Circulating Cell‐Free Fetal Nucleic Acid Analysis May Be a Novel Marker of Fetomaternal Hemorrhage after Elective First‐Trimester Termination of Pregnancy

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Abstract
Abstract: Analysis of cell‐free fetal DNA (fDNA) and RNA in maternal plasma could be useful in the diagnosis and management of complications of pregnancy. In this review, we discuss our studies to investigate the potential of fetal nucleic acid measurement in maternal plasma as a marker of fetomaternal hemorrhage (FMH) after elective first‐trimester termination of pregnancy (TOP). Using quantitative real‐time PCR amplification of the DYS1 sequence, elevation of plasma fDNA levels after TOP was observed, especially in the late first trimester. This corresponds with the functional development of the placental vascular structure and fetal hematopoiesis. This Y sequence‐based PCR amplification assay, however, limits the analysis to pregnant women carrying male fetuses. Therefore, we also developed a real‐time quantitative reverse‐transcriptase PCR assay of the γ‐globin transcript as a marker of fetal erythroid cells. Although plasma γ‐globin mRNA levels were decreased after TOP in many patients, an elevation was observed in some patients at greater than 9 weeks' gestation, which is consistent with the increase in plasma fDNA levels. Our data suggest that fetal hematopoietic cells contribute to the pool of fetal nucleic acids in the maternal circulation. Measurement of cell‐free fetal nucleic acid levels in maternal plasma may have clinical application as a novel marker of FMH after 9 weeks of gestation.