Cell-free fetal DNA and pregnancy-related complications (Review)

Sifakis,Stavros; Koukou,Zeta; Spandidos,Demetrios  A.

doi:10.3892/mmr.2014.3118

Cell-free fetal DNA and pregnancy-related complications (Review)

Authors:
- Stavros Sifakis
- Zeta Koukou
- Demetrios A. Spandidos
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, University Hospital of Heraklion, Heraklion, Crete, Greece, Department of Clinical Virology, School of Medicine, University of Crete, Heraklion, Crete, Greece
Published online on: December 19, 2014 https://doi.org/10.3892/mmr.2014.3118
Pages: 2367-2372
Copyright: © Sifakis et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cell‑free fetal DNA (cff‑DNA) is a novel promising biomarker that has been applied in various aspects of obstetrical research, notably in prenatal diagnosis and complicated pregnancies. It is easily detected by semi‑quantitative PCR for the SRY target gene. It is well recognized that the levels of circulating cff‑DNA play a role in various complications of pregnancy. In this review, we explore the implications of the detection of cff‑DNA in a range of pregnancy-related complications, such as preeclampsia, intrauterine growth restriction (IUGR), preterm labor, placenta previa and hyperemesis gravidarum. cff‑DNA is released due to apoptotic mechanisms occurring on trophoblastic cells, although recent in vivo studies support the existence of additional mechanisms. The increase in the levels of cff‑DNA can be used to predict pregnancy-related complications and has great value in the field of prenatal diagnosis and in common pregnancy-related complications, as it precedes the clinical symptoms of the disease. Gestational age is a factor that determines the elevation in cff‑DNA levels in response to pathological conditions. In conclusion, the detection of cff‑DNA levels has a number of valuable applications in prenatal screening; however, the detection of cff‑DNA levels has not yet been applied in clinical practice for the diagnosis of pregnancy-related disorders. Thus, studies are focusing on unraveling the etiology of alterations in its levels under pathological conditions during pregnancy, in order to determine the potenial predictive and diagnostic applications of this biomarker.

View Figures

View References

1	Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW and Wainscoat JS: Presence of fetal DNA in maternal plasma and serum. Lancet. 350:485–487. 1997. View Article : Google Scholar : PubMed/NCBI
2	Lo YM: Fetal DNA in maternal plasma: biology and diagnostic applications. Clin Chem. 46:1903–1906. 2000.PubMed/NCBI
3	Hahn S, Huppertz B and Holzgreve W: Fetal cells and cell free fetal nucleic acids in maternal blood: new tools to study abnormal placentation? Placenta. 26:515–526. 2005. View Article : Google Scholar : PubMed/NCBI
4	Masuzaki H, Miura K, Yoshiura KI, Yoshimura S, Niikawa N and Ishimaru T: Detection of cell free placental DNA in maternal plasma: direct evidence from three cases of confined placental mosaicism. J Med Genet. 41:289–292. 2004. View Article : Google Scholar : PubMed/NCBI
5	Litton C, Stone J, Eddleman K and Lee MJ: Noninvasive prenatal diagnosis: past, present, and future. Mt Sinai J Med. 76:521–528. 2009. View Article : Google Scholar : PubMed/NCBI
6	Sifakis S, Papantoniou N, Kappou D and Antsaklis A: Noninvasive prenatal diagnosis of Down syndrome: current knowledge and novel insights. J Perinat Med. 40:319–327. 2012. View Article : Google Scholar : PubMed/NCBI
7	Lo YM, Leung TN, Tein MS, Sargent IL, Zhang J, Lau TK, Haines CJ and Redman CW: Quantitative abnormalities of fetal DNA in maternal serum in preeclampsia. Clin Chem. 45:184–188. 1999.PubMed/NCBI
8	Leung TN, Zhang J, Lau TK, Chan LY and Lo YM: Increased maternal plasma fetal DNA concentrations in women who eventually develop preeclampsia. Clin Chem. 47:137–139. 2001.PubMed/NCBI
9	Zhong XY, Holzgreve W and Hahn S: The levels of circulatory cell free fetal DNA in maternal plasma are elevated prior to the onset of preeclampsia. Hypertens Pregnancy. 21:77–83. 2002. View Article : Google Scholar : PubMed/NCBI
10	Wataganara T and Bianchi DW: Fetal cell-free nucleic acids in the maternal circulation: new clinical applications. Ann N Y Acad Sci. 1022:90–99. 2004. View Article : Google Scholar : PubMed/NCBI
11	Levine RJ, Qian C, Leshane ES, Yu KF, England LJ, Schisterman EF, Wataganara T, Romero R and Bianchi DW: Two-stage elevation of cell-free fetal DNA in maternal sera before onset of preeclampsia. Am J Obstet Gynecol. 190:707–713. 2004. View Article : Google Scholar : PubMed/NCBI
12	Zimmermann B, El-Sheikhah A, Nicolaides K, Holzgreve W and Hahn S: Optimized real-time quantitative PCR measurement of male fetal DNA in maternal plasma. Clin Chem. 51:1598–1604. 2005. View Article : Google Scholar : PubMed/NCBI
13	Crowley A, Martin C, Fitzpatrick P, Sheils O, O’ Herlihy C, O’ Leary JJ and Byrne BM: Free fetal DNA is not increased before 20 weeks in intrauterine growth restriction or pre-eclampsia. Prenat Diagn. 27:174–179. 2007. View Article : Google Scholar
14	Poon LC, Musci T, Song K, Syngelaki A and Nicolaides KH: Maternal plasma cell-free fetal and maternal DNA at 11–13 weeks’ gestation: relation to fetal and maternal characteristics and pregnancy outcomes. Fetal Diagn Ther. 33:215–223. 2013. View Article : Google Scholar
15	Stein W, Müller S, Gutensohn K, Emons G and Legler T: Cell-free fetal DNA and adverse outcome in low risk pregnancies. Eur J Obstet Gynecol Reprod Biol. 166:10–13. 2013. View Article : Google Scholar
16	Sifakis S, Zaravinos A, Maiz N, Spandidos DA and Nicolaides KH: First-trimester maternal plasma cell-free fetal DNA and preeclampsia. Am J Obstet Gynecol. 201:e1–e7. 2009. View Article : Google Scholar : PubMed/NCBI
17	Scharfe-Nugent A, Corr SC, Carpenter SB, Keogh L, Doyle B, Martin C, Fitzgerald KA, Daly S, O’Leary JJ and O’Neill LA: TLR9 provokes inflammation in response to fetal DNA: mechanism for fetal loss in preterm birth and preeclampsia. J Immunol. 188:5706–5712. 2012. View Article : Google Scholar : PubMed/NCBI
18	Gourvas V, Dalpa E, Konstantinidou A, Vrachnis N, Spandidos DA and Sifakis S: Angiogenic factors in placentas from pregnancies complicated by fetal growth restriction (Review). Mol Med Rep. 6:23–27. 2012.PubMed/NCBI
19	Sekizawa A, Jimbo M, Saito H, Iwasaki M, Matsuoka R, Okai T and Farina A: Cell-free fetal DNA in the plasma of pregnant women with severe fetal growth restriction. Am J Obstet Gynecol. 188:480–484. 2003. View Article : Google Scholar : PubMed/NCBI
20	Smid M, Galbiati S, Lojacono A, Valsecchi L, Platto C, Cavoretto P, Calza S, Ferrari A, Ferrari M and Cremonesi L: Correlation of fetal DNA levels in maternal plasma with Doppler status in pathological pregnancies. Prenat Diagn. 26:785–790. 2006. View Article : Google Scholar : PubMed/NCBI
21	Alberry MS, Maddocks DG, Hadi MA, Metawi H, Hunt LP, Abdel-Fattah SA, Avent ND and Soothill PW: Quantification of cell free fetal DNA in maternal plasma in normal pregnancies and in pregnancies with placental dysfunction. Am J Obstet Gynecol. 200:e1–e6. 2009. View Article : Google Scholar : PubMed/NCBI
22	Al Nakib M, Desbriere R, Bonello N, Bretelle F, Boubli L, Gabert J and Levi-Mozziconacci A: Total and fetal cell-free DNA analysis in maternal blood as markers of placental insufficiency in intrauterine growth restriction. Fetal Diagn Ther. 26:24–28. 2009. View Article : Google Scholar : PubMed/NCBI
23	Simons FE and Schatz M: Anaphylaxis during pregnancy. J Allergy Clin Immunol. 130:597–606. 2012. View Article : Google Scholar : PubMed/NCBI
24	Hoesli I, Danek M, Lin D, Li Y, Hahn S and Holzgreve W: Circulating erythroblasts in maternal blood are not elevated before onset of preterm labor. Obstet Gynecol. 100:992–996. 2002. View Article : Google Scholar : PubMed/NCBI
25	Farina A, LeShane ES, Romero R, Gomez R, Chaiworapongsa T, Rizzo N and Bianchi DW: High levels of fetal cell-free DNA in maternal serum: a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol. 193:421–425. 2005. View Article : Google Scholar : PubMed/NCBI
26	Illanes S, Gomez R, Fornes R, Figueroa-Diesel H, Schepeler M, Searovic P, Serra R, Perez A and Nien JK: Free fetal DNA levels in patients at risk of preterm labour. Prenat Diagn. 31:1082–1085. 2011. View Article : Google Scholar : PubMed/NCBI
27	Jakobsen TR, Clausen FB, Rode L, Dziegiel MH and Tabor A: High levels of fetal DNA are associated with increased risk of spontaneous preterm delivery. Prenat Diagn. 32:840–845. 2012.PubMed/NCBI
28	El-Garf W, Sheba M, Salama S, Fouad R, El-Shenawy M, Bibers M and Azmy O: Assesment of plasma cell-free fetal DNA using hypermethylated RASSF1A in maternal plasma in cases of spontaneous preterm labor. Gynecol Obstet. 12:49–52. 2013.
29	Quezada MS, Francisco C, Dumitrascu-Biris K, Nicolaides KH and Poon LC: Fetal fraction of cell-free DNA in maternal plasma in the prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol. 34:274–282. 2014.
30	Vora NL, Johnson KL, Basu S, Catalano PM, Hauguel-De Mouzon S and Bianchi DW: A multifactorial relationship exists between total circulating cell-free DNA levels and maternal BMI. Prenat Diagn. 32:912–914. 2012.PubMed/NCBI
31	Haghiac M, Vora NL, Basu S, Johnson KL, Presley L, Bianchi DW and Hauguel-De Mouzon S: Increased death of adipose cells, a path to release cell free DNA into systemic circulation of obese women. Obesity (Silver Spring). 20:2213–2219. 2012. View Article : Google Scholar
32	Kim MJ, Kim SY, Park SY, Ahn HK, Chung JH and Ryu HM: Association of fetal derived hypermethylated RASSF1A concentration in placenta-mediated pregnancy complications. Placenta. 34:57–61. 2013. View Article : Google Scholar
33	Sekizawa A, Sugito Y, Iwasaki M, Watanabe A, Jimbo M, Hoshi S, Saito H and Okai T: Cell-free fetal DNA is increased in plasma of women with hyperemesis gravidarum. Clin Chem. 47:2164–2165. 2001.PubMed/NCBI
34	Sugito Y, Sekizawa A, Farina A, Yukimoto Y, Saito H, Iwasaki M, Rizzo N and Okai T: Relationship between severity of hyperemesis gravidarum and fetal DNA concentration in maternal plasma. Clin Chem. 49:1667–1669. 2003. View Article : Google Scholar : PubMed/NCBI
35	Minagawa M, Narita J, Tada T, Maruyama S, Shimizu T, Bannai M, et al: Mechanisms underlying immunologic states during pregnancy: possible association of the sympathetic nervous system. Cell Immunol. 196:1–13. 1999. View Article : Google Scholar : PubMed/NCBI