Circulating fetal DNA: Its origin and diagnostic potential - A review

Objective: In contrast to the traditional teaching that the placenta forms an impermeable barrier, multiple studies show that both intact fetal cells and cell-free nucleic acids circulate freely in maternal blood. Complications of pregnancy, such as pre-eclampsia, or fetal cytogenetic abnormalities, such as trisomy 21, increase transfusion of both intact fetal cells and cell-free fetal nucleic acids into the maternal circulation. The objective of our research is to show that abnormal feto-maternal trafficking of nucleic acids is associated with fetal and placental pathology, and that these observations may lead to novel non-invasive diagnostic and screening tests. Methods: Real-time quantitative PCR amplification of DYS1 is used to measure the levels of male fetal DNA in case-control sets of serum or plasma taken from pregnant women. In our laboratory, we use DYS1, a Y-chromosome specific gene, as a uniquely fetal DNA marker for the development of gestation-specific normal values and theoretical models. Results: Women carrying fetuses with trisomies 21 or 13 (but not 18) have increased levels of fetal DNA in their fresh or archived serum and/or plasma samples. Women destined to develop pre-eclampsia have a characteristic bi-phasic elevation of cell-free fetal DNA that precedes clinical symptoms. Data obtained from a variety of clinical scenarios suggest that the placenta is the predominant source of the circulating fetal nucleic acids, although apoptotic haematopoietic cells may contribute to the pool as well. Conclusions: Fetal cell-free DNA is elevated in a number of conditions associated with placental pathology. Widespread clinical implementation of fetal DNA as a screening tool awaits discovery of a reliable gender-independent marker, which may be DNA polymorphisms, epigenetic markers, or mRNA. Fetal cell-free nucleic acids have potential for non-invasive monitoring of placental pathology. (C) 2004 IFPA and Elsevier Ltd. All rights reserved.