessment of large chromosomal imbalances has yet to be demonstrated; as such, the clinical implementation of this testing is premature.