Low Fetal Fraction and Birth Weight in Women with Negative First-Trimester Cell-Free DNA ScreeningFunding None.
30 August 2019
22 September 2019
18 November 2019 (online)
Objective To determine the association between low fetal fraction and birth weight among women with a negative cell-free DNA (cfDNA) result for common aneuploidies in the first trimester.
Study Design This is a retrospective cohort of women who delivered a singleton between July 2016 and June 2018 at a single institution and had normal cfDNA testing in the first trimester. The primary variable of interest was “low fetal fraction,” which was defined as fetal fractions less than 5th percentile among all fetal fractions in the cohort (fetal fraction < 5.34%). The primary outcomes were birth weight ≤ 5th and ≤ 10th percentiles. Multivariable logistic regressions assessed for the association between low fetal fraction and birth weight.
Results A total of 7,478 women delivered a singleton at ≥24 weeks' gestation, of which 2,387 (32%) underwent genetic screening through cfDNA; the majority were in the first trimester (n = 2,052 [86%]). 2,035 met the inclusion criteria. Birth weight ≤ 5th percentile was significantly higher in the low fetal fraction group (6.9 vs. 3.2%; p = 0.04). A low fetal fraction was associated with higher odds of an infant with a low birth weight: adjusted odds ratio (aOR) of 2.32 (95% CI 1.15–4.67) for birth weight ≤ 10th percentile (p = 0.02) and aOR of 3.73 (95% CI 1.40–9.03) for birth weight ≤ 5th percentile (p = 0.004).
Conclusion Low fetal fractions of ≤ 5th percentile were associated with an increased risk of birth weights ≤ 5th and ≤ 10th percentiles in women with negative cfDNA screening in the first trimester. Future work is needed to further investigate this relationship and to determine the potential clinical implications, such as third-trimester screening for growth restriction in women with low fetal fractions and negative cfDNA screening results.
Keywordsgenetic screening - cell-free DNA - aneuploidy - low birth weight - intrauterine growth restriction
The findings from this study were presented as a poster at the Society for Maternal-Fetal Medicine's 2019 Pregnancy Meeting, Las Vegas, NV, February 11–16, 2019.
- 1 Harris S, Reed D, Vora NL. Screening for fetal chromosomal and subchromosomal disorders. Semin Fetal Neonatal Med 2018; 23 (02) 85-93
- 2 Larion S, Warsof SL, Romary L, Mlynarczyk M, Peleg D, Abuhamad AZ. Uptake of noninvasive prenatal testing at a large academic referral center. Am J Obstet Gynecol 2014; 211 (06) 651.e1-651.e7
- 3 Norton ME, Baer RJ, Wapner RJ, Kuppermann M, Jelliffe-Pawlowski LL, Currier RJ. Cell-free DNA vs sequential screening for the detection of fetal chromosomal abnormalities. Am J Obstet Gynecol 2016; 214 (06) 727.e1-727.e6
- 4 Committee Opinion No. Committee Opinion No. 640: cell-free DNA screening for fetal aneuploidy. Obstet Gynecol 2015; 126 (03) e31-e37
- 5 Committee on Practice Bulletins—Obstetrics, Committee on Genetics, and the Society for Maternal-Fetal Medicine. Practice Bulletin No. 163: screening for fetal aneuploidy. Obstet Gynecol 2016; 127 (05) e123-e137
- 6 Norton ME, Brar H, Weiss J. , et al. Non-Invasive Chromosomal Evaluation (NICE) Study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012; 207 (02) 137.e1-137.e8
- 7 Sparks AB, Struble CA, Wang ET, Song K, Oliphant A. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012; 206 (04) 319.e1-319.e9
- 8 Chiu RWK, Lo YMD. Noninvasive prenatal diagnosis empowered by high-throughput sequencing. Prenat Diagn 2012; 32 (04) 401-406
- 9 Ashoor G, Syngelaki A, Poon LCY, Rezende JC, Nicolaides KH. Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks' gestation: relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol 2013; 41 (01) 26-32
- 10 Zhou Y, Zhu Z, Gao Y. , et al. Effects of maternal and fetal characteristics on cell-free fetal DNA fraction in maternal plasma. Reprod Sci 2015; 22 (11) 1429-1435
- 11 Kinnings SL, Geis JA, Almasri E. , et al. Factors affecting levels of circulating cell-free fetal DNA in maternal plasma and their implications for noninvasive prenatal testing. Prenat Diagn 2015; 35 (08) 816-822
- 12 Rolnik DL, Yong Y, Lee TJ, Tse C, McLennan AC, da Silva Costa F. Influence of body mass index on fetal fraction increase with gestation and cell-free DNA test failure. Obstet Gynecol 2018; 132 (02) 436-443
- 13 Bauer M, Hutterer G, Eder M. , et al. A prospective analysis of cell-free fetal DNA concentration in maternal plasma as an indicator for adverse pregnancy outcome. Prenat Diagn 2006; 26 (09) 831-836
- 14 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
- 15 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
- 16 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
- 17 Morano D, Rossi S, Lapucci C, Pittalis MC, Farina A. Cell-free DNA (cfDNA) fetal fraction in early- and late-onset fetal growth restriction. Mol Diagn Ther 2018; 22 (05) 613-619
- 18 Krantz D, Goetzl L, Simpson JL. , et al; First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study Group. Association of extreme first-trimester free human chorionic gonadotropin-beta, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes. Am J Obstet Gynecol 2004; 191 (04) 1452-1458
- 19 Spencer K, Cowans NJ, Avgidou K, Molina F, Nicolaides KH. First-trimester biochemical markers of aneuploidy and the prediction of small-for-gestational age fetuses. Ultrasound Obstet Gynecol 2008; 31 (01) 15-19
- 20 Leung TY, Sahota DS, Chan LW. , et al. Prediction of birth weight by fetal crown-rump length and maternal serum levels of pregnancy-associated plasma protein-A in the first trimester. Ultrasound Obstet Gynecol 2008; 31 (01) 10-14
- 21 Copel JA, Bahtiyar MO. A practical approach to fetal growth restriction. Obstet Gynecol 2014; 123 (05) 1057-1069
- 22 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: 6
- 23 Suzumori N, Sekizawa A, Ebara T. , et al. Fetal cell-free DNA fraction in maternal plasma for the prediction of hypertensive disorders of pregnancy. Eur J Obstet Gynecol Reprod Biol 2018; 224: 165-169
- 24 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
- 25 Bianchi DW, Platt LD, Goldberg JD, Abuhamad AZ, Sehnert AJ, Rava RP. ; MatErnal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol 2012; 119 (05) 890-901
- 26 Palomaki GE, Deciu C, Kloza EM. , et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med 2012; 14 (03) 296-305