Cell-free DNA testing in maternal blood provides the most effective method of screening for trisomy 21, with a reported detection rate of 99% and a false positive rate of less than 0.1%. After many years of research, this method is now commercially available and is carried out in an increasing number of patients, and there is an expanding number of conditions that can be screened for. However, the application of these methods in clinical practice requires a careful analysis. Current first-trimester screening strategies are based on a complex combination of tests, aiming at detecting fetal defects and predicting the risk of main pregnancy complications. It is therefore necessary to define the optimal way of combining cell-free DNA testing with current first-trimester screening methods. In this concise review we describe the basis of cell-free DNA testing and discuss the potential approaches for its implementation in combination with current tests in the first trimester.

Keywords:
Cell-free DNA testing, Fetal aneuploidies, Trisomies 21, 18 and 13
1.
Wright D, Syngelaki A, Bradburi I, Akolekar R, Nicolaides KH: First-trimester screening for trisomies 21, 18 and 13 by ultrasound and biochemical testing. Fetal Diagn Ther 2014;35:118-126.
2.
Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, Wainscoat JS: Presence of fetal DNA in maternal plasma and serum. Lancet 1997;350:485-487.
3.
Lo YM, Hjelm NM, Fidler C, Sargent IL, Murphy MF, Chamberlain PF, Poon PM, Redman CW, Wainscoat JS: Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. N Engl J Med 1998;339:1734-1738.
4.
Akolekar R, Finning K, Kuppusamy R, Daniels G, Nicolaides KH: Fetal RHD genotyping in maternal plasma at 11-13 weeks of gestation. Fetal Diagn Ther 2011;29:301-306.
5.
Gil MM, Akolekar R, Quezada MS, Bregant B, Nicolaides KH: Analysis of cell-free DNA in maternal blood in screening for aneuploidies: meta-analysis. Fetal Diagn Ther 2014;35:156-173.
6.
Nicolaides KH, Syngelaki A, Ashoor G, Birdir C, Touzet G: Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am J Obstet Gynecol 2012;207:374.e1-e6.
7.
Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF, Craig JA, Chudova DI, Devers PL, Jones KW, Oliver K, Rava RP, Sehnert AJ; CARE Study Group: DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014;370:799-808.
8.
Syngelaki A, Pergament E, Homfray T, Akolekar R, Nicolaides KH: Replacing the combined test by cell-free DNA testing in screening for trisomies 21, 18 and 13: impact on the diagnosis of other chromosomal abnormalities. Fetal Diagn Ther 2014;35:174-184.
9.
Nicolaides KH: Turning the pyramid of prenatal care. Fetal Diagn Ther 2011;29:183-196.
10.
Poon LC, Syngelaki A, Akolekar R, Lai J, Nicolaides KH: Combined screening for preeclampsia and small for gestational age at 11-13 weeks. Fetal Diagn Ther 2013;33:16-27.
11.
Greco E, Gupta R, Syngelaki A, Poon LC, Nicolaides KH: First-trimester screening for spontaneous preterm delivery with maternal characteristics and cervical length. Fetal Diagn Ther 2012;31:154-161.
12.
American College of Obstetricians and Gynecologists Committee on Genetics: Committee Opinion No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol 2012;120:1532-1534.
13.
Benn P, Borell A, Chiu R, Cuckle H, Dugoff L, Faas B, Gross S, Johnson J, Maymon R, Norton M, Odibo A, Schielen P, Spencer K, Huang T, Wright D, Yaron Y: Position statement from the Aneuploidy Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn 2013;33:622-629.
14.
Devers PL, Cronister A, Ormond KE, Facio F, Brasington CK, Flodman P: Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors. J Genet Couns 2013;22:291-295.
15.
Lo YM: Non-invasive prenatal testing using massively parallel sequencing of maternal plasma DNA: from molecular karyotyping to fetal whole-genome sequencing. Reprod Biomed Online 2013;27:593-598.
16.
Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR: Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl Acad Sci USA 2008;105:266-271.
17.
Chiu RW, Chan KC, Gao Y, Lau VY, Zheng W, Leung TY, Foo CH, Xie B, Tsui NB, Lun FM, Zee BC, Lau TK, Cantor CR, Lo YM: Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl Acad Sci USA 2008;105:20458-20463.
18.
Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Deciu C, Grody WW, Nelson SF, Canick JA: DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011;13:913-920.
19.
Bianchi DW, Platt LD, Goldberg JD, Abuhamad AZ, Sehnert AJ, Rava RP: Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol 2012;119:890-901.
20.
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;206:319.e1-e9.
21.
Ashoor G, Syngelaki A, Wagner M, Birdir C, Nicolaides KH: Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012;206:322.e1-e5.
22.
Norton ME, Brar H, Weiss J, Karimi A, Laurent LC, Caughey AB, Rodriguez MH, Williams J 3rd, Mitchell ME, Adair CD, Lee H, Jacobsson B, Tomlinson MW, Oepkes D, Hollemon D, Sparks AB, Oliphant A, Song K: 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;207:137.e1-e8.
23.
Zimmermann B, Hill M, Gemelos G, Demko Z, Banjevic M, Baner J, Ryan A, Sigurjonsson S, Chopra N, Dodd M, Levy B, Rabinowitz M: Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y using targeted sequencing of polymorphic loci. Prenat Diag 2012;32:1233-1241.
24.
Nicolaides KH, Syngelaki A, Gil M, Atanasova V, Markova D: Validation study of maternal blood cell-free DNA testing by targeted sequencing of single-nucleotide polymorphisms at chromosomes 13, 18, 21, X, and Y. Prenat Diagn 2013;33:575-579.
25.
Nicolaides KH, Syngelaki A, Gil MM, Quezada MS, Zinevich Y: Prenatal detection of triploidy from cell-free DNA testing in maternal blood. Fetal Diagn Ther 2014;35:212-217.
26.
Wang J, Pang GS, Chong SS, Lee CG: SNP web resources and their potential applications in personalized medicine. Curr Drug Metab 2012;13:978-990.
27.
Chow KC, Chiu RW, Tsui NB, Ding C, Lau TK, Leung TN, Lo YM: Mass spectrometric detection of an SNP panel as an internal positive control for fetal DNA analysis in maternal plasma. Clin Chem 2007;53:141-142.
28.
Gil MM, Quezada MS, Bregant B, Syngelaki A, Nicolaides KH: Cell-free DNA analysis for trisomy risk assessment in first-trimester twin pregnancies. Fetal Diagn Ther 2014;35:204-211.
29.
Struble CA, Syngelaki A, Oliphant A, Song K, Nicolaides KH: Fetal fraction estimate in twin pregnancies using directed cell-free DNA analysis. Fetal Diagn Ther 2014;35:199-203.
30.
Huang X, Zheng J, Chen M, Zhao Y, Zhang C, Liu L, Xie W, Shi S, Wei Y, Lei D, Xu C, Wu Q, Guo X, Shi X, Zhou Y, Liu Q, Gao Y, Jiang F, Zhang H, Su F, Ge H, Li X, Pan X, Chen S, Chen F, Fang Q, Jiang H, Lau TK, Wang W: Noninvasive prenatal testing of trisomies 21 and 18 by massively parallel sequencing of maternal plasma DNA in twin pregnancies. Prenat Diagn 2014;34:335-340.
31.
Ashoor G, Poon L, Syngelaki A, Mosimann B, Nicolaides KH: Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks' gestation: effect of maternal and fetal factors. Fetal Diagn Ther 2012;31:237-243.
32.
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;33:215-223.
33.
Gil MM, Quezada MS, Bregant B, Ferraro M, Nicolaides KH: Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies. Ultrasound Obstet Gynecol 2013;42:34-40.
34.
Nicolaides KH, Syngelaki A, Poon LC, Gil MM, Wright D: First-trimester contingent screening for trisomies 21, 18 and 13 by biomarkers and maternal blood cell-free DNA testing. Fetal Diagn Ther 2014;35:185-192.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.