Cell-Free Total and Fetal DNA in First Trimester Maternal Serum and Subsequent Development of Preeclampsia

Abstract

Objective The objective of this study was to assess the relationship between first trimester cell-free total and fetal DNA in maternal plasma and the subsequent development of preeclampsia.

Study Design Nested case–control study of patients enrolled in the Combined Antioxidant and Preeclampsia Prediction Studies prediction study of 175 women who did and 175 women who did not develop preeclampsia. The predictive values of cell-free total and fetal DNA and the subsequent development of preeclampsia were measured using receiver operating characteristic curves.

Results Cell-free total DNA was higher in African American (median; 25–75%; 6.15; 0.14–28.73; p = 0.02) and Hispanic (4.95; 0.20–26.82; p = 0.037) compared with white women (2.33; 0.03–13.10). Levels of cell-free total DNA were also associated with maternal body mass index (BMI) (p = 0.02). Cell-free total DNA levels were similar between women who later developed preeclampsia (3.52; 0.11–25.3) and controls (3.74; 0.12–21.14, p = 0.96).

Conclusion There is no significant difference in levels of cell-free total DNA in the first trimester in women who subsequently develop preeclampsia. Levels of cell-free total DNA in the first trimester are increased in African American and Hispanic compared with white women, and levels increase with increasing BMI.

Keywords

preeclampsia - cell-free DNA - placenta - fetal fraction

• References

• 1 Bujold E, Roberge S, Lacasse Y , et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010; 116 (2 Pt 1): 402-414
• 2 Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol 2005; 105 (2) 402-410
• 3 Myatt L, Clifton RG, Roberts JM , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network (MFMU). The utility of uterine artery Doppler velocimetry in prediction of preeclampsia in a low-risk population. Obstet Gynecol 2012; 120 (4) 815-822
• 4 Myatt L, Clifton RG, Roberts JM , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol 2012; 119 (6) 1234-1242
• 5 Hahn S, Huppertz B, Holzgreve W. Fetal cells and cell free fetal nucleic acids in maternal blood: new tools to study abnormal placentation?. Placenta 2005; 26 (7) 515-526
• 6 Askelund KJ, Chamley LW. Trophoblast deportation part I: review of the evidence demonstrating trophoblast shedding and deportation during human pregnancy. Placenta 2011; 32 (10) 716-723
• 7 Farina A, Sekizawa A, Iwasaki M, Matsuoka R, Ichizuka K, Okai T. Total cell-free DNA (beta-globin gene) distribution in maternal plasma at the second trimester: a new prospective for preeclampsia screening. Prenat Diagn 2004; 24 (9) 722-726
• 8 Sekizawa A, Farina A, Koide K , et al. beta-globin DNA in maternal plasma as a molecular marker of pre-eclampsia. Prenat Diagn 2004; 24 (9) 697-700
• 9 Crowley A, Martin C, Fitzpatrick P , et al. Free fetal DNA is not increased before 20 weeks in intrauterine growth restriction or pre-eclampsia. Prenat Diagn 2007; 27 (2) 174-179
• 10 Caramelli E, Rizzo N, Concu 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 (5) 367-371
• 11 Alberry MS, Maddocks DG, Hadi MA , et al. Quantification of cell free fetal DNA in maternal plasma in normal pregnancies and in pregnancies with placental dysfunction. Am J Obstet Gynecol 2009; 200 (1) 98.e1-98.e6
• 12 Tjoa ML, Oudejans CB, van Vugt JM, Blankenstein MA, van Wijk IJ. Markers for presymptomatic prediction of preeclampsia and intrauterine growth restriction. Hypertens Pregnancy 2004; 23 (2) 171-189
• 13 Zhong XY, Holzgreve W, Hahn S. The levels of circulatory cell free fetal DNA in maternal plasma are elevated prior to the onset of preeclampsia. Hypertens Pregnancy 2002; 21 (1) 77-83
• 14 Roberts JM, Myatt L, Spong CY , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med 2010; 362 (14) 1282-1291
• 15 Alexander GR, Kogan MD, Himes JH. 1994-1996 U.S. singleton birth weight percentiles for gestational age by race, Hispanic origin, and gender. Matern Child Health J 1999; 3 (4) 225-231
• 16 Chim SS, Tong YK, Chiu RW , et al. Detection of the placental epigenetic signature of the maspin gene in maternal plasma. Proc Natl Acad Sci U S A 2005; 102 (41) 14753-14758
• 17 Zhao F, Wang J, Liu R , et al. Quantification and application of the placental epigenetic signature of the RASSF1A gene in maternal plasma. Prenat Diagn 2010; 30 (8) 778-782
• 18 Poon LC, Musci T, Song K, Syngelaki A, 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 2013; 33 (4) 215-223
• 19 Legler TJ, Liu Z, Mavrou A , et al. Workshop report on the extraction of foetal DNA from maternal plasma. Prenat Diagn 2007; 27 (9) 824-829
• 20 Barrett AN, Zimmermann BG, Wang D, Holloway A, Chitty LS. Implementing prenatal diagnosis based on cell-free fetal DNA: accurate identification of factors affecting fetal DNA yield. PLoS ONE 2011; 6 (10) e25202 DOI: 10.1371/journal.pone.0025202.
• 21 Nygren AO, Dean J, Jensen TJ , et al. Quantification of fetal DNA by use of methylation-based DNA discrimination. Clin Chem 2010; 56 (10) 1627-1635
• 22 Sparks AB, Wang ET, Struble CA , et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat Diagn 2012; 32 (1) 3-9
• 23 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 (2) 480-484
• 24 Illanes S, Parra M, Serra R , et al. Increased free fetal DNA levels in early pregnancy plasma of women who subsequently develop preeclampsia and intrauterine growth restriction. Prenat Diagn 2009; 29 (12) 1118-1122
• 25 Palomaki GE, Kloza EM, Lambert-Messerlian GM , et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011; 13 (11) 913-920
• 26 Chiu RWK, Lo YMD. Noninvasive prenatal diagnosis empowered by high-throughput sequencing. Prenat Diagn 2012; 32 (4) 401-406
• 27 Lapaire O, Volgmann T, Grill S , et al. Significant correlation between maternal body mass index at delivery and in the second trimester, and second trimester circulating total cell-free DNA levels. Reprod Sci 2009; 16 (3) 274-279
• 28 Lazar L, Rigó Jr J, Nagy B , et al. Relationship of circulating cell-free DNA levels to cell-free fetal DNA levels, clinical characteristics and laboratory parameters in preeclampsia. BMC Med Genet 2009; 10: 120 DOI: 10.1186/1471-2350-10-120.
• 29 Wataganara T, Peter I, Messerlian GM, Borgatta L, Bianchi DW. Inverse correlation between maternal weight and second trimester circulating cell-free fetal DNA levels. Obstet Gynecol 2004; 104 (3) 545-550
• 30 Gerovassili A, Nicolaides KH, Thein SL, Rees DC. Cell-free DNA levels in pregnancies at risk of sickle-cell disease and significant ethnic variation. Br J Haematol 2006; 135 (5) 738-741
• 31 Paré E, Parry S, McElrath TF, Pucci D, Newton A, Lim KH. Clinical risk factors for preeclampsia in the 21st century. Obstet Gynecol 2014; 124 (4) 763-770