Quantification of cell free fetal DNA in maternal plasma in normal pregnancies and in pregnancies with placental dysfunction


      To assess the normal levels of free fetal DNA in maternal plasma through pregnancy compared with those in pregnancies complicated with placental dysfunction manifested by preeclampsia and/or fetal growth restriction.

      Study Design

      Maternal blood samples from 138 singleton male pregnancies were divided into 3 groups; normal pregnancies (77), preeclampsia (49), and fetal growth restriction (12). Royston and Wright's methods were used to calculate gestational age-related reference limits of free fetal DNA in the 3 groups. The DYS14 gene of the Y chromosome was quantified and compared in maternal plasma by using real-time quantitative polymerase chain reaction.


      Free fetal DNA in normal pregnancies increased with gestational age. Results were significantly higher in preeclampsia and fetal growth restriction groups than in normal pregnancy and were higher in severe preeclampsia than in milder disease.


      Free fetal DNA is a potential marker for placental dysfunction in pregnancy. Large prospective studies are now needed to investigate its role in the prediction of pregnancy complications and severity and or timing of delivery.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Lo Y.M.
        • Corbetta N.
        • Chamberlain P.F.
        • et al.
        Presence of fetal DNA in maternal plasma and serum.
        Lancet. 1997; 350: 485-487
        • Finning K.M.
        • Martin P.G.
        • Soothill P.W.
        • Avent N.D.
        Prediction of fetal D status from maternal plasma: introduction of a new noninvasive fetal RHD genotyping service.
        Transfusion. 2002; 42: 1079-1085
        • Lo Y.M.
        Fetal DNA in maternal plasma: biology and diagnostic applications.
        Clin Chem. 2000; 46: 1903-1906
        • Gonzalez M.C.
        • Garcıa H.M.
        • Trujillo M.J.
        Prenatal detection of a cystic fibrosis mutation in fetal DNA from maternal plasma.
        Prenat Diagn. 2002; 22: 946-948
        • Chiu W.K.
        • Lau T.K.
        • Lo Y.M.
        Prenatal exclusion of β-thalassaemia major by examination of maternal plasma.
        Lancet. 2002; 360: 998-1000
        • Lo Y.M.
        • Leung T.N.
        • Tein M.S.
        • et al.
        Quantitative abnormalities of fetal DNA in maternal serum in preeclampsia.
        Clin Chem. 1999; 45: 184-188
        • Caramelli E.
        • Rizzo N.
        • Councu M.
        • et al.
        Cell-free fetal DNA concentration in plasma of patients with abnormal uterine artery Doppler waveform and intrauterine growth restriction—a pilot study.
        Prenat Diagn. 2003; 23: 367-371
        • Leung T.N.
        • Zhang J.
        • Lau T.K.
        • Hjelm N.M.
        • Lo Y.M.
        Maternal plasma fetal DNA as a marker for preterm labour.
        Lancet. 1998; 352: 1904-1905
        • Sekizawa A.
        • Sugito Y.
        • Iwasaki M.
        • et al.
        Cell-free fetal DNA is increased in plasma of women with hyperemesis gravidarum.
        Clin Chem. 2001; 47: 2164-2165
        • Farina A.
        • LeShane E.S.
        • Lambert M.
        Evaluation of cell-free fetal DNA as a second-trimester maternal serum marker of Down syndrome pregnancy.
        Clin Chem. 2003; 49: 239-242
        • Zimmermann G.
        • Holzgreve W.
        • Avent N.
        • Hahn S.
        Optimized real-time quantitative PCR measurement of male fetal DNA in maternal plasma.
        Ann N Y Acad Sci. 2006; 1075: 347-349
        • Zimmermann B.
        • El-Sheikhah A.
        • Nicolaides K.
        • Holzgreve W.
        • Hahn S.
        Optimized real-time quantitative PCR measurement of male fetal DNA in maternal plasma.
        Clin Chem. 2005; 51: 1598-1604
        • Tuffnell D.J.
        • Jankowicz D.
        • Lindow S.W.
        • et al.
        Outcomes of severe pre-eclampsia/ eclampsia in Yorkshire 1999/2003.
        BJOG. 2005; 112: 875-880
        • Douglas K.A.
        • Redman C.W.
        Eclampsia in the United Kingdom.
        BMJ. 1994; 309: 1395-1400
        • Chang T.C.
        • Robson S.C.
        • Spencer J.A.
        • Gallivan S.
        Identification of fetal growth retardation: comparison of Doppler waveform indices and serial ultrasound measurements of abdominal circumference and fetal weight.
        Obstet Gynecol. 1993; 82: 230-236
        • Zhong X.Y.
        • Laivuori H.
        • Livingston J.C.
        Elevation of both maternal and fetal extracellular circulating deoxyribonucleic acid concentrations in the plasma of pregnant women with preeclampsia.
        Am J Obstet Gynecol. 2001; 184: 414-419
        • Levine R.J.
        • Qian C.
        • Leshane E.S.
        • et al.
        Two-stage elevation of cell-free fetal DNA in maternal sera before onset of preeclampsia.
        Am J Obstet Gynecol. 2004; 190: 707-713
        • Swinkels D.W.
        • de Kok J.B.
        • Hendriks J.C.
        • Wiegerinck E.
        • Zusterzeel P.L.
        • Steegers E.A.
        Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome as a complication of preeclampsia in pregnant women increases the amount of cell-free fetal and maternal DNA in maternal plasma and serum.
        Clin Chem. 2002; 48: 650-653
        • Altman D.
        • Carroli G.
        • Duley L.
        • et al.
        • Magpie trial collaboration group
        Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate?.
        Lancet. 2002; 359: 1877-1890
        • Alberry M.
        • Soothill P.
        Management of fetal growth restriction.
        Arch Dis Child Fetal Neonatal. 2007; 92: 62-67
        • Bobrow C.S.
        • Holmes R.P.
        • Muttukrishna S.
        • et al.
        Maternal serum activin A, inhibin A, and follistatin in pregnancies with appropriately grown and small-for-gestational-age fetuses classified by umbilical artery Doppler ultrasound.
        Am J Obstet Gynecol. 2002; 186: 283-287
        • Royston P.
        • Altman D.G.
        Regression using fractional polynomials of continuous covariates: parsimonious parametric modelling (with discussion).
        Appl Statist. 1994; 43: 429-467
        • Royston P.
        • Wright E.M.
        How to construct ‘normal ranges’ for fetal variables.
        Ultrasound Obstet Gynecol. 1998; 11: 30-38
        • Royston P.
        • Wright E.M.
        A method for estimating age-specific reference intervals (‘normal ranges’) based on fractional polynomials and exponential transformation.
        J Roy Statist Soc. 1998; 161: 79-101
        • Lo Y.M.
        • Tein M.S.
        • Lau T.K.
        • et al.
        Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis.
        Am J Hum Genet. 1998; 62: 768-775
        • Alberry M.
        • Maddocks D.
        • Jones M.
        • et al.
        Free fetal DNA in maternal plasma in anembryonic pregnancies: confirmation that the origin is the trophoblast.
        Prenat Diagn. 2007; 27: 415-418
        • Zhong X.Y.
        • Holzgreve W.
        • Hahn S.
        Cell-free fetal DNA maternal circulation does not stem from transplacental passage fetal erythroblast.
        Mol Hum Reprod. 2002; 8: 864-870
        • Bobrow C.S.
        • Soothill P.W.
        Fetal growth velocity: a cautionary tale.
        Lancet. 1999; 353: 1460
        • Sekizawa A.
        • Jimbo M.
        • Saito H.
        • et al.
        Cell-free fetal DNA in the plasma of pregnant women with severe fetal growth restriction.
        Am J Obstet Gynecol. 2003; 188: 480-484
        • Tong Y.K.
        • Ding C.
        • Chiu R.W.
        • et al.
        Noninvasive prenatal detection of fetal trisomy 18 by epigenetic allelic ratio analysis in maternal plasma: theoretical and empirical considerations.
        Clin Chem. 2006; 52: 2194-2202