High Fetal Fraction on First Trimester Cell-Free DNA Aneuploidy Screening and Adverse Pregnancy Outcomes

Abstract

Objective To test the hypothesis that high fetal fraction (FF) on first trimester cell-free deoxyribonucleic acid (cfDNA) aneuploidy screening is associated with adverse perinatal outcomes.

Study Design This is a single-institution retrospective cohort study of women who underwent cfDNA screening at <14 weeks' gestation and delivered a singleton infant between July 2016 and June 2018. Women with abnormal results were excluded. Women with high FF (≥95th percentile) were compared with women with normal FF (5th–95th percentiles). Outcomes investigated were preterm birth, small for gestational age, and hypertensive disorders of pregnancy.

Results A total of 2,033 women met inclusion criteria. The mean FF was 10.0%, and FF >16.5% was considered high (n = 102). Women with high FF had a greater chance of delivering a small for gestational age infant <fifth percentile, with an adjusted odds ratio of 2.4 (95% confidence interval: 1.1–4.8, p = 0.039). There was no significant association between high FF and either preterm birth or hypertensive disorders of pregnancy.

Conclusion Women with a high FF in the first trimester are at increased risk of delivering a small for gestational age infant <fifth percentile. Further investigation into the clinical implications of a high FF is warranted.

Keywords

aneuploidy screening - cell-free DNA - fetal fraction - adverse pregnancy outcomes - fetal growth restriction

Note

This study was presented as poster abstract (no. 901) at SMFM's 39th Annual Pregnancy Meeting, Las Vegas, NV, February 11–16, 2019.

• References

• 1 Lo YM, Corbetta N, Chamberlain PF. , et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997; 350 (9076): 485-487
• 2 Huppertz B, Kingdom JC. Apoptosis in the trophoblast--role of apoptosis in placental morphogenesis. J Soc Gynecol Investig 2004; 11 (06) 353-362
• 3 Taglauer ES, Wilkins-Haug L, Bianchi DW. Review: cell-free fetal DNA in the maternal circulation as an indication of placental health and disease. Placenta 2014; 35 (Suppl): S64-S68
• 4 Sekizawa A, Jimbo M, Saito H. , et al. Increased cell-free fetal DNA in plasma of two women with invasive placenta. Clin Chem 2002; 48 (02) 353-354
• 5 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
• 6 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 (02) 480-484
• 7 Farina A, LeShane ES, Romero R. , et al. High levels of fetal cell-free DNA in maternal serum: a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol 2005; 193 (02) 421-425
• 8 Jakobsen TR, Clausen FB, Rode L, Dziegiel MH, Tabor A. High levels of fetal DNA are associated with increased risk of spontaneous preterm delivery. Prenat Diagn 2012; 32 (09) 840-845
• 9 Thurik FF, Lamain-de Ruiter M, Javadi A. , et al. Absolute first trimester cell-free DNA levels and their associations with adverse pregnancy outcomes. Prenat Diagn 2016; 36 (12) 1104-1111
• 10 van Boeckel SR, Davidson DJ, Norman JE, Stock SJ. Cell-free fetal DNA and spontaneous preterm birth. Reproduction 2018; 155 (03) R137-R145
• 11 Dugoff L, Barberio A, Whittaker PG, Schwartz N, Sehdev H, Bastek JA. Cell-free DNA fetal fraction and preterm birth. Am J Obstet Gynecol 2016; 215 (02) 231.e1-231.e7
• 12 Leung TN, Zhang J, Lau TK, Hjelm NM, Lo YM. Maternal plasma fetal DNA as a marker for preterm labour. Lancet 1998; 352 (9144): 1904-1905
• 13 Phillippe M. Cell-free fetal DNA--a trigger for parturition. N Engl J Med 2014; 370 (26) 2534-2536
• 14 Kim SK, Hannum G, Geis J. , et al. Determination of fetal DNA fraction from the plasma of pregnant women using sequence read counts. Prenat Diagn 2015; 35 (08) 810-815
• 15 ACOG practice bulletin no. 204: fetal growth restriction. Obstet Gynecol 2019; 133 (02) e97-e109
• 16 Getahun D, Ananth CV, Kinzler WL. Risk factors for antepartum and intrapartum stillbirth: a population-based study. Am J Obstet Gynecol 2007; 196 (06) 499-507
• 17 Oken E, Kleinman KP, Rich-Edwards J, Gillman MW. A nearly continuous measure of birth weight for gestational age using a United States national reference. BMC Pediatr 2003; 3 (01) 6
• 18 Krishna I, Badell M, Loucks TL, Lindsay M, Samuel A. Adverse perinatal outcomes are more frequent in pregnancies with a low fetal fraction result on noninvasive prenatal testing. Prenat Diagn 2016; 36 (03) 210-215
• 19 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 (05) 367-371
• 20 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 (01) 98.e1-98.e6
• 21 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 (04) 215-223
• 22 Stein W, Müller S, Gutensohn K, Emons G, Legler T. Cell-free fetal DNA and adverse outcome in low risk pregnancies. Eur J Obstet Gynecol Reprod Biol 2013; 166 (01) 10-13
• 23 Contro E, Bernabini D, Farina A. Cell-free fetal DNA for the prediction of pre-eclampsia at the first and second trimesters: a systematic review and meta-analysis. Mol Diagn Ther 2017; 21 (02) 125-135
• 24 Bender WR, Koelper NC, Sammel MD, Dugoff L. Association of fetal fraction of cell-free DNA and hypertensive disorders of pregnancy. Am J Perinatol 2019; 36 (03) 311-316
• 25 Quezada MS, Francisco C, Dumitrascu-Biris D, Nicolaides KH, Poon LC. Fetal fraction of cell-free DNA in maternal plasma in the prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol 2015; 45 (01) 101-105
• 26 Wataganara T, Bui T-H, Choy KW, Leung TY. Debates on fetal fraction measurement and DNA-based noninvasive prenatal screening: time for standardisation?. BJOG 2016; 123 (Suppl. 03) 31-35