Fetal cell-free nucleic acids in the maternal circulation: new clinical applications

Six years after the demonstration of the presence of cell-free fetal nucleic acids in maternal plasma, perinatal clinical applications continue to expand. The focus of this article is on advances that have occurred since the CNAPS II conference held in Hong Kong in 2001. Circulating fetal DNA levels (fDNA) are elevated in pregnancies complicated by fetal trisomies 13 and 21 but not 18. Measurement of fDNA levels improves the performance of the current standard maternal serum screen, by increasing the detection of Down syndrome cases by 5% with no increase in the false-positive rate. fDNA levels are elevated in women who have developed clinical symptoms of preeclampsia, but they are also elevated by the early second trimester in women who will eventually develop preeclampsia. fDNA and mRNA gamma globin measurement may have clinical utility as markers for fetomaternal hemorrhage in the late first trimester. Cell-free fetal DNA levels are quite high in the amniotic fluid, permitting fetal genomic isolation and analysis using comparative genomic hybridization techniques. Fetal DNA crosses the blood-brain barrier and is detectable in maternal cerebrospinal fluid in a subset of pregnant women. The biological implications of this are currently unknown. Review of the literature suggests that the placenta is the predominant source of the circulating fetal nucleic acids. However, detection of gamma globin mRNA sequences in the plasma of pregnant women suggests that fetal blood cells also contribute to the pool of nucleic acids. Widespread incorporation of fetal nucleic acid measurement into routine prenatal care depends on the identification of a readily accessible gender-independent fetal marker.