Considerable quantities of cell-free fetal DNA circulate in the maternal blood during human pregnancy, but the origin of the DNA remains uncertain. Circumstantial evidence suggests the placenta is the principal source, so we tested the hypothesis that release occurs from the syncytiotrophoblast after the induction of apoptotic changes. Villous explants from normal placentas delivered by elective caesarean section were cultured under normoxic conditions (10% oxygen) for up to 20 hours or exposed to hypoxia (0.5% oxygen) for 1 hour followed by reoxygenation. The concentration of -globin cell-free DNA in the supernatant, measured using realtime polymerase chain reaction methodology, was significantly increased at 20 hours after hypoxia-reoxygenation. Release was associated with increased apoptosis, confirmed by increased activation of caspase-3 on Western blotting, and immunolocalized to the syncytiotrophoblast; necrosis was also evidenced by release of lactate dehydrogenase. Both release of cell-free DNA and apoptosis could be significantly reduced by the addition of antioxidant vitamins C and E to the culture medium. This study provides the first evidence of a mechanistic and quantitative link between placental apoptosis/necrosis and release of cell-free DNA, hence confirming that maternal serum/plasma concentrations of cell-free DNA may act as a biomarker of trophoblast well-being during pregnancy.
This review describes the status of circulating trophoblast, but is considered in the perspective that only a specific subset of trophoblast cells circulates in the maternal blood. The consequences for isolation, identification and clinical potential are described.
Preeclampsia and intrauterine growth restriction are both characterized by placental malfunction. The pathological processes of abnormal trophoblast invasion, partial absence of maternal spiral artery modification, increased apoptosis of trophoblast cells, and placental ischemia are all associated with the release of specific molecules. These proteins, as well as cell-free fetal DNA and RNA might be detected in the maternal peripheral circulation, quantified, and used for early identification and prediction of preeclampsia and intrauterine growth restriction, prior to the appearance of the clinical symptoms. As preeclampsia and intrauterine growth restriction are associated with increased maternal, perinatal, and neonatal morbidity and mortality, early identification of these pregnancy associated complications will permit the design of appropriate preventive measures. In this review a variety of factors reported to be useful as potential markers for early detection of pregnancies at increased risk will be discussed. Molecules associated with the establishment of the placenta and essential in fetal-maternal interactions, like interleukin 2-receptor, insulinlike growth factor-1, and insulinlike growth factor binding protein-1, placenta growth factor, hepatocyte growth factor, inhibin A, activin A, and human chorionic gonadotrophin seem to be the most likely candidates for presymptomatic markers for preeclampsia and/or intrauterine growth restriction. Detection and discrimination of these molecules through the placental RNA in maternal plasma based strategy has become a realistic option.
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