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Fetal DNA in Maternal Plasma: Biology and Diagnostic Applications

¹ Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region. Fax 852-2194-6171; e-mail loym{at}cuhk.edu.hk

	Abstract

Top Abstract Introduction Demonstration of Fetal DNA... Prenatal Diagnostic Applications Pathological Associations Clearance of Fetal DNA... Future Directions References

 
Background: Molecular analysis of plasma DNA during human pregnancy has led to the discovery that maternal plasma contains both fetal and maternal DNA. This valuable source of fetal DNA opens up new possibilities for noninvasive prenatal diagnosis.

Approach: Published data from the last 3 years demonstrating the feasibility and utility of analyzing fetal DNA in maternal plasma are reviewed.

Content: The detection of fetal DNA in maternal plasma is much simpler and more robust than detecting fetal nucleated cells in maternal blood, and does not require prior enrichment. This approach has been shown to have application in the prenatal diagnosis of fetal rhesus D status, sex-linked disorders, and other paternally inherited genetic disorders. Abnormal fetal DNA concentrations in maternal plasma and serum have been found in common pregnancy-associated disorders, including preterm labor and preeclampsia, as well as in pregnancies complicated by fetal trisomy 21. After delivery, fetal DNA is cleared rapidly from maternal plasma, with a half-life in the order of minutes. These clearance kinetics exhibit an important difference from fetal cell clearance, where long-term persistence has been demonstrated.

Summary: It has been only 3 years since fetal DNA was first detected in maternal plasma, and much remains to be learned about the biology of this phenomenon. In addition, additional diagnostic applications beyond those discussed here can be expected in the near future.

	Introduction

Top Abstract Introduction Demonstration of Fetal DNA... Prenatal Diagnostic Applications Pathological Associations Clearance of Fetal DNA... Future Directions References

 
During pregnancy, the fetal and maternal circulations are separated by the placental membranes. However, a variety of evidence has pointed toward the incompleteness of this barrier to cellular trafficking. Of special relevance to this review, fetal nucleated cells have been demonstrated in maternal circulation (1)(2) and have been widely pursued as potential substrates for noninvasive prenatal diagnosis (3). However, the rarity of such fetal cells in maternal blood has been a major obstacle to the routine application of this concept.

Recently, there has been much interest in the use of the noncellular portion of blood, namely plasma, for molecular analysis. This interest has been stimulated mainly by the finding of tumor-derived DNA in the plasma and serum of cancer patients (4)(5)(6). These findings thus open up the possibility that circulating DNA may also be found in other clinical scenarios. In particular, there is much similarity between the placenta and a malignant tumor, leading some investigators to term the placenta "pseudomalignant" (7). Such a similarity suggests that just as tumor DNA can be found in the circulation of cancer patients, fetal DNA may also be found in maternal plasma.

	Demonstration of Fetal DNA in Maternal Plasma

Top Abstract Introduction Demonstration of Fetal DNA... Prenatal Diagnostic Applications Pathological Associations Clearance of Fetal DNA... Future Directions References

 
This line of reasoning led Lo et al. (8) in 1997 to look for fetal DNA in maternal plasma and serum, using the detection of Y-chromosomal DNA sequences derived from a male fetus as a model system. This work produced the first demonstration of fetal DNA in maternal plasma and serum and the realization that maternal plasma DNA is a chimeric mixture of fetal and maternal DNA. Before the demonstration of this fetomaternal plasma DNA chimerism, plasma and serum frequently were discarded by investigators looking for fetal nucleated cells in the maternal circulation. The finding of circulating fetal DNA has now been confirmed by other groups of investigators (9)(10).

The original protocol described by Lo et al. (8) utilized boiling as a method for plasma/serum DNA extraction and conventional "Hot-Start" PCR for detection. This protocol had sensitivities for fetal DNA detection in maternal plasma and serum of 80% and 70%, respectively. Using commercial column-based DNA extraction methods and a sensitive real-time PCR technique, this group has been able to push the sensitivity close to 100% for the detection of a fetal-derived Y-chromosomal sequence from maternal plasma and serum (11). Using a sensitive nested-PCR protocol, Smid et al. (9) have also been able to obtain very reliable detection of Y-chromosomal targets from maternal plasma in women carrying male fetuses.

In addition to improving the sensitivity of detection, the real-time PCR system described by Lo et al. (11) can also be used to measure the concentration of fetal DNA in maternal plasma and serum. Thus, Lo et al. (11) reported mean fractional fetal DNA concentrations of 3.4% and 6.2% in maternal plasma during early (i.e., late first to mid-second trimester) and late (i.e., late third trimester) pregnancies, respectively. The corresponding values for maternal serum were 0.13% and 1%, respectively, presumably reflecting the liberation of background maternal DNA during the clotting process. Furthermore, by serially following pregnant women throughout gestation, Lo et al. (11) found that the absolute concentration of fetal DNA in maternal serum increases with gestational age, with a sharp rise near the end of the pregnancy.

	Prenatal Diagnostic Applications

Top Abstract Introduction Demonstration of Fetal DNA... Prenatal Diagnostic Applications Pathological Associations Clearance of Fetal DNA... Future Directions References

 
The discovery of fetal DNA in maternal plasma/serum and the demonstration of the relative ease and reliability with which it can be detected have opened up new possibilities for noninvasive prenatal diagnosis. The detection of fetal-derived Y-chromosomal sequences in maternal plasma has potential application for the prenatal diagnosis of sex-linked disorders (9)(10)(11)(12). Outside the Y-chromosome, the first genetic locus to which investigators have turned their attention has been the RHD gene, the presence of which produces the rhesus D-positive phenotype (13). The detection of fetal-derived RHD sequence in the plasma or serum of a rhesus D-negative pregnant woman (who does not have the RHD gene) indicates the presence of a rhesus D-positive fetus. This approach has been taken by several groups, using different regions of the RHD gene as targets (12)(14)(15)(16). Most reports have demonstrated that this method is highly reliable (12)(14)(15), especially from the second trimester of pregnancy onward (14).

Other groups have focused on the detection of paternally inherited microsatellite polymorphisms from maternal plasma. Thus, Pertl et al. (17) have described the detection of microsatellite polymorphisms on chromosomes 13, 18, and 21. On the other hand, Tang et al. (18) have demonstrated the detectability of paternally inherited X-chromosomal microsatellite polymorphisms in the plasma of pregnant women carrying female fetuses. These reports have illustrated the potential applicability of maternal plasma DNA analysis for the prenatal diagnosis of a wide variety of disorders. This latter possibility has indeed been realized by several groups. Amicucci et al. (19) have demonstrated that paternally inherited disease-causing expansions of the dystrophia myotonica protein kinase (DMPK) gene can be detected from maternal plasma. Using microsatellite analysis of maternal plasma, Chen et al. (20) have reported the detection of a paternally inherited chromosomal translocation in the distal chromosome 3p.

One of the most important indications for prenatal diagnosis is the detection of fetal trisomy 21. Lo et al. (21) have described an increase in fetal DNA in maternal plasma in pregnancies affected by fetal trisomy 21. This observation opens up the possibility of using fetal DNA in maternal plasma for the screening of fetal chromosomal aneuploidies, especially in conjunction with other established serum biochemical markers. An additional possibility of using maternal plasma fetal DNA for fetal chromosomal aneuploidy detection has been suggested recently by van Wijk et al. (22), who reported that part of the fetal DNA present in maternal plasma exists in the form of cells. This observation suggests that it may be possible to perform fluorescence in situ hybridization analysis on such fetal cells isolated from maternal plasma for a definite diagnosis of fetal chromosomal aneuploidies.

	Pathological Associations

Top Abstract Introduction Demonstration of Fetal DNA... Prenatal Diagnostic Applications Pathological Associations Clearance of Fetal DNA... Future Directions References

 
The establishment of the concentrations of fetal DNA in maternal plasma in healthy pregnant women has formed the platform on which fetal DNA abnormalities in pregnancy-associated disorders can be studied. The finding of a gradual increase in fetal DNA concentration in maternal serum as gestation progresses (11) suggested the possibility that this increase may occur earlier in pregnancies complicated by preterm labor. This hypothesis has indeed been shown to be correct by Leung et al. (23), who demonstrated higher fetal DNA concentrations in preterm than term pregnancies.

Another common pregnancy-associated disorder is preeclampsia, which continues to cause considerable fetomaternal morbidity and mortality. Lo et al. (24) demonstrated a fivefold increase in fetal DNA concentration in serum obtained from women affected by preeclampsia, compared with controls. Increased trafficking of fetal nucleated cells has also been reported in preeclamptic pregnancies (25)(26). The relationship between increased cellular and cell-free DNA transfer in preeclampsia remains to be elucidated. In addition, the question of whether increased fetal DNA may be detected before the onset of preeclampsia is an important question that needs to be answered. In this regard, recent data have demonstrated that increased fetal erythroblast trafficking can be observed a few weeks before the onset of preeclampsia (27).

	Clearance of Fetal DNA from Maternal Plasma

Top Abstract Introduction Demonstration of Fetal DNA... Prenatal Diagnostic Applications Pathological Associations Clearance of Fetal DNA... Future Directions References

 
The clearance of fetal DNA from maternal plasma has been established by the study of women just before and after vaginal delivery and cesarean section (28). This study demonstrated that fetal DNA is cleared rapidly from maternal plasma, with a half-life of minutes. The conclusion from this study parallels that from earlier work involving the injection of exogenous DNA into the circulation of laboratory animals, which showed rapid elimination kinetics (29)(30).

The rapid clearance kinetics of plasma fetal DNA demonstrate important differences from the clearance of fetal nucleated cells from maternal blood. In the latter scenario, although most of the cells are cleared within weeks from the maternal circulation (31), a cell subpopulation has been shown to persist for up to decades after delivery (32). Recent studies have even demonstrated a potential pathogenic effect of such fetal cell persistence on the development of "autoimmune" diseases such as systemic sclerosis (33)(34).

The notable differences between fetal cell and cell-free DNA clearance suggest that the predominant cell populations involved may be distinct. For example, it is possible that the trophoblasts may be the predominant cell population involved in the liberation of fetal DNA into the cell-free fractions. Fetal erythroblasts, on the other hand, have been postulated to be the predominant fetal cell population found in maternal blood (3).

The organ systems involved in fetal DNA clearance from maternal plasma remain to be studied. Recent data by Botezatu et al. (35) show that the kidneys may play a role in the clearance in plasma DNA because fetal DNA was found in the urine of pregnant women carrying male fetuses. These results therefore not only demonstrate important biological pathways involved in the clearance of plasma DNA, but also open up a highly noninvasive method for prenatal diagnosis by molecular analysis of urine (36).

	Future Directions

Top Abstract Introduction Demonstration of Fetal DNA... Prenatal Diagnostic Applications Pathological Associations Clearance of Fetal DNA... Future Directions References

 
It has been 3 years since fetal DNA was first found in maternal plasma. Much remains to be learned regarding this phenomenon. Biologically, the mechanisms of fetal DNA release remain to be elucidated. One possibility is that fetal DNA is released from dying cells (37). The identity of the cell types predominantly involved in such DNA release also needs to be resolved.

The full diagnostic potential of circulating fetal DNA in maternal plasma remains to be realized. It is expected that future improvement in methods for extracting fetal DNA from plasma and simplification in detection methods may widen the availability of this type of testing.

Another interesting question that is unanswered is whether the fetal DNA circulating in maternal plasma is transcriptionally active. Excitingly, in certain experimental models, functionality of circulating tumor DNA has been implied (38). If fetal DNA is indeed transcriptionally active, it opens up new possibilities for interactions between the mother and fetus.

Finally, it has recently been realized that fetomaternal plasma DNA chimerism, similar to cellular chimerism (39), is also a bidirectional phenomenon (40). In other words, just as fetal DNA can be found in maternal plasma, maternal DNA can also be detected in fetal plasma (40). The bidirectionality and bimodality (i.e., cell and cell-free DNA) of fetomaternal trafficking thus opens up numerous future research opportunities to improve our understanding of the fetomaternal relationship.

	Acknowledgments

 
Y.M.D.L. is supported by the Hong Kong Research Grants Council and the Industrial Support Fund. The author is a member of the Hong Kong Cancer Genetics Research Group supported by the Kadoorie Charitable Foundation.

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Top Abstract Introduction Demonstration of Fetal DNA... Prenatal Diagnostic Applications Pathological Associations Clearance of Fetal DNA... Future Directions References

 

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This Article Abstract Full Text (PDF) Submit an electronic Letter to the Editor about this paper Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (39) Citing Articles via Google Scholar Google Scholar Articles by Lo, Y.M. D. Search for Related Content PubMed PubMed Citation Articles by Lo, Y.M. D. Related Collections Molecular Diagnostics and Genetics