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Ecografía del primer trimestre sola o en combinación con pruebas séricas del primer trimestre para la detección del síndrome de Down

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References

References to studies included in this review

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Acacio 2001 {published data only}

Acacio GL, Barini R, Pinto Júnior W, Ximenes RL, Pettersen H, Faria M. Nuchal translucency: an ultrasound marker for fetal chromosomal abnormalities. Sao Paulo Medical Journal = Revista Paulista de Medicina. 2001;119(1):19‐23. CENTRAL

Audibert 2001 {published data only}

Audibert F, Dommergues M, Benattar C, Taieb J, Thalabard JC, Frydman R. Screening for Down syndrome using first‐trimester ultrasound and second‐trimester maternal serum markers in a low‐risk population: a prospective longitudinal study. Ultrasound in Obstetrics & Gynecology. 2001;18(1):26‐31. CENTRAL

Babbur 2005 {published data only}

Babbur V, Lees CC, Goodburn SF, Morris N, Breeze AC, Hackett GA. Prospective audit of a one‐centre combined nuchal translucency and triple test programme for the detection of trisomy 21. Prenatal Diagnosis 2005;25(6):465‐9. CENTRAL

Barrett 2008 {published data only}

Barrett SL, Bower C, Hadlow NC. Use of the combined first‐trimester screen result and low PAPP‐A to predict risk of adverse fetal outcomes. Prenatal Diagnosis 2008;28(1):28‐35. CENTRAL

Belics 2011 {published data only}

Belics Z, Fekete T, Beke A, Szabo I. Prenatal ultrasonographic measurement of the fetal iliac angle during the first and second trimester of pregnancy. Prenatal Diagnosis 2011;31(4):351‐5. CENTRAL

Benattar 1999 {published data only}

Benattar C, Audibert F, Taieb J, Ville Y, Roberto A, Lindenbaum A, et al. Efficiency of ultrasound and biochemical markers for Down's syndrome risk screening. A prospective study. Fetal Diagnosis and Therapy 1999;14(2):112‐7. CENTRAL

Bestwick 2010 {published data only}

Bestwick JP, Huttly WJ, Wald NJ. Distribution of nuchal translucency in antenatal screening for Down's syndrome.[Erratum appears in J Med Screen. 2010 Jun;17(2):106]. Journal of Medical Screening 2010;17(1):8‐12. CENTRAL
Bestwick JP, Huttly WJ, Wald NJ. Evaluation of a proposed mixture model to specify the distributions of nuchal translucency measurements in antenatal screening for Down's syndrome. Journal of Medical Screening 2010;17(1):13‐8. CENTRAL

Biagiotti 1998 {published data only}

Biagiotti R, Brizzi L, Periti E, d'Agata A, Vanzi E, Cariati E. First trimester screening for Down's syndrome using maternal serum PAPP‐A and free beta‐hCG in combination with fetal nuchal translucency thickness. British Journal of Obstetrics and Gynaecology 1998;105(8):917‐20. CENTRAL

Borenstein 2008 {published data only}

Borenstein M, Cavoretto P, Allan L, Huggon I, Nicolaides KH. Aberrant right subclavian artery at 11 + 0 to 13 + 6 weeks of gestation in chromosomally normal and abnormal fetuses. Ultrasound in Obstetrics & Gynecology 2008;31(1):20‐4. CENTRAL

Borrell 2005 {published data only}

Borrell A, Casals E, Fortuny A, Farre MT, Gonce A, Sanchez A, et al. First‐trimester screening for trisomy 21 combining biochemistry and ultrasound at individually optimal gestational ages. An interventional study. Prenatal Diagnosis 2004;24(7):541‐5. CENTRAL
Borrell A, Gonce A, Martinez JM, Borobio V, Fortuny A, Coll O, et al. First‐trimester screening for Down syndrome with ductus venosus Doppler studies in addition to nuchal translucency and serum markers. Prenatal Diagnosis 2005;25(10):901‐5. CENTRAL

Borrell 2009 {published data only}

Borrell A, Borobio V, Bestwick JP, Wald NJ. Ductus venosus pulsatility index as an antenatal screening marker for Down's syndrome: use with the Combined and Integrated tests. Journal of Medical Screening 2009;16(3):112‐8. CENTRAL

Brameld 2008 {published data only}

Brameld KJ, Dickinson JE, O'Leary P, Bower C, Goldblatt J, Hewitt B, et al. First trimester predictors of adverse pregnancy outcomes. Australian & New Zealand Journal of Obstetrics & Gynaecology 2008;48(6):529‐35. CENTRAL

Brizot 2001 {published data only}

Brizot ML, Carvalho MH, Liao AW, Reis NS, Armbruster‐Moraes E, Zugaib M. First‐trimester screening for chromosomal abnormalities by fetal nuchal translucency in a Brazilian population. Ultrasound in Obstetrics & Gynecology 2001;18(6):652‐5. CENTRAL

Centini 2005 {published data only}

Centini G, Rosignoli L, Scarinci R, Faldini E, Morra C, Centini G, et al. Re‐evaluation of risk for Down syndrome by means of the combined test in pregnant women of 35 years or more. Prenatal Diagnosis 2005;25(2):133‐6. CENTRAL

Chasen 2003 {published data only}

Chasen ST, Sharma G, Kalish RB, Chervenak FA. First‐trimester screening for aneuploidy with fetal nuchal translucency in a United States population. Ultrasound in Obstetrics & Gynecology 2003;22(2):149‐51. CENTRAL

Chen 2009 {published data only}

Chen M, Yang X, Leung TY, Sahota DS, Fung TY, Chan LW, et al. Study on the applicability of frontomaxillary facial angle in the first‐trimester trisomy 21 fetuses in Chinese population. Prenatal Diagnosis 2009;29(12):1141‐4. CENTRAL

Christiansen 2005 {published data only}

Christiansen M, Norgaard‐Pedersen B. Inhibin A is a maternal serum marker for Down's syndrome early in the first trimester. Clinical Genetics 2005;68(1):35‐9. CENTRAL

Christiansen 2009 {published data only}

Christiansen M. Placental growth hormone and growth hormone binding protein are first trimester maternal serum markers of Down syndrome. Prenatal Diagnosis 2009;29(13):1249‐55. CENTRAL

Christiansen 2010 {published data only}

Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenatal Diagnosis 2010;30(2):110‐4. CENTRAL

Cicero 2004a {published data only}

Cicero S, Curcio P, Rembouskos G, Sonek J, Nicolaides KH. Maxillary length at 11‐14 weeks of gestation in fetuses with trisomy 21. Ultrasound in Obstetrics & Gynecology 2004;24(1):19‐22. CENTRAL

Cicero 2006 {published data only}

Cicero S, Avgidou K, Rembouskos G, Kagan KO, Nicolaides KH. Nasal bone in first‐trimester screening for trisomy 21.[see comment]. American Journal of Obstetrics and Gynecology 2006;195(1):109‐14. CENTRAL
Cicero S, Bindra R, Rembouskos G, Spencer K, Nicolaides KH. Integrated ultrasound and biochemical screening for trisomy 21 using fetal nuchal translucency, absent fetal nasal bone, free beta‐hCG and PAPP‐A at 11 to 14 weeks. Prenatal Diagnosis 2003;23(4):306‐10. CENTRAL
Cicero S, Bindra R, Rembouskos G, Tripsanas C, Nicolaides KH. Fetal nasal bone length in chromosomally normal and abnormal fetuses at 11‐14 weeks of gestation. Journal of Maternal‐Fetal & Neonatal Medicine 2002;11(6):400‐2. CENTRAL
Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Absence of nasal bone in fetuses with trisomy 21 at 11‐14 weeks of gestation: an observational study. Lancet 2001;358(9294):1665‐7. CENTRAL
Cicero S, Longo D, Rembouskos G, Sacchini C, Nicolaides KH. Absent nasal bone at 11‐14 weeks of gestation and chromosomal defects. Ultrasound in Obstetrics & Gynecology 2003;22(1):31‐5. CENTRAL
Cicero S, Rembouskos G, Vandecruys H, Hogg M, Nicolaides KH. Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11‐14‐week scan. Ultrasound in Obstetrics & Gynecology 2004;23(3):218‐23. CENTRAL
Cicero S, Spencer K, Avgidou K, Faiola S, Nicolaides KH. Maternal serum biochemistry at 11‐13(+6) weeks in relation to the presence or absence of the fetal nasal bone on ultrasonography in chromosomally abnormal fetuses: An updated analysis of integrated ultrasound and biochemical screening. Prenatal Diagnosis 2005;25(11):977‐83. CENTRAL

Cocciolone 2008 FTS {published data only}

Cocciolone R, Brameld K, O'Leary P, Haan E, Muller P, Shand K. Combining first and second trimester markers for Down syndrome screening: think twice. Australian & New ZealandJournal of Obstetrics & Gynaecology 2008;48(5):492‐500. CENTRAL

Cowans 2009 {published data only}

Cowans NJ, Stamatopoulou A, Maiz N, Spencer K, Nicolaides KH. The impact of fetal gender on first trimester nuchal translucency and maternal serum free beta‐hCG and PAPP‐A MoM in normal and trisomy 21 pregnancies. Prenatal Diagnosis 2009;29(6):578‐81. CENTRAL

Cowans 2010 {published data only}

Cowans NJ, Stamatopoulou A, Spencer K. First trimester maternal serum placental growth factor in trisomy 21 pregnancies. Prenatal Diagnosis 2010;30(5):449‐53. CENTRAL

Crossley 2002 {published data only}

Crossley JA, Aitken DA, Cameron AD, McBride E, Connor JM. Combined ultrasound and biochemical screening for Down's syndrome in the first trimester: a Scottish multicentre study. BJOG: international journal of obstetrics and gynaecology 2002;109(6):667‐76. CENTRAL

De Graaf 1999 {published data only}

De Graaf I, Pajkrt E, Bilardo CM, Leschot NJ, Cuckle HS, Van Lith JM. Early pregnancy screening for fetal aneuploidy with serum markers and nuchal translucency. Prenatal Diagnosis 1999;19(5):458‐62. CENTRAL

Ekelund 2008 {published data only}

Ekelund CK, Jorgensen FS, Petersen OB, Sundberg K, Tabor A, Danish Fetal Medicine Research Group. Impact of a new national screening policy for Down's syndrome in Denmark: population based cohort study. BMJ 2008;337:a2547. CENTRAL

Gasiorek‐Wiens 2001 {published data only}

Gasiorek‐Wiens A, Tercanli S, Kozlowski P, Kossakiewicz A, Minderer S, Meyberg H, et al. Screening for trisomy 21 by fetal nuchal translucency and maternal age: a multicenter project in Germany, Austria and Switzerland. Ultrasound in Obstetrics & Gynecology. 2001;18(6):645‐8. CENTRAL

Gasiorek‐Wiens 2010 {published data only}

Gasiorek‐Wiens A, Kotsis S, Staboulidou I, Stumm M, Wegner RD, Soergel P, et al. A mixture model of nuchal translucency thickness in screening for chromosomal defects: validation of a single operator dataset. Prenatal Diagnosis 2010;30(11):1100‐6. CENTRAL

Go 2005 {published data only}

Go AT, Hupkes HW, Lomecky M, Twisk J, Blankenstein JM, van Vugt JM. [Evaluation of a programme for the prenatal screening for Down's syndrome by ultrasonographic nuchal translucency measurement and serum determinations in the first trimester of pregnancy].[see comment]. [Dutch]. Nederlands Tijdschrift voor Geneeskunde 2005;149(50):2795‐9. CENTRAL

Gyselaers 2005 {published data only}

Gyselaers WJ, Vereecken AJ, Van Herck EJ, Straetmans DP, de Jonge ET, Ombelet WU, et al. Population screening for fetal trisomy 21: easy access to screening should be balanced against a uniform ultrasound protocol. Prenatal Diagnosis 2005;25(11):984‐90. CENTRAL

Habayeb 2010 {published data only}

Habayeb O, Goodburn S, Chudleigh T, Brockelsby J, Missfelder‐Lobos H, Hackett G, et al. The NTplus method of screening for Down syndrome: achieving the 2010 targets?. Prenatal Diagnosis 2010;30(5):434‐7. CENTRAL

Hadlow 2005 {published data only}

Hadlow NC, Hewitt BG, Dickinson JE, Jacoby P, Bower C. Community‐based screening for Down's Syndrome in the first trimester using ultrasound and maternal serum biochemistry. BJOG: international journal of obstetrics and gynaecology 2005;112(11):1561‐4. CENTRAL

Hafner 1998 {published data only}

Hafner E, Schuchter K, Liebhart E, Philipp K. Results of routine fetal nuchal translucency measurement at weeks 10‐13 in 4233 unselected pregnant women. Prenatal Diagnosis 1998;18(1):29‐34. CENTRAL

Has 2008 {published data only}

Has R, Kalelioglu I, Yuksel A, Ibrahimoglu L, Ermis H, Yildirim A. Fetal nasal bone assessment in first trimester down syndrome screening. Fetal Diagnosis and Therapy 2008;24(1):61‐6. CENTRAL

Hewitt 1996 {published data only}

Hewitt BG, de Crespigny L, Sampson AJ, Ngu AC, Shekleton P, Robinson HP. Correlation between nuchal thickness and abnormal karyotype in first trimester fetuses. Medical Journal of Australia 1996;165(7):365‐8. CENTRAL

Hormansdorfer 2011 {published data only}

Hormansdorfer C, Corral A, Scharf A, Vaske B, Hillemanns P, Schmidt P. [Comparison of current methods of prenatal screening for down syndrome]. [Spanish]. Revista Espanola de Salud Publica 2010;84(1):43‐51. CENTRAL
Hormansdorfer C, Golatta M, Scharf A, Hillemanns P, Schmidt P. Age‐independent first trimester screening for Down syndrome: analysis of three modified software programs with 6,508 pregnancies. Archives of Gynecology and Obstetrics 2011;283(4):749‐54. CENTRAL
Hormansdorfer C, Scharf A, Golatta M, Vaske B, Corral A, Hillemanns P, et al. Comparison of Prenatal Risk Calculation (PRC) with PIA Fetal Database software in first‐trimester screening for fetal aneuploidy. Ultrasound in Obstetrics & Gynecology 2009;33(2):147‐51. CENTRAL
Hormansdorfer C, Scharf A, Golatta M, Vaske B, Hillemanns P, Schmidt P. Preliminary analysis of the new 'Prenatal Risk Calculation (PRC)' software. Archives of Gynecology and Obstetrics 2009;279(4):511‐5. CENTRAL

Huang 2010 {published data only}

Huang SY, Shaw SW, Cheuh HY, Cheng PJ. Intracardiac echogenic focus and trisomy 21 in a population previously evaluated by first‐trimester combined screening. Acta Obstetricia et Gynecologica Scandinavica 2010;89(8):1017‐23. CENTRAL

Jaques 2007 {published data only}

Jaques AM, Halliday JL, Francis I, Bonacquisto L, Forbes R, Cronin A, et al. Follow up and evaluation of the Victorian first‐trimester combined screening programme for Down syndrome and trisomy 18. BJOG: international journal of obstetrics and gynaecology 2007;114(7):812‐8. CENTRAL

Jaques 2010 FTS {published data only}

Jaques AM, Collins VR, Muggli EE, Amor DJ, Francis I, Sheffield LJ, et al. Uptake of prenatal diagnostic testing and the effectiveness of prenatal screening for Down syndrome. Prenatal Diagnosis 2010;30(6):522‐30. CENTRAL

Kagan 2010 {published data only}

Kagan KO, Cicero S, Staboulidou I, Wright D, Nicolaides KH. Fetal nasal bone in screening for trisomies 21, 18 and 13 and Turner syndrome at 11‐13 weeks of gestation. Ultrasound in Obstetrics & Gynecology 2009;33(3):259‐64. CENTRAL
Kagan KO, Staboulidou I, Cruz J, Wright D, Nicolaides KH. Two‐stage first‐trimester screening for trisomy 21 by ultrasound assessment and biochemical testing. Ultrasound in Obstetrics & Gynecology 2010;36(5):542‐7. CENTRAL
Kagan KO, Valencia C, Livanos P, Wright D, Nicolaides KH. Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11+0 to 13+6 weeks of gestation. Ultrasound in Obstetrics & Gynecology 2009;33(1):18‐22. CENTRAL
Kagan KO, Wright D, Valencia C, Maiz N, Nicolaides KH. Screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency, fetal heart rate, free beta‐hCG and pregnancy‐associated plasma protein‐A. Human Reproduction 2008;23(9):1968‐75. CENTRAL

Kim 2006 {published data only}

Kim MH, Park SH, Cho HJ, Choi JS, Kim JO, Ahn HK, et al. Threshold of nuchal translucency for the detection of chromosomal aberration: comparison of different cut‐offs. Journal of Korean Medical Science 2006;21(1):11‐4. CENTRAL

Koster 2011 {published data only}

Koster MP, Wortelboer EJ, Stoutenbeek P, Visser GH, Schielen PC. Modeling Down syndrome screening performance using first‐trimester serum markers. Ultrasound in Obstetrics & Gynecology 2011;38(2):134‐9. CENTRAL

Kozlowski 2007 GC {published data only}

Kozlowski P, Knippel AJ, Stressig R. Comparing first trimester screening performance: routine care gynaecologists' practices vs. prenatal centre. Ultraschall in der Medizin 2007;28(3):291‐5. CENTRAL

Kozlowski 2007 PC {published data only}

Kozlowski P, Knippel AJ, Stressig R. Comparing first trimester screening performance: routine care gynaecologists' practices vs. prenatal centre. Ultraschall in der Medizin 2007;28(3):291‐5. CENTRAL

Krantz 2000 {published data only}

Krantz DA, Hallahan TW, Orlandi F, Buchanan P, Larsen JW, Macri JN. First‐trimester Down syndrome screening using dried blood biochemistry and nuchal translucency. Obstetrics & Gynecology 2000;96(2):207‐13. CENTRAL

Kublickas 2009 {published data only}

Kublickas M, Crossley J, Aitken D. Screening for Down's syndrome in the first trimester: combined risk calculation, methodology, and validation of a web‐based system. Acta Obstetricia et Gynecologica Scandinavica 2009;88(6):635‐8. CENTRAL

Kuc 2010 {published data only}

Kuc S, Koster MP, Visser GH, Schielen PC. Performance of first‐trimester serum screening for trisomy 21 before and from 11 + 0 weeks of gestational age in The Netherlands. Prenatal Diagnosis 2010;30(9):906‐8. CENTRAL

Lam 2002 {published data only}

Lam YH, Lee CP, Sin SY, Tang R, Wong HS, Wong SF, et al. Comparison and integration of first trimester fetal nuchal translucency and second trimester maternal serum screening for fetal Down syndrome. Prenatal Diagnosis 2002;22(8):730‐5. CENTRAL

Leung 2009 {published data only}

Leung TY, Chan LW, Law LW, Sahota DS, Fung TY, Leung TN, et al. First trimester combined screening for Trisomy 21 in Hong Kong: outcome of the first 10,000 cases. Journal of Maternal‐Fetal & Neonatal Medicine 2009;22(4):300‐4. CENTRAL

MacRae 2008 {published data only}

MacRae R, Ojutiku D, Duke‐MacRae J, Usifo F, Ekong M. Evaluating nuchal translucency scans performed for trisomy screening in a district general hospital between July 1998 and January 2004. Journal of Obstetrics and Gynaecology 2008;28(7):683‐7. CENTRAL

Maiz 2007 {published data only}

Maiz N, Dagklis T, Huggon I, Allan L, Nicolaides KH. The mitral gap at 11 + 0 to 13 + 6 weeks: marker of trisomy 21 or artifact?. Ultrasound in Obstetrics & Gynecology 2007;30(6):813‐8. CENTRAL

Maiz 2009 {published data only}

Maiz N, Valencia C, Kagan KO, Wright D, Nicolaides KH. Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11‐13 weeks of gestation. Ultrasound in Obstetrics & Gynecology 2009;33(5):512‐7. CENTRAL

Malone 2004 {published data only}

Malone FD, Ball RH, Nyberg DA, Comstock CH, Saade G, Berkowitz RL, et al. First‐trimester nasal bone evaluation for aneuploidy in the general population. Obstetrics and Gynecology 2004 Dec;104(6):1222‐8. CENTRAL

Malone 2005 {published data only}

Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First‐trimester or second‐trimester screening, or both, for Down's syndrome.[see comment]. New England Journal of Medicine 2005;353(19):2001‐11. CENTRAL

Marchini 2010 {published data only}

Marchini G, Rosati A, Ribiani E, Romanelli M, Porcaro G, Clerici G. [Nuchal translucency and combined test: what are the implications in clinical practice?]. [Italian]. Minerva Ginecologica 2010;62(3):187‐93. CENTRAL

Marsis 2004 {published data only}

Marsis IO. Screening for down syndrome using nuchal translucency thickness and nasal bone examination at advanced maternal age in Jakarta: A preliminary report. Journal of Medical Ultrasound 2004;12(1):1‐6. CENTRAL

Marsk 2006 {published data only}

Marsk A, Grunewald C, Saltvedt S, Valentin L, Almstrom H. If nuchal translucency screening is combined with first‐trimester serum screening the need for fetal karyotyping decreases. Acta Obstetricia et Gynecologica Scandinavica 2006;85(5):534‐8. CENTRAL

Matias 1998 {published data only}

Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 10‐14 weeks: the role of ductus venosus blood flow. Ultrasound in Obstetrics & Gynecology 1998;12(6):380‐4. CENTRAL

Matias 2001 {published data only}

Matias A, Montenegro N. Ductus venosus blood flow in chromosomally abnormal fetuses at 11 to 14 weeks of gestation. Seminars in Perinatology 2001;25(1):32‐7. CENTRAL

Mavrides 2002 {published data only}

Mavrides E, Sairam S, Hollis B, Thilaganathan B. Screening for aneuploidy in the first trimester by assessment of blood flow in the ductus venosus. BJOG: an international journal of obstetrics and gynaecology 2002;109(9):1015‐9. CENTRAL

Maxwell 2011 FTS {published data only}

Maxwell S, Brameld K, Bower C, Dickinson JE, Goldblatt J, Hadlow N, et al. Socio‐demographic disparities in the uptake of prenatal screening and diagnosis in Western Australia. Australian & New Zealand Journal of Obstetrics & Gynaecology 2011;51(1):9‐16. CENTRAL

Maymon 2005 {published data only}

Maymon R, Sharony R, Grinshpun‐Cohen J, Itzhaky D, Herman A, Reish O. The best marker combination using the integrated screening test approach for detecting various chromosomal aneuploidies. Journal of Perinatal Medicine 2005;33(5):392‐8. CENTRAL

Maymon 2008 {published data only}

Maymon R, Zimerman AL, Weinraub Z, Herman A, Cuckle H. Correlation between nuchal translucency and nuchal skin‐fold measurements in Down syndrome and unaffected fetuses. Ultrasound in Obstetrics & Gynecology 2008;32(4):501‐5. CENTRAL

Merz 2011 {published data only}

Merz E, Thode C, Eiben B, Faber R, Hackeloer BJ, Huesgen G, et al. Individualized correction for maternal weight in calculating the risk of chromosomal abnormalities with first‐trimester screening data. Ultraschall in der Medizin 2011;32(1):33‐9. CENTRAL

Michailidis 2001 {published data only}

Michailidis GD, Spencer K, Economides DL. The use of nuchal translucency measurement and second trimester biochemical markers in screening for Down's syndrome. BJOG: an international journal of obstetrics and gynaecology 2001;108(10):1047‐52. CENTRAL

Molina 2010 high risk {published data only}

Molina Garcia FS, Carrillo Badillo MP, Zaragoza Garcia EA, Fernandez de Santos AG, Montoya Ventoso F. Analysis of secondary ultrasound markers in the first trimester before chorionic villus sampling. Prenatal Diagnosis 2010;30(12):1117‐20. CENTRAL

Molina 2010 screening {published data only}

Molina Garcia FS, Carrillo Badillo MP, Zaragoza Garcia EA, Fernandez de Santos AG, Montoya Ventoso F. Analysis of secondary ultrasound markers in the first trimester before chorionic villus sampling. Prenatal Diagnosis 2010;30(12):1117‐20. CENTRAL

Monni 2005 {published data only}

Monni G, Zoppi MA, Ibba RM, Floris M, Manca F, Axiana C. Nuchal translucency and nasal bone for trisomy 21 screening: single center experience. Croatian Medical Journal 2005;46(5):786‐91. CENTRAL
Zoppi MA, Ibba RM, Axiana C, Floris M, Manca F, Monni G. Absence of fetal nasal bone and aneuploidies at first‐trimester nuchal translucency screening in unselected pregnancies. Prenatal Diagnosis 2003;23(6):496‐500. CENTRAL

Montalvo 2005 {published data only}

Montalvo J, Gómez ML, Ortega MD, Soler P, Herraiz I, Herraiz MA. First trimester combined screening for chromosomal defects: Our results in a population with a high percent of women aged 35 or older. Ultrasound Review of Obstetrics and Gynecology 2005;5(3):178‐85. CENTRAL

Moon 2007 {published data only}

Moon MH, Cho JY, Lee YM, Jung SI, Yang JH, Kim MY, et al. First‐trimester screening for Down syndrome; the role of nasal bone assessment in the Korean population. Prenatal Diagnosis 2007;27(9):830‐4. CENTRAL

Muller 2003 {published data only}

Muller F, Benattar C, Audibert F, Roussel N, Dreux S, Cuckle H. First‐trimester screening for Down syndrome in France combining fetal nuchal translucency measurement and biochemical markers. Prenatal Diagnosis 2003;23(10):833‐6. CENTRAL

Nicolaides 1992 {published data only}

Nicolaides K, Azar G, Byrne D, Mansur C, Marks K. Fetal nuchal translucency: ultrasound screening for chromosomal defects in the first trimester of pregnancy. BMJ 1992;304:867‐9. CENTRAL

Nicolaides 2005 {published data only}

Avgidou K, Papageorghiou A, Bindra R, Spencer K, Nicolaides KH. Prospective first‐trimester screening for trisomy 21 in 30,564 pregnancies. American Journal of Obstetrics and Gynecology 2005;192(6):1761‐7. CENTRAL
Bindra R, Heath V, Liao A, Spencer K, Nicolaides KH. One‐stop clinic for assessment of risk for trisomy 21 at 11‐14 weeks: a prospective study of 15 030 pregnancies. Ultrasound in Obstetrics & Gynecology. 2002;20(3):219‐25. CENTRAL
Nicolaides KH, Spencer K, Avgidou K, Faiola S, Falcon O. Multicenter study of first‐trimester screening for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact of individual risk‐orientated two‐stage first‐trimester screening. Ultrasound in Obstetrics & Gynecology 2005;25(3):221‐6. CENTRAL
Spencer K, Spencer CE, Power M, Dawson C, Nicolaides K. Screening for chromosomal abnormalities in the first trimester using ultrasound and maternal serum biochemistry in a one‐stop clinic: a review of three years prosepctive experience. BJOG: an international journal of obstetrics and gynaecology 2003;110:281‐6. CENTRAL
Spencer K, Spencer CE, Power M, Moakes A, Nicolaides KH. One stop clinic for assessment of risk for fetal anomalies: a report of the first year of prospective screening for chromosomal anomalies in the first trimester. BJOG: an international journal of obstetrics and gynaecology 2000;107(10):1271‐5. CENTRAL

Niemimaa 2001 {published data only}

Niemimaa M, Suonpaa M, Perheentupa A, Seppala M, Heinonen S, Laitinen P, et al. Evaluation of first trimester maternal serum and ultrasound screening for Down's syndrome in Eastern and Northern Finland. European Journal of Human Genetics 2001;9(6):404‐8. CENTRAL

Noble 1995 {published data only}

Brizot ML, Snijders RJM, Butler J, Bersinger NA, Nicolaides KH. Maternal serum hCG and fetal nuchal translucency thickness for the prediction of fetal trisomies in the first trimester of pregnancy. British Journal of Obstetrics and Gynaecology 1995;102:127‐32. CENTRAL
Noble PL, Abraha HD, Snijders RJ, Sherwood R, Nicolaides KH. Screening for fetal trisomy 21 in the first trimester of pregnancy: maternal serum free beta‐hCG and fetal nuchal translucency thickness. Ultrasound in Obstetrics & Gynecology 1995;6(6):390‐5. CENTRAL

O'Callaghan 2000 {published data only}

O'Callaghan SP, Giles WB, Raymond SP, McDougall V, Morris K, Boyd J. First trimester ultrasound with nuchal translucency measurement for Down syndrome risk estimation using software developed by the Fetal Medicine Foundation, United Kingdom‐‐the first 2000 examinations in Newcastle, New South Wales, Australia. Australian & New Zealand Journal of Obstetrics & Gynaecology 2000;40(3):292‐5. CENTRAL

O'Leary 2006 {published data only}

O'Leary P, Breheny N, Dickinson JE, Bower C, Goldblatt J, Hewitt B, et al. First‐trimester combined screening for Down syndrome and other fetal anomalies. Obstetrics & Gynecology 2006;107(4):869‐76. CENTRAL

Okun 2008 FTS {published data only}

Okun N, Summers AM, Hoffman B, Huang T, Winsor E, Chitayat D, et al. Prospective experience with integrated prenatal screening and first trimester combined screening for trisomy 21 in a large Canadian urban center. Prenatal Diagnosis 2008;28(11):987‐92. CENTRAL

Orlandi 1997 {published data only}

Orlandi F, Damiani G, Hallahan TW, Krantz DA, Macri JN. First‐trimester screening for fetal aneuploidy: biochemistry and nuchal translucency. Ultrasound in Obstetrics & Gynecology 1997;10(6):381‐6. CENTRAL

Orlandi 2003 {published data only}

Orlandi F, Bilardo CM, Campogrande M, Krantz D, Hallahan T, Rossi C, et al. Measurement of nasal bone length at 11‐14 weeks of pregnancy and its potential role in Down syndrome risk assessment. Ultrasound in Obstetrics & Gynecology 2003;22(1):36‐9. CENTRAL

Orlandi 2005 {published data only}

Orlandi F, Rossi C, Orlandi E, Jakil MC, Hallahan TW, Macri VJ, et al. First‐trimester screening for trisomy‐21 using a simplified method to assess the presence or absence of the fetal nasal bone. American Journal of Obstetrics and Gynecology 2005;192(4):1107‐11. CENTRAL

Otaño 2002 {published data only}

Otaño L, Aiello H, Igarzábal L, Matayoshi T, Gadow EC. Association between first trimester absence of fetal nasal bone on ultrasound and Down syndrome. Prenatal Diagnosis 2002;22(10):930‐2. CENTRAL

Pajkrt 1998 {published data only}

Pajkrt E, Van Lith JM, Mol BW, Bleker OP, Bilardo CM. Screening for Down's syndrome by fetal nuchal translucency measurement in a general obstetric population. Ultrasound in Obstetrics & Gynecology 1998;12(3):163‐9. CENTRAL

Pajkrt 1998a {published data only}

Pajkrt E, Bilardo CM, Van Lith JM, Mol BW, Hansson K, van Prooijen Knegt AC, et al. Ultrasound screening for fetal trisomies at 10‐14 weeks' gestation. Early Human Development 1996;47 Suppl:S35‐6. CENTRAL
Pajkrt E, Mol BW, Van Lith JM, Bleker OP, Bilardo CM. Screening for Down's syndrome by fetal nuchal translucency measurement in a high‐risk population. Ultrasound in Obstetrics & Gynecology 1998;12(3):156‐62. CENTRAL

Palomaki 2007 FTS {published data only}

Palomaki GE, Neveux LM, Haddow JE, Wyatt P. Hyperglycosylated‐hCG (h‐hCG) and Down syndrome screening in the first and second trimesters of pregnancy. Prenatal Diagnosis 2007;27(9):808‐13. CENTRAL

Perni 2006 {published data only}

Perni SC, Predanic M, Kalish RB, Chervenak FA, Chasen ST. Clinical use of first‐trimester aneuploidy screening in a United States population can replicate data from clinical trials. American Journal of Obstetrics and Gynecology 2006;194(1):127‐30. CENTRAL

Prefumo 2005 {published data only}

Prefumo F, Sethna F, Sairam S, Bhide A, Thilaganathan B. First‐trimester ductus venosus, nasal bones, and Down syndrome in a high‐risk population. Obstetrics & Gynecology 2005;105(6):1348‐54. CENTRAL

Prefumo 2006 {published data only}

Prefumo F, Sairam S, Bhide A, Thilaganathan B. First‐trimester nuchal translucency, nasal bones, and trisomy 21 in selected and unselected populations. American Journal of Obstetrics and Gynecology 2006;3:828‐33. CENTRAL

Ramos‐Corpas 2006 {published data only}

Ramos Corpas D, Santiago JC, Montoya F. Ultrasonographic evaluation of fetal nasal bone in a low‐risk population at 11‐13 + 6 gestational weeks. Prenatal Diagnosis 2006;26(2):112‐7. CENTRAL

Rissanen 2007 {published data only}

Rissanen A, Niemimaa M, Suonpaa M, Ryynanen M, Heinonen S. First trimester Down's syndrome screening shows high detection rate for trisomy 21, but poor performance in structural abnormalities‐‐regional outcome results. Fetal Diagnosis and Therapy 2007;22(1):45‐50. CENTRAL

Rozenberg 2002 {published data only}

Rozenberg P, Malagrida L, Cuckle H, Durand‐Zaleski I, Nisand I, Audibert F, et al. Down's syndrome screening with nuchal translucency at 12(+0)‐14(+0) weeks and maternal serum markers at 14(+1)‐17(+0) weeks: a prospective study. Human Reproduction 2002;17(4):1093‐8. CENTRAL

Rozenberg 2007 {published data only}

Rozenberg P, Bussieres L, Chevret S, Bernard JP, Malagrida L, Cuckle H, et al. [Screening for Down syndrome using first‐trimester combined screening followed by second trimester ultrasound examination in an unselected population]. [French]. Gynecologie, Obstetrique & Fertilite 2007;35(4):303‐11. CENTRAL

Sahota 2010 {published data only}

Sahota DS, Leung TY, Chan LW, Law LW, Fung TY, Chen M, et al. Comparison of first‐trimester contingent screening strategies for Down syndrome. Ultrasound in Obstetrics & Gynecology 2010;35(3):286‐91. CENTRAL

Salomon 2010 {published data only}

Salomon LJ, Chevret S, Bussieres L, Ville Y, Rozenberg P. Down syndrome screening using first‐trimester combined tests and contingent use of femur length at routine anomaly scan. Prenatal Diagnosis 2010;30(8):783‐9. CENTRAL

Santiago 2007 {published data only}

Santiago JC, Ramos‐Corpas D. Delta‐NT and center‐specific ultrasound nuchal translucency medians. Ultrasound in Obstetrics & Gynecology 2007;30(7):934‐40. CENTRAL

Sau 2001 {published data only}

Sau A, Langford K, Auld B, Maxwell D. Screening for trisomy 21: The significance of a positive second trimester serum screen in women screen negative after a nuchal translucency scan. Journal of Obstetrics and Gynaecology 2001;21(2):145‐8. CENTRAL

Schaelike 2009 {published data only}

Schaelike M, Kossakiewicz M, Kossakiewicz A, Schild RL. Examination of a first‐trimester Down syndrome screening concept on a mix of 11,107 high‐ and low‐risk patients at a private center for prenatal medicine in Germany. European Journal of Obstetrics, Gynecology, & Reproductive Biology 2009;144(2):140‐5. CENTRAL

Schielen 2006 {published data only}

Schielen PC, van Leeuwen‐Spruijt M, Belmouden I, Elvers LH, Jonker M, Loeber JG. Multi‐centre first‐trimester screening for Down syndrome in the Netherlands in routine clinical practice. Prenatal Diagnosis 2006;26(8):711‐8. CENTRAL

Schuchter 2001 {published data only}

Schuchter K, Hafner E, Stangl G, Ogris E, Philipp K. Sequential screening for trisomy 21 by nuchal translucency measurement in the first trimester and maternal serum biochemistry in the second trimester in a low‐risk population. Ultrasound in Obstetrics & Gynecology 2001;18(1):23‐5. CENTRAL

Schuchter 2002 {published data only}

Schuchter K, Hafner E, Stangl G, Metzenbauer M, Hofinger D, Philipp K. The first trimester 'combined test' for the detection of Down syndrome pregnancies in 4939 unselected pregnancies. Prenatal Diagnosis 2002;22(3):211‐5. CENTRAL

Schwarzler 1999 {published data only}

Schwarzler P, Carvalho JS, Senat MV, Masroor T, Campbell S, Ville Y. Screening for fetal aneuploidies and fetal cardiac abnormalities by nuchal translucency thickness measurement at 10‐14 weeks of gestation as part of routine antenatal care in an unselected population. British Journal of Obstetrics and Gynaecology 1999;106(10):1029‐34. CENTRAL

Scott 2004 {published data only}

Scott F, Peters H, Bonifacio M, McLennan A, Boogert A, Kesby G, et al. Prospective evaluation of a first trimester screening program for Down syndrome and other chromosomal abnormalities using maternal age, nuchal translucency and biochemistry in an Australian population. Australian & New Zealand Journal of Obstetrics & Gynaecology 2004;44(3):205‐9. CENTRAL

Sepulveda 2007 {published data only}

Sepulveda W, Wong AE, Dezerega V. First‐trimester ultrasonographic screening for trisomy 21 using fetal nuchal translucency and nasal bone. Obstetrics & Gynecology 2007;109(5):1040‐5. CENTRAL

Snijders 1998 {published data only}

Nicolaides KH, Brizot ML, Snijders RJM. Fetal nuchal translucency: Ultrasound screening for fetal trisomy in the first trimester of pregnancy. British Journal of Obstetrics and Gynaecology 1994;101(9):782‐6. CENTRAL
Pandya PP, Snijders RJ, Johnson SP, De Lourdes Brizot M, Nicolaides KH. Screening for fetal trisomies by maternal age and fetal nuchal translucency thickness at 10 to 14 weeks of gestation.[see comment]. British Journal of Obstetrics and Gynaecology 1995;102(12):957‐62. CENTRAL
Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal‐translucency thickness at 10‐14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group.[see comment][comment]. Lancet 1998;352(9125):343‐6. CENTRAL

Sorensen 2011 {published data only}

Sorensen S, Momsen G, Sundberg K, Friis‐Hansen L, Jorgensen FS. First‐trimester risk calculation for trisomy 13, 18, and 21: comparison of the screening efficiency between 2 locally developed programs and commercial software. Clinical Chemistry 2011;57(7):1023‐31. CENTRAL

Spencer 1999 {published data only}

Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening program for trisomy 21 at 10‐14 weeks using fetal nuchal translucency, maternal serum free beta‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A.[see comment]. Ultrasound in Obstetrics & Gynecology 1999;13(4):231‐7. CENTRAL

Spencer 2002 {published data only}

Spencer K, Talbot JA, Abushoufa RA. Maternal serum hyperglycosylated human chorionic gonadotrophin (HhCG) in the first trimester of pregnancies affected by Down syndrome, using a sialic acid‐specific lectin immunoassay.[see comment]. Prenatal Diagnosis 2002;22(8):656‐62. CENTRAL

Spencer 2008 {published data only}

Spencer K, Cowans NJ, Uldbjerg N, Torring N. First‐trimester ADAM12s as early markers of trisomy 21: a promise still unfulfilled?. Prenatal Diagnosis 2008;28(4):338‐42. CENTRAL

Stenhouse 2004 {published data only}

Stenhouse EJ, Crossley JA, Aitken DA, Brogan K, Cameron AD, Connor JM. First‐trimester combined ultrasound and biochemical screening for Down syndrome in routine clinical practice. Prenatal Diagnosis 2004;24(10):774‐80. CENTRAL

Strah 2008 {published data only}

Strah DM, Pohar M, Gersak K. Risk assessment of trisomy 21 by maternal age and fetal nuchal translucency thickness in 7,096 unselected pregnancies in Slovenia. Journal of Perinatal Medicine 2008;36(2):145‐50. CENTRAL

Theodoropoulos 1998 {published data only}

Theodoropoulos P, Lolis D, Papageorgiou C, Papaioannou S, Plachouras N, Makrydimas G. Evaluation of first‐trimester screening by fetal nuchal translucency and maternal age. Prenatal Diagnosis 1998;18(2):133‐7. CENTRAL

Thilaganathan 1999 {published data only}

Thilaganathan B, Sairam S, Michailidis G, Wathen NC. First trimester nuchal translucency: effective routine screening for Down's syndrome. British Journal of Radiology 1999;72(862):946‐8. CENTRAL

Timmerman 2010 {published data only}

Timmerman E, Rengerink KO, Pajkrt E, Opmeer BC, van der Post JA, Bilardo CM. Ductus venosus pulsatility index measurement reduces the false‐positive rate in first‐trimester screening. Ultrasound in Obstetrics & Gynecology 2010;36(6):661‐7. CENTRAL

Torring 2010 {published data only}

Torring N, Ball S, Wright D, Sarkissian G, Guitton M, Darbouret B. First trimester screening for trisomy 21 in gestational week 8‐10 by ADAM12‐S as a maternal serum marker. Reproductive Biology & Endocrinology 2010;8:129. CENTRAL

Vadiveloo 2009 {published data only}

Vadiveloo T, Crossley JA, Aitken DA. First‐trimester contingent screening for Down syndrome can reduce the number of nuchal translucency measurements required. Prenatal Diagnosis 2009;29(1):79‐82. CENTRAL

Valinen 2007 {published data only}

Valinen Y, Rapakko K, Kokkonen H, Laitinen P, Tekay A, Ahola T, et al. Clinical first‐trimester routine screening for Down syndrome in singleton pregnancies in northern Finland. American Journal of Obstetrics and Gynecology 2007;196(3):278‐5. CENTRAL

Viora 2003 {published data only}

Viora E, Masturzo B, Errante G, Sciarrone A, Bastonero S, Campogrande M. Ultrasound evaluation of fetal nasal bone at 11 to 14 weeks in a consecutive series of 1906 fetuses. Prenatal Diagnosis 2003;23(10):784‐7. CENTRAL

Wald 2003 {published data only}

Wald NJ, Rodeck C, Hackshaw AK, Rudnicka A. SURUSS in perspective. Seminars in Perinatology 2005;29(4):225‐35. CENTRAL
Wald NJ, Rodeck C, Hackshaw AK, Rudnicka A. SURUSS in perspective.[see comment]. BJOG: an international journal of obstetrics and gynaecology 2004;111(6):521‐31. CENTRAL
Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Journal of Medical Screening 2003;10(2):56‐104. CENTRAL
Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM, et al. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technology Assessment (Winchester, England) 2003;7(11):1‐77. CENTRAL

Wapner 2003 {published data only}

Wapner R, Thom E, Simpson JL, Pergament E, Silver R, Filkins K, et al. First‐trimester screening for trisomies 21 and 18.[see comment]. New England Journal of Medicine 2003;349(15):1405‐13. CENTRAL
Wapner RJ. First trimester screening: the BUN study. Seminars in Perinatology 2005;29(4):236‐9. CENTRAL

Wax 2009 {published data only}

Wax JR, Pinette MG, Cartin A, Blackstone J. Second‐trimester genetic sonography after first‐trimester combined screening for trisomy 21. Journal of Ultrasound in Medicine 2009;28(3):321‐5. CENTRAL

Wojdemann 2005 {published data only}

Wojdemann KR, Shalmi AC, Christiansen M, Larsen SO, Sundberg K, Brocks V, et al. Improved first‐trimester Down syndrome screening performance by lowering the false‐positive rate: a prospective study of 9941 low‐risk women. Ultrasound in Obstetrics & Gynecology 2005;25(3):227‐33. CENTRAL

Wortelboer 2009 {published data only}

Wortelboer EJ, Koster MP, Stoutenbeek P, Elvers LH, Loeber JG, Visser GH, et al. First‐trimester Down syndrome screening performance in the Dutch population; how to achieve further improvement?. Prenatal Diagnosis 2009;29(6):588‐92. CENTRAL

Wright 2008 {published data only}

Wright D, Kagan KO, Molina FS, Gazzoni A, Nicolaides KH. A mixture model of nuchal translucency thickness in screening for chromosomal defects. Ultrasound in Obstetrics & Gynecology 2008;31(4):376‐83. CENTRAL

Wright 2010 {published data only}

Wright D, Spencer K, Kagan KK, Torring N, Petersen OB, Christou A, et al. First‐trimester combined screening for trisomy 21 at 7‐14 weeks' gestation. Ultrasound in Obstetrics & Gynecology 2010;36(4):404‐11. CENTRAL

Zoppi 2001 {published data only}

Zoppi MA, Ibba RM, Floris M, Monni G. Fetal nuchal translucency screening in 12495 pregnancies in Sardinia. Ultrasound in Obstetrics & Gynecology 2001;18(6):649‐51. CENTRAL
Zoppi MA, Ibba RM, Putzolu M, Floris M, Monni G. Assessment of risk for chromosomal abnormalities at 10‐14 weeks of gestation by nuchal translucency and maternal age in 5210 fetuses at a single centre. Fetal Diagnosis and Therapy 2000;15(3):170‐3. CENTRAL

References to studies excluded from this review

Jump to:

Abbas 1995 {published data only}

Abbas A, Chard T, Nicolaides K. Fetal and maternal hCG concentration in aneuploid pregnancies. British Journal of Obstetrics and Gynaecology 1995;102(7):561‐3. CENTRAL

Abdul‐Hamid 2004 {published data only}

Abdul‐Hamid S, Fox R, Martin I. Maternal serum screening for trisomy 21 in women with a false positive result in last pregnancy. Journal of Obstetrics & Gynaecology 2004;24(4):374‐6. CENTRAL

Abraha 1999 {published data only}

Abraha HD, Noble PL, Nicolaides KH, Sherwood RA. Maternal serum S100 protein in normal and Down syndrome pregnancies. Prenatal Diagnosis 1999;19(4):334‐6. CENTRAL

Abu‐Rustum 2010 {published data only}

Abu‐Rustum RS, Daou L, Abu‐Rustum SE. Role of first‐trimester sonography in the diagnosis of aneuploidy and structural fetal anomalies. Journal of Ultrasound in Medicine 2010;29(10):1445‐52. CENTRAL

Achiron 2010 {published data only}

Achiron R, Gindes L, Gilboa Y, Weissmann‐Brenner A, Berkenstadt M. Umbilical vein anomaly in fetuses with Down syndrome. Ultrasound in Obstetrics & Gynecology 2010;35(3):297‐301. CENTRAL

Adekunle 1999 {published data only}

Adekunle O, Gopee A, el‐Sayed M, Thilaganathan B. Increased first trimester nuchal translucency: pregnancy and infant outcomes after routine screening for Down's syndrome in an unselected antenatal population. British Journal of Radiology 1999;72(857):457‐60. CENTRAL

Agaard‐Tillery 2010 {published data only}

Agaard‐Tillery KM, Flint Porter T, Malone FD, Nyberg DA, Collins J, Comstock CH, et al. Influence of maternal BMI on genetic sonography in the FaSTER trial. Prenatal Diagnosis 2010;30(1):14‐22. CENTRAL

Aitken 1993 {published data only}

Aitken DA, McCaw G, Crossley JA, Berry E, Connor JM, Spencer K, et al. First‐trimester biochemical screening for fetal chromosome abnormalities and neural tube defects. Prenatal Diagnosis 1993;13(8):681‐9. CENTRAL

Aitken 1996 {published data only}

Aitken DA, Syvertsen BS, Crossley JA, Berry E, Connor JM. Heat‐stable and immunoreactive placental alkaline phosphatase in maternal serum from Down's syndrome and trisomy 18 pregnancies.[see comment]. Prenatal Diagnosis 1996;16(11):1051‐4. CENTRAL

Aitken 1996a {published data only}

Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric Inhibin A as a marker for Down's syndrome in early pregnancy. New England Journal of Medicine 1996;334(19):1231‐6. CENTRAL

Ajayi 2011 {published data only}

Ajayi GO. Is there any effect of fetal gender on the markers of first trimester Down's syndrome screening?. Clinical & Experimental Obstetrics & Gynecology 2011;38(2):162‐4. CENTRAL

Akbas 2001 {published data only}

Akbas SH, Ozben T, Alper O, Ugur A, Yucel G, Luleci G. Maternal serum screening for Down's syndrome, open neural tube defects and trisomy 18. Clinical Chemistry & Laboratory Medicine 2001;39(6):487‐90. CENTRAL

Alexioy 2009 {published data only}

Alexioy E, Alexioy E, Trakakis E, Kassanos D, Farmakidis G, Kondylios A, et al. Predictive value of increased nuchal translucency as a screening test for the detection of fetal chromosomal abnormalities. Journal of Maternal‐Fetal & Neonatal Medicine 2009;22(10):857‐62. CENTRAL

Allingham‐Hawkins 2011 {published data only}

Allingham‐Hawkins DJ, Chitayat D, Cirigliano V, Summers A, Tokunaga J, Winsor E, et al. Prospective validation of quantitative fluorescent polymerase chain reaction for rapid detection of common aneuploidies. Genetics in Medicine 2011;13(2):140‐7. CENTRAL

American College 2009 {published data only}

American College of Nurse‐Midwives. [Share with women. Prenatal tests for Down syndrome]. [Spanish]. Journal of Midwifery & Women's Health 2009;54(6):527‐8. CENTRAL

Antona 1998 {published data only}

Antona D, Wallace EM, Shearing C, Ashby JP, Groome NP. Inhibin A and pro‐alphaC Inhibin Ain Down syndrome and normal pregnancies. Prenatal Diagnosis 1998;18(11):1122‐6. CENTRAL

Antsaklis 1999 {published data only}

Antsaklis A, Papantoniou N, Mesogitis S, Michalas S, Aravantinos D. Pregnant women of 35 years of age or more: Maternal serum markers or amniocentesis?. Journal of Obstetrics and Gynaecology 1999;19(3):253‐6. CENTRAL

Anuwutnavin 2009 {published data only}

Anuwutnavin S, Wanitpongpan P, Chanprapaph P. Specificity of fetal tricuspid regurgitation in prediction of Down syndrome in Thai fetuses at 17‐23 weeks of gestation. Journal of the Medical Association of Thailand 2009;92(9):1123‐30. CENTRAL

Ashwood 1987 {published data only}

Ashwood ER, Cheng E, Luthy DA. Maternal serum alpha‐fetoprotein and fetal trisomy‐21 in women 35 years and older: implications for alpha‐fetoprotein screening programs. American Journal of Medical Genetics 1987;26(3):531‐9. CENTRAL

Asrani 2005 {published data only}

Asrani CH. Triple marker. National Journal of Homoeopathy 2005;7(3):174. CENTRAL

Audibert 2001b {published data only}

Audibert F, Dommergues M, Benattar C, Taieb J, Thalabard JC, Frydman R. Screening for Down syndrome using first‐trimester ultrasound and second‐trimester maternal serum markers in a low‐risk population: a prospective longitudinal study. Ultrasound in Obstetrics & Gynecology 2001;18(1):26‐31. CENTRAL

Axt‐Fleidner 2006 {published data only}

Axt Fliedner, Schwarze A, Kreiselmaier P, Krapp M, Smrcek J, Diedrich K. Umbilical cord diameter at 11‐14 weeks of gestation: Relationship to nuchal translucency, ductus venous blood flow and chromosomal defects. Fetal Diagnosis and Therapy 2006;21(4):390‐5. CENTRAL

Azuma 2002 {published data only}

Azuma M, Yamamoto R, Wakui Y, Minobe S, Satomura S, Fujimoto S. A novel method for the detection of Down syndrome with the use of four serum markers. American Journal of Obstetrics and Gynecology 2002;187(1):197‐201. CENTRAL

Baghagho 2004 {published data only}

Baghagho EE, Kharboush IF, El‐Kaffash DM, KarKour TA, Ismail SR, Mortada MM. Maternal serum alpha fetoprotein among pregnant females in Alexandria. Journal of the Egyptian Public Health Association 2004;79(1‐2):59‐81. CENTRAL

Bahado‐Singh 1995 {published data only}

Bahado Singh R, Goldstein I, Uerpairojkit B, Copel JA, Mahoney MJ, Baumgarten A. Normal nuchal thickness in the midtrimester indicates reduced risk of Down syndrome in pregnancies with abnormal triple‐screen results. American Journal of Obstetrics and Gynecology 1995;173(4):1106‐10. CENTRAL

Bahado‐Singh 1996 {published data only}

Bahado‐Singh R, Tan A, Deren O, Hunter D, Copel J, Mahoney MJ. Risk of Down syndrome and any clinically significant chromosome defect in pregnancies with abnormal triple‐screen and normal targeted ultrasonographic results. American Journal of Obstetrics and Gynecology 1996;175(4 I):824‐9. CENTRAL

Bahado‐Singh 1999b {published data only}

Bahado‐Singh R, Oz AU, Flores D, Cermik D, Acuna E, Mahoney MJ, et al. Nuchal thickness, urine ß‐core fragment level, and maternal age for down syndrome screening. American Journal of Obstetrics and Gynecology 1999;180(2 I):491‐5. CENTRAL

Bahado‐Singh 2002 {published data only}

Bahado‐Singh R, Shahabi S, Karaca M, Mahoney MJ, Cole L, Oz UA. The comprehensive midtrimester test: High‐sensitivity Down syndrome test. American Journal of Obstetrics and Gynecology 2002;186(4):803‐8. CENTRAL

Bahado‐Singh 2003 {published data only}

Bahado‐Singh R, Cheng CC, Matta P, Small M, Mahoney MJ. Combined serum and ultrasound screening for detection of fetal aneuploidy. Seminars in Perinatology 2003;27(2):145‐51. CENTRAL

Ball 2007 {published data only}

Ball RH, Caughey AB, Malone FD, Nyberg DA, Comstock CH, Saade GR, et al. First‐ and second‐trimester evaluation of risk for Down syndrome. Obstetrics & Gynecology 2007;110(1):10‐7. CENTRAL

Bar‐Hava 2001 {published data only}

Bar‐Hava I, Yitzhak M, Krissi H, Shohat M, Shalev J, Czitron B, et al. Triple‐test screening in in vitro fertilization pregnancies. Journal of Assisted Reproduction and Genetics 2001;18(4):226‐9. CENTRAL

Barkai 1996 {published data only}

Barkai G, Goldman B, Ries L, Chaki R, Dor J, Cuckle H. Down's syndrome screening marker levels following assisted reproduction. Prenatal Diagnosis 1996;16(12):1111‐4. CENTRAL

Barnabei 1995 {published data only}

Barnabei VM, Krantz DA, Macri JN, Larsen JW. Enhanced twin pregnancy detection within an open neural tube defect and Down syndrome screening protocol using free‐ß hCG and AFP. Prenatal Diagnosis 1995;15(12):1131‐4. CENTRAL

Bartels 1988 {published data only}

Bartels I, Lindemann A. Maternal levels of pregnancy‐specific ß 1‐glycoprotein (SP‐1) are elevated in pregnancies affected by Down's syndrome. Human Genetics 1988;80(1):46‐8. CENTRAL

Bartels 1993 {published data only}

Bartels I, Hoppe‐Sievert B, Bockel B, Herold S, Caesar J. Adjustment formulae for maternal serum alpha‐fetoprotein, human chorionic gonadotropin, and unconjugated oestriol to maternal weight and smoking. Prenatal Diagnosis 1993;13(2):123‐30. CENTRAL

Barth 1991 {published data only}

Barth WH, Frigoletto FD, Krauss CM, MacMillin MD, Stryker JM, Benacerraf BR. Ultrasound detection of fetal aneuploidy in women with elevated maternal serum alpha‐fetoprotein. Obstetrics & Gynecology 1991;77(6):897‐900. CENTRAL

Bas‐Budecka 2007 {published data only}

Bas‐Budecka E, Perenc M, Sieroszewski P. [Abnormal second trimester screening for fetal chromosomal abnormalities as a predictor of adverse pregnancy outcome]. [Polish]. Ginekologia Polska 2007;78(11):877‐80. CENTRAL

Baviera 2004 {published data only}

Baviera G, Carbone C, Corrado F, Mastrantonio P. Placental growth hormone in Down's syndrome screening. Journal of Maternal‐Fetal & Neonatal Medicine 2004;16(4):241‐3. CENTRAL

Bazzett 1998 {published data only}

Bazzett LB, Yaron Y, O'Brien JE, Critchfield G, Kramer RL, Ayoub M, et al. Fetal gender impact on multiple‐marker screening results. American Journal of Medical Genetics 1998;76(5):369‐71. CENTRAL

Beke 2008 {published data only}

Beke A, Barakonyi E, Belics Z, Joo JG, Csaba A, Papp C, et al. Risk of chromosome abnormalities in the presence of bilateral or unilateral choroid plexus cysts. Fetal Diagnosis and Therapy 2008;23(3):185‐91. CENTRAL

Bellver 2005 {published data only}

Bellver J, Lara C, Soares SR, Ramirez A, Pellicer A, Remohi J, et al. First trimester biochemical screening for Down's syndrome in singleton pregnancies conceived by assisted reproduction. Human Reproduction 2005;20(9):2623‐7. CENTRAL

Benn 1995 {published data only}

Benn PA, Horne D, Briganti S, Greenstein RM. Prenatal diagnosis of diverse chromosome abnormalities in a population of women identified by triple‐marker testing as screen positive for Down syndrome. American Journal of Obstetrics and Gynecology 1995;173(2):496‐501. CENTRAL

Benn 1996 {published data only}

Benn PA, Horne D, Craffey A, Collins R, Ramsdell L, Greenstein R. Maternal serum screening for birth defects: results of a Connecticut regional program. Connecticut Medicine 1996;60(6):323‐7. CENTRAL

Benn 1997 {published data only}

Benn PA, Clive JM, Collins R. Medians for second‐trimester maternal serum alpha‐fetoprotein, human chorionic gonadotropin, and unconjugated estriol; differences between races or ethnic groups. Clinical Chemistry 1997;43(2):333‐7. CENTRAL

Benn 1998 {published data only}

Benn PA. Preliminary evidence for associations between second‐trimester human chorionic gonadotropin and unconjugated oestriol levels with pregnancy outcome in Down syndrome pregnancies. Prenatal Diagnosis 1998;18(4):319‐24. CENTRAL

Benn 2001 {published data only}

Benn PA, Ying J, Beazoglou T, Egan JF. Estimates for the sensitivity and false‐positive rates for second trimester serum screening for Down syndrome and trisomy 18 with adjustment for cross‐identification and double‐positive results. Prenatal Diagnosis 2001;21(1):46‐51. CENTRAL

Benn 2002 {published data only}

Benn PA, Kaminsky LM, Ying J, Borgida AF, Egan JF. Combined second‐trimester biochemical and ultrasound screening for Down syndrome. Obstetrics & Gynecology 2002;100(6):1168‐76. CENTRAL

Benn 2003 {published data only}

Benn PA, Fang M, Egan JFX, Horne D, Collins R. Incorporation of inhibin‐A in second‐trimester screening for Down syndrome. Obstetrics and Gynecology 2003;101(3):451‐4. CENTRAL

Benn 2003a {published data only}

Benn P. Improved antenatal screening for Down's syndrome. Lancet 2003;361(9360):794‐5. CENTRAL

Benn 2005 {published data only}

Benn P, Wright D, Cuckle H. Practical strategies in contingent sequential screening for Down syndrome. Prenatal Diagnosis 2005;25(8):645‐52. CENTRAL

Benn 2005a {published data only}

Benn P, Donnenfeld AE. Sequential Down syndrome screening: the importance of first and second trimester test correlations when calculating risk. Journal of Genetic Counseling 2005;14(6):409‐13. CENTRAL

Benn 2007 {published data only}

Benn PA, Campbell WA, Zelop CM, Ingardia C, Egan JF. Stepwise sequential screening for fetal aneuploidy. American Journal of Obstetrics and Gynecology 2007;197(3):312‐5. CENTRAL

Berry 1995 {published data only}

Berry E, Aitken DA, Crossley JA, Macri JN, Connor JM. Analysis of maternal serum alpha‐fetoprotein and free ß human chorionic gonadotrophin in the first trimester: implications for Down's syndrome screening. Prenatal Diagnosis 1995;15(6):555‐65. CENTRAL

Berry 1997 {published data only}

Berry E, Aitken DA, Crossley JA, Macri JN, Connor JM. Screening for Down's syndrome: changes in marker levels and detection rates between first and second trimesters. British Journal of Obstetrics and Gynaecology 1997;104(7):811‐7. CENTRAL

Bersinger 1994 {published data only}

Bersinger NA, Brizot ML, Johnson A, Snijders RJ, Abbott J, Schneider H, et al. First trimester maternal serum pregnancy‐associated plasma protein A and pregnancy‐specific ß 1‐glycoprotein in fetal trisomies. British Journal of Obstetrics and Gynaecology 1994;101(11):970‐4. CENTRAL

Bersinger 2000 {published data only}

Bersinger NA, Xin WZ. Glycosylation of pregnancy‐associated plasma protein a (PAPP‐A) and pregnancy‐specific (ß)(1)‐glycoprotein (SP1): Relevance for fetal down syndrome screening and for placental function studies. Immuno‐Analyse et Biologie Specialisee 2000;15(6):402‐8. CENTRAL

Bersinger 2001 {published data only}

Bersinger NA, Chanson A, Crazzolara S, Hänggi W, Pescia G, Scheier M, et al. Serum levels of placenta protein markers: The relevance of differences between spontaneous and after in vitro fertilization pregnancies for fetal trisomy screening. Journal fur Fertilitat und Reproduktion 2001;11(3):7‐13. CENTRAL

Bersinger 2003 {published data only}

Bersinger NA, Noble P, Nicolaides KH. First‐trimester maternal serum PAPP‐A, SP1 and M‐CSF levels in normal and trisomic twin pregnancies. Prenatal Diagnosis 2003;23(2):157‐62. CENTRAL

Bersinger 2004 {published data only}

Bersinger NA, Wunder D, Vanderlick F, Chanson A, Pescia G, Janecek P, et al. Maternal serum levels of placental proteins after in vitro fertilisation and their implications for prenatal screening. Prenatal Diagnosis 2004;24(6):471‐7. CENTRAL

Bersinger 2005 {published data only}

Bersinger NA, Vanderlick F, Birkhäuser MH, Janecek P, Wunder D. First trimester serum concentrations of placental proteins in singleton and multiple IVF pregnancies: Implications for Down syndrome screening. Immuno‐Analyse et Biologie Specialisee 2005;20(1):21‐7. CENTRAL

Bestwick 2008 {published data only}

Bestwick JP, Huttly WJ, Wald NJ. First trimester Down's syndrome screening marker values and cigarette smoking: new data and a meta‐analysis on free beta human chorionic gonadotophin, pregnancy‐associated plasma protein‐A and nuchal translucency. Journal of Medical Screening 2008;15(4):204‐6. CENTRAL

Biggio 2004 {published data only}

Biggio Jr, Morris TC, Owen J, Stringer JSA. An outcomes analysis of five prenatal screening strategies for trisomy 21 in women younger than 35 years. American Journal of Obstetrics and Gynecology 2004;190(3):721‐9. CENTRAL

Bilardo 2011 {published data only}

Bilardo CM, Timmerman E, De Medina PG, Clur SA. Low‐resistance hepatic artery flow in first‐trimester fetuses: an ominous sign. Ultrasound in Obstetrics & Gynecology 2011;37(4):438‐43. CENTRAL

Bindra 2002 {published data only}

Bindra R, Heath V, Nicolaides KH. Screening for chromosomal defects by fetal nuchal translucency at 11 to 14 weeks. Clinical Obstetrics and Gynecology 2002;45(3):661‐70. CENTRAL

Blundell 1999 {published data only}

Blundell G, Ashby JP, Martin C, Shearing CH, Langdale‐Brown B, Keeling J, et al. Clinical follow‐up of high mid‐trimester maternal serum intact human chorionic gonadotrophin concentrations in singleton pregnancies. Prenatal Diagnosis 1999;19(3):219‐23. CENTRAL

Boormans 2010 {published data only}

Boormans EM, Birnie E, Oepkes D, Galjaard RJ, Schuring‐Blom GH, van Lith JM, et al. Comparison of multiplex ligation‐dependent probe amplification and karyotyping in prenatal diagnosis. Obstetrics & Gynecology 2010;115(2 Pt 1):297‐303. CENTRAL

Boots 1989 {published data only}

Boots LR, Davis RO, Foster JM, Goldenberg RL. Maternal serum alpha‐fetoprotein prenatal screening for Down syndrome. Alabama Medicine 1989;59(1):25‐7. CENTRAL

Bornstein 2009 {published data only}

Bornstein E, Lenchner E, Donnenfeld A, Barnhard Y, Seubert D, Divon MY. Advanced maternal age as a sole indication for genetic amniocentesis; risk‐benefit analysis based on a large database reflecting the current common practice. Journal of Perinatal Medicine 2009;37(2):99‐102. CENTRAL

Bornstein 2009a {published data only}

Bornstein E, Lenchner E, Donnenfeld A, Kapp S, Keeler SM, Divon MY. Comparison of modes of ascertainment for mosaic vs complete trisomy 21. American Journal of Obstetrics and Gynecology 2009;200(4):440‐5. CENTRAL

Bornstein 2010 {published data only}

Bornstein E, Lenchner E, Donnenfeld A, Jodicke C, Keeler SM, Kapp S, et al. Complete trisomy 21 vs translocation Down syndrome: a comparison of modes of ascertainment. American Journal of Obstetrics and Gynecology 2010;203(4):391‐5. CENTRAL

Borowski 2007 {published data only}

Borowski D, Czuba B, Cnota W, Hincz P, Czekierdowski A, Gajewska J, et al. [Evaluation of pregnancy‐associated plasma protein A (PAPP‐A) and free beta subunit of human chorionic gonadotropin (beta hCG) levels and sonographic assesement of fetal nuchal translucency (NT) in singleton pregnancies between 11 and 14 weeks of gestation‐‐Polish multi‐centre research]. [Polish]. Ginekologia Polska 2007;78(5):384‐7. CENTRAL

Borrell 2007 {published data only}

Borrell A, Mercade I, Casals E, Borobio V, Seres A, Soler A, et al. Combining fetal nuchal fold thickness with second‐trimester biochemistry to screen for trisomy 21. Ultrasound in Obstetrics & Gynecology 2007;30(7):941‐5. CENTRAL

Borrell 2009a {published data only}

Borrell A, Borobio V, Bestwick JP, Wald NJ. Ductus venosus pulsatility index as an antenatal screening marker for Down's syndrome: use with the Combined and Integrated tests. Journal of Medical Screening 2009;16(3):112‐8. CENTRAL

Borruto 2002 {published data only}

Borruto F, Comparetto C, Acanfora L, Bertini G, Rubaltelli FF. Role of ultrasound evaluation of nuchal translucency in prenatal diagnosis. Clinical & Experimental Obstetrics & Gynecology 2002;29(4):235‐41. CENTRAL

Bottalico 2009 {published data only}

Bottalico JN, Chen X, Tartaglia M, Rosario B, Yarabothu D, Nelson L. Second‐trimester genetic sonogram for detection of fetal chromosomal abnormalities in a community‐based antenatal testing unit. Ultrasound in Obstetrics & Gynecology 2009;33(2):161‐8. CENTRAL

Boue 1990 {published data only}

Boue A, Muller F. Screening for Down's syndrome with maternal serum human chorionic gonadotropin at midtrimester. Current Opinion in Pediatrics 1990;2(6):1157‐60. CENTRAL

Bradley 1994 {published data only}

Bradley LA, Horwitz JA, Dowman AC, Ponting NR, Peterson LM. Triple marker screening for fetal Down syndrome. International Pediatrics 1994;9(3):168‐74. CENTRAL

Braithwaite 1996 {published data only}

Braithwaite JM, Economides DL. Nuchal translucency and screening for Down's syndrome. Contemporary Reviews in Obstetrics and Gynaecology 1996;8(2):75‐81. CENTRAL

Brambati 1995 {published data only}

Brambati B, Cislaghi C, Tului L, Alberti E, Amidani M, Colombo U, et al. First‐trimester Down's syndrome screening using nuchal translucency: a prospective study in women undergoing chorionic villus sampling. Ultrasound in Obstetrics & Gynecology 1995;5(1):9‐14. CENTRAL

Brambati 1996 {published data only}

Brambati B, Tului L, Alberti E. Sonography in the first trimester screening of trisomy 21 and other fetal aneuploidies. Early Pregnancy 1996;2(3):155‐67. CENTRAL

Brizot 1995 {published data only}

Brizot ML, Bersinger NA, Xydias G, Snijders RJ, Nicolaides KH. Maternal serum Schwangerschafts protein‐1 (SP1) and fetal chromosomal abnormalities at 10‐13 weeks' gestation. Early Human Development 1995;43(1):31‐6. CENTRAL

Brizot 1995a {published data only}

Brizot ML, Kuhn P, Bersinger NA, Snijders RJ, Nicolaides KH. First trimester maternal serum alpha‐fetoprotein in fetal trisomies. British Journal of Obstetrics and Gynaecology 1995;102(1):31‐4. CENTRAL

Brizzi 1989a {published data only}

Brizzi L, Cariati E, Periti E, Nannini R, Torricelli F, Cappelli G, et al. Evaluation of maternal serum alpha‐fetoprotein and ultrasound examination to screen fetal chromosomal abnormalities. Journal of Nuclear Medicine & Allied Sciences 1989;33(3 Suppl):85‐8. CENTRAL

Brock 1990 {published data only}

Brock DJ, Barron L, Holloway S, Liston WA, Hillier SG, Seppala M. First‐trimester maternal serum biochemical indicators in Down syndrome. Prenatal Diagnosis 1990;10(4):245‐51. CENTRAL

Calda 2010 {published data only}

Calda P, Sipek A, Gregor V. Gradual implementation of first trimester screening in a population with a prior screening strategy: population based cohort study. Acta Obstetricia et Gynecologica Scandinavica 2010;89(8):1029‐33. CENTRAL

Campogrande 2001 {published data only}

Campogrande M, Viora E, Errante G, Bastonero S, Sciarrone A, Grassi Pirrone P, et al. Correlations between first and second trimester markers for Down's syndrome screening. Journal of Medical Screening 2001;8(3):163‐4. CENTRAL

Canick 1988 {published data only}

Canick JA, Knight GJ, Palomaki GE, Haddow JE, Cuckle HS, Wald NJ. Low second trimester maternal serum unconjugated oestriol in pregnancies with Down's syndrome. British Journal of Obstetrics and Gynaecology 1988;95(4):330‐3. CENTRAL

Canick 1995b {published data only}

Canick JA, Kellner LH, Saller Jr, Palomaki GE, Walker RP, Osathanondh R. Second‐trimester levels of maternal urinary gonadotropin peptide in down syndrome pregnancy. Prenatal Diagnosis 1995;15(8):739‐44. CENTRAL

Canini 2002 {published data only}

Canini S, Prefumo F, Famularo L, Venturini PL, Palazzese V, De Biasio P. Comparison of first trimester, second trimester and integrated Down's syndrome screening results in unaffected pregnancies. Clinical Chemistry & Laboratory Medicine 2002;40(6):600‐3. CENTRAL

Cans 1998 {published data only}

Cans C, Amblard F, Devillard F, Pison H, Jalbert P, Jouk PS. Population screening for aneuploidy using maternal age and ultrasound. Prenatal Diagnosis 1998;18(7):683‐92. CENTRAL

Carreras 1991 {published data only}

Carreras de Paz JJ, Silva Mendoza JM, Violante Diaz M, Cerrillo Hinojosa M, Ahued Ahued JR. [Proposed normal values for alpha fetoprotein in maternal serum for the detection of neural tube closure defects and Down syndrome. Preliminary study]. [Spanish]. Ginecologia y Obstetricia de Mexico 1991;59:261‐4. CENTRAL

Caughey 2007 {published data only}

Caughey AB, Musci TJ, Belluomini J, Main D, Otto C, Goldberg J. Nuchal translucency screening: how do women actually utilize the results?. Prenatal Diagnosis 2007;27(2):119‐23. CENTRAL

Cebesoy 2008 {published data only}

Cebesoy FB. Combining 'nasal bone length assessment as MoM' with other markers for trisomy 21 screening: could it be more effective?. American Journal of Obstetrics and Gynecology 2008;198(6):726‐7. CENTRAL

Chelli 2008 {published data only}

Chelli D, Dimassi K, Chaabouni M, Ben Saad M, Mssaed H, Bchir F, et al. [Prenatal diagnosis of trisomy 21: the Tunisian experience]. [French]. Sante 2008;18(4):199‐203. CENTRAL

Chen 1999 {published data only}

Chen FM. Integrated screening for Down's syndrome. Journal of Family Practice 1999;48(11):846‐7. CENTRAL

Chen 2002 {published data only}

Chen M, Lam YH, Tang MH, Lee CP, Sin SY, Tang R, et al. The effect of ethnic origin on nuchal translucency at 10‐14 weeks of gestation. Prenatal Diagnosis 2002;22(7):576‐8. CENTRAL

Chen 2004 {published data only}

Chen M, Lam YH, Lee CP, Tang MHY. Ultrasound screening of fetal structural abnormalities at 12 to 14 weeks in Hong Kong. Prenatal Diagnosis 2004;24(2):92‐7. CENTRAL

Chen 2005 {published data only}

Chen CP, Lin CJ, Wang W. Impact of second‐trimester maternal serum screening on prenatal diagnosis of Down syndrome and the use of amniocentesis in the Taiwanese population. Taiwanese Journal of Obstetrics and Gynecology 2005;44(1):31‐5. CENTRAL

Chen 2008 {published data only}

Chen M, Lee CP, Lam YH, Tang RY, Chan BC, Wong SF, et al. Comparison of nuchal and detailed morphology ultrasound examinations in early pregnancy for fetal structural abnormality screening: a randomized controlled trial. Ultrasound in Obstetrics & Gynecology 2008;31(2):136‐46. CENTRAL

Cheng 1993 {published data only}

Cheng EY, Luthy DA, Zebelman AM, Williams MA, Lieppman RE, Hickok DE. A prospective evaluation of a second‐trimester screening test for fetal Down syndrome using maternal serum alpha‐fetoprotein, hCG, and unconjugated estriol. Obstetrics & Gynecology 1993;81(1):72‐7. CENTRAL

Cheng 1999 {published data only}

Cheng PJ, Liu CM, Chang SD, Lin YT, Soong YK. Elevated second‐trimester maternal serum hCG in women undergoing haemodialysis. Prenatal Diagnosis 1999;19(10):955‐8. CENTRAL

Cheng 2004 {published data only}

Cheng CC, Bahado‐Singh RO, Chen SC, Tsai MS. Pregnancy outcomes with increased nuchal translucency after routine Down syndrome screening. International Journal of Gynaecology & Obstetrics 2004;84(1):5‐9. CENTRAL

Cheng 2004a {published data only}

Cheng PJ, Chu DC, Chueh HY, See LC, Chang HC, Weng DR. Elevated maternal midtrimester serum free ß‐human chorionic gonadotropin levels in vegetarian pregnancies that cause increased false‐positive Down syndrome screening results. American Journal of Obstetrics and Gynecology. 2004;190(2):442‐7. CENTRAL

Chitayat 2002 {published data only}

Chitayat D, Farrell SA, Huang T, Meier C, Wyatt PR, Summers AM. Double‐positive maternal serum screening results for down syndrome and open neural tube defects: An indicator for fetal structural or chromosomal abnormalities and adverse obstetric outcomes. American Journal of Obstetrics and Gynecology 2002;187(3):758‐63. CENTRAL

Chiu 2011 {published data only}

Chiu RW, Akolekar R, Zheng YW, Leung TY, Sun H, Chan KC, et al. Non‐invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ 2011;342:c7401. CENTRAL

Cho 2009 {published data only}

Cho EH, Park BY, Kang YS, Lee EH. Validation of QF‐PCR in a Korean population. Prenatal Diagnosis 2009;29(3):213‐6. CENTRAL

Chou 2009 {published data only}

Chou CY, Hsieh FJ, Cheong ML, Lee FK, She BQ, Tsai MS. First‐trimester Down syndrome screening in women younger than 35 years old and cost‐effectiveness analysis in Taiwan population. Journal of Evaluation in Clinical Practice 2009;15(5):789‐96. CENTRAL

Christiansen 2002 {published data only}

Christiansen M, Hogdall EV, Larsen SO, Hogdall C. The variation of risk estimates through pregnancy in second trimester maternal serum screening for Down syndrome. Prenatal Diagnosis 2002;22(5):385‐7. CENTRAL

Christiansen 2007a {published data only}

Christiansen M, Spencer K, Laigaard J, Cowans NJ, Larsen SO, Wewer UM. ADAM 12 as a second‐trimester maternal serum marker in screening for Down syndrome. Prenatal Diagnosis 2007;27(7):611‐5. CENTRAL

Christiansen 2008 {published data only}

Christiansen M, Sorensen TL, Larsen SO, Norgaard‐Pedersen B. First‐trimester maternal serum progesterone in aneuploid pregnancies. Prenatal Diagnosis 2008;28(4):319‐22. CENTRAL

Chung 2000 {published data only}

Chung BL, Kim YP, Nam MH. The application of three‐dimensional ultrasound to nuchal translucency thickness measurement at 10‐14 weeks of gestation. Prenatal and Neonatal Medicine 2000;5(1):17‐21. CENTRAL

CNGOF 1996 {published data only}

Anon. Blood screening of Down's syndrome (Trisomy 21) and reimbursement of karyotype for women under 38. Revue Francaise de Gynecologie et d'Obstetrique 1996;91(11):575‐7. CENTRAL

Cocciolone 2008 {published data only}

Cocciolone R, Brameld K, O'Leary P, Haan E, Muller P, Shand K. Combining first and second trimester markers for Down syndrome screening: think twice. Australian & New Zealand Journal of Obstetrics & Gynaecology 2008;48(5):492‐500. CENTRAL

Cole 1996 {published data only}

Cole L, Isozaki T, Palomaki G, Canick J, Iles R, Kellner L, et al. Detection of ß‐core fragment in second trimester Down's syndrome pregnancies. [Review]. Early Human Development 1996;47(Suppl):S47‐8. CENTRAL

Comas 2001 {published data only}

Comas C, Antolín E, Torrents M, Muñoz A, Figueras F, Echevarría M, et al. Early screening for chromosomal abnormalities: New strategies combining biochemical, sonographic and doppler parameters. Prenatal and Neonatal Medicine 2001;6(2):95‐102. CENTRAL

Comas 2002 {published data only}

Comas C, Torrents M, Munoz A, Antolin E, Figueras F, Echevarria M. Measurement of nuchal translucency as a single strategy in trisomy 21 screening: should we use any other marker?. Obstetrics & Gynecology 2002;100(4):648‐54. CENTRAL

Comas 2002a {published data only}

Comas C, Carrera JM. Early sonographic screening for chromosomal abnormalities. Ultrasound Review of Obstetrics and Gynecology 2002;2(2):88‐91. CENTRAL

Comstock 2006 {published data only}

Comstock CH, Malone FD, Ball RH, Nyberg DA, Saade GR, Berkowitz RL, et al. Is there a nuchal translucency millimeter measurement above which there is no added benefit from first trimester serum screening?. American Journal of Obstetrics and Gynecology. 2006;195(3):843‐7. CENTRAL

Conde‐Agudelo 1998 {published data only}

Conde‐Agudelo A, Kafury‐Goeta AC. Triple‐marker test as screening for down syndrome: A meta‐analysis. Obstetrical and Gynecological Survey 1998;53(6):369‐76. CENTRAL

Cowans 2011 {published data only}

Cowans NJ, Stamatopoulou A, Torring N, Spencer K. Early first‐trimester maternal serum placental growth factor in trisomy 21 pregnancies. Ultrasound in Obstetrics & Gynecology 2011;37(5):515‐9. CENTRAL

Crossley 1991 {published data only}

Crossley JA, Aitken DA, Connor JM. Prenatal screening for chromosome abnormalities using maternal serum chorionic gonadotrophin, alpha‐fetoprotein, and age. Prenatal Diagnosis 1991;11(2):83‐101. CENTRAL

Crossley 1993 {published data only}

Crossley JA, Aitken DA, Connor JM. Second‐trimester unconjugated oestriol levels in maternal serum from chromosomally abnormal pregnancies using an optimized assay.[see comment]. Prenatal Diagnosis 1993;13(4):271‐80. CENTRAL

Crossley 1996 {published data only}

Crossley JA, Berry E, Aitken DA, Connor JM. Insulin‐dependent diabetes mellitus and prenatal screening results: current experience from a regional screening programme. Prenatal Diagnosis 1996;16(11):1039‐42. CENTRAL

Crossley 2002a {published data only}

Crossley JA, Aitken DA, Waugh SM, Kelly T, Connor JM. Maternal smoking: age distribution, levels of alpha‐fetoprotein and human chorionic gonadotrophin, and effect on detection of Down syndrome pregnancies in second‐trimester screening. Prenatal Diagnosis 2002;22(3):247‐55. CENTRAL

Cuckle 1984 {published data only}

Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha‐fetoprotein measurement: a screening test for Down syndrome. Lancet 1984;i(8383):926‐9. CENTRAL

Cuckle 1987 {published data only}

Cuckle HS, Wald NJ, Thompson SG. Estimating a woman's risk of having a pregnancy associated with Down's syndrome using her age and serum alpha‐fetoprotein level. British Journal of Obstetrics and Gynaecology 1987;94(5):387‐402. CENTRAL

Cuckle 1987a {published data only}

Cuckle HS, Nanchahal K, Wald NJ. Maternal serum alpha‐fetoprotein and ethnic origin. British Journal of Obstetrics and Gynaecology 1987;94(11):1111‐2. CENTRAL

Cuckle 1990 {published data only}

Cuckle HS, Wald NJ, Densem JW, Royston P, Knight GJ, Haddow JE, et al. The effect of smoking in pregnancy on maternal serum alpha‐fetoprotein, unconjugated oestriol, human chorionic gonadotrophin, progesterone and dehydroepiandrosterone sulphate levels. British Journal of Obstetrics and Gynaecology 1990;97(3):272‐4. CENTRAL

Cuckle 1996 {published data only}

Cuckle HS, Holding S, Jones R, Groome NP, Wallace EM. Combining Inhibin A with existing second‐trimester markers in maternal serum screening for Down's syndrome. Prenatal Diagnosis 1996;16(12):1095‐100. CENTRAL

Cuckle 1999b {published data only}

Cuckle HS, Sehmi I, Jones R, Evans LW. Maternal serum activin A and follistatin levels in pregnancies with Down syndrome. Prenatal Diagnosis 1999;19(6):513‐6. CENTRAL

Cuckle 1999c {published data only}

Cuckle HS, Van Lith JM. Appropriate biochemical parameters in first‐trimester screening for Down syndrome.[see comment]. Prenatal Diagnosis 1999;19(6):505‐12. CENTRAL

Cullen 1990 {published data only}

Cullen MT, Gabrielli S, Green JJ, Rizzo N, Mahoney MJ, Salafia C, et al. Diagnosis and significance of cystic hygroma in the first trimester. Prenatal Diagnosis 1990;10(10):643‐51. CENTRAL

Cusick 2004 {published data only}

Cusick W, Provenzano J, Sullivan CA, Gallousis FM, Rodis JF. Fetal nasal bone length in euploid and aneuploid fetuses between 11 and 20 weeks' gestation: a prospective study. Journal of Ultrasound in Medicine 2004;23(10):1327‐33. CENTRAL

Cusick 2007 {published data only}

Cusick W, Shevell T, Duchan LS, Lupinacci CA, Terranova J, Crombleholme WR. Likelihood ratios for fetal trisomy 21 based on nasal bone length in the second trimester: how best to define hypoplasia?. Ultrasound in Obstetrics & Gynecology 2007;30(3):271‐4. CENTRAL

Dancoine 2001 {published data only}

Dancoine F, Couplet G, Mainardi A, Sukno F, Jaumain P, Nowak E, et al. Antenatal screening for Dawn's syndrome with serum markers: Influence of maternal weight, smoking habits and diabetes. Immuno‐Analyse et Biologie Specialisee 2001;16(6):381‐9. CENTRAL

Dane 2008 {published data only}

Dane B, Dane C, Cetin A, Kiray M, Sivri D, Yayla M. Pregnancy outcome in fetuses with increased nuchal translucency. Journal of Perinatology 2008;28(6):400‐4. CENTRAL

De Biasio, 1999 {published data only}

De Biasio P, Siccardi M, Volpe G, Famularo L, Santi F, Canini S. First‐trimester screening for down syndrome using nuchal translucency measurement with free ß‐hCG and PAPP‐A between 10 and 13 weeks of pregnancy ‐ The combined test. Prenatal Diagnosis 1999;19(4):360‐3. CENTRAL

De Biasio, 2001 {published data only}

De BiasioP, Ferrero S, Prefumo F, Canini S, Marchini P, Bruzzone I, et al. Down's syndrome: First trimester approach. Italian Journal of Gynaecology and Obstetrics 2001;13(1):22‐6. CENTRAL

De Biasio 2000 {published data only}

De Biasio P, Canini S, Prefumo F, Famularo L, Venturini PL. Extent of correlation between first and second trimester markers for Down's syndrome screening. Journal of Medical Screening 2000;7(3):163. CENTRAL

De Graaf 1991 {published data only}

De Graaf I, Cuckle HS, Pajkrt E, Leschot NJ, Bleker OP, Van Lith JM. Co‐variables in first trimester maternal serum screening. Prenatal Diagnosis 1991;20(3):186‐9. CENTRAL

Del Carmen Saucedo 2009 {published data only}

Del Carmen Saucedo M, DeVigan C, Vodovar V, Lelong N, Goffinet F, Khoshnood B. Measurement of nuchal translucency and the prenatal diagnosis of Down syndrome. Obstetrics & Gynecology 2009;114(4):829‐38. CENTRAL

DeVore 2001 {published data only}

DeVore GR, Romero R. Combined use of genetic sonography and maternal serum triple‐marker screening: an effective method for increasing the detection of trisomy 21 in women younger than 35 years.[see comment]. Journal of Ultrasound in Medicine 2001;20(6):645‐54. CENTRAL

Dhaifalah 2007 {published data only}

Dhaifalah I, Mickova I, Vrbicka D, Santavy J, Curtisova V. [Advanced maternal age as an indication for invasive prenatal diagnostics?]. [Czech]. Ceska Gynekologie 2007;72(3):181‐4. CENTRAL

Dhaifalah 2007a {published data only}

Dhaifalah I, Mickova I, Santavy J, Vrbicka D, Zapletalova D, Curtisova V. [Efficiency of measuring nasal bone as an ultrasound marker of Down syndrome in 11th to 13th+6 week of pregnancy]. [Czech]. Ceska Gynekologie 2007;72(1):19‐23. CENTRAL

Dhallan 2007 {published data only}

Dhallan R, Guo X, Emche S, Damewood M, Bayliss P, Cronin M, et al. A non‐invasive test for prenatal diagnosis based on fetal DNA present in maternal blood: a preliminary study. Lancet 2007;369(9560):474‐81. CENTRAL

Dickerson 1994 {published data only}

Dickerson VM. Multiple marker screening. Western Journal of Medicine 1994;161(2):161. CENTRAL

Dimaio 1987 {published data only}

Dimaio MS, Baumgarten A, Greenstein RM, Saal HM, Mahoney MJ. Screening for fetal Down's syndrome in pregnancy by measuring maternal serum alpha‐fetoprotein levels. New England Journal of Medicine 1987;317(6):342‐6. CENTRAL

Doran 1986 {published data only}

Doran TA, Cadesky K, Wong PY, Mastrogiacomo C, Capello T. Maternal serum alpha‐fetoprotein and fetal autosomal trisomies. American Journal of Obstetrics and Gynecology 1986;154(2):277‐81. CENTRAL

Dreux 2008 {published data only}

Dreux S, Olivier C, Dupont JM, Leporrier N, Study Group, Oury JF, et al. Maternal serum screening in cases of mosaic and translocation Down syndrome. Prenatal Diagnosis 2008;28(8):699‐703. CENTRAL

Drugan 1996 {published data only}

Drugan A, Reichler A, Bronstein M, Johnson MP, Sokol RJ, Evans MI. Abnormal biochemical serum screening versus 2nd‐trimester ultrasound‐detected minor anomalies as predictors of aneuploidy in low‐risk women. Fetal Diagnosis and Therapy 1996;11(5):301‐5. CENTRAL

Drugan 1996a {published data only}

Drugan A, O'Brien JE, Dvorin E, Krivchenia EL, Johnson MP, Sokol RJ, et al. Multiple marker screening in multifetal gestations: failure to predict adverse pregnancy outcomes. Fetal Diagnosis and Therapy 1996;11(1):16‐9. CENTRAL

Drysdale 2002 {published data only}

Drysdale K, Ridley D, Walker K, Higgins B, Dean T. First‐trimester pregnancy scanning as a screening tool for high‐risk and abnormal pregnancies in a district general hospital setting. Journal of Obstetrics and Gynaecology 2002;22(2):159‐65. CENTRAL

Dugoff 2008 {published data only}

Dugoff L, Cuckle HS, Hobbins JC, Malone FD, Belfort MA, Nyberg DA, et al. Prediction of patient‐specific risk for fetal loss using maternal characteristics and first‐ and second‐trimester maternal serum Down syndrome markers. American Journal of Obstetrics and Gynecology 2008;199(3):290‐6. CENTRAL

Ebell 1999 {published data only}

Ebell M. Is the integrated test better for screening for Down's syndrome than the traditional triple test?. Evidence‐Based Practice 1999;2(11):4‐5. CENTRAL

Economides 1998 {published data only}

Economides DL, Whitlow BJ, Kadir R, Lazanakis M, Verdin SM. First trimester sonographic detection of chromosomal abnormalities in an unselected population. British Journal of Obstetrics and Gynaecology 1998;105(1):58‐62. CENTRAL

Erickson 2004 {published data only}

Erickson JA, Ashwood ER, Gin CA. Evaluation of a dimeric inhibin‐A assay for assessing fetal Down syndrome: establishment, comparison, and monitoring of median concentrations for normal pregnancies. Archives of Pathology & Laboratory Medicine 2004;128(4):415‐20. CENTRAL

Evans 1996 {published data only}

Evans MI, O'Brien JE, Dvorin E, Krivchenia EL, Drugan A, Hume RF, et al. Similarity of insulin‐dependent diabetics' and non‐insulin‐dependent diabetics' levels of ß‐hCG and unconjugated estriol with controls: no need to adjust as with alpha‐fetoprotein. Journal of the Society for Gynecologic Investigation 1996;3(1):20‐2. CENTRAL

Evans 2007 {published data only}

Evans MI, Galen RS. Comparison of serum markers in first‐trimester down syndrome screening. Obstetrics & Gynecology 2007;109(3):782. CENTRAL

Falcon 2005 {published data only}

Falcon O, Cavoretto P, Peralta CF, Csapo B, Nicolaides KH. Fetal head‐to‐trunk volume ratio in chromosomally abnormal fetuses at 11 + 0 to 13 + 6 weeks of gestation. Ultrasound in Obstetrics & Gynecology 2005;26(7):755‐60. CENTRAL

Falcon 2006 {published data only}

Falcon O, Faiola S, Huggon I, Allan L, Nicolaides KH. Fetal tricuspid regurgitation at the 11 + 0 to 13 + 6‐week scan: association with chromosomal defects and reproducibility of the method. Ultrasound in Obstetrics & Gynecology 2006;27(6):609‐12. CENTRAL

Ford 1998 {published data only}

Ford C, Moore AJ, Jordan PA, Bartlett WA, Wyldes MP, Jones AF, et al. The value of screening for Down's syndrome in a socioeconomically deprived area with a high ethnic population.[see comment]. British Journal of Obstetrics and Gynaecology 1998;105(8):855‐9. CENTRAL

Frishman 1997 {published data only}

Frishman GN, Canick JA, Hogan JW, Hackett RJ, Kellner LH, Saller DN. Serum triple‐marker screening in in vitro fertilization and naturally conceived pregnancies. Obstetrics & Gynecology 1997;90(1):98‐101. CENTRAL

Fukada 2000 {published data only}

Fukada Y, Takizawa M, Amemiya A, Yoda H, Kohno K, Hoshi K. Detection of aneuploidy with fetal nuchal translucency and maternal serum markers in Japanese women. Acta Obstetricia et Gynecologica Scandinavica 2000;79(12):1124‐5. CENTRAL

Gaudry 2009 {published data only}

Gaudry P, Lebbar A, Choiset A, Girard S, Lewin F, Tsatsaris V, et al. Is rapid aneuploidy screening used alone acceptable in prenatal diagnosis? An evaluation of the possible role of ultrasound examination. Fetal Diagnosis and Therapy 2009;25(2):285‐90. CENTRAL

Gebb 2009 {published data only}

Gebb J, Dar P. Should the first‐trimester aneuploidy screen be maternal age adjusted? Screening by absolute risk versus risk adjusted to maternal age. Prenatal Diagnosis 2009;29(3):245‐7. CENTRAL

Geerts 2008 {published data only}

Geerts L. Prenatal diagnosis of chromosomal abnormalities in a resource‐poor setting. International Journal of Gynaecology & Obstetrics 2008;103(1):16‐21. CENTRAL

Geipel 2010 {published data only}

Geipel A, Willruth A, Vieten J, Gembruch U, Berg C. Nuchal fold thickness, nasal bone absence or hypoplasia, ductus venosus reversed flow and tricuspid valve regurgitation in screening for trisomies 21, 18 and 13 in the early second trimester. Ultrasound in Obstetrics & Gynecology 2010;35(5):535‐9. CENTRAL

Gekas 2009 {published data only}

Gekas J, Gagne G, Bujold E, Douillard D, Forest JC, Reinharz D, et al. Comparison of different strategies in prenatal screening for Down's syndrome: cost effectiveness analysis of computer simulation. BMJ 2009;338:b138. CENTRAL

Gekas 2011 {published data only}

Gekas J, van den Berg DG, Durand A, Vallee M, Wildschut HI, Bujold E, et al. Rapid testing versus karyotyping in Down's syndrome screening: cost‐effectiveness and detection of clinically significant chromosome abnormalities. European Journal of Human Genetics 2011;19(1):3‐9. CENTRAL

Gekas 2011a {published data only}

Gekas J, Durand A, Bujold E, Vallee M, Forest JC, Rousseau F, et al. Cost‐effectiveness and accuracy of prenatal Down syndrome screening strategies: should the combined test continue to be widely used?. American Journal of Obstetrics and Gynecology 2011;204(2):175‐8. CENTRAL

Gerovassili 2007 {published data only}

Gerovassili A, Garner C, Nicolaides KH, Thein SL, Rees DC. Free fetal DNA in maternal circulation: a potential prognostic marker for chromosomal abnormalities?. Prenatal Diagnosis 2007;27(2):104‐10. CENTRAL

Ghidini 1998 {published data only}

Ghidini A, Spong CY, Grier RE, Walker CN, Pezzullo JC. Is maternal serum triple screening a better predictor of Down syndrome in female than in male fetuses?. Prenatal Diagnosis 1998;18(2):123‐6. CENTRAL

Goetzinger 2010 {published data only}

Goetzinger KR, Dicke JM, Gray DL, Stamilio DM, Macones GA, Odibo AO. The effect of fetal gender in predicting Down syndrome using long bone ultrasonographic measurements. Prenatal Diagnosis 2010;30(10):950‐5. CENTRAL

Goldie 1995 {published data only}

Goldie DJ, Astley JP, Beaman JM, Bickley DA, Gunneberg A, Jones SR. Screening for Down's syndrome: the first two years experience in Bristol. Journal of Medical Screening 1995;2(4):207‐10. CENTRAL

Gollo 2008 {published data only}

Gollo CA, Murta CG, Bussamra LC, Santana RM, Moron AF. [Predictive value for fetal outcome of Doppler velocimetry of the ductus venosus between the 11th and the 14th gestation week]. [Portuguese]. Revista Brasileira de Ginecologia e Obstetricia 2008;30(1):5‐11. CENTRAL

Gonçalves 2004 {published data only}

Gonçalves LF, Espinoza J, Lee W, Schoen ML, Devers P, Mazor M, et al. Phenotypic characteristics of absent and hypoplastic nasal bones in fetuses with down syndrome: Description by 3‐dimensional ultrasonography and clinical significance. Journal of Ultrasound in Medicine 2004;23(12):1619‐27. CENTRAL

Goodburn 1994 {published data only}

Goodburn SF, Yates JR, Raggatt PR, Carr C, Ferguson‐Smith ME, Kershaw AJ, et al. Second‐trimester maternal serum screening using alpha‐fetoprotein, human chorionic gonadotrophin, and unconjugated oestriol: experience of a regional programme. Prenatal Diagnosis 1994;14(5):391‐402. CENTRAL

Gorduza 2007 {published data only}

Gorduza EV, Onofriescu M, Martiniuc V, Grigore M, Mihalceanu E, Iliev G. [FISH technique in aneuplodies prenatal diagnosis]. [Romanian]. Revista Medico‐Chirurgicala a Societatii de Medici Si Naturalisti Din Iasi 2007;111(4):990‐5. CENTRAL

Grace 2010 {published data only}

Grace D, Eggers P, Glantz JC, Ozcan T. Mitral valve‐tricuspid valve distance as a sonographic marker of trisomy 21. Ultrasound in Obstetrics & Gynecology 2010;35(2):172‐7. CENTRAL

Grati 2010 {published data only}

Grati FR, Barlocco A, Grimi B, Milani S, Frascoli G, Di Meco AM, et al. Chromosome abnormalities investigated by non‐invasive prenatal testing account for approximately 50% of fetal unbalances associated with relevant clinical phenotypes. American Journal of Medical Genetics 2010;Part A. 152A(6):1434‐42. CENTRAL

Gray 2009 {published data only}

Gray DL, Dicke JM, Dickerson R, McCourt C, Odibo AO. Reevaluating humeral length for the detection of fetal trisomy 21. Journal of Ultrasound in Medicine 2009;28(10):1325‐30. CENTRAL

Gregor 2007 {published data only}

Gregor V, Sipek A, Horacek J. [Birth defects in the Czech Republic‐‐the prenatal diagnostic]. [Czech]. Ceska Gynekologie 2007;72(4):262‐8. CENTRAL

Gregor 2009 {published data only}

Gregor V, Sipek A, Sipek AJ, Horacek J, Langhammer P, Petrzilkova L, et al. [Prenatal diagnostics of chromosomal aberrations Czech Republic: 1994‐2007]. [Czech]. Ceska Gynekologie 2009;74(1):44‐54. CENTRAL

Grether 2009 {published data only}

Grether Gonzalez P, Aguinaga Rios M, Colegio Mexicano de Especialistas en Ginecologia. [Prenatal genetic screening: biochemical markers of the first and second quarter]. [Spanish]. Ginecologia y Obstetricia de Mexico 2009;77(2):S27‐46. CENTRAL

Grozdea 2002 {published data only}

Grozdea J, De La Farge F, Bourrouillou G, Calot M, Cambus JP, Valdiguie P. Maternal serum urea resistant alkaline phosphatase in Down syndrome pregnancy. Early Human Development 2002;67(1‐2):55‐9. CENTRAL

Guo 2010 {published data only}

Guo Q, Zhou Y, Wang X, Li Q. Simultaneous detection of trisomies 13, 18, and 21 with multiplex ligation‐dependent probe amplification‐based real‐time PCR. Clinical Chemistry 2010;56(9):1451‐9. CENTRAL

Gyselaers 2004 {published data only}

Gyselaers WJ, Vereecken AJ, Van Herck EJ, Straetmans DP, Martens GE, de Jonge ET, et al. Screening for trisomy 21 in Flanders: a 10 years review of 40.490 pregnancies screened by maternal serum. European Journal of Obstetrics, Gynecology, & Reproductive Biology 2004;115(2):185‐9. CENTRAL

Gyselaers 2004a {published data only}

Gyselaers WJA, Vereecken AJ, Van Herck E, Straetmans DPL, De Jonge ET, Ombelet WUA, et al. Single‐step maternal serum screening for trisomy 21 in the era of combined or integrated screening. Gynecologic and Obstetric Investigation 2004;58(4):221‐4. CENTRAL

Gyselaers 2006 {published data only}

Gyselaers WJ, Vereecken AJ, Van Herck EJ, Straetmans DP, Ombelet WU, Nijhuis JG. Nuchal translucency thickness measurements for fetal aneuploidy screening: Log NT‐MoM or Delta‐NT, performer‐specific medians and ultrasound training. Journal of Medical Screening 2006;13(1):4‐7. CENTRAL

Gyselaers 2006a {published data only}

Gyselaers WJ, Roets ER, Van Holsbeke CD, Vereecken AJ, Van Herck EJ, Straetmans DP, et al. Sequential triage in the first trimester may enhance advanced ultrasound scanning in population screening for trisomy 21. Ultrasound in Obstetrics & Gynecology 2006;27(6):622‐7. CENTRAL

Hackshaw 1995 {published data only}

Hackshaw AK, Densem J, Wald NJ. Repeat maternal serum testing for Down's syndrome screening using multiple markers with special reference to free alpha and free ß‐hCG. Prenatal Diagnosis 1995;15(12):1125‐30. CENTRAL

Hackshaw 2001 {published data only}

Hackshaw AK, Wald NJ. Repeat testing in antenatal screening for Down syndrome using dimeric inhibin‐A in combination with other maternal serum markers. Prenatal Diagnosis 2001;21(1):58‐61. CENTRAL

Haddow 1992 {published data only}

Haddow JE, Palomaki GE, Knight GJ, Williams J, Pulkkinen A, Canick J, et al. Prenatal screening for Down's syndrome with use of maternal serum markers. New England Journal of Medicine 1992;327(9):588‐93. CENTRAL

Hadzsiev 2007 {published data only}

Hadzsiev K, Czako M, Veszpremi B, Kosztolanyi G. [Rapid diagnosis of fetal chromosomal abnormalities by fluorescence in situ hybridization]. [Hungarian]. Orvosi Hetilap 2007;148(30):1401‐4. CENTRAL

Hafner 1995 {published data only}

Hafner E, Schuchter K, Philipp K. Screening for chromosomal abnormalities in an unselected population by fetal nuchal translucency. Ultrasound in Obstetrics & Gynecology 1995;6(5):330‐3. CENTRAL

Hallahan 1998 {published data only}

Hallahan TW, Krantz DA, Tului L, Alberti E, Buchanan PD, Orlandi F, et al. Comparison of urinary free ß (hCG) and ß‐core (hCG) in prenatal screening for chromosomal abnormalities. Prenatal Diagnosis 1998;18(9):893‐900. CENTRAL

Han 2008 {published data only}

Han SH, An JW, Jeong GY, Yoon HR, Lee A, Yang YH, et al. Clinical and cytogenetic findings on 31,615 mid‐trimester amniocenteses. Korean Journal of Laboratory Medicine 2008;28(5):378‐85. CENTRAL

Harper 2010 {published data only}

Harper LM, Gray D, Dicke J, Stamilio DM, Macones GA, Odibo AO. Do race‐specific definitions of short long bones improve the detection of down syndrome on second‐trimester genetic sonograms?. Journal of Ultrasound in Medicine 2010;29(2):231‐5. CENTRAL

Harrison 2006 {published data only}

Harrison G, Goldie D. Second‐trimester Down's syndrome serum screening: double, triple or quadruple marker testing?. Annals of Clinical Biochemistry 2006;43(1):67‐72. CENTRAL

Harry 2006 {published data only}

Harry WG, Reed KL. Nuchal translucency and first‐trimester screening. Journal of the Society for Gynecologic Investigation 2006;13(3):153‐4. CENTRAL

Hayashi 1995 {published data only}

Hayashi M, Kozu H. Maternal urinary ß‐core fragment of hCG/creatinine ratios and fetal chromosomal abnormalities in the second trimester of pregnancy. Prenatal Diagnosis 1995;15(1):11‐6. CENTRAL

Hayashi 1996 {published data only}

Hayashi M, Kozu H, Takei H. Maternal urinary free ß‐subunit of human chorionic gonadotrophin: Creatinine ratios and fetal chromosomal abnormalities in the second trimester of pregnancy. British Journal of Obstetrics and Gynaecology 1996;103(6):577‐80. CENTRAL

Heikkila 1997 {published data only}

Heikkila A, Ryynanen M, Kirkinen P, Saarikoski S. Results and views of women in population‐wide pregnancy screening for trisomy 21 in east Finland. Fetal Diagnosis and Therapy 1997;12(2):93‐6. CENTRAL

Heinig 2007 {published data only}

Heinig J, Steinhard J, Schmitz R, Nofer JR, Kiesel L, Klockenbusch W. Maternal serum free beta‐hCG and PAPP‐A in patients with habitual abortion‐influence on first‐trimester screening for chromosomal abnormalities. Prenatal Diagnosis 2007;27(9):814‐6. CENTRAL

Heinonen 1996 {published data only}

Heinonen S, Ryynanen M, Kirkinen P, Hippelainen M, Saarikoski S. Effect of in vitro fertilization on human chorionic gonadotropin serum concentrations and Down's syndrome screening. Fertility and Sterility 1996;66(3):398‐403. CENTRAL

Herman 2000 {published data only}

Herman A, Weinraub Z, Dreazen E, Arieli S, Rozansky S, Bukovsky I, et al. Combined first trimester nuchal translucency and second trimester biochemical screening tests among normal pregnancies. Prenatal Diagnosis 2000;20(10):781‐4. CENTRAL

Herman 2003 {published data only}

Herman Ae, Dreazen E, Tovbin Y, Reish O, Bukovsky I, Maymon R. Correlation and overlapping between nuchal translucency and triple test among Down syndrome‐affected pregnancies. Fetal Diagnosis and Therapy 2003;18(3):196‐200. CENTRAL

Herrou 1992 {published data only}

Herrou M, Leporrier N, Leymarie P. Screening for fetal Down syndrome with maternal serum hCG and oestriol: a prospective study. Prenatal Diagnosis 1992;12(11):887‐92. CENTRAL

Hershey 1985 {published data only}

Hershey DW, Crandall BF, Schroth PS. Maternal serum alpha‐fetoprotein screening of fetal trisomies. American Journal of Obstetrics and Gynecology 1985;153(2):224‐5. CENTRAL

Hershey 1986 {published data only}

Hershey DW, Crandall BF, Perdue S. Combining maternal age and serum alpha‐fetoprotein to predict the risk of Down syndrome. Obstetrics & Gynecology 1986;68(2):177‐80. CENTRAL

Hewitt 1993 {published data only}

Hewitt B. Nuchal translucency in the first trimester. Australian & New Zealand Journal of Obstetrics & Gynaecology 1993;33(4):389‐91. CENTRAL

Hills 2010 {published data only}

Hills A, Donaghue C, Waters J, Waters K, Sullivan C, Kulkarni A, et al. QF‐PCR as a stand‐alone test for prenatal samples: the first 2 years' experience in the London region. Prenatal Diagnosis 2010;30(6):509‐17. CENTRAL

Ho 2010 {published data only}

Ho SS, Choolani MA. FlashFISH: "same day" prenatal diagnosis of common chromosomal aneuploidies. Methods in Molecular Biology 2010;659:261‐8. CENTRAL

Hogdall 1992 {published data only}

Hogdall CK, Hogdall EV, Arends J, Norgaard‐Pedersen B, Smidt‐Jensen S, Larsen SO. CA‐125 as a maternal serum marker for Down's syndrome in the first and second trimesters. Prenatal Diagnosis 1992;12(3):223‐7. CENTRAL

Hong Kong Practitioner {published data only}

Anon. Screening tests in pregnancy. Hong Kong Practitioner 2001;23(10):461‐5. CENTRAL

Hoogendoorn 2008 {published data only}

Hoogendoorn M, Evers SM, Schielen PC, van Genugten ML, de Wit GA, Ament AJ. Costs and effects of prenatal screening methods for Down syndrome and neural tube defects. Community Genetics 2008;11(6):359‐67. CENTRAL

Howe 2000 {published data only}

Howe DT, Gornall R, Wellesley D, Boyle T, Barber J. Six year survey of screening for Down's syndrome by maternal age and mid‐trimester ultrasound scans.[see comment]. BMJ 2000;320(7235):606‐10. CENTRAL

Hsiao 1991 {published data only}

Hsiao KJ, Lee SY, Chuang HC. [Antenatal screening of maternal alpha‐fetoprotein with dried‐blood spot samples on filter paper]. [Chinese]. Journal of the Formosan Medical Association 1991;90(6):598‐604. CENTRAL

Hsieh 1999 {published data only}

Hsieh TT, Hsu JJ, Lo LM, Liou JD, Soong YK. Maternal urine alpha‐fetoprotein concentrations between 14 and 21 weeks of gestation. Changgeng Yi Xue Za Zhi 1999;22(2):234‐9. CENTRAL

Hsu 1997a {published data only}

Hsu JJ, Hsieh TT, Soong YK. Influence of maternal age and weight on second‐trimester serum alpha‐fetoprotein, total and free ß human chorionic gonadotropin levels. Changgeng Yi Xue Za Zhi. 1997;20(3):181‐6. CENTRAL

Hsu 1998a {published data only}

Hsu JJ, Hsieh TT, Hung TH, Chiang CH. Midtrimester maternal serum free ß‐human chorionic gonadotropin levels: normal reference values for Taiwanese women. Changgeng Yi Xue Za Zhi 1998;21(3):277‐82. CENTRAL

Hsu 1999b {published data only}

Hsu JJ, Hsieh TT, Hung TH, Chen KC, Soong YK. Urine free ß‐human chorionic gonadotropin levels between 14 and 21 weeks of gestation in Taiwanese pregnancies. Changgeng Yi Xue Za Zhi 1999;22(1):11‐6. CENTRAL

Hu 2007 {published data only}

Hu YL, Birth Defect Intervention Group of Jiangsu Province. [Serum screening of fetal chromosome abnormality during second pregnancy trimester: results of 26,803 pregnant women in Jiangsu Province]. [Chinese]. Chung‐Hua i Hsueh Tsa Chih [Chinese Medical Journal] 2007;87(35):2476‐80. CENTRAL

Huang 2003 {published data only}

Huang T, Summers AM, Wyatt PR, Meier C, Cote GB. Maternal serum marker medians in Aboriginal Canadian women. Prenatal Diagnosis 2003;23(2):98‐100. CENTRAL

Huang 2007 {published data only}

Huang T, Boucher K, Summers AM. Second trimester prenatal screening for Down syndrome: the associations between the levels of serum markers in successive pregnancies. Prenatal Diagnosis 2007;27(12):1138‐42. CENTRAL

Huang 2007a {published data only}

Huang T, Wang FL, Boucher K, O'Donnell A, Rashid S, Summers AM. Racial differences in first trimester nuchal translucency. Prenatal Diagnosis 2007;27(12):1174‐6. CENTRAL

Huggon 2004 {published data only}

Huggon IC, Turan O, Allan LD. Doppler assessment of cardiac function at 11‐14 weeks' gestation in fetuses with normal and increased nuchal translucency. Ultrasound in Obstetrics & Gynecology 2004;24(4):390‐8. CENTRAL

Hui 2003 {published data only}

Hui PW, Tang MH, Lam YH, NG EH, Yeung WS, Ho PC. Maternal serum hCG and alpha‐fetoprotein levels in pregnancies conceived after IVF or ICSI with fresh and frozen‐thawed embryos. Human Reproduction 2003;18(3):572‐5. CENTRAL

Hui 2005 {published data only}

Hui PW, Tang MH, Lam YH, Yeung WS, NG EH, Ho PC. Nuchal translucency in pregnancies conceived after assisted reproduction technology. Ultrasound in Obstetrics & Gynecology 2005;25(3):234‐8. CENTRAL

Hultén 2004 {published data only}

Hultén M. Combined serum and nuchal translucency screening in the first trimester achieves 85% to 90% detection rate for Down and Edward syndromes. Evidence‐Based Healthcare 2004;8(2):82‐4. CENTRAL

Hung 2003 {published data only}

Hung JH, Fu CY, Yuan CC, Chen CL, Yang ML, Shu LP, et al. Nuchal translucence incorporated into a one‐stage multifactorial screening model for Down syndrome prediction at second‐trimester pregnancy. Ultrasound in Medicine & Biology 2003;29(12):1667‐74. CENTRAL

Hung 2008 {published data only}

Hung JH, Fu CY, Chen CY, Chao KC, Hung J. Fetal nasal bone length and Down syndrome during the second trimester in a Chinese population. Journal of Obstetrics & Gynaecology Research 2008;34(4):518‐23. CENTRAL

Hurley 1993 {published data only}

Hurley PA, Ward RH, Teisner B, Iles RK, Lucas M, Grudzinskas JG. Serum PAPP‐A measurements in first‐trimester screening for Down syndrome. Prenatal Diagnosis 1993;13(10):903‐8. CENTRAL

Huttly 2004 {published data only}

Huttly W, Rudnicka A, Wald NJ. Second‐trimester prenatal screening markers for Down syndrome in women with insulin‐dependent diabetes mellitus. Prenatal Diagnosis 2004;24(10):804‐7. CENTRAL

Hwa 2004 {published data only}

Hwa HL, Yen MF, Hsieh FJ, Ko TM, Chen TH. Evaluation of second trimester maternal serum screening for Down's Syndrome using the Spiegelhalter‐Knill‐Jones (S‐KJ) approach. Journal of Perinatal Medicine 2004;32(5):407‐12. CENTRAL

Iles 1996 {published data only}

Iles RK. Urinary analysis for Down's syndrome: Is the measurement of urinary ß‐core the future of biochemical screening for Down's syndrome. Early Human Development 1996;47(Suppl):S41‐S45. CENTRAL

Ind 1994 {published data only}

Ind TEJ, Iles RK, Cuckle HS, Chard T. Second trimester maternal serum placental alkaline phosphatase concentrations in Down's syndrome. Journal of Obstetrics and Gynaecology 1994;14(5):305‐8. CENTRAL

Ivorra‐Deleuze 2010 {published data only}

Ivorra‐Deleuze D, Bretelle F, Heinemann M, Levy A, Toga C, Philip N, et al. [Combined screening for Down syndrome in Marseille multidisciplinary prenatal centers]. [French]. Gynecologie, Obstetrique & Fertilite 2010;38(12):786‐8. CENTRAL

Jakobsen 2011 {published data only}

Jakobsen TR, Sogaard K, Tabor A. Implications of a first trimester Down syndrome screening program on timing of malformation detection. Acta Obstetricia et Gynecologica Scandinavica 2011;90(7):728‐36. CENTRAL

Jean‐Pierre 2005 {published data only}

Jean Pierre. Fetal nasal bone: Review of first trimester findings. Ultrasound Review of Obstetrics and Gynecology 2005;5(2):102‐4. CENTRAL

Johnson 1991 {published data only}

Johnson A, Cowchock FS, Darby M, Wapner R, Jackson LG. First‐trimester maternal serum alpha‐fetoprotein and chorionic gonadotropin in aneuploid pregnancies. Prenatal Diagnosis 1991;11(7):443‐50. CENTRAL

Johnson 1993 {published data only}

Johnson MP, Johnson A, Holzgreve W, Isada NB, Wapner RJ, Treadwell MC, et al. First‐trimester simple hygroma: cause and outcome. American Journal of Obstetrics and Gynecology 1993;168(1):156‐61. CENTRAL

Jorgensen 1999 {published data only}

Jorgensen FS, Valentin L, Salvesen KA, Jorgensen C, Jensen FR, Bang J, et al. MULTISCAN‐‐a Scandinavian multicenter second trimester obstetric ultrasound and serum screening study. Acta Obstetricia et Gynecologica Scandinavica 1999;78(6):501‐10. CENTRAL

Jorgez 2007 {published data only}

Jorgez CJ, Dang DD, Wapner R, Farina A, Simpson JL, Bischoff FZ. Elevated levels of total (maternal and fetal) beta‐globin DNA in maternal blood from first trimester pregnancies with trisomy 21. Human Reproduction 2007;22(8):2267‐72. CENTRAL

Josefsson 1998 {published data only}

Josefsson A, Molander E, Selbing A. Nuchal translucency as a screening test for chromosomal abnormalities in a routine first trimester ultrasound examination. Acta Obstetricia et Gynecologica Scandinavica 1998;77(5):497‐9. CENTRAL

Jou 2001 {published data only}

Jou HJ, Shih JC, Wu SC, Li TC, Tzeng CY, Hsieh FJ. First‐trimester Down's syndrome screening by fetal nuchal translucency measurement in Taiwan. Journal of the Formosan Medical Association 2001;100(4):257‐61. CENTRAL

Jung 2007 {published data only}

Jung E, Won HS, Lee PR, Kim A. Ultrasonographic measurement of fetal nasal bone length in the second trimester in Korean population. Prenatal Diagnosis 2007;27(2):154‐7. CENTRAL

Jun‐Tao 2003 {published data only}

Liu JT, Hao N, Sun NH, Wang FY, Xu YH, Gai MY, et al. [Screening by maternal serum markers for Down's syndrome]. [Chinese]. Chung‐Kuo i Hsueh Ko Hsueh Yuan Hsueh Pao Acta Academiae Medicinae Sinicae 2003;25(2):156‐9. CENTRAL

Kagan 2006 {published data only}

Kagan KO, Avgidou K, Molina FS, Gajewska K, Nicolaides KH. Relation between increased fetal nuchal translucency thickness and chromosomal defects.[see comment]. Obstetrics & Gynecology 2006;107(1):6‐10. CENTRAL

Kagan 2007 {published data only}

Kagan KO, Frisova V, Nicolaides KH, Spencer K. Dose dependency between cigarette consumption and reduced maternal serum PAPP‐A levels at 11‐13+6 weeks of gestation. Prenatal Diagnosis 2007;27(9):849‐53. CENTRAL

Kagan 2008 {published data only}

Kagan KO, Anderson JM, Anwandter G, Neksasova K, Nicolaides KH. Screening for triploidy by the risk algorithms for trisomies 21, 18 and 13 at 11 weeks to 13 weeks and 6 days of gestation. Prenatal Diagnosis 2008;28(13):1209‐13. CENTRAL

Kalelioglu 2007 {published data only}

Kalelioglu IH. Humerus length measurement in Down syndrome screening. Clinical & Experimental Obstetrics & Gynecology 2007;34(2):93‐5. CENTRAL

Kautzmann 1995 {published data only}

Kautzmann M, Solis RL, Luberta A, Fernandez JL, Navarro J, Rodriguez L, et al. Study of the efficiency of screening for trisomy 21 based on maternal serum levels of AFP and hCG combined with maternal age. Journal of Clinical Ligand Assay 1995;18(3):181‐5. CENTRAL

Kazerouni 2009 {published data only}

Kazerouni NN, Currier B, Malm L, Riggle S, Hodgkinson C, Smith S, et al. Triple‐marker prenatal screening program for chromosomal defects. Obstetrics & Gynecology 2009;114(1):50‐8. CENTRAL

Keith 1992 {published data only}

Keith D. Maternal serum screening for neural tube defects and Down syndrome. Clinical Laboratory Science 1992;5(5):274‐6. CENTRAL

Kelekci 2004 {published data only}

Kelekci S, Yazicioglu HF, Oguz S, Inan I, Yilmaz B, Sonmez S. Nasal bone measurement during the 1st trimester: is it useful?. Gynecologic & Obstetric Investigation 2004;58(2):91‐5. CENTRAL

Kellner 1995 {published data only}

Kellner LH, Weiner Z, Weiss RR, Neuer M, Martin GM, Mueenuddin M, et al. Triple marker (alpha‐fetoprotein, unconjugated estriol, human chorionic gonadotropin) versus alpha‐fetoprotein plus free‐ß subunit in second‐trimester maternal serum screening for fetal Down syndrome: a prospective comparison study.[see comment]. American Journal of Obstetrics and Gynecology 1995;173(4):1306‐9. CENTRAL

Kellner 1995a {published data only}

Kellner LH, Weiss RR, Weiner Z, Neuer M, Martin GM, Schulman H, et al. The advantages of using triple‐marker screening for chromosomal abnormalities. American Journal of Obstetrics and Gynecology 1995;172(3):831‐6. CENTRAL

Kellner 1997 {published data only}

Kellner LH, Canick JA, Palomaki GE, Neveux LM, Saller DN, Walker RP, et al. Levels of urinary ß‐core fragment, total oestriol, and the ratio of the two in second‐trimester screening for Down syndrome. Prenatal Diagnosis 1997;17(12):1135‐41. CENTRAL

Kirkegaard 2008 {published data only}

Kirkegaard I, Petersen OB, Uldbjerg N, Torring N. Improved performance of first‐trimester combined screening for trisomy 21 with the double test taken before a gestational age of 10 weeks. Prenatal Diagnosis 2008;28(9):839‐44. CENTRAL

Kjaergaard 2008 {published data only}

Kjaergaard S, Hahnemann JM, Skibsted L, Jensen LN, Sperling L, Zingenberg H, et al. [Prenatal diagnosis of chromosome aberrations after implementation of screening for Down's syndrome]. [Danish]. Ugeskrift for Laeger 2008;170(14):1152‐6. CENTRAL

Knight 1990 {published data only}

Knight GJ, Palomaki GE. Maternal serum alpha fetoprotein screening for fetal down syndrome. Journal of Clinical Immunoassay 1990;13(1):23‐9. CENTRAL

Knight 2001 {published data only}

Knight GJ, Palomaki GE, Neveux LM, Haddow JE, Lambert‐Messerlian GM. Clinical validation of a new dimeric inhibin‐A assay suitable for second trimester Down's syndrome screening. Journal of Medical Screening 2001;8(1):2‐7. CENTRAL

Knight 2005 {published data only}

Knight GJ, Palomaki GE, Neveux LM, Smith DE, Kloza EM, Pulkkinen A, et al. Integrated serum screening for Down syndrome in primary obstetric practice. Prenatal Diagnosis 2005;25(12):1162‐7. CENTRAL

Koos 2006 {published data only}

Koos BJ. First‐trimester screening: Lessons from clinical trials and implementation. Current Opinion in Obstetrics and Gynecology 2006;18(2):152‐5. CENTRAL

Kornman 1996 {published data only}

Kornman LH, Morssink LP, Beekhuis JR, de Wolf BT, Heringa MP, Mantingh A. Nuchal translucency cannot be used as a screening test for chromosomal abnormalities in the first trimester of pregnancy in a routine ultrasound practice.[see comment]. Prenatal Diagnosis 1996;16(9):797‐805. CENTRAL

Kornman 1997 {published data only}

Kornman LH, Morssink LP, Wortelboer MJ, Beekhuis JR, de Wolf BT, Pratt JJ, et al. Maternal urinary ß‐core hCG in chromosomally abnormal pregnancies in the first trimester. Prenatal Diagnosis 1997;17(2):135‐9. CENTRAL

Kotaska 2007 {published data only}

Kotaska A. Prenatal screening for fetal aneuploidy. Journal of Obstetrics & Gynaecology Canada: JOGC 2007;29(6):499‐500. CENTRAL

Kramer 1998 {published data only}

Kramer RL, Yaron Y, O'Brien JE, Critchfield G, Ayoub M, Johnson MP, et al. Effect of adjustment of maternal serum alpha‐fetoprotein levels in insulin‐dependent diabetes mellitus. American Journal of Medical Genetics 1998;75(2):176‐8. CENTRAL

Krantz 1996 {published data only}

Krantz DA, Larsen JW, Buchanan PD, Macri JN. First‐trimester Down syndrome screening: free ß‐human chorionic gonadotropin and pregnancy‐associated plasma protein A. American Journal of Obstetrics and Gynecology 1996;174(2):612‐6. CENTRAL

Krantz 2005 {published data only}

Krantz DA, Hallahan TW, Macri VJ, Macri JN. Maternal weight and ethnic adjustment within a first‐trimester Down syndrome and trisomy 18 screening program. Prenatal Diagnosis 2005;25(8):635‐40. CENTRAL

Krantz 2007 {published data only}

Krantz DA, Hallahan TW, Macri VJ, Macri JN. Genetic sonography after first‐trimester Down syndrome screening. Ultrasound in Obstetrics & Gynecology 2007;29(6):666‐70. CENTRAL

Kulch 1993 {published data only}

Kulch P, Keener S, Matsumoto M, Crandall BF. Racial differences in maternal serum human chorionic gonadotropin and unconjugated oestriol levels. Prenatal Diagnosis 1993;13(3):191‐5. CENTRAL

Lai 1998 {published data only}

Lai FM, Yeo GS. Down syndrome screening in Singapore‐‐the effectiveness of a second trimester serum screening policy modelled on 29,360 pregnancies in KK Women's and Children's Hospital. Singapore Medical Journal 1998;39(2):69‐75. CENTRAL

Lai 2003 {published data only}

Lai TH, Chen SC, Tsai MS, Lee FK, Wei CF. First‐trimester screening for down syndrome in singleton pregnancies achieved by intrauterine insemination. Journal of Assisted Reproduction and Genetics 2003;20(8):327‐31. CENTRAL

Laigaard 2006 {published data only}

Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM12 levels in Down and Edwards' syndrome pregnancies at 9‐12 weeks' gestation. Prenatal Diagnosis 2006;26(8):689‐91. CENTRAL

Laigaard 2006b {published data only}

Laigaard J, Spencer K, Christiansen M, Cowans NJ, Larsen SO, Pedersen BN, et al. ADAM 12 as a first‐trimester maternal serum marker in screening for Down syndrome. Prenatal Diagnosis 2006;26(10):973‐9. CENTRAL

Lam 1997 {published data only}

Lam YH, Tang MH, Tang LC, Lee CP, Ho PK. Second‐trimester maternal urinary gonadotrophin peptide screening for fetal Down syndrome in Asian women. Prenatal Diagnosis 1997;17(12):1101‐6. CENTRAL

Lam 1998 {published data only}

Lam YH, Ghosh A, Tang MH, Tang LC, Lee CP, Sin SY, et al. Second‐trimester maternal serum alpha‐fetoprotein and human chorionic gonadotrophin screening for Down's syndrome in Hong Kong. Prenatal Diagnosis 1998;18(6):585‐9. CENTRAL

Lam 1999 {published data only}

Lam YH, Yeung WS, Tang MH, NG EH, So WW, Ho PC. Maternal serum alpha‐fetoprotein and human chorionic gonadotrophin in pregnancies conceived after intracytoplasmic sperm injection and conventional in‐vitro fertilization. Human Reproduction 1999;14(8):2120‐3. CENTRAL

Lam 1999a {published data only}

Lam YH, Tang MH. Second‐trimester maternal serum inhibin‐A screening for fetal Down syndrome in Asian women. Prenatal Diagnosis 1999;19(5):463‐7. CENTRAL

Lam 2000 {published data only}

Lam YH, Tang MH, Lee CP, Sin SY, Tang R, Wong HS, et al. Acceptability of serum screening as an alternative to cytogenetic diagnosis of down syndrome among women 35 years or older in Hong Kong. Prenatal Diagnosis 2000;20(6):487‐90. CENTRAL

Lam 2001 {published data only}

Lam YH, Tang MH. The effect of fetal gender on second‐trimester maternal serum inhibin‐A concentration. Prenatal Diagnosis 2001;21(8):662‐4. CENTRAL

Lambert‐Messerlian 1996 {published data only}

Lambert‐Messerlian GM, Canick JA, Palomaki GE, Schneyer AL. Second trimester levels of maternal serum Inhibin A, total inhibin, alpha Inhibin Aprecursor, and activin in Down's syndrome pregnancy. Journal of Medical Screening 1996;3(2):58‐62. CENTRAL

Lambert‐Messerlian 1998 {published data only}

Lambert Messerlian GM, Luisi S, Florio P, Mazza V, Canick JA, Petraglia F. Second trimester levels of maternal serum total activin A and placental inhibin/activin alpha and ßA subunit messenger ribonucleic acids in Down syndrome pregnancy. European Journal of Endocrinology 1998;138(4):425‐9. CENTRAL

Lauria 2007 {published data only}

Lauria MR, Branch MD, LaCroix VH, Harris RD, Baker ER. Clinical impact of systematic genetic sonogram screening in a low‐risk population. Journal of Reproductive Medicine 2007;52(5):359‐64. CENTRAL

Lehavi 2005 {published data only}

Lehavi O, Aizenstein O, Evans MI, Yaron Y. 2nd‐trimester maternal serum human chorionic gonadotropin and alpha‐fetoprotein levels in male and female fetuses with Down syndrome. Fetal Diagnosis and Therapy 2005;20(3):235‐8. CENTRAL

Leung 2006 {published data only}

Leung TY, Spencer K, Leung TN, Fung TY, Lau TK. Higher median levels of free ß‐hCG and PAPP‐A in the first trimester of pregnancy in a Chinese ethnic group. Implication for first trimester combined screening for Down's syndrome in the Chinese population. Fetal Diagnosis and Therapy 2006;21(1):140‐3. CENTRAL

Leymarie 1993 {published data only}

Leymarie P, Leporrier N. Maternal serum markers and prenatal screening for Down syndrome. Archives Francaises de Pediatrie 1993;50(5):455‐7. CENTRAL

Li 1998 {published data only}

Li G, Huang X. [Clinical uses of maternal serum markers in the prenatal diagnosis] [Chinese]. Chung‐Hua Fu Chan Ko Tsa Chih 1998;33(4):252‐4. CENTRAL

Li 1999 {published data only}

Li W, Zhou Y. [Measurement of pregnancy‐associated plasma protein A in maternal peripheral blood and Down syndrome] [Chinese]. Chung‐Hua Fu Chan Ko Tsa Chih 1999;34(10):631‐3. CENTRAL

Li 2010 {published data only}

Li HW, Hui PW, Tang MH, Lau ET, Yeung WS, Ho PC, et al. Maternal serum anti‐Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies. Prenatal Diagnosis 2010;30(4):320‐4. CENTRAL

Liao 1997 {published data only}

Liao S, Wang Y, Ye G. [AFP, uE3, ß‐hCG levels applied for prenatal diagnosis of Down's syndrome]. [Chinese]. Chung‐Hua Fu Chan Ko Tsa Chih 1997;32(11):655‐8. CENTRAL

Liao 2001 {published data only}

Liao AW, Heath V, Kametas N, Spencer K, Nicolaides KH. First‐trimester screening for trisomy 21 in singleton pregnancies achieved by assisted reproduction. Human Reproduction 2001;16(7):1501‐4. CENTRAL

Lim 2002 {published data only}

Lim KI, Pugash D, Dansereau J, Wilson RD. Nuchal index: a gestational age independent ultrasound marker for the detection of Down syndrome. Prenatal Diagnosis 2002;22(13):1233‐7. CENTRAL

Lippman 1987 {published data only}

Lippman A, Evans JA. Screening for maternal serum alpha‐fetoprotein: what about the low side?. CMAJ: Canadian Medical Association Journal 1987;136(8):801‐4. CENTRAL

Liu 2010 {published data only}

Liu YH, Li LF, Wu YM. [Analysis of Down syndrome screening by maternal serum detection in mid‐pregnancy]. [Chinese]. Nan Fang Yi Ke Da Xue Xue Bao = Journal of Southern Medical University 2010;30(3):532‐4. CENTRAL

Lo 2010 {published data only}

Lo TK, Lai FK, Leung WC, Lau WL, Tang LC, Chin RK. A new policy for prenatal screening and diagnosis of Down syndrome for pregnant women with advanced maternal age in a public hospital. Journal of Maternal‐Fetal & Neonatal Medicine 2010;23(8):914‐9. CENTRAL

Lustig 1988 {published data only}

Lustig L, Clarke S, Cunningham G, Schonberg R, Tompkinson G. California's experience with low MS‐AFP results. American Journal of Medical Genetics 1988;31(1):211‐22. CENTRAL

Luthgens 2008 {published data only}

Luthgens K. Comparison of the new PRC software with the established algorithm of the FMF UK for the detection of trisomy 21 and 18/13. Fetal Diagnosis and Therapy 2008;24(4):376‐84. CENTRAL

MacDonald 1991 {published data only}

MacDonald ML, Wagner RM, Slotnick RN. Sensitivity and specificity of screening for Down syndrome with alpha‐fetoprotein, hCG, unconjugated estriol, and maternal age.[see comment]. Obstetrics & Gynecology 1991;77(1):63‐8. CENTRAL

Macintosh 1994 {published data only}

Macintosh MCM, Iles R, Teisner B, Sharma K, Chard T, Grudzinskas J, et al. Maternal serum human chorionic gonadotrophin and pregnancy‐associated plasma protein A, markers for fetal Down syndrome at 8‐14 weeks. Prenatal Diagnosis 1994;14(3):203‐8. CENTRAL

Macintosh 1997 {published data only}

Macintosh MCM, Nicolaides KH, Noble P, Chard T, Gunn L, Iles R. Urinary ß‐core hCG: Screening for aneuploidies in early pregnancy (11‐14 weeks' gestation). Prenatal Diagnosis 1997;17(5):401‐5. CENTRAL

MacRae 2010 {published data only}

MacRae AR, Chodirker BN, Davies GA, Palomaki GE, Knight GJ, Minett J, et al. Second and first trimester estimation of risk for Down syndrome: implementation and performance in the SAFER study. Prenatal Diagnosis 2010;30(5):459‐66. CENTRAL

Macri 1994 {published data only}

Macri JN, Kasturi RV, Krantz DA, Cook EJ, Moore ND, Young JA, et al. Maternal serum Down syndrome screening: free ß‐protein is a more effective marker than human chorionic gonadotropin.[see comment]. American Journal of Obstetrics and Gynecology 1990;163(4):1248‐53. CENTRAL
Macri JN, Spencer K, Garver K, Buchanan PD, Say B, Carpenter NJ, et al. Maternal serum free ß hCG screening: results of studies including 480 cases of Down syndrome.[see comment]. Prenatal Diagnosis 1994;14(2):97‐103. CENTRAL
Spencer K, Macri JN. Early detection of Down's syndrome using free ß human choriogonadotropin. Annals of Clinical Biochemistry 1992;19(3):349‐50. CENTRAL

Macri 1996 {published data only}

Macri JN, Anderson RW, Krantz DA, Larsen JW, Buchanan PD. Prenatal maternal dried blood screening with alpha‐fetoprotein and free ß‐human chorionic gonadotropin for open neural tube defect and Down syndrome. American Journal of Obstetrics and Gynecology 1996;174(2):566‐72. CENTRAL

Malone 1998 {published data only}

Malone FD, D'Alton ME. Ultrasound clinics. Fetal nuchal fold translucency screening. Contemporary OB/GYN 1998;43(3):117‐8. CENTRAL

Malone 2003 {published data only}

Malone FD, D'Alton ME. First‐trimester sonographic screening for Down syndrome. Obstetrics and Gynecology 2003;102(5):1066‐79. CENTRAL

Mandryka‐Stankewycz 2009 {published data only}

Mandryka‐Stankewycz S, Perenc M, Dec G, Sieroszewski P. [Noninvasive prenatal test in the first trimester of pregnancy (NT and estimation of beta‐hCG and PAPP‐A) in the diagnosis of fetal abnormalities in Polish population‐‐comparison of the biochemistry own normal ranges and literature reported data]. [Polish]. Ginekologia Polska 2009;80(11):851‐5. CENTRAL

Mangione 2001 {published data only}

Mangione R, Guyon F, Taine L, Wen ZQ, Roux D, Vergnaud A, et al. Pregnancy outcome and prognosis in fetuses with increased first‐trimester nuchal translucency. Fetal Diagnosis and Therapy 2001;16(6):360‐3. CENTRAL

Markov 2008 {published data only}

Markov D, Dimitrova V. [Ultrasound screening for chromosomal anomalies by assessment of the fetal nasal bone during 11‐14 weeks of gestation‐‐a pilot study]. [Bulgarian]. Akusherstvo i Ginekologiia 2008;47(1):3‐9. CENTRAL

Maymon 2001 {published data only}

Maymon R, Shulman A. Comparison of triple serum screening and pregnancy outcome in oocyte donation versus IVF pregnancies. Human Reproduction 2001;16(4):691‐5. CENTRAL

Maymon 2001a {published data only}

Maymon R, Dreazen E, Buckovsky I, Weinraub Z, Herman A. Does a 'notched' nuchal translucency indicate Down syndrome fetuses or other adverse pregnancy outcome?. Prenatal Diagnosis 2001;21(5):403‐8. CENTRAL

Maymon 2002 {published data only}

Maymon R, Shulman A. Serial first‐ and second‐trimester Down's syndrome screening tests among IVF‐versus naturally‐conceived singletons. Human Reproduction 2002;17(4):1081‐5. CENTRAL

Maymon 2004a {published data only}

Maymon R, Shulman A. Integrated first‐ and second‐trimester Down syndrome screening test among unaffected IVF pregnancies. Prenatal Diagnosis 2004;24(2):125‐9. CENTRAL

Maymon 2005a {published data only}

Maymon R, Cuckle H, Jones R, Reish O, Sharony R, Herman A. Predicting the result of additional second‐trimester markers from a woman's first‐trimester marker profile: A new concept in Down syndrome screening. Prenatal Diagnosis 2005;25(12):1102‐6. CENTRAL

McDuffie 1996 {published data only}

McDuffie Jr, Haverkamp AD, Stark CF, Haverkamp C, Barth CK. Prenatal screening using maternal serum alpha‐fetoprotein, human chorionic gonadotropin, and unconjugated estriol: Two‐year experience in a health maintenance organization. Journal of Maternal‐Fetal Medicine 1996;5(2):70‐3. CENTRAL

Meier 2002 {published data only}

Meier C, Huang T, Wyatt PR, Summers AM. Accuracy of expected risk of Down syndrome using the second‐trimester triple test. Clinical Chemistry 2002;48(4):653‐5. CENTRAL

Merkatz 1984 {published data only}

Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha‐fetoprotein and fetal chromosomal abnormalities. American Journal of Obstetrics and Gynecology 1984;148(7):886‐94. CENTRAL

Merz 2005 {published data only}

Merz E. The fetal nasal bone in the first trimester ‐ Precise assessment using 3D sonography. Ultraschall in der Medizin 2005;26(5):365‐6. CENTRAL

Merz 2008 {published data only}

Merz E, Thode C, Alkier A, Eiben B, Hackeloer BJ, Hansmann M, et al. A new approach to calculating the risk of chromosomal abnormalities with first‐trimester screening data. Ultraschall in der Medizin 2008;29(6):639‐45. CENTRAL

Metzenbauer 2001 {published data only}

Metzenbauer M, Hafner E, Hoefinger D, Schuchter K, Stangl G, Ogris E, et al. Three‐dimensional ultrasound measurement of the placental volume in early pregnancy: method and correlation with biochemical placenta parameters. Placenta 2001;22(6):602‐5. CENTRAL

Metzenbauer 2002 {published data only}

Metzenbauer M, Hafner E, Schuchter K, Philipp K. First‐trimester placental volume as a marker for chromosomal anomalies: preliminary results from an unselected population. Ultrasound in Obstetrics & Gynecology 2002;19(3):240‐2. CENTRAL

Mikic 1999 {published data only}

Mikic TS, Johnson P. Second trimester maternal serum ß human chorionic gonadotrophin and pregnancy outcome. British Journal of Obstetrics and Gynaecology 1999;106(6):598‐600. CENTRAL

Miller 1991 {published data only}

Miller CH, O'Brien TJ, Chatelain S, Butler BB, Quirk JG. Alteration in age‐specific risks for chromosomal trisomy by maternal serum alpha‐fetoprotein and human chorionic gonadotropin screening. Prenatal Diagnosis 1991;11(3):153‐8. CENTRAL

Milunsky 1989 {published data only}

Milunsky A, Jick SS, Bruell CL, Maclaughlin DS, Tsung Y‐K, Jick H, et al. Predictive values relative risks and overall benefits of high and low maternal serum alpha fetoprotein screening in singleton pregnancies ‐ new epidemiological data. American Journal of Obstetrics and Gynecology 1989;161(2):291‐7. CENTRAL

Milunsky 1996 {published data only}

Milunsky A, Nebiolo L. Maternal serum triple analyte screening and adverse pregnancy outcome. Fetal Diagnosis and Therapy 1996;11(4):249‐53. CENTRAL

Minobe 2002 {published data only}

Minobe S. [A study on the screening of prenatal trisomy 21 using the fucosylated alpha‐fetoprotein ratio measured by a liquid‐phase binding assay]. [Japanese]. Hokkaido Igaku Zasshi ‐ Hokkaido Journal of Medical Science 2002;77(6):527‐32. CENTRAL

Miron 2008 {published data only}

Miron P, Cote YP, Lambert J. Effect of maternal smoking on prenatal screening for Down syndrome and trisomy 18 in the first trimester of pregnancy. Prenatal Diagnosis 2008;28(3):180‐5. CENTRAL

Miron 2009 {published data only}

Miron P, Cote YP, Lambert J. Nuchal translucency thresholds in prenatal screening for Down syndrome and trisomy 18. Journal of Obstetrics & Gynaecology Canada: JOGC 2009;31(3):227‐35. CENTRAL

Miron 2010 {published data only}

Miron P, Lambert J, Marcil A, Cowans NJ, Stamatopoulou A, Spencer K. Maternal plasma levels of follistatin‐related gene protein in the first trimester of pregnancies with Down syndrome. Prenatal Diagnosis 2010;30(3):224‐8. CENTRAL

Miyamura 1999 {published data only}

Miyamura T, Saito N, Touno A, Nagata S, Hidaki T, Ishimaru T, et al. Multicenter study for maternal serum triple markers to establish Japanese standards: Maternal serum marker study group, Japan Association of Prenatal Diagnostics. Acta Obstetrica et Gynaecologica Japonica 1999;51(11):1042‐8. CENTRAL

Moghadam 1998 {published data only}

Moghadam S, Engel W, Bougoussa M, Hennen G, Igout A, Sancken U. Maternal serum placental growth hormone and insulinlike growth factor binding proteins 1 and 3 in pregnancies affected by fetal aneuploidy and other abnormalities: implications for prenatal diagnosis of trisomy 21. Fetal Diagnosis and Therapy 1998;13(5):291‐7. CENTRAL

Monni 2000 {published data only}

Monni G, Zoppi MA, Ibba RM, Putzolu M, Floris M. Nuchal translucency in multiple pregnancies. Croatian Medical Journal 2000;41(3):266‐9. CENTRAL

Monni 2002 {published data only}

Monni G, Zoppi MA. New ultrasonographic markers of aneuploidies: Nasal bones. Ultrasound Review of Obstetrics and Gynecology 2002;2(4):229‐34. CENTRAL

Mooney 1994 {published data only}

Mooney RA, Peterson CJ, French CA, Saller DN, Arvan DA. Effectiveness of combining maternal serum alpha‐fetoprotein and hCG in a second‐trimester screening program for Down syndrome. Obstetrics and Gynecology 1994;84(2):298‐303. CENTRAL

Muhcu 2008 {published data only}

Muhcu M, Mungen E, Atay V, Ipcioglu OM, Dundar O, Ergur R, et al. First trimester screening for Down syndrome in rhesus negative women. Prenatal Diagnosis 2008;28(5):404‐7. CENTRAL

Muller 1994 {published data only}

Muller F, Bussieres L, Pelissier MC, Oury JF, Boue C, Uzan S, et al. Do racial differences exist in second‐trimester maternal hCG levels? A study of 23,369 women. Prenatal Diagnosis 1994;14(7):633‐6. CENTRAL

Muller 1996a {published data only}

Muller F, Dommergues M, Bussieres L, Aegerter P, Le Fiblec B, Uzan S, et al. Prenatal screening for Down syndrome: should first trimester ultrasound replace maternal serum screening?. Early Human Development 1996;47(Suppl):S37‐9. CENTRAL

Muller 1999 {published data only}

Muller F, Ngo S, Rebiffe M, Oury JF, Uzan S, Satge D. Maternal serum s100b protein is ineffective for Down syndrome screening. Prenatal Diagnosis 1999;19(11):1086. CENTRAL

Muller 2002 {published data only}

Muller F, Dreux S, Oury JF, Luton D, Uzan S, Uzan M, et al. Down syndrome maternal serum marker screening after 18 weeks' gestation. Prenatal Diagnosis 2002;22(11):1001‐4. CENTRAL

Muller 2002a {published data only}

Muller F, Forestier F, Dingeon B, ABA Study Group. Second trimester trisomy 21 maternal serum marker screening. Results of a countrywide study of 854,902 women.[see comment]. Prenatal Diagnosis 2002;22(10):925‐9. CENTRAL

Muller 2003b {published data only}

Muller F, Dreux S, Lemeur A, Sault C, Desgres J, Bernard MA, et al. Medically assisted reproduction and second‐trimester maternal serum marker screening for Down syndrome. Prenatal Diagnosis 2003;23(13):1073‐6. CENTRAL

Murta 2002 {published data only}

Murta CG, Moron AF, Avila MA, Weiner CP. Application of ductus venosus Doppler velocimetry for the detection of fetal aneuploidy in the first trimester of pregnancy. Fetal Diagnosis and Therapy 2002;17(5):308‐14. CENTRAL

Musone 2000 {published data only}

Musone R, Bonafiglia R, Menditto A, Paccone M, Cassese E, Russo G, et al. Fetuses with cystic hygroma. A retrospective study. Panminerva Medica 2000;42(1):39‐43. CENTRAL

Musto 1986 {published data only}

Musto JD, Pizzolante JM, Chesarone VP, Sassi AM, Sane R. Alpha‐fetoprotein: an enhanced‐sensitivity assay for neural tube defect and Down syndrome evaluation. Clinical Chemistry 1986;32(7):1412. CENTRAL

Myrick 1990 {published data only}

Myrick JE, Caudill SP, Hubert IL, Robinson MK, Adams MJ, Pueschel SM. Identification of haptoglobin alpha‐2FF variants in mid‐trimester maternal serum as potential markers for Down syndrome. Applied & Theoretical Electrophoresis 1990;1(5):233‐41. CENTRAL

Naidoo 2008 {published data only}

Naidoo P, Erasmus I, Jeebodh J, Nicolaou E, van Gelderen CJ. Nuchal translucency as a method of first‐trimester screening for aneuploidy. South African Medical Journal 2008;Suid‐Afrikaanse Tydskrif Vir Geneeskunde. 98(4):295‐9. CENTRAL

Nau 2009 {published data only}

Nau JY. [Screening for trisomy 21 in France]. [French]. Revue Medicale Suisse 2009;5(211):1531. CENTRAL

Nau 2009a {published data only}

Nau JY. [Trisomy 21, after a half century]. [French]. Revue Medicale Suisse 2009;5(190):380. CENTRAL

Neveux 1996 {published data only}

Neveux LM, Palomaki GE, Larrivee DA, Knight GJ, Haddow JE. Refinements in managing maternal weight adjustment for interpreting prenatal screening results. Prenatal Diagnosis 1996;16(12):1115‐9. CENTRAL

Neveux 1996a {published data only}

Neveux LM, Palomaki GE, Knight GJ, Haddow JE. Multiple marker screening for Down syndrome in twin pregnancies. Prenatal Diagnosis 1996;16(1):29‐34. CENTRAL

Ng 2004 {published data only}

Ng EK, El‐Sheikhah A, Chiu RW, Chan KC, Hogg M, Bindra R, et al. Evaluation of human chorionic gonadotropin ß‐subunit mRNA concentrations in maternal serum in aneuploid pregnancies: a feasibility study. Clinical Chemistry 2004;50(6):1055‐7. CENTRAL

Nicolaides 1992a {published data only}

Nicolaides KH, Azar G, Snijders RJM, Gosden CM. Fetal nuchal oedema associated malformations and chromosomal defects. Fetal Diagnosis and Therapy 1992;7(2):123‐31. CENTRAL

Nicolaides 2000 {published data only}

Nicolaides KH, Cicero S, Liao AW. One‐stop clinic for assessment of risk of chromosomal defects at 12 weeks of gestation. Prenatal and Neonatal Medicine 2000;5(3):145‐54. CENTRAL

Nicolaides 2004 {published data only}

Nicolaides KH. Nuchal translucency and other first‐trimester sonographic markers of chromosomal abnormalities. American Journal of Obstetrics and Gynecology 2004;191(1):45‐67. CENTRAL

Nicolaides 2005a {published data only}

Nicolaides KH, Wegrzyn P. [First trimester diagnosis of chromosomal defects][Polish]. Ginekologia Polska 2005;76(1):1‐8. CENTRAL

Nicolaides 2005b {published data only}

Nicolaides KH, Wegrzyn P. [Sonographic features of chromosomal defects at 11(+0) to 13(+6) weeks of gestation] [Polish]. Ginekologia Polska 2005;76(6):423‐30. CENTRAL

Nicolaides 2005c {published data only}

Nicolaides KH, Wegrzyn P. [Increased nuchal translucency with normal karyotype]. [Polish]. Ginekologia Polska 2005;76(8):593‐601. CENTRAL

Nicolaides 2005d {published data only}

Nicolaides KH, Wegrzyn P. [Fetal nuchal translucency]. [Polish]. Ginekologia Polska 2005;76(3):179‐86. CENTRAL

Nicolaides 2005e {published data only}

Nicolaides KH, Wegrzyn P. [Fetal nuchal translucency thickness and risk for chromosomal defects]. [Polish]. Ginekologia Polska 2005;76(4):257‐63. CENTRAL

Nicolaides 2005f {published data only}

Nicolaides Kypros H. First‐trimester screening for chromosomal abnormalities. Seminars in Perinatology (Philadelphia) 2005;29(4):190‐4. CENTRAL

Niemimaa 2001b {published data only}

Niemimaa M, Heinonen S, Seppala M, Hippelainen M, Martikainen H, Ryynanen M. First‐trimester screening for Down's syndrome in in vitro fertilization pregnancies. Fertility & Sterility 2001;76(6):1282‐3. CENTRAL

Niemimaa 2002 {published data only}

Niemimaa M, Suonpaa M, Heinonen S, Seppala M, Bloigu R, Ryynanen M. Maternal serum human chorionic gonadotrophin and pregnancy‐associated plasma protein A in twin pregnancies in the first trimester. Prenatal Diagnosis 2002;22(3):183‐5. CENTRAL

Niemimaa 2003 {published data only}

Niemimaa M, Heinonen S, Seppala M, Ryynanen M. The influence of smoking on the pregnancy‐associated plasma protein A, free ß human chorionic gonadotrophin and nuchal translucency. BJOG: an international journal of obstetrics and gynaecology 2003;110(7):664‐7. CENTRAL

Noble 1997b {published data only}

Noble PL, Snijders RJ, Abraha HD, Sherwood RA, Nicolaides KH. Maternal serum free ß‐hCG at 10 to 14 weeks of gestation in trisomic twin pregnancies. British Journal of Obstetrics and Gynaecology 1997;104(6):741‐3. CENTRAL

Norgaard 1990 {published data only}

Norgaard Pedersen B, Larsen SO, Arends J, Svenstrup B, Tabor A. Maternal serum markers in screening for Down syndrome. Clinical Genetics 1990;37(1):35‐43. CENTRAL

Norton 1992 {published data only}

Norton ME, Golbus MS. Maternal serum CA 125 for aneuploidy detection in early pregnancy. Prenatal Diagnosis 1992;12(9):779‐81. CENTRAL

Novakov‐Mikic 2007 {published data only}

Novakov‐Mikic A, Potic Z, Pjevic A. [Ultrasound screening program for chromosomal abnormalities‐‐the first 2000 women]. [Serbian]. Medicinski Pregled 2007;60(1‐2):66‐70. CENTRAL

O'Brien 1997a {published data only}

O'Brien JE, Dvorin E, Yaron Y, Ayoub M, Johnson MP, Hume RF, et al. Differential increases in AFP, hCG, and uE3 in twin pregnancies: Impact on attempts to quantify Down syndrome screening calculations. American Journal of Medical Genetics 1997;73(2):109‐12. CENTRAL

O'Brien 1997b {published data only}

O'Brien JE, Dvorin E, Drugan A, Johnson MP, Yaron Y, Evans MI. Race‐ethnicity‐specific variation in multiple‐marker biochemical screening: Alpha‐fetoprotein, hCG, and estriol. Obstetrics and Gynecology 1997;89(3):355‐8. CENTRAL

Odibo 2004 {published data only}

Odibo AO, Sehdev HM, Dunn L, McDonald R, Macones GA. The association between fetal nasal bone hypoplasia and aneuploidy. Obstetrics & Gynecology 2004;104(6):1229‐33. CENTRAL

Odibo 2007 {published data only}

Odibo AO, Sehdev HM, Stamilio DM, Cahill A, Dunn L, Macones GA. Defining nasal bone hypoplasia in second‐trimester Down syndrome screening: does the use of multiples of the median improve screening efficacy?. American Journal of Obstetrics and Gynecology 2007;197(4):361‐4. CENTRAL

Odibo 2008 {published data only}

Odibo AO, Sehdev HM, Gerkowicz S, Stamilio DM, Macones GA. Comparison of the efficiency of second‐trimester nasal bone hypoplasia and increased nuchal fold in Down syndrome screening. American Journal of Obstetrics and Gynecology 2008;199(3):281‐5. CENTRAL

Odibo 2009 {published data only}

Odibo AO, Schoenborn JA, Haas K, Macones GA. Does the combination of fronto‐maxillary facial angle and nasal bone evaluation improve the detection of Down syndrome in the second trimester?. Prenatal Diagnosis 2009;29(10):947‐51. CENTRAL

Offerdal 2008 {published data only}

Offerdal K, Blaas HG, Eik‐Nes SH. Prenatal detection of trisomy 21 by second‐trimester ultrasound examination and maternal age in a non‐selected population of 49 314 births in Norway. Ultrasound in Obstetrics & Gynecology 2008;32(4):493‐500. CENTRAL

Ognibene 1999 {published data only}

Ognibene A, Ciuti R, Tozzi P, Messeri G. Maternal serum superoxide dismutase (SOD): a possible marker for screening Down syndrome affected pregnancies.[see comment]. Prenatal Diagnosis 1999;19(11):1058‐60. CENTRAL

Oh 2007 {published data only}

Oh C, Harman C, Baschat AA. Abnormal first‐trimester ductus venosus blood flow: a risk factor for adverse outcome in fetuses with normal nuchal translucency. Ultrasound in Obstetrics & Gynecology 2007;30(2):192‐6. CENTRAL

Olajide 1989 {published data only}

Olajide F, Kitau MJ, Chard T. Maternal serum AFP levels in the first trimester of pregnancy. European Journal of Obstetrics, Gynecology, & Reproductive Biology 1989;30(2):123‐8. CENTRAL

Onda 1996 {published data only}

Onda T, Kitagawa M, Takeda O, Sago H, Kubonoya K, Iinuma K, et al. Triple marker screening in native Japanese women. Prenatal Diagnosis 1996;16(8):713‐7. CENTRAL

Onda 1998 {published data only}

Onda T, Tanaka T, Takeda O, Kitagawa M, Kuwabara Y, Yamamoto H, et al. Agreement between predicted risk and prevalence of Down syndrome in second‐trimester triple‐marker screening in Japan. Prenatal Diagnosis 1998;18(9):956‐8. CENTRAL

Onda 2000 {published data only}

Onda T, Tanaka T, Yoshida K, Nakamura Y, Kudo R, Yamamoto H, et al. Triple marker screening for trisomy 21, trisomy 18 and open neural tube defects in singleton pregnancies of native Japanese pregnant women. Journal of Obstetrics & Gynaecology Research 2000;26(6):441‐7. CENTRAL

Orlandi 2002 {published data only}

Orlandi F, Rossi C, Allegra A, Krantz D, Hallahan T, Orlandi E, et al. First trimester screening with free ß‐hCG, PAPP‐A and nuchal translucency in pregnancies conceived with assisted reproduction. Prenatal Diagnosis 2002;22(8):718‐21. CENTRAL

Ottavio 1997 {published data only}

Ottavio G, Meir YJ, Rustico MA, Pecile V, Fischer Tamaro L, Conoscenti G, et al. Screening for fetal anomalies by ultrasound at 14 and 21 weeks. Ultrasound in Obstetrics and Gynecology 1997;10(6):375‐80. CENTRAL

Ozkaya 2010 {published data only}

Ozkaya O, Sezik M, Ozbasar D, Kaya H. Abnormal ductus venosus flow and tricuspid regurgitation at 11‐14 weeks' gestation have high positive predictive values for increased risk in first‐trimester combined screening test: results of a pilot study. Taiwanese Journal of Obstetrics & Gynecology 2010;49(2):145‐50. CENTRAL

Páez 2004 {published data only}

Páez L, Peña E, González F, Bello F, Bellorín J, Espinoza F, et al. Plasma protein "A" and chorionic gonadotropin at first trimester pregnancy. Informe Medico 2004;6(2):99‐109. CENTRAL

Paladini 2007 {published data only}

Paladini D, Sglavo G, Penner I, Pastore G, Nappi C. Fetuses with Down syndrome have an enlarged anterior fontanelle in the second trimester of pregnancy. Ultrasound in Obstetrics & Gynecology 2007;30(6):824‐9. CENTRAL

Palka 1998 {published data only}

Palka G, Guanciali Franchi P, Papponetti M, Marcuccitti J, Morizio E, Calabrese G, et al. Prenatal diagnosis using the triple test. Minerva Ginecologica 1998;50(10):411‐5. CENTRAL

Palomaki 1989 {published data only}

Palomaki GE, Williams J, Haddow JE. Combining maternal serum alpha‐fetoprotein measurements and age to screen for Down syndrome in pregnant women under age 35. American Journal of Obstetrics and Gynecology 1989;160(3):575‐81. CENTRAL

Palomaki 1993 {published data only}

Palomaki GE, Knight GJ, Haddow JE, Canick JA, Wald NJ, Kennard A. Cigarette smoking and levels of maternal serum alpha‐fetoprotein, unconjugated estriol, and hCG: Impact on Down syndrome screening. Obstetrics and Gynecology 1993;81(5):675‐8. CENTRAL

Palomaki 1994 {published data only}

Palomaki GE, Knight GJ, Haddow JE. Human chorionic gonadotropin and unconjugated oestriol measurements in insulin‐dependent diabetic pregnant women being screened for fetal Down syndrome. Prenatal Diagnosis 1994;14(1):65‐8. CENTRAL

Palomaki 1996 {published data only}

Palomaki GE, Neveux LM, Haddow JE. Can reliable Down's syndrome detection rates be determined from prenatal screening intervention trials?. Journal of Medical Screening 1996;3(1):12‐7. CENTRAL

Palomaki 2005 {published data only}

Palomaki GE, Knight GJ, Neveux LM, Pandian R, Haddow JE. Maternal serum invasive trophoblast antigen and first‐trimester Down syndrome screening. Clinical Chemistry 2005;51(8):1499‐504. CENTRAL

Panburana 2001 {published data only}

Panburana P, Ajjimakorn S, Tungkajiwangoon P. First trimester Down Syndrome screening by nuchal translucency in a Thai population. International Journal of Gynaecology & Obstetrics 2001;75(3):311‐2. CENTRAL

Pandya 1994 {published data only}

Pandya PP, Brizot ML, Kuhn P, Snijders RJ, Nicolaides KH. First‐trimester fetal nuchal translucency thickness and risk for trisomies. Obstetrics & Gynecology 1994;84(3):420‐3. CENTRAL

Pandya 1995b {published data only}

Pandya PP, Santiago C, Snijders RJM, Nicolaides KH. First trimester fetal nuchal translucency. Current Opinion in Obstetrics and Gynecology 1995;7(2):95‐102. CENTRAL

Papadopoulou 2008 {published data only}

Papadopoulou E, Sifakis S, Giahnakis E, Fragouli Y, Karkavitsas N, Koumantakis E, et al. Human placental growth hormone is increased in maternal serum in pregnancies affected by Down syndrome. Fetal Diagnosis and Therapy 2008;23(3):211‐6. CENTRAL

Parra‐Cordero 2007 {published data only}

Parra‐Cordero M, Quiroz L, Rencoret G, Pedraza D, Munoz H, Soto‐Chacon E, et al. Screening for trisomy 21 during the routine second‐trimester ultrasound examination in an unselected Chilean population. Ultrasound in Obstetrics & Gynecology 2007;30(7):946‐51. CENTRAL

Paterlini‐Brechot 2007 {published data only}

Paterlini‐Brechot P. [Non invasive prenatal diagnosis of trisomy 21: dream or reality?]. [French]. M S‐Medecine Sciences 2007;23(6‐7):592‐4. CENTRAL

Paul 2001 {published data only}

Paul C, Krampl E, Skentou C, Jurkovic D, Nicolaides KH. Measurement of fetal nuchal translucency thickness by three‐dimensional ultrasound. Ultrasound in Obstetrics & Gynecology 2001;18(5):481‐4. CENTRAL

Peralta 2005 {published data only}

Peralta CF, Falcon O, Wegrzyn P, Faro C, Nicolaides KH. Assessment of the gap between the fetal nasal bones at 11 to 13 + 6 weeks of gestation by three‐dimensional ultrasound. Ultrasound in Obstetrics & Gynecology 2005;25(5):464‐7. CENTRAL

Perenc 1998 {published data only}

Perenc M, Dudarewicz L, Kaluzewski B. Analysis of triple test results in 27 cases of twin pregnancies. Acta Geneticae Medicae et Gemellologiae 1998;47(3‐4):249‐54. CENTRAL

Perheentupa 2002 {published data only}

Perheentupa A, Ruokonen A, Tuomivaara L, Ryynänen M, Martikainen H. Maternal serum (ß)‐HCG and (alpha)‐fetoprotein concentrations in singleton pregnancies following assisted reproduction. Human Reproduction 2002;17(3):794‐7. CENTRAL

Perona 1998 {published data only}

Perona M, Mancini G, Dall'Amico D, Guaraldo V, Carbonara A. Influence of smoking habits on Down's syndrome risk evaluation at mid‐trimester through biochemical screening. International Journal of Clinical & Laboratory Research 1998;28(3):179‐82. CENTRAL

Persico 2008 {published data only}

Persico N, Borenstein M, Molina F, Azumendi G, Nicolaides KH. Prenasal thickness in trisomy‐21 fetuses at 16‐24 weeks of gestation. Ultrasound in Obstetrics & Gynecology 2008;32(6):751‐4. CENTRAL

Petervari 2000 {published data only}

Petervari L, Varga A, Tanko A, Szabo L, Godo G. [Significance of nuchal edema in fetuses of pregnant women under 35 years of age]. [Hungarian]. Orvosi Hetilap 2000;141(8):399‐402. CENTRAL

Petrocik 1989 {published data only}

Petrocik E, Wassman ER, Kelly JC. Prenatal screening for Down syndrome with maternal serum human chorionic gonadotropin levels.[see comment]. American Journal of Obstetrics and Gynecology 1989;161(5):1168‐73. CENTRAL

Phillips 1992 {published data only}

Phillips OP, Elias S, Shulman LP, Andersen RN, Morgan CD, Simpson JL. Maternal serum screening for fetal Down syndrome in women less than 35 years of age using alpha‐fetoprotein, hCG, and unconjugated estriol: a prospective 2‐year study. Obstetrics & Gynecology 1992;80(3):353‐8. CENTRAL

Phillips 1993 {published data only}

Phillips OP, Shulman LP, Elias S, Simpson JL. Maternal serum screening for fetal Down syndrome using alpha‐ fetoprotein, human chorionic gonadotrophin, and unconjugated estriol in adolescents. Adolescent and Pediatric Gynecology 1993;6(2):91‐4. CENTRAL

Pihl 2008 {published data only}

Pihl K, Larsen T, Jonsson L, Hougaard D, Krebs L, Norgaard‐Pedersen B, et al. [Quality control of prenatal screening]. [Danish]. Ugeskrift for Laeger 2008;170(35):2691‐5. CENTRAL

Pinette 2003 {published data only}

Pinette MG, Egan JF, Wax JR, Blackstone J, Cartin A, Benn PA. Combined sonographic and biochemical markers for Down syndrome screening. Journal of Ultrasound in Medicine 2003;22(11):1185‐90. CENTRAL

Platt 2004 {published data only}

Platt LD, Greene N, Johnson A, Zachary J, Thom E, Krantz D, et al. Sequential pathways of testing after first‐trimester screening for trisomy 21. Obstetrics and Gynecology 2004;104(4):661‐6. CENTRAL

Podobnik 1995 {published data only}

Podobnik M, Singer Z, Podobnik Sarkanji S, Bulic M. First trimester diagnosis of cystic hygromata using transvaginal ultrasound and cytogenetic evaluation. Journal of Perinatal Medicine 1995;23(4):283‐91. CENTRAL

Poon 2009 {published data only}

Poon LC, Chelemen T, Minekawa R, Frisova V, Nicolaides KH. Maternal serum ADAM12 (A disintegrin and metalloprotease) in chromosomally abnormal pregnancy at 11‐13 weeks. American Journal of Obstetrics and Gynecology 2009;200(5):508‐6. CENTRAL

Prefumo 2002 {published data only}

Prefumo F, Thilaganathan B. Agreement between predicted risk and prevalence of Down syndrome in first trimester nuchal translucency screening. Prenatal Diagnosis 2002;22(10):917‐8. CENTRAL

Prefumo 2004 {published data only}

Prefumo F, Sairam S, Bhide A, Penna L, Hollis B, Thilaganathan B. Maternal ethnic origin and fetal nasal bones at 11‐14 weeks of gestation. BJOG: an international journal of obstetrics and gynaecology 2004;111(2):109‐12. CENTRAL

Price 1998 {published data only}

Price KM, Van Lith JM, Silman R, Mantingh A, Grudzinskas JG. First trimester maternal serum concentrations of fetal antigen 2 in normal pregnancies and those affected by trisomy 21. Human Reproduction 1998;13(6):1706‐8. CENTRAL

Raty 2000 {published data only}

Raty R, Virtanen A, Koskinen P, Laitinen P, Forsstrom J, Salonen R, et al. Maternal midtrimester serum AFP and free ß‐hCG levels in in vitro fertilization twin pregnancies. Prenatal Diagnosis 2000;20(3):221‐3. CENTRAL

Räty 2002 {published data only}

Räty R, Virtanen A, Koskinen P, Anttila L, Forsström J, Laitinen P, et al. Serum free (ß)‐HCG and alpha‐fetoprotein levels in IVF, ICSI and frozen embryo transfer pregnancies in maternal mid‐trimester serum screening for Down's syndrome. Human Reproduction 2002;17(2):481‐4. CENTRAL

Rembouskos 2004 {published data only}

Rembouskos G, Cicero S, Longo D, Vandecruys H, Nicolaides KH. Assessment of the fetal nasal bone at 11‐14 weeks of gestation by three‐dimensional ultrasound. Ultrasound in Obstetrics & Gynecology 2004;23(3):232‐6. CENTRAL

Ren 1992 {published data only}

Ren S‐G, Braunstein GD. Human chorionic gonadotropin. Seminars in Reproductive Endocrinology 1992;10(2):95‐105. CENTRAL

Renier 1998 {published data only}

Renier MA, Vereecken A, van Herck E, Straetmans D, Ramaekers P, Buytaert P. Second trimester maternal dimeric inhibin‐A in the multiple‐marker screening test for Down's syndrome. Human Reproduction 1998;13(3):744‐8. CENTRAL

Resta 1990 {published data only}

Resta RG, Nyberg D. The role of ultrasound in screening for Down syndrome. Birth Defects: Original Article Series 1990;26(3):104. CENTRAL

Reynders 1997 {published data only}

Reynders CS, Pauker SP, Benacerraf BR. First trimester isolated fetal nuchal lucency: significance and outcome. Journal of Ultrasound in Medicine 1997;16(2):101‐5. CENTRAL

Reynolds 1989 {published data only}

Reynolds TM, Penney MD. The mathematical basis of multivariate risk screening: with special reference to screening for Down's syndrome associated pregnancy. Annals of Clinical Biochemistry 1989;27(5):452‐8. CENTRAL

Reynolds 1999 {published data only}

Reynolds TM, Schaeffer HJ, Schlensker S. Estimation of Down's syndrome risks in the first trimester of pregnancy: Experience of testing with PAPP‐A, total hCG and free ß‐ hCG levels in maternal blood samples in a German population. Clinical Laboratory 1999;45(1‐2):49‐53. CENTRAL

Reynolds 2008 {published data only}

Reynolds TM, Aldis J. Median parameters for Down's syndrome screening should be calculated using a moving time‐window method. Annals of Clinical Biochemistry 2008;45(Pt 6):567‐70. CENTRAL

Ribbert 1996 {published data only}

Ribbert LS, Kornman LH, de Wolf BT, Simons AH, Jansen CA, Beekhuis JR, et al. Maternal serum screening for fetal Down syndrome in IVF pregnancies. Prenatal Diagnosis 1996;16(1):35‐8. CENTRAL

Rice 2005 {published data only}

Rice JD, McIntosh SF, Halstead AC. Second‐trimester maternal serum screening for Down syndrome in in vitro fertilization pregnancies. Prenatal Diagnosis 2005;25(3):234‐8. CENTRAL

Rich 1991 {published data only}

Rich N, Boots L, Davis R, Finley S. Efficiency of maternal serum hCG AFP and free estriol in the identification of trisomy 21 and other complications of pregnancy. Journal of the Alabama Academy of Science 1991;62(2‐3):135. CENTRAL

Roberts 1995 {published data only}

Roberts LJ, Bewley S, Mackinson AM, Rodeck CH. First trimester fetal nuchal translucency: problems with screening the general population. 1. British Journal of Obstetrics and Gynaecology 1995;102(5):381‐5. CENTRAL

Robertson 1991 {published data only}

Robertson EF. Maternal serum screening for neural tube defects and Down's syndrome.[see comment]. Medical Journal of Australia 1991;155(2):67‐8. CENTRAL

Rode 2003 {published data only}

Rode L, Wojdemann KR, Shalmi AC, Larsen SO, Sundberg K, Norgaard‐Pedersen B, et al. Combined first‐ and second‐trimester screening for Down syndrome: an evaluation of proMBP as a marker. Prenatal Diagnosis 2003;23(7):593‐8. CENTRAL

Ronge 2006 {published data only}

Ronge R. Combined first trimester screening for Down's syndrome is superior to quadruple test. Geburtshilfe und Frauenheilkunde 2006;66(4):332. CENTRAL

Rose 1995 {published data only}

Rose NC, Mennuti MT. Multiple marker screening for women 35 and older. Contemporary OB/GYN 1995;40(9):55‐6. CENTRAL

Ross 1997 {published data only}

Ross HL, Elias S. Maternal serum screening for fetal genetic disorders. Obstetrics & Gynecology Clinics of North America 1997;24(1):33‐47. CENTRAL

Rotmensch 1996 {published data only}

Rotmensch S, Liberati M, Kardana A, Copel JA, Ben‐Rafael Z, Cole LA. Nicked free ß‐subunit of human chorionic gonadotropin: A potential new marker for Down syndrome screening. American Journal of Obstetrics and Gynecology 1996;174(2):609‐11. CENTRAL

Rotmensch 1999 {published data only}

Rotmensch S, Celentano C, Shalev J, Vishne TH, Lipitz S, Ben‐Rafael Z, et al. Midtrimester maternal serum screening after multifetal pregnancy reduction in pregnancies conceived by in vitro fertilization. Journal of Assisted Reproduction and Genetics 1999;16(1):8‐12. CENTRAL

Rozenberg 2006 {published data only}

Rozenberg P, Bussieres L, Chevret S, Bernard JP, Malagrida L, Cuckle H, et al. Screening for Down syndrome using first‐trimester combined screening followed by second‐trimester ultrasound examination in an unselected population. American Journal of Obstetrics and Gynecology 2006;195(5):1379‐87. CENTRAL

Rudnicka 2002 {published data only}

Rudnicka AR, Wald NJ, Huttly W, Hackshaw AK. Influence of maternal smoking on the birth prevalence of Down syndrome and on second trimester screening performance. Prenatal Diagnosis 2002;22(10):893‐7. CENTRAL

Ryall 1992 {published data only}

Ryall RG, Staples AJ, Robertson EF, Pollard AC. Improved performance in a prenatal screening programme for Down's syndrome incorporating serum‐free hCG subunit analyses. Prenatal Diagnosis 1992;12(4):251‐61. CENTRAL

Ryall 2001 {published data only}

Ryall RG, Callen D, Cocciolone R, Duvnjak A, Esca R, Frantzis N, et al. Karyotypes found in the population declared at increased risk of Down syndrome following maternal serum screening. Prenatal Diagnosis 2001;21(7):553‐7. CENTRAL

Sabriá 2002 {published data only}

Sabriá J, Cabrero D, Bach C. Aneuploidy screening: Ultrasound versus biochemistry. Ultrasound Review of Obstetrics and Gynecology 2002;2(4):221‐8. CENTRAL

Sacchini 2003 {published data only}

Sacchini C, El‐Sheikhah A, Cicero S, Rembouskos G, Nicolaides KH. Ear length in trisomy 21 fetuses at 11‐14 weeks of gestation. Ultrasound in Obstetrics & Gynecology 2003;22(5):460‐3. CENTRAL

Sahota 2009 {published data only}

Sahota DS, Leung TY, Chan LW, Law LW, Fung TY, Chan OK, et al. First‐trimester fetal nasal bone length in an ethnic Chinese population. Ultrasound in Obstetrics & Gynecology 2009;34(1):33‐7. CENTRAL

Sahota 2010a {published data only}

Sahota DS, Leung TY, Chen M, Chan LW, Fung TY, Lau TK. Comparison of likelihood ratios of first‐trimester nuchal translucency measurements: multiples of median, delta or mixture. Ultrasound in Obstetrics & Gynecology 2010;36(1):15‐9. CENTRAL

Salazar 2007 {published data only}

Salazar Lopez R, Ibarra Gallardo AL, Iduma Melendrez M, Leyva Bojorquez R. [Specificity of biochemical markers of pregnancy second trimester]. [Spanish]. Ginecologia y Obstetricia de Mexico 2007;75(10):608‐14. CENTRAL

Salazar 2008 {published data only}

Salazar Lopez R, Ibarra Gallardo AL, Iduma Melendrez M, Leyva R. [Evaluation of plasmatic A protein as only marker during first trimester of pregnancy]. [Spanish]. Ginecologia y Obstetricia de Mexico 2008;76(10):576‐81. CENTRAL

Saller 1997 {published data only}

Saller DN, Canick JA, Kellner LH, Rose NC, Garza J, French CA, et al. Maternal serum analyte levels in pregnancies with fetal Down syndrome resulting from translocations. American Journal of Obstetrics and Gynecology 1997;177(4):879‐81. CENTRAL

Salomon 2001 {published data only}

Salomon LJ, Bernard JP, Taupin P, Benard C, Ville Y. Relationship between nuchal translucency at 11‐14 weeks and nuchal fold at 20‐24 weeks of gestation. Ultrasound in Obstetrics & Gynecology 2001;18(6):636‐7. CENTRAL

Salonen 1997 {published data only}

Salonen R, Turpeinen U, Kurki L, Lappalainen M, Ammala P, Hiilesmaa V, et al. Maternal serum screening for Down's syndrome on population basis. Acta Obstetricia et Gynecologica Scandinavica 1997;76(9):817‐21. CENTRAL

Saltvedt 2005 {published data only}

Saltvedt S, Almstrom H, Kublickas M, Valentin L, Bottinga R, Bui TH, et al. Screening for Down syndrome based on maternal age or fetal nuchal translucency: a randomized controlled trial in 39,572 pregnancies. Ultrasound in Obstetrics & Gynecology 2005;25(6):537‐45. CENTRAL

Saridogan 1996 {published data only}

Saridogan E, Djahanbakhch O, Naftalin AA. Screening for Down's syndrome: experience in an inner city health district. British Journal of Obstetrics and Gynaecology 1996;103(12):1205‐11. CENTRAL

Savoldelli 1993 {published data only}

Savoldelli G, Binkert F, Achermann J, Schmid W. Ultrasound screening for chromosomal anomalies in the first trimester of pregnancy. Prenatal Diagnosis 1993;13(6):513‐8. CENTRAL

Schielen 2009 {published data only}

Schielen PC, Wildschut HI, Loeber JG. Down syndrome screening: determining the cutoff level of risk for invasive testing. Prenatal Diagnosis 2009;29(2):190‐2. CENTRAL

Schiott 2006 {published data only}

Schiott KM, Christiansen M, Petersen OB, Sorensen TL, Uldbjerg N. The "Consecutive Combined Test"‐‐using double test from week 8 + 0 and nuchal translucency scan, for first trimester screening for Down syndrome. Prenatal Diagnosis 2006;26(12):1105‐9. CENTRAL

Schmidt 2007a {published data only}

Schmidt P, Rom J, Maul H, Vaske B, Hillemanns P, Scharf A. Advanced first trimester screening (AFS): an improved test strategy for the individual risk assessment of fetal aneuploidies and malformations. Archives of Gynecology & Obstetrics 2007;276(2):159‐66. CENTRAL

Schmidt 2007b {published data only}

Schmidt P, Staboulidou I, Soergel P, Wustemann M, Hillemanns P, Scharf A. Comparison of Nicolaides' risk evaluation for Down's syndrome with a novel software: an analysis of 1,463 cases. Archives of Gynecology & Obstetrics 2007;275(6):469‐74. CENTRAL

Schmidt 2007c {published data only}

Schmidt P, Pruggmayer M, Steinborn A, Schippert C, Staboulidou I, Hillemanns P, et al. Are nuchal translucency, pregnancy associated plasma protein‐A or free‐beta‐human chorionic gonadotropin depending on maternal age? A multicenter study of 8,116 pregnancies. Archives of Gynecology & Obstetrics 2007;276(3):259‐62. CENTRAL

Schmidt 2008a {published data only}

Schmidt P, Hormansdorfer C, Pruggmayer M, Schutte C, Neumann A, Gerritzen A, et al. Improved prenatal aneuploidy screening using the novel advanced first‐trimester screening algorithm: a multicenter study of 10,017 pregnancies. Journal of Clinical Ultrasound 2008;36(7):397‐402. CENTRAL

Schmidt 2008b {published data only}

Schmidt P, Staboulidou I, Elsasser M, Vaske B, Hillemanns P, Scharf A. How imprecise may the measurement of fetal nuchal translucency be without worsening first‐trimester screening?. Fetal Diagnosis and Therapy 2008;24(3):291‐5. CENTRAL

Schmidt 2008c {published data only}

Schmidt P, Hormansdorfer C, Oehler K, Hartel H, Hillemanns P, Scharf A. [Three‐dimensional scatter plot analysis to estimate the risk of foetal aneuloidy]. [German]. Zeitschrift fur Geburtshilfe und Neonatologie 2008;212(4):127‐35. CENTRAL

Schmidt 2010 {published data only}

Schmidt P, Hormansdorfer C, Golatta M, Scharf A. Analysis of the distribution shift of detected aneuploidies by age independent first trimester screening. Archives of Gynecology & Obstetrics 2010;281(3):393‐9. CENTRAL

Schuchter 1998 {published data only}

Schuchter K, Wald N, Hackshaw AK, Hafner E, Liebhart E. The distribution of nuchal translucency at 10‐13 weeks of pregnancy. Prenatal Diagnosis 1998;18(3):281‐6. CENTRAL

Scott 1995 {published data only}

Scott F, Boogert A, Smart S, Anderson J. Maternal serum screening and routine 18‐week ultrasound in the detection of all chromosomal abnormalities. Australian & New Zealand Journal of Obstetrics & Gynaecology 1995;35(2):165‐8. CENTRAL

Seeds 1990 {published data only}

Seeds JW, Watson WJ. Ultrasound and maternal serum alpha‐fetoprotein screening: A complementary relationship. Ultrasound Quarterly 1990;8(2):145‐66. CENTRAL

Seki 1995 {published data only}

Seki K, Mitsui C, Nagata I. Measurement of urinary free ß‐human chorionic gonadotropin by immunoradiometric assay. Gynecologic and Obstetric Investigation 1995;40(3):162‐7. CENTRAL

Shenhav 2003 {published data only}

Shenhav S, Gemer O, Sherman DJ, Peled R, Segal S. Midtrimester triple‐test levels in women with chronic hypertension and altered renal function. Prenatal Diagnosis 2003;23(2):166‐7. CENTRAL

Shintaku 1989 {published data only}

Shintaku Y, Takabayashi T, Sasaki H, Ozawa N, Shinkawa O, Hamazaki Y, et al. [Screening for chromosomal anomalies with maternal serum alpha‐fetoprotein]. [Japanese]. Nippon Sanka Fujinka Gakkai Zasshi ‐ Acta Obstetrica et Gynaecologica Japonica 1989;41(2):185‐90. CENTRAL

Shulman 2003 {published data only}

Shulman A, Maymon R. Mid‐gestation Down syndrome screening test and pregnancy outcome among unstimulated assisted‐conception pregnancies. Prenatal Diagnosis 2003;23(8):625‐8. CENTRAL

Sieroszewski 2008 {published data only}

Sieroszewski P, Perenc M, Budecka EB, Sobala W, Deutinger J. Sonographical integrated test for detection of chromosomal aberrations. Ultraschall in der Medizin 2008;29(2):190‐6. CENTRAL

Simon‐Bouy 1999 {published data only}

Simon‐Bouy B. [Markers for trisomy 21][French]. Fertilite Contraception Sexualite 1999;27(9):289‐91. CENTRAL

Simpson 1986 {published data only}

Simpson JL, Baum LD, Marder R, Elias S, Ober C, Martin AO. Maternal serum alpha‐fetoprotein screening: low and high values for detection of genetic abnormalities. American Journal of Obstetrics and Gynecology 1986;155(3):593‐7. CENTRAL

Smith 1990 {published data only}

Smith C, Grube GL, Wilson S. Maternal serum alpha‐fetoprotein screening and the role of ultrasound. Journal of Diagnostic Medical Sonography 1990;6(6):312‐6. CENTRAL

Smith 1996 {published data only}

Smith ER, Petersen J, Okorodudu AO, Bissell MG. Does the addition of unconjugated estriol in maternal serum screening improve the detection of trisomy 21? A meta‐analysis. Clinical Laboratory Management Review 1996;10(2):176‐81. CENTRAL

Smith 1999 {published data only}

Smith NC, Hau C. A six year study of the antenatal detection of fetal abnormality in six Scottish health boards. British Journal of Obstetrics and Gynaecology 1999;106(3):206‐12. CENTRAL

Smith‐Bindman 2001 {published data only}

Smith‐Bindman R, Hosmer W, Feldstein VA, Deeks JJ, Goldberg JD. Second‐trimester ultrasound to detect fetuses with Down syndrome: a meta‐analysis.[see comment]. JAMA 2001;285(8):1044‐55. CENTRAL

Smith‐Bindman 2003 {published data only}

Smith‐Bindman R, Chu P, Bacchetti P, Waters JJ, Mutton D, Alberman E. Prenatal screening for Down syndrome in England and Wales and population‐based birth outcomes. American Journal of Obstetrics and Gynecology 2003;187(4):980‐5. CENTRAL

Snijders 1995 {published data only}

Snijders RJM, Sebire NJ, Nicolaides KH. Maternal age and gestational age‐specific risk for chromosomal defects. Fetal Diagnosis and Therapy 1995;10(6):356‐67. CENTRAL

Snijders 1999 {published data only}

Snijders RJM, Sundberg K, Holzgreve W, Henry G, Nicolaides KH. Maternal age‐ and gestation‐specific risk for trisomy 21. Ultrasound in Obstetrics and Gynecology 1999;13(3):167‐70. CENTRAL

Soergel 2006 {published data only}

Soergel P, Pruggmayer M, Schwerdtfeger R, Muhlhaus K, Scharf A. Screening for trisomy 21 with maternal age, fetal nuchal translucency and maternal serum biochemistry at 11‐14 weeks: a regional experience from Germany. Fetal Diagnosis and Therapy 2006;21(3):264‐8. CENTRAL

Sokol 1998 {published data only}

Sokol AI, Kramer RL, Yaron Y, O'Brien JE, Muller F, Johnson MP, et al. Age‐specific variation in aneuploidy incidence among biochemical screening programs. American Journal of Obstetrics and Gynecology 1998;179(4):971‐3. CENTRAL

Sonek 2003 {published data only}

Sonek JD. Nasal bone evaluation with ultrasonography: A marker for fetal aneuploidy. Ultrasound in Obstetrics and Gynecology 2003;22(1):11‐5. CENTRAL

Sonek 2007 {published data only}

Sonek J, Borenstein M, Downing C, McKenna D, Neiger R, Croom C, et al. Frontomaxillary facial angles in screening for trisomy 21 at 14‐23 weeks' gestation. American Journal of Obstetrics and Gynecology 2007;197(2):160‐5. CENTRAL

Sood 2010 {published data only}

Sood M, Rochelson B, Krantz D, Ravens R, Tam Tam H, Vohra N, et al. Are second‐trimester minor sonographic markers for Down syndrome useful in patients who have undergone first‐trimester combined screening?. American Journal of Obstetrics and Gynecology 2010;203(4):408‐4. CENTRAL

Sooklim 2010 {published data only}

Sooklim R, Manotaya S. Fetal facial sonographic markers for second trimester Down syndrome screening in a Thai population. International Journal of Gynaecology & Obstetrics 2010;111(2):144‐7. CENTRAL

Spencer 1985 {published data only}

Spencer K, Carpenter P. Screening for Down's syndrome using serum alpha fetoprotein: a retrospective study indicating caution. British Medical Journal Clinical Research Education 1985;290(6486):1940‐3. CENTRAL

Spencer 1991a {published data only}

Spencer K. Evaluation of an assay of the free ß‐subunit of choriogonadotropin and its potential value in screening for Down's syndrome. Clinical Chemistry 1991;37(6):809‐14. CENTRAL

Spencer 1991b {published data only}

Spencer K. Maternal serum CA125 is not a second trimester marker for Down's syndrome. Annals of Clinical Biochemistry 1991;28(3):299‐300. CENTRAL

Spencer 1992 {published data only}

Spencer K, Coombes EJ, Mallard AS, Ward AM. Free ß human choriogonadotropin in Down's syndrome screening: a multicentre study of its role compared with other biochemical markers.[see comment]. Annals of Clinical Biochemistry 1992;29(5):506‐18. CENTRAL

Spencer 1993a {published data only}

Spencer K, Carpenter P. Prospective study of prenatal screening for Down's syndrome with free ß human chorionic gonadotrophin.[see comment]. BMJ 1993;307(6907):764‐9. CENTRAL

Spencer 1993b {published data only}

Spencer K, Macri JN, Carpenter P, Anderson R, Krantz DA. Stability of intact chorionic gonadotropin (hCG) in serum, liquid whole blood, and dried whole‐blood filter‐paper spots: impact on screening for Down syndrome by measurement of free ß‐hCG subunit. Clinical Chemistry 1993;39(6):1064‐8. CENTRAL

Spencer 1993c {published data only}

Spencer K, Wood PJ, Anthony FW. Elevated levels of maternal serum Inhibin Aimmunoreactivity in second trimester pregnancies affected by Down's syndrome. Annals of Clinical Biochemistry 1993;30(2):219‐20. CENTRAL

Spencer 1993d {published data only}

Spencer K, Macri JN, Anderson RW, Aitken DA, Berry E, Crossley JA, et al. Dual analyte immunoassay in neural tube defect and Down's syndrome screening: results of a multicentre clinical trial. Annals of Clinical Biochemistry 1993;30(4):394‐401. CENTRAL

Spencer 1993e {published data only}

Spencer K. Free alpha‐subunit of human chorionic gonadotropin in Down syndrome. American Journal of Obstetrics and Gynecology 1993;168(1):132‐5. CENTRAL

Spencer 1995a {published data only}

Spencer K. The influence of gravidity on Down's syndrome screening with free ß hCG. Prenatal Diagnosis 1995;15(1):87‐9. CENTRAL

Spencer 1996b {published data only}

Spencer K, Wallace EM, Ritoe S. Second‐trimester dimeric inhibin‐A in Down's syndrome screening. Prenatal Diagnosis 1996;16(12):1101‐10. CENTRAL

Spencer 1997 {published data only}

Spencer K, Noble P, Snijders RJ, Nicolaides KH. First‐trimester urine free ß hCG, ß core, and total oestriol in pregnancies affected by Down's syndrome: implications for first‐trimester screening with nuchal translucency and serum free ß hCG. Prenatal Diagnosis 1997;17(6):525‐38. CENTRAL

Spencer 1998a {published data only}

Spencer K. The influence of smoking on maternal serum AFP and free ß hCG levels and the impact on screening for Down syndrome. Prenatal Diagnosis 1998;18(3):225‐34. CENTRAL

Spencer 1998b {published data only}

Spencer K, Carpenter P. Is prostate‐specific antigen a marker for pregnancies affected by Down syndrome?. Clinical Chemistry 1998;44(11):2362‐5. CENTRAL

Spencer 1999a {published data only}

Spencer K. Second trimester prenatal screening for Down's syndrome using alpha‐fetoprotein and free ß hCG: a seven year review. British Journal of Obstetrics and Gynaecology 1999;106(12):1287‐93. CENTRAL

Spencer 1999b {published data only}

Spencer K. Accuracy of Down's syndrome risks produced in a prenatal screening program. Annals of Clinical Biochemistry 1999;36(1):101‐3. CENTRAL

Spencer 2000a {published data only}

Spencer K, Berry E, Crossley JA, Aitken DA, Nicolaides KH. Is maternal serum total hCG a marker of trisomy 21 in the first trimester of pregnancy?. Prenatal Diagnosis 2000;20(4):311‐7. CENTRAL

Spencer 2000b {published data only}

Spencer K. Screening for trisomy 21 in twin pregnancies in the first trimester using free ß‐hCG and PAPP‐A, combined with fetal nuchal translucency thickness. Prenatal Diagnosis 2000;20(2):91‐5. CENTRAL

Spencer 2000c {published data only}

Spencer K. The influence of smoking on maternal serum PAPP‐A and free ß hCG levels in the first trimester of pregnancy. Prenatal Diagnosis 1999;19(11):1065‐6. CENTRAL

Spencer 2000d {published data only}

Spencer K, Ong CY, Liao AW, Nicolaides KH. The influence of parity and gravidity on first trimester markers of chromosomal abnormality. Prenatal Diagnosis 2000;20(10):792‐4. CENTRAL

Spencer 2000e {published data only}

Spencer K. The influence of fetal sex in screening for Down syndrome in the second trimester using AFP and free ß‐hCG. Prenatal Diagnosis 2000;20(8):648‐51. CENTRAL

Spencer 2000f {published data only}

Spencer K, Ong CY, Liao AW, Nicolaides KH. The influence of ethnic origin on first trimester biochemical markers of chromosomal abnormalities. Prenatal Diagnosis 2000;20(6):491‐4. CENTRAL

Spencer 2000g {published data only}

Spencer K, Tul N, Nicolaides KH. Maternal serum free ß‐hCG and PAPP‐A in fetal sex chromosome defects in the first trimester. Prenatal Diagnosis 2000;20(5):390‐4. CENTRAL

Spencer 2000h {published data only}

Spencer K. Second‐trimester prenatal screening for Down syndrome and the relationship of maternal serum biochemical markers to pregnancy complications with adverse outcome. Prenatal Diagnosis 2000;20(8):652‐6. CENTRAL

Spencer 2000i {published data only}

Spencer K, Ong CY, Liao AW, Papademetriou D, Nicolaides KH. The influence of fetal sex in screening for trisomy 21 by fetal nuchal translucency, maternal serum free ß‐hCG and PAPP‐A at 10‐14 weeks of gestation. Prenatal Diagnosis 2000;20(8):673‐5. CENTRAL

Spencer 2001a {published data only}

Spencer K. Age related detection and false positive rates when screening for Down's syndrome in the first trimester using fetal nuchal translucency and maternal serum free ßhCG and PAPP‐A. BJOG: an international journal of obstetrics and gynaecology 2001;108(10):1043‐6. CENTRAL

Spencer 2001b {published data only}

Spencer K, Liao AW, Ong CY, Geerts L, Nicolaides KH. First trimester maternal serum placenta growth factor (PIGF)concentrations in pregnancies with fetal trisomy 21 or trisomy 18. Prenatal Diagnosis 2001;21(9):718‐22. CENTRAL

Spencer 2001c {published data only}

Spencer K, Liao AW, Ong CY, Geerts L, Nicolaides KH. Maternal serum levels of dimeric Inhibin A in pregnancies affected by trisomy 21 in the first trimester. Prenatal Diagnosis 2001;21(6):441‐4. CENTRAL

Spencer 2001d {published data only}

Spencer K, Liao AW, Skentou H, Ong CY, Nicolaides KH. Maternal serum levels of total activin‐A in first‐trimester trisomy 21 pregnancies. Prenatal Diagnosis 2001;21(4):270‐3. CENTRAL

Spencer 2001e {published data only}

Spencer K. Screening for trisomy 21 in twin pregnancies in the first trimester: does chorionicity impact on maternal serum free ß‐hCG or PAPP‐A levels?. Prenatal Diagnosis 2001;21(9):715‐7. CENTRAL

Spencer 2002a {published data only}

Spencer K, Nicolaides KH. A first trimester trisomy 13/trisomy 18 risk algorithm combining fetal nuchal translucency thickness, maternal serum free ß‐hCG and PAPP‐A. Prenatal Diagnosis 2002;22(10):877‐9. CENTRAL

Spencer 2002b {published data only}

Spencer K. Accuracy of Down syndrome risks produced in a first‐trimester screening programme incorporating fetal nuchal translucency thickness and maternal serum biochemistry. Prenatal Diagnosis 2002;22(3):244‐6. CENTRAL

Spencer 2002c {published data only}

Spencer K, Cuckle HS. Screening for chromosomal anomalies in the first trimester: does repeat maternal serum screening improve detection rates?. Prenatal Diagnosis 2002;22(10):903‐6. CENTRAL

Spencer 2002d {published data only}

Spencer K, Crossley JA, Aitken DA, Nix AB, Dunstan FD, Williams K. Temporal changes in maternal serum biochemical markers of trisomy 21 across the first and second trimester of pregnancy. Annals of Clinical Biochemistry 2002;39(6):567‐76. CENTRAL

Spencer 2003a {published data only}

Spencer K, Crossley JA, Aitken DA, Nix AB, Dunstan FD, Williams K. The effect of temporal variation in biochemical markers of trisomy 21 across the first and second trimesters of pregnancy on the estimation of individual patient‐specific risks and detection rates for Down's syndrome. Annals of Clinical Biochemistry 2003;40(3):219‐31. CENTRAL

Spencer 2003b {published data only}

Spencer K. The influence of different sample collection types on the levels of markers used for Down's syndrome screening as measured by the Kryptor Immunosassay system. Annals of Clinical Biochemistry 2003;40(2):166‐8. CENTRAL

Spencer 2003c {published data only}

Spencer K, Bindra R, Nicolaides KH. Maternal weight correction of maternal serum PAPP‐A and free ß‐hCG MoM when screening for trisomy 21 in the first trimester of pregnancy. Prenatal Diagnosis 2003;23(10):851‐5. CENTRAL

Spencer 2003d {published data only}

Spencer K, Nicolaides KH. Screening for trisomy 21 in twins using first trimester ultrasound and maternal serum biochemistry in a one‐stop clinic: a review of three years experience. BJOG: an international journal of obstetrics and gynaecology 2003;110(3):279‐80. CENTRAL

Spencer 2004 {published data only}

Spencer K, Bindra R, Cacho AM, Nicolaides KH. The impact of correcting for smoking status when screening for chromosomal anomalies using maternal serum biochemistry and fetal nuchal translucency thickness in the first trimester of pregnancy. Prenatal Diagnosis 2004;24(3):169‐73. CENTRAL

Spencer 2005a {published data only}

Spencer K, Cicero S, Atzei A, Otigbah C, Nicolaides KH. The influence of maternal insulin‐dependent diabetes on fetal nuchal translucency thickness and first‐trimester maternal serum biochemical markers of aneuploidy. Prenatal Diagnosis 2005;25(10):927‐9. CENTRAL

Spencer 2005b {published data only}

Spencer K, Heath V, El‐Sheikhah A, Ong CY, Nicolaides KH. Ethnicity and the need for correction of biochemical and ultrasound markers of chromosomal anomalies in the first trimester: a study of Oriental, Asian and Afro‐Caribbean populations. Prenatal Diagnosis 2005;25(5):365‐9. CENTRAL

Spencer 2005c {published data only}

Spencer K. First trimester maternal serum screening for Down's syndrome: an evaluation of the DPC Immulite 2000 free ß‐hCG and pregnancy‐associated plasma protein‐A assays.[see comment]. Annals of Clinical Biochemistry 2005;42(1):30‐40. CENTRAL

Spencer 2008a {published data only}

Spencer K, Cowans NJ, Uldbjerg N, Vereecken A, Torring N. First trimester intact hCG as an early marker of trisomy 21: a promise unrecognised?. Prenatal Diagnosis 2008;28(12):1156‐9. CENTRAL

Spong 1999 {published data only}

Spong CY, Ghidini A, Stanley‐Christian H, Meck JM, Seydel FD, Pezzullo JC. Risk of abnormal triple screen for Down syndrome is significantly higher in women with female fetuses. Prenatal Diagnosis. 1999;19(4):337‐9. CENTRAL

Staboulidou 2009 {published data only}

Staboulidou I, Galindo A, Maiz N, Karagiannis G, Nicolaides KH. First‐trimester uterine artery Doppler and serum pregnancy‐associated plasma protein‐a in preeclampsia and chromosomal defects. Fetal Diagnosis and Therapy 2009;25(3):336‐9. CENTRAL

Stevens 1998 {published data only}

Stevens SL. The use of nuchal lucency as a screening tool in first trimester sonography. Journal of Diagnostic Medical Sonography 1998;14(6):251‐4. CENTRAL

Stoll 1992 {published data only}

Stoll C. A new approach of prenatal prevention of constiutional disabilities ‐ the study of markers of maternal serum. Journal de Medecine de Strasbourg 1992;23(1):25‐7. CENTRAL

Stressig 2011 {published data only}

Stressig R, Kozlowski P, Froehlich S, Siegmann HJ, Hammer R, Blumenstock G, et al. Assessment of the ductus venosus, tricuspid blood flow and the nasal bone in second‐trimester screening for trisomy 21. Ultrasound in Obstetrics & Gynecology 2011;37(4):444‐9. CENTRAL

Su 2002a {published data only}

Su YN, Hsu JJ, Lee CN, Cheng WF, Kung CC, Hsieh FJ. Raised maternal serum placenta growth factor concentration during the second trimester is associated with Down syndrome. Prenatal Diagnosis 2002;22(1):8‐12. CENTRAL

Suchet 1995 {published data only}

Suchet IB. Ultrasonography of the fetal neck in the first and second trimesters. Part 2. Anomalies of the posterior nuchal region. Canadian Association of Radiologists Journal 1995;46(5):344‐52. CENTRAL

Suchy 1990 {published data only}

Suchy SF, Yeager MT. Down syndrome screening in women under 35 with maternal serum hCG. Obstetrics & Gynecology 1990;76(1):20‐4. CENTRAL

Summers 2003a {published data only}

Summers AM, Farrell SA, Huang T, Meier C, Wyatt PR. Maternal serum screening in Ontario using the triple marker test. Journal of Medical Screening 2003;10(3):107‐11. CENTRAL

Summers 2003b {published data only}

Summers AM, Huang T, Meier C, Wyatt PR. The implications of a false positive second‐trimester serum screen for Down syndrome. Obstetrics & Gynecology 2003;101(6):1301‐6. CENTRAL

Suntharasaj 2005 {published data only}

Suntharasaj T, Ratanasiri T, Chanprapaph P, Kengpol C, Kor‐anantakul O, Leetanaporn R, et al. Variability of nuchal translucency measurement: a multicenter study in Thailand. Gynecologic & Obstetric Investigation 2005;60(4):201‐5. CENTRAL

Susman 2010 {published data only}

Susman MR, Amor DJ, Muggli E, Jaques AM, Halliday J. Using population‐based data to predict the impact of introducing noninvasive prenatal diagnosis for Down syndrome. Genetics in Medicine 2010;12(5):298‐303. CENTRAL

Sutton 2004 {published data only}

Sutton JM, Cole LA. Sialic acid‐deficient invasive trophoblast antigen (sd‐ITA): a new urinary variant for gestational Down syndrome screening. Prenatal Diagnosis 2004;24(3):194‐7. CENTRAL

Suzuki 1998 {published data only}

Suzuki Y, Takada J, Iwaki T, Isaka K, Takayama M. Screening for trisomy 21 in the first trimester by measurement of serum PAPP‐A and free ß‐hCG. Acta Obstetrica et Gynaecologica Japonica 1998;50(1):37‐40. CENTRAL

Tabor 1987 {published data only}

Tabor A, Larsen SO, Nielsen J, Nielsen J, Philip J, Pilgaard B, et al. Screening for Down's syndrome using an iso‐risk curve based on maternal age and serum alpha‐fetoprotein level. British Journal of Obstetrics and Gynaecology 1987;94(7):636‐42. CENTRAL

Tanski 1999 {published data only}

Tanski S, Rosengren SS, Benn PA. Predictive value of the triple screening test for the phenotype of Down syndrome. American Journal of Medical Genetics 1999;85(2):123‐6. CENTRAL

Thilaganathan 1998 {published data only}

Thilaganathan B, Khare M, Williams B, Wathen NC. Influence of ethnic origin on nuchal translucency screening for Down's syndrome. Ultrasound in Obstetrics & Gynecology 1998;12(2):112‐4. CENTRAL

Thilaganathan 1999b {published data only}

Thilaganathan B. First‐trimester nuchal translucency and maternal serum biochemical screening for Down's syndrome: A happy union?. Ultrasound in Obstetrics and Gynecology 1999;13(4):229‐30. CENTRAL

Tislaric 2002 {published data only}

Tislaric D, Brajenovic‐Milic B, Ristic S, Latin V, Zuvic‐Butorac M, Bacic J, et al. The influence of smoking and parity on serum markers for Down's syndrome screening. Fetal Diagnosis and Therapy 2002;17(1):17‐21. CENTRAL

Torok 1997 {published data only}

Torok O, Veress L, Szabo M, Zsupan I, Buczko Z, Bolodar A, et al. [Biochemical and ultrasonic screening of chromosomal aneuploidies in the second trimester of pregnancy]. [Hungarian]. Orvosi Hetilap 1997;138(3):123‐7. CENTRAL

Torring 2009 {published data only}

Torring N. Performance of first‐trimester screening between gestational weeks 7 and 13. Clinical Chemistry 2009;55(8):1564‐7. CENTRAL

Trninic‐Pjevic 2007 {published data only}

Trninic‐Pjevic A, Novakov‐Mikic A. [First trimester ultrasound screening of chromosomal abnormalities]. [Serbian]. Srpski Arhiv Za Celokupno Lekarstvo 2007;135(3‐4):153‐6. CENTRAL

Tsai 2001 {published data only}

Tsai MS, Huang YY, Hwa KY, Cheng CC, Lee FK. Combined measurement of fetal nuchal translucency, maternal serum free ß‐hCG, and pregnancy‐associated plasma protein A for first‐trimester Down's syndrome screening. Journal of the Formosan Medical Association 2001;100(5):319‐25. CENTRAL

Valerio 1996 {published data only}

Valerio D, Aiello R, Altieri V, Fagnoni P. Maternal serum screening of fetal chromosomal abnormalities by AFP, UE3, hCG and free‐ß hCG. Prospective and retrospective results. Minerva Ginecologica 1996;48(5):169‐73. CENTRAL

Van Blerk 1992 {published data only}

Van Blerk M, Smitz J, De Catte L, Kumps C, Van der Elst J, Van Steirteghem AC. Second‐trimester cancer antigen 125 and Down's syndrome.[see comment]. Prenatal Diagnosis 1992;12(12):1062‐6. CENTRAL

Van Dyke 2007 {published data only}

Van Dyke DL, Ebrahim SA, Al Saadi AA, Powell SA, Zenger‐Hain JL, Micale MA, et al. The impact of maternal serum screening programs for Down syndrome in southeast Michigan, 1988‐2003. Prenatal Diagnosis 2007;27(6):583‐4. CENTRAL

Van Heesch, 2006 {published data only}

Van Heesch, Schielen PCJ I, Wildhagen MF, Den Hollander, Steegers EAP, Wildschut HIJ. Combined first trimester screening for trisomy 21: Lack of agreement between risk calculation methods. Journal of Perinatal Medicine 2006;34(2):162‐5. CENTRAL

Van Lith, 1993 {published data only}

Van Lith, Mantingh A, De Bruijn. Maternal serum CA 125 levles in pregnancies with chromosomally‐normal and ‐abnormal fetuses. Prenatal Diagnosis 1993;13(12):1123‐31. CENTRAL

Van Lith, 1994 {published data only}

Van Lith, Mantingh A, Pratt JJ. First‐Trimester maternal serum immunoreactive Inhibin Ain chromosomally normal and abnormal pregnancies. Obstetrics and Gynecology 1994;83(5 I):661‐4. CENTRAL

Van Lith 1991 {published data only}

Van Lith JM, Mantingh A, Beekhuis JR, de Bruijn HW, Breed AS. First trimester CA 125 and Down's syndrome.[see comment]. British Journal of Obstetrics and Gynaecology 1991;98(5):493‐4. CENTRAL

Veress 1986 {published data only}

Veress L, Szabo M, Horvath K, Polgar K, Papp Z. [Low maternal serum alpha‐fetoprotein concentration and Down syndrome]. [Hungarian]. Orvosi Hetilap 1986;127(20):1232‐3. CENTRAL

Veress 1988 {published data only}

Veress L, Szabo M, Polgar K, Takacs L, Papp Z. [Prenatal screening for Down's syndrome by measuring the AFP concentration in the maternal serum]. [Hungarian]. Orvosi Hetilap 1988;129(31):1677. CENTRAL

Vergani 2008 {published data only}

Vergani P, Ghidini A, Weiner S, Locatelli A, Pozzi E, Biffi A. Risk assessment for Down syndrome with genetic sonogram in women at risk. Prenatal Diagnosis 2008;28(12):1144‐8. CENTRAL

Vintzileos 2003 {published data only}

Vintzileos A, Walters C, Yeo L. Absent nasal bone in the prenatal detection of fetuses with trisomy 21 in a high‐risk population. Obstetrics & Gynecology 2003;101(5):905‐8. CENTRAL

Wald 1988a {published data only}

Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston P, Chard T, et al. Maternal serum screening for Down's syndrome in early pregnancy. BMJ 1988;297(6653):883‐7. CENTRAL

Wald 1988b {published data only}

Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. British Journal of Obstetrics and Gynaecology 1988;95(4):334‐41. CENTRAL

Wald 1991 {published data only}

Wald N, Cuckle H, Wu TS, George L. Maternal serum unconjugated oestriol and human chorionic gonadotrophin levels in twin pregnancies: implications for screening for Down's syndrome. British Journal of Obstetrics and Gynaecology 1991;98(9):905‐8. CENTRAL

Wald 1992a {published data only}

Wald NJ, Kennard A, Densem JW, Cuckle HS, Chard T, Butler L. Antenatal maternal serum screening for Down's syndrome: results of a demonstration project.[see comment]. BMJ 1992;305(6850):391‐4. CENTRAL

Wald 1992b {published data only}

Wald NJ, Cuckle HS, Densem JW, Stone RB. Maternal serum unconjugated oestriol and human chorionic gonadotrophin levels in pregnancies with insulin‐dependent diabetes: implications for screening for Down's syndrome. British Journal of Obstetrics and Gynaecology 1992;99(1):51‐3. CENTRAL

Wald 1992c {published data only}

Wald NJ, Cuckle HS, Densem JW, Kennard A, Smith D. Maternal serum screening for Down's syndrome: the effect of routine ultrasound scan determination of gestational age and adjustment for maternal weight.[see comment]. British Journal of Obstetrics and Gynaecology 1992;99(2):144‐9. CENTRAL

Wald 1993 {published data only}

Wald N, Densem J, Stone R, Cheng R. The use of free ß‐hCG in antenatal screening for Down's syndrome.[see comment]. British Journal of Obstetrics and Gynaecology 1993;100(6):550‐7. CENTRAL

Wald 1994a {published data only}

Wald NJ, Densem JW. Maternal serum free alpha‐human chorionic gonadotrophin levels in twin pregnancies: implications for screening for Down's syndrome. Prenatal Diagnosis 1994;14(8):717‐9. CENTRAL

Wald 1994b {published data only}

Wald NJ, Watt HC. Choice of serum markers in antenatal screening for Down's syndrome. Journal of Medical Screening 1994;1(2):117‐20. CENTRAL

Wald 1996a {published data only}

Wald NJ, Watt HC. Serum markers for Down's syndrome in relation to number of previous births and maternal age. Prenatal Diagnosis 1996;16(8):699‐703. CENTRAL

Wald 1996b {published data only}

Wald NJ, George L, Smith D, Densem JW, Petterson K. Serum screening for Down's syndrome between 8 and 14 weeks of pregnancy. International Prenatal Screening Research Group.[see comment]. British Journal of Obstetrics and Gynaecology 1996;103(5):407‐12. CENTRAL

Wald 1996c {published data only}

Wald NJ, Watt HC, George L. Maternal serum inhibin‐A in pregnancies with insulin‐dependent diabetes mellitus: implications for screening for Down's syndrome. Prenatal Diagnosis 1996;16(10):923‐6. CENTRAL

Wald 1996d {published data only}

Wald NJ, Densem JW, George L, Muttukrishna S, Knight PG. Prenatal screening for Down's syndrome using inhibin‐A as a serum marker. Prenatal Diagnosis 1996;16(2):143‐53. CENTRAL

Wald 1997 {published data only}

Wald NJ, Hackshaw AK. Combining ultrasound and biochemistry in first‐trimester screening for Down's syndrome.[see comment]. Prenatal Diagnosis 1997;17(9):821‐9. CENTRAL

Wald 1998 {published data only}

Wald NJ, Watt HC, Haddow JE, Knight GJ. Screening for Down syndrome at 14 weeks of pregnancy. Prenatal Diagnosis 1998;18(3):291‐3. CENTRAL

Wald 1999a {published data only}

Wald NJ, Hackshaw AK, Diamandis EP, Melegos DN. Maternal serum prostate‐specific antigen and Down syndrome in the first and second trimesters of pregnancy. Prenatal Diagnosis 1999;19(7):674‐6. CENTRAL

Wald 1999b {published data only}

Wald NJ, Watt HC, Norgaard Pederson B, Christiansen M. SP1 in pregnancies with Down syndrome in the first trimester of pregnancy. Prenatal Diagnosis 1999;19(6):517‐20. CENTRAL

Wald 1999c {published data only}

Wald NJ, White N, Morris JK, Huttly WJ, Canick JA. Serum markers for Down's syndrome in women who have had in vitro fertilisation: implications for antenatal screening. British Journal of Obstetrics and Gynaecology 1999;106(12):1304‐6. CENTRAL

Wald 1999d {published data only}

Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters.[see comment]. New England Journal of Medicine 1999;341(7):461‐7. CENTRAL

Wald 2003b {published data only}

Wald NJ, Rish S, Hackshaw AK. Combining nuchal translucency and serum markers in prenatal screening for Down syndrome in twin pregnancies. Prenatal Diagnosis 2003;23(7):588‐92. CENTRAL

Wald 2003c {published data only}

Wald NJ, Huttly WJ, Hackshaw AK. Antenatal screening for Down's syndrome with the quadruple test.[see comment]. Lancet 2003;361(9360):835‐6. CENTRAL

Wald 2006 {published data only}

Wald NJ, Rudnicka AR, Bestwick JP. Sequential and contingent prenatal screening for Down syndrome. Prenatal Diagnosis 2006;26(9):769‐77. CENTRAL

Wallace 1994 {published data only}

Wallace EM, Harkness LM, Burns S, Liston WA. Evaluation of maternal serum immunoreactive Inhibin Aas a first trimester marker of Down's syndrome. Clinical Endocrinology 1994;41(4):483‐6. CENTRAL

Wallace 1997 {published data only}

Wallace EM, Crossley JA, Ritoe SC, Groome NP, Aitken DA. Maternal serum inhibin‐A in pregnancies complicated by insulin dependent diabetes mellitus. British Journal of Obstetrics and Gynaecology 1997;104(8):946‐8. CENTRAL

Wang 2010 {published data only}

Wang E, Chen C, Glimco E, Grobman W. The performance of second trimester long bone ratios for Down syndrome screening is influenced by gestational age. Journal of Maternal‐Fetal & Neonatal Medicine 2010;23(7):642‐5. CENTRAL

Ward 2005 {published data only}

Ward A. Nuchal translucency measurement. Synergy (http://www.highbeam.com/doc/1P3‐866108421.html) (accessed 2007)2005. CENTRAL

Watt 1996a {published data only}

Watt HC, Wald NJ, Smith D, Kennard A, Densem J. Effect of allowing for ethnic group in prenatal screening for Down's syndrome. Prenatal Diagnosis 1996;16(8):691‐8. CENTRAL

Watt 1996b {published data only}

Watt HC, Wald NJ, George L. Maternal serum inhibin‐A levels in twin pregnancies: implications for screening for Down's syndrome. Prenatal Diagnosis 1996;16(10):927‐9. CENTRAL

Wax 2007 {published data only}

Wax JR, Pinette MG, Cartin A, Blackstone J. Optimal crown‐rump length for measuring the nuchal translucency. Journal of Clinical Ultrasound 2007;35(6):302‐4. CENTRAL

Weinans 2001 {published data only}

Weinans MJN, Pratt JJ, De Wolf, Mantingh A. First‐trimester maternal serum human thyroid‐stimulating hormone in chromosomally normal and Down syndrome pregnancies. Prenatal Diagnosis 2001;21(9):723‐5. CENTRAL

Weinans 2004 {published data only}

Weinans MJN, Kooij L, Müller MA, Bilardo KM, Van Lith, Tymstra T. A comparison of the impact of screen‐positive results obtained from ultrasound and biochemical screening for Down syndrome in the first trimester: A pilot study. Prenatal Diagnosis 2004;24(5):347‐51. CENTRAL

Weisz 2007 {published data only}

Weisz B, Pandya P, Chitty L, Jones P, Huttly W, Rodeck C. Practical issues drawn from the implementation of the integrated test for Down syndrome screening into routine clinical practice. BJOG: an international journal of obstetrics and gynaecology 2007;114(4):493‐7. CENTRAL

Welborn 1994 {published data only}

Welborn JL, Timm NS. Trisomy 21 and cystic hygromas in early gestational age fetuses. American Journal of Perinatology 1994;11(1):19‐20. CENTRAL

Wenstrom 1993 {published data only}

Wenstrom KD, Williamson RA, Grant SS, Hudson JD, Getchell JP. Evaluation of multiple‐marker screening for Down syndrome in a statewide population. American Journal of Obstetrics and Gynecology 1993;169(4):793‐7. CENTRAL

Wenstrom 1995a {published data only}

Wenstrom KD, Owen J, Boots L, Ethier M. The influence of maternal weight on human chorionic gonadotropin in the multiple‐marker screening test for fetal Down syndrome. American Journal of Obstetrics and Gynecology 1995;173(4):1297‐300. CENTRAL

Wenstrom 1995b {published data only}

Wenstrom KD, Desai R, Owen J, Dubard MB, Boots L. Comparison of multiple‐marker screening with amniocentesis for the detection of fetal aneuploidy in women greater than or equal35 years old. American Journal of Obstetrics and Gynecology 1995;173(4):1287‐92. CENTRAL

Wetta 2011 {published data only}

Wetta L, Biggio J, Owen J. Use of ethnic‐specific medians for Hispanic patients reduces ethnic disparities in multiple marker screening. Prenatal Diagnosis 2011;31(4):331‐3. CENTRAL

Whitlow 1998a {published data only}

Whitlow BJ, Lazanakis ML, Kadir RA, Chatzipapas I, Economides DL. The significance of choroid plexus cysts, echogenic heart foci and renal pyelectasis in the first trimester. Ultrasound in Obstetrics & Gynecology 1998;12(6):385‐90. CENTRAL

Whitlow 1998b {published data only}

Whitlow BJ, Economides DL. First trimester detection of fetal abnormalities in an unselected population. Contemporary Reviews in Obstetrics and Gynaecology 1998;10(4):245‐53. CENTRAL

Whitlow 1999 {published data only}

Whitlow BJ, Chatzipapas IK, Lazanakis ML, Kadir RA, Economides DL. The value of sonography in early pregnancy for the detection of fetal abnormalities in an unselected population. British Journal of Obstetrics and Gynaecology 1999;106(9):929‐36. CENTRAL

Williamson 1994 {published data only}

Williamson R. Expanded maternal serum alpha fetoprotein screening. Iowa Medicine 1994;84(9):397‐400. CENTRAL

Wilson 2000 {published data only}

Wilson K. New first‐trimester prenatal screening for down syndrome. Laboratory Medicine 2000;31(11):591. CENTRAL

Wojdemann 2001 {published data only}

Wojdemann KR, Larsen SO, Shalmi A, Sundberg K, Christiansen M, Tabor A. First trimester screening for Down syndrome and assisted reproduction: no basis for concern. Prenatal Diagnosis 2001;21(7):563‐5. CENTRAL

Wong 2003 {published data only}

Wong SF, Choi H, Ho LC. Nasal bone hypoplasia: is it a common finding amongst chromosomally normal fetuses of southern Chinese women?. Gynecologic & Obstetric Investigation 2003;56(2):99‐101. CENTRAL

Wright 2006 {published data only}

Wright D, Bradbury I, Cuckle H, Gardosi J, Tonks A, Standing S, et al. Three‐stage contingent screening for Down syndrome. Prenatal Diagnosis 2006;26(6):528‐34. CENTRAL

Wright 2007 {published data only}

Wright D, Spencer K, Nix B. First trimester screening for Down syndrome using free beta hCG, total hCG and PAPP‐A: an exploratory study. Prenatal Diagnosis 2007;27(12):1118‐22. CENTRAL

Xie 2010 {published data only}

Xie Z, Lu S, Li H. Contingent triple‐screening for Down syndrome in the second trimester: a feasibility study in Mainland Chinese population. Prenatal Diagnosis 2010;30(1):74‐6. CENTRAL

Yagel 1998 {published data only}

Yagel S, Anteby EY, Hochner‐Celnikier D, Ariel I, Chaap T, Ben Neriah Z. The role of midtrimester targeted fetal organ screening combined with the "triple test" and maternal age in the diagnosis of trisomy 21: a retrospective study. American Journal of Obstetrics and Gynecology 1998;178(1):40‐4. CENTRAL

Yamamoto 2001a {published data only}

Yamamoto R, Azuma M, Kishida T, Yamada H, Satomura S, Fujimoto S. Total alpha‐fetoprotein and Lens culinaris agglutinin‐reactive alpha‐fetoprotein in fetal chromosomal abnormalities. BJOG: an international journal of obstetrics and gynaecology 2001;108(11):1154‐8. CENTRAL

Yamamoto 2001b {published data only}

Yamamoto R, Azuma M, Hoshi N, Kishida T, Satomura S, Fujimoto S. Lens culinaris agglutinin‐reactive alpha‐fetoprotein, an alternative variant to alpha‐fetoprotein in prenatal screening for Down's syndrome. Human Reproduction 2001;16(11):2438‐44. CENTRAL

Yamamoto 2001c {published data only}

Yamamoto R, Azuma M, Wakui Y, Kishida T, Yamada H, Okuyama K, et al. Alpha‐fetoprotein microheterogeneity: a potential biochemical marker for Down's syndrome. Clinica Chimica Acta 2001;304(1‐2):137‐41. CENTRAL

Yaron 2001 {published data only}

Yaron Y, Wolman I, Kupferminc MJ, Ochshorn Y, Many A, Orr‐Urtreger A. Effect of fetal gender on first trimester markers and on Down syndrome screening. Prenatal Diagnosis 2001;21(12):1027‐30. CENTRAL

Ye 1995 {published data only}

Ye Guoling Liao Shixiu, Zhao Xiaolan. The possibility of prenatal screening for fetal abnormalities in second‐trimester pregnancies by measuring AFP, ß‐HCG and uE‐3 levels. Xi'an Yike Daxue Xuebao 1995;16(4):408‐11. CENTRAL

Yoshida 2000 {published data only}

Yoshida K, Kuwabara Y, Tanaka T, Onda T, Kudo R, Yamamoto H, et al. Dimeric Inhibin A as a fourth marker for Down's syndrome maternal serum screening in native Japanese women. Journal of Obstetrics and Gynaecology Research 2000;26(3):171‐4. CENTRAL

Zalel 2008 {published data only}

Zalel Y, Achiron R, Yagel S, Kivilevitch Z. Fetal aberrant right subclavian artery in normal and Down syndrome fetuses. Ultrasound in Obstetrics & Gynecology 2008;31(1):25‐9. CENTRAL

Zeitune 1991 {published data only}

Zeitune M, Aitken DA, Crossley JA, Yates JRW, Cooke A, Ferguson‐Smith A. Estimating the risk of a fetal autosomal trisomy at mid‐trimester using maternal serum alpha‐fetoprotein and age: A retrospective study of 142 pregnancies. Prenatal Diagnosis 1991;11(11):847‐57. CENTRAL

Zelop 2005 {published data only}

Zelop CM, Milewski E, Brault K, Benn P, Borgida AF, Egan JFX. Variation of fetal nasal bone length in second‐trimester fetuses according to race and ethnicity. Journal of Ultrasound in Medicine 2005;24(11):1487‐9. CENTRAL

Zhang 2011 {published data only}

Zhang J, Lambert‐Messerlian G, Palomaki GE, Canick JA. Impact of smoking on maternal serum markers and prenatal screening in the first and second trimesters. Prenatal Diagnosis 2011;31(6):583‐8. CENTRAL

Zhao 1998 {published data only}

Zhao Xiaolan, Ye Guoling, Liu Qi. Using maternal serum PAPP‐A and other pregnancy‐associated proteins in screening for fetal abnormalities. Xi'an Yike Daxue Xuebao 1998;19(1):94‐6, 110. CENTRAL

Zhong 2011 {published data only}

Zhong Y, Longman R, Bradshaw R, Odibo AO. The genetic sonogram: comparing the use of likelihood ratios versus logistic regression coefficients for Down syndrome screening. Journal of Ultrasound in Medicine 2011;30(4):463‐9. CENTRAL

Zoppi 2003a {published data only}

Zoppi MA, Ibba RM, Floris M, Manca F, Axiana C, Monni G. Changes in nuchal translucency thickness in normal and abnormal karyotype fetuses. BJOG: an international journal of obstetrics and gynaecology 2003;110(6):584‐8. CENTRAL

Additional references

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Akolekar 2015

Akolekar R, Beta J, Picciarelli G, Ogilvie C, D'Antonio F. Procedure‐related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta‐analysis. Ultrasound in Obstetrics & Gynecology 2015;45(1):16‐26.

Alfirevic 2003

Alfirevic Z, Sundberg K, Brigham S. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database of Systematic Reviews 2003, Issue 3. [DOI: 10.1002/14651858.CD003252]

Alfirevic 2004

Alfirevic Z, Neilson JP. Antenatal screening for Down's syndrome. BMJ 2004;9(329(7470)):811‐2.

Alldred 2010

Alldred SK, Deeks JJ, Neilson JP, Alfirevic Z. Antenatal screening for Down's syndrome: generic protocol. Cochrane Database of Systematic Reviews 2010, Issue 4. [DOI: 10.1002/14651858.CD007384.pub2]

Alldred 2012

Alldred SK, Deeks JJ, Guo B, Neilson JP, Alfirevic Z. Second trimester serum tests for Down's Syndrome screening. Cochrane Database of Systematic Reviews 2012, Issue 6. [DOI: 10.1002/14651858.CD009925]

Alldred 2015

Alldred SK, Takwoingi Y, Guo B, Pennant M, Deeks JJ, Neilson JP, et al. First trimester serum tests for Down's syndrome screening. Cochrane Database of Systematic Reviews 2015, Issue 11. [DOI: 10.1002/14651858.CD011975]

Alldred 2015a

Alldred SK, Guo B, Takwoingi Y, Pennant M, Wisniewski S, Deeks JJ, Neilson JP, et al. Urine tests for Down's syndrome screening. Cochrane Database of Systematic Reviews 2015, Issue 12. [DOI: 10.1002/14651858.CD011984]

Badeau 2015

Badeau M, Lindsay C, Blais J, Takwoingi Y, Langlois S, Légaré F, et al. Genomics‐based non‐invasive prenatal testing for detection of fetal chromosomal aneuploidy in pregnant women. Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd, 2015, issue 7. [DOI: 10.1002/14651858.CD011767]

Bersinger 1995

Bersinger NA, Zakher A, Huber U, Pescia G, Schneider H. A sensitive enzyme immunoassay for pregnancy‐associated plasma protein A (PAPP‐A): a possible first trimester method of screening for Down syndrome and other trisomies. Archives of Gynecology and Obstetrics 1995;256(4):185‐92.

Bogart 1987

Bogart MH, Pandian MR, Jones OW. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenatal Diagnosis 1987;7(9):623‐30.

Cole 1999

Cole LA, Rinne KM, Mahajan SM, Oz UA, Shahabi S, Mahoney MJ, et al. Urinary screening tests for fetal Down syndrome: I. Fresh beta‐core fragment.[see comment]. Prenatal Diagnosis 1999;19(4):340‐50.

Cuckle 1995

Cuckle HS, Holding S, Jones R, Wallace EM, Groome NP. Maternal serum dimeric inhibin A in second‐trimester Down's syndrome pregnancies. Prenatal Diagnosis1995; Vol. 15, issue 4:385‐6.

Macri 1990

Macri JN, Kasturi RV, Krantz DA, Cook EJ, Moore ND, Young JA, et al. Maternal serum Down syndrome screening: free beta‐protein is a more effective marker than human chorionic gonadotropin. American Journal of Obstetrics and Gynecology 1990;163(4 Pt 1):1248‐53.

Macri 1993

Macri JN, Spencer K, Aitken D, Garver K, Buchanan PD, Muller F, et al. First‐trimester free beta (hCG) screening for Down syndrome. Prenatal Diagnosis 1993;13(7):557‐62.

Mol 1999

Mol BW, Lijmer JG, van der Meulen J, Pajkrt E, Bilardo CM, Bossuyt PM. Effect of study design on the association between nuchal translucency measurement and Down syndrome. Obstetrics and Gynecology 1999;94(5 Pt 2):864‐9.

Penrose 1933

Penrose LS. The relative effects of parental and maternal age in mongolism. Journal of Genetics 1933;27:219‐24.

Steele 1966

Steele MW, Breg WR. Chromosome analysis of human amniotic‐fluid cells . Lancet 1966;i:383‐5.

Valenti 1968

Valenti C, Schutta EJ, Kehaty T. Prenatal diagnosis of Down's syndrome. Lancet 1968;ii:220.

Wald 2003a

Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technology Assessment 2003;7(11):1‐77.

Wallace 1995

Wallace EM, Grant VE, Swanston IA, Groome NP. Evaluation of maternal serum dimeric inhibin A as a first‐trimester marker of Down's syndrome. Prenatal Diagnosis 1995;15(4):359‐62.

Whiting 2003

Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS:  A tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Medical Research Methodology 2003;3:25.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Acacio 2001

Clinical features and settings

High‐risk referral for invasive testing

Participants

230 participants

Brazil ‐ private centres

Dates not specified

Pregnant women

Mean age 35.8 years (21‐45 years)

Singleton pregnancies

Karyotyping performed at same time as NT

10‐14 weeks' gestation

Study design

Diagnostic validation study to determine the best ROC cut‐off for NT

Retrospective study of patient notes

Target condition and reference standard(s)

Down's syndrome: 12 cases

Reference standards: chorionic villus biopsy, amniocentesis or blood or placenta used for fetal karyotyping

Index and comparator tests

NT with cut‐off of 2.5 mm (found to be optimum cut‐off from ROC) (Sequoia, Aspen 128XP10‐Acuson and Toshiba SH140)

Follow‐up

100% karyotyping

Aim of study

To define the best fixed cut‐off point for NT, and the accuracy of this cut‐off for all fetal aneuploidy screening and for trisomy of chromosome 21

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice

Acceptable reference standard?
All tests

Yes

Karyotyping 

Partial verification avoided?
All tests

Yes

All patients received a reference standard

Differential verification avoided?
All tests

No

Women had different reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Audibert 2001

Clinical features and settings

Routine screening

Participants

4130 participants

France ‐ single centre

May 1994 to December 1997

Pregnant women

Mean maternal age 30.1 years (all under 38 years), 86% < 35, 14% ≥ 35

Singleton pregnancies

10‐14 weeks' gestation

Crown‐rump length between 38 mm and 84 mm

Study design

Prospective consecutive series study

Target condition and reference standard(s)

Down's syndrome: 12 cases

Reference standards: prenatal karyotyping conducted (in 7.6% of patients) depending on presence of risk > 125, high maternal age, parental anxiety, history of chromosomal defects or parental translocation or abnormal second trimester scan age

Cytogenetic testing of newborns with suspected abnormalities

Postmortem on terminations of pregnancy or miscarriages

Follow‐up to neonatal examination in newborn

Index and comparator tests

Maternal age

First trimester NT planned at 12‐13 weeks, 3 mm risk cut‐off

Second trimester serum hCG between 14 and 17 weeks (Amerlite, Orthoclinical diagnostics machine), cut‐off 1:250 (Prenata software)

Second trimester serum AFP between 14 and 17 weeks (Amerlite, Orthoclinical diagnostics machine), cut‐off 1:250 (Prenata software)

Serum tests in 3790 women

Follow‐up

Delivery and postnatal paediatric examination

35 lost to follow‐up and excluded from analysis

Pregnancy loss in 37 women due to spontaneous abortion (n = 21) or intrauterine death (n = 16)

340 women had first trimester NT but not second trimester serum testing

Aim of study

To compare first trimester NT and second trimester maternal serum measurements as alternative methods of antenatal screening in a low‐risk population and to evaluate the consequence of combining the results in the estimation of risk.

Notes

Women lost to follow‐up are excluded in the final analysis. All antenatally detected cases were terminated.

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

NT was not measured or not recorded in 219 women and these patients were excluded from the study

Withdrawals explained?
All tests

Yes

340 women who did not want second trimester serum screening withdrew from that part of the study

Babbur 2005

Clinical features and settings

Women requesting screening (self‐paying service) and women attending on account of previous pregnancy history of fetal abnormality

Participants

3188 participants

Cambridge, UK ‐ Maternity Hospital

August 2001‐March 2004

Singleton pregnancies

Pregnant women

Median age 37 years (19‐46 years)

11‐14 weeks' gestation

45‐84 mm crown‐rump length

Viable fetus

Study design

Prospective cohort study

Target condition and reference standard(s)

Down's syndrome: 25 cases

Reference standards: invasive testing offered to women with NT > 3 mm or risk > 1:250 as defined by combined NT and serum results (chorionic villus sampling from 11 weeks, amniocentesis from 15 weeks). Rapid in situ hybridisation test in patients with risk > 1:30. No details given of any follow‐up to birth

Index and comparator tests

First trimester NT in all women (FMF methods)

Second trimester serum biochemistry (AutoDELFIA(TM) time‐resolved fluorimmunoassay (Perkin Elmer)) at 14 weeks. Offered to patients with negative first trimester NT (2725 accepted, 85%)

Follow‐up

Details of follow‐up to birth not given

Aim of study

To determine the detection and false positive rates for trisomy 21 using 2‐stage combined nuchal translucency and triple testing whilst disclosing abnormal NT measurements at the scan

Notes

Women with miscarriages excluded

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

Yes

463 patients having NT did not go on to have serum testing
Barrett 2008

Clinical features and settings

Routine screening

Participants

10,273 participants with complete screening and outcome data

Australia ‐ screening programme, independent ultrasound practices

24‐month period (dates not specified)

Pregnant women

Mean maternal age 34.9 years (screen positive) and 30.5 years (screen negative)

Singleton pregnancies

11‐13 weeks' gestation

Study design

Cohort study

Target condition and reference standard(s)

Down's syndrome: 32 cases

Reference standard: karyotyping or follow‐up to birth

Index and comparator tests

NT (FMF protocol)

First trimester PAPP‐A and free ßhCG (90.2% by time resolved amplified cryptate emission technology, Kryptor random access immunoassay analyzer, Brahms, 9.8% by manual Ortho Clinical Diagnostic Immunometric I125 immunoassay for PAPP‐A, and Ortho Clinical Diagnostics Vitros ECi automated analyzer for ßhCG)

Risk cut‐off 1:300

Follow‐up

Linkage to data collected by the Midwives Notification System and the Western Australia Birth Defects Registry and by searching laboratory records of all prenatal cytogenetics services in the state.

162 women lost to follow‐up were excluded

Pregnancy loss in 54 women due to miscarriage (n = 35), stillbirth (n = 17) and neonatal death (n = 2)

Aim of study

To investigate associations between combined first‐trimester screen result, pregnancy associated plasma protein level and adverse fetal outcomes in women

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Belics 2011

Clinical features and settings

High‐risk referral for invasive testing

Participants

2032 participants with adequate imaging on ultrasound screening

Budapest ‐ single centre

January 2003 ‐ February 2010

Pregnant women

Mean age 36.4 years (15‐46 years) (Down's syndrome) and 29.8 years (15‐49 years) (no Down's syndrome)

11‐20 weeks' gestation

Study design

Cohort study

Target condition and reference standard(s)

Down's syndrome: 52 cases

Reference standards: amniocentesis or CVS (85% of women), or follow‐up to birth

Index and comparator tests

First and second trimester fetal iliac angle (GE Medical System Kretztechnik GmbH & Co OHG, AC2‐5 transabdominal and IC5‐9 transvaginal curved array transducer and Medison Co., LTD EC4‐9ES transvaginal and C3‐7IM transabdominal curved array transducer)

Measurement taken from a transverse section of the fetal pelvis

Cut‐off angles of 75‐100o

Follow‐up

Followed up to delivery (no cases were detected at birth)

Aim of study

To present results of the sonographic measurement of the fetal iliac angle during the first and second trimesters of pregnancy

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Different reference standards used

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

95.2% had adequate imaging

Withdrawals explained?
All tests

No

No details of withdrawals given
Benattar 1999

Clinical features and settings

Routine screening

Participants

1656 participants

France ‐ single centre

January to December 1995

Singleton pregnancies

Pregnant women

Mean age 32 years (16‐46 years), 8.3% > 35 years

Enrolled before 13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 5 cases

Reference standards: amniocentesis due to maternal age > 38 years (6.1% or women). Karyotyping encouraged for women with positive result on 1 or more index test. No details of reference standard for index test negative women

Index and comparator tests

Maternal age

NT at 12‐14 weeks (Toshiba SSA 270), risk cut‐point 1:250

First trimester (12‐14 weeks) serum AFP and free ßhCG (Elsa AFP and Elsa free ßhCG; Cis‐Bio International)

Second trimester (15‐18 weeks) serum AFP and total hCG (AFP‐2T and hCG‐60; Ortho‐Clinical Diagnostics)

All women had NT and serum testing

Follow‐up

Details of follow‐up are not stated. Unclear whether women were followed up to birth.

Of the 1656 women, 12 (0.7%) were lost to follow‐up, 2 had miscarriages, 2 had preterm premature ruptures of the membranes and 2 had intrauterine deaths.

Aim of study

To evaluate the sequential combination of ultrasound screening for fetal aneoploidy at 11‐14 weeks with maternal biochemistry at 12‐14 and 15‐18 weeks of gestation

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Bestwick 2010

Clinical features and settings

Routine screening

Participants

22,746 participants

London ‐ 2 antenatal clinics

January 2003 ‐ December 2008

Pregnant women

Median age 39 years (Down's syndrome) and 34 years (non‐Down's syndrome)

11‐13 and 14‐22 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 106 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

First trimester NT, PAPP‐A and free ßhCG (details not reported)

Second trimester AFP, uE3, free ßhCG and inhibin A (details not reported)  

Results in multiple publications

Follow‐up

Data obtained from the Hospitals, the regional cytogenetic unit and the National Down Syndrome Cytogenetic Register

Aim of study

To determine whether the standard deviation of NT measurements has decreased over time and, if so, to revise the estimate and assess the effect of revising the estimate of the standard deviation on the performance of antenatal screening for Down's syndrome

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Biagiotti 1998

Clinical features and settings

High‐risk referral for invasive testing

Participants

232 participants (all had NT and serum testing)

32 cases of Down's and 200 randomly selected controls (selected from series of 3731 women)

Italy ‐ single centre

July 1993 ‐ December 1996

Pregnant women

10 to 13 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 32 cases

Reference standards: CVS or amniocentesis

Index and comparator tests

Maternal age

First trimester NT (in longitudinal section of the fetus with caliper measurements to the nearest 0.1 mm)

First trimester PAPP‐A (Amerlex‐M PAPP‐A IRMA, Ortho‐Clinical Diagnostics)

First trimester free ßhCG (Elsa9free ßhCG CIS)

Follow‐up

100% karyotyping

Aim of study

To evaluate the potential effectiveness of maternal serum PAPP‐A and free ßhCG in combination with NT measurement in the first trimester of pregnancy

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice 

Acceptable reference standard?
All tests

Yes

Karyotyping

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

Yes

All women had the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Borenstein 2008

Clinical features and settings

High‐risk referral for invasive testing

Participants

516 participants

London ‐ hospital birth centre

Dates not reported

Pregnant women

Median maternal age 35 years (range 17‐49 years)

11‐13 weeks' gestation

16‐24 weeks' gestation in a sub‐sample of 183 women

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 51 cases

Reference standard: CVS

Index and comparator tests

First trimester fetal echocardiography (transabdominally with a 4‐8 MHz curvilinear transducer, Voluson 730 Expert, GE Medical Systems) in all women (425 successfully examined) and in the second trimester in 183 women

Follow‐up

100% karyotyping

Aim of study

To establish the feasibility of examining the subclavian artery at 11 + 0 to 13 + 6 weeks of gestation and to determine the prevalence of aberrant right subclavian artery (ARSA) in chromosomally normal and abnormal fetuses

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

Yes

All women received the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

425/516 (82.4%) of women were successfully examined

Withdrawals explained?
All tests

No

No details of withdrawals given
Borrell 2005

Clinical features and settings

Routine screening

Participants

3731 participants

Spain

October 1999 ‐ December 2002

Pregnant women

10 to 14 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 25 cases

Reference standards: CVS (high‐risk women) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester (10‐14 weeks) Ductus venous Doppler studies

First trimester (10‐14 weeks) NT (FMF method)

First trimester (10 weeks) serum PAPP‐A and free ßhCG (time‐resolved fluorescent assays, Perkin‐Elmer Life Sciences)

Risk cutoffs 1:200, 1:250 or 1:300

DV ‐ Saggital view of quiescent fetus. When optimal record of DV obtained, measured only once. When reversed end diastolic flow present, 3 separated samples obtained. Maximum velocity manually drawn in 3 waveforms and PIV automatically obtained by software linked to equipment

Follow‐up

Details given in Borrel 2004: follow‐up through phone enquiry, contact with attending obstetrician, births defects registry of Barcelona. Cases with missing follow‐up or unknown karyotype excluded from further analysis

Aim of study

To estimate the improvement in screening efficiency when fetal ductus venosus Doppler studies are added to existing first trimester Down's syndrome screening protocols

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth (described in Borrel 2004)

Partial verification avoided?
All tests

Yes

All patients received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

4 unaffected pregnancies could not be assessed with NT

Withdrawals explained?
All tests

No

No details of withdrawals given
Borrell 2009

Clinical features and settings

Routine screening and high‐risk referral

Participants

7250 participants:

6940 women undergoing routine screening (October 1999 ‐ December 2006)

310 women referred for CVS (October 1999 ‐ December 2007)

Barcelona ‐ hospital clinic

Pregnant women

Mean maternal age 32 years

10‐13 and 15‐20 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 66 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT and ductus venosus pulsivity index (DVPI)  (transabdominal ultrasound, Eccocee SSA and Power‐Vision 400, Toshiba Medical Systems, Voluson PRO, General Electrics Healthcare)

First trimester PAPP‐A and free ßhCG (details not reported)

Second trimester AFP, uE3, free ßhCG and inhibin A (details not reported)

Follow‐up

From hospital clinic records, telephoning women or from the attending obstetrician. Obtained in 97.4% of pregnancies

Aim of study

To assess the value of ductus venosus blood flow (expressed as pulsatility index, DVPI) in antenatal Down's syndrome screening when used with the combined and integrated tests

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population and selective testing of high‐risk women as done in practice

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Ductus venosus measurements were not obtained in 3.3% of pregnancies

Withdrawals explained?
All tests

No

No details of withdrawals given
Brameld 2008

Clinical features and settings

Routine screening

Participants

22,280 participants with complete screening results and outcome data

August 2001 ‐ October 2003

Australia ‐ State‐wide screening programme evaluation

Pregnant women

Median maternal age 31 years (range 14‐47 years), 20% ≥ 35

Singleton pregnancies

10‐14 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 60 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester PAPP‐A, free ßhCG and NT (details not reported)

Risk cut‐point 1:300

Follow‐up

Data on outcome from the Western Australia Midwives data collection, Birth Defects Registry and hospital morbidity and mortality data

Aim of study

To identify first trimester indicators of adverse pregnancy outcomes

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐ up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Brizot 2001

Clinical features and settings

Routine screening

Participants

2996 participants

Brazil ‐ University Hospital

Estimated date of delivery pre December 1999

Pregnant women

Median age 28 years (13‐46 years), 19.4% ≥ 35 years

Singleton pregnancies

10‐14 weeks' gestation (mean 12 weeks)

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 10 cases

Reference standards: antenatal karyotyping (5.9% of pregnancies: 62% of high‐risk, 29% of medium‐risk and 3% of the low‐risk women) or follow‐up to birth (85.3% of women)

Index and comparator tests

Maternal age

First trimester (10‐14 weeks) NT

Risk cut‐off 1:300

Follow‐up

85.3% of women were followed up to birth. Of these, 65 were spontaneous miscarriages or intrauterine death with no karyotyping

Aim of study

To assess the detection rate of chromosomal abnormalities using NT

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Centini 2005

Clinical features and settings

High‐risk patients undergoing routine screening

Participants

408 participants

Italy

Dates not reported

Pregnant women

Singleton pregnancies

Aged ≥ 35 years (range 35‐44 years)

10‐13 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 6 cases

Reference standards: amniocentesis in women high risk on screening (16.2%) or follow‐up to birth in women who were low risk on screening

Index and comparator tests

Maternal age

NT with cut‐point 3 mm

Serum free ßhCG (Schering RIA) and PAPP‐A (Chematil ELISA)

Risk score cut‐point 1:250

Follow‐up

Follow‐up at birth in all by collaboration with mothers

Women who miscarried were excluded from the study

Aim of study

To evaluate the combined test of NT, serum markers and age in pregnant women 35 years of age and over to detect Down's syndrome

Notes

No live births were Down's syndrome. All detected cases were terminated. 7 women were excluded due to miscarriages

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Chasen 2003

Clinical features and settings

Routine screening

Participants

2131 women with 2339 fetuses

New York ‐ single centre

April 2000 to November 2002

Pregnant women

Singleton or multifetal pregnancies

Median age 33 years (interquartile range 31‐36), 36.2% ≥ 35 years

Study design

Prospective consecutive cohort

Target condition and reference standard(s)

Down's syndrome: 12 cases

Reference standards: karyotyping or follow‐up to birth in 96.1% of patients

Index and comparator tests

Maternal age

NT (FMF methods)

Combined risk score cut‐point 1:300

Each fetus with a separate chorion was considered individually when calculating the performance of NT but for monochorionic twins, only the fetus with the higher risk calculation was included

Follow‐up

Attempted to obtain results for cytogenetic testing following miscarriage or termination or where Down's suspected at birth. Karyotype results or documented evidence of phenotypically normal baby was recorded in 96.1% of patients

Aim of study

To examine the detection rate of chromosomal abnormalities using a combination of nuchal translucency and maternal age

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

No

Reference standard results were available for only 96% of patients

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

19 patients could not be imaged

Withdrawals explained?
All tests

No

No details of withdrawals given
Chen 2009

Clinical features and settings

Routine screening

Participants

242 participants: 22 cases and 220 randomly selected controls

China ‐ hospital screening programme

August 2003 ‐ March 2007

Pregnant women

Median maternal age, cases 30 years (20‐44 years) and controls 32 years (19‐40 years)

12‐14 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 22 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

First trimester frontomaxillary facial (FMF) angle (transabdominal ultrasound, ATL HDI 5000, Philips Medical Systems or Voluson 730 Pro, GE Medical systems, by clinicians accredited by the FMF)

Measured with a protractor from printed and filed images

Angle > 95th percentile taken as positive test result

Follow‐up

Pregnancy outcome obtained from obstetric and neonatal files

Aim of study

To evaluate the measurement of FMF angle at 11‐13 weeks, 6 days in a Chinese population and its applicability in screening for fetal trisomy 21

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Unclear

Unclear if index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Unclear

Only the most optimal images were included in the study and the proportion of images that were not included is not stated

Withdrawals explained?
All tests

No

No details of withdrawals given
Christiansen 2005

Clinical features and settings

Screening programmes for syphilis and Down's syndrome

Participants

108 participants (27 cases of Down's syndrome, 81 controls)

Denmark ‐ Statens Serum Institute

Dates not specified

Pregnant women

5‐11 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 27 affected cases (18 diagnosed in 2nd trimester, 9 at birth)

Reference standard: karyotyping

Index and comparator tests

Maternal age

First trimester (week 11‐14) NT

Frozen samples tested for:

First trimester (week 5‐11) inhibin A (dimer assay kit MCA 950KZZ, Serotec)

First trimester (week 5‐11) ßhCG (available for some samples)

First trimester (week 5‐11) PAPP‐A (available for some samples) (combined PAPP‐A and ßhCG TrIFMA assay)

Risk cutpoints of 1:100, 1:250 and 1:400

Performance assessed with SPlus algorithm

Follow‐up

All diagnosis were verified by karyotyping

Aim of study

To investigate whether inhibin A can be used in the first trimester for Down's syndrome screening

Notes

Identified through the Danish central cytogenetic registry as part of quality assurance programme

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping

Partial verification avoided?
All tests

Yes

All women had a reference standard

Differential verification avoided?
All tests

Yes

All women had the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Christiansen 2009

Clinical features and settings

Routine screening

Participants

335 participants: 74 cases and 261 controls matched for length of sample storage and maternal age

Denmark ‐ screening programme

Dates not reported

Pregnant women

Singleton pregnancies

Median maternal age cases 37.5 years and controls 36.4 years

8‐13 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 74 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (details not reported)

Fresh serum samples tested for:

First trimester PAPP‐A and free ßhCG (AutoDelfia, PerkinElmer, Turku or Kryptor, Brahms)

Frozen serum samples tested for:

First trimester placental growth hormone (double monoclonal ELISA, DSL‐10‐19 200, Diagnostic Systems Laboratory Inc)

Growth hormone binding protein (enzyme‐amplified ELISA, DSL‐10‐48 100, Diagnostic Systems Laboratory Inc)

Follow‐up

Cross‐referencing with the Danish Cytogenetic Central Registry

Aim of study

To examine the potential of placental growth hormone and growth hormone binding protein as maternal serum screening markers for Down's syndrome

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of some index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Christiansen 2010

Clinical features and settings

Routine screening

Participants

531 participants: 28 cases and 503 controls

Denmark ‐ screening programme

Dates not specified

Pregnant women

Singleton pregnancies

Median age cases 36 years (range 25‐44 years) and controls 29 years (range 17‐45 years)

8‐14 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 28 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (details not reported)

First trimester PAPP‐A and free ßhCG (details not reported)

First trimester ADAM12s (AutoDELFIA/Delfia ADAM12 Research kit 4025‐0010, PerkinElmer Life and Analytical Sciences, on the 1235 AutoDELFIA automatic immunoassay system)

Follow‐up

Cross‐referencing with the Danish Cytogenetic Central Registry

Aim of study

To examine the efficiency of a second generation assay for ADAM12

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of some index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Cicero 2004a

Clinical features and settings

High‐risk referral for invasive testing

Participants

970 fetuses (20 twin and 1 triplet pregnancy)

UK

Dates not specified

Pregnant women

Median age 37 years (16‐48 years)

11‐14 weeks' gestation (median 12 weeks)

Study design

Prospective cohort study

Target condition and reference standard(s)

Down's syndrome: 88 cases

Reference standard: CVS

Index and comparator tests

Maxillary bone length

Mid‐saggital view of fetal profile obtained for nasal bone. Transducer angled laterally so that the maxillary bone and mandible including the ramus and condylar process can be seen. Maxillary length measured with callipers. Magnified to 0.1 mm increment

Follow‐up

100% karyotyping

Aim of study

To determine the value of measuring maxillary length at 11‐14 weeks' gestation in screening for trisomy 21

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice 

Acceptable reference standard?
All tests

Yes

CVS

Partial verification avoided?
All tests

Yes

All women had a reference standard

Differential verification avoided?
All tests

Yes

All women had the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Study reports that measurements were made successfully in all cases

Withdrawals explained?
All tests

No

No details of withdrawals given
Cicero 2006

Clinical features and settings

Routine screening

Participants

20, 418 participants

UK ‐ Fetal Medicine Centre

October 2001‐2004

Pregnant women

Singleton pregnancies

Median age 35 years (18‐50 years)

11‐13 weeks' gestation

Study design

Prospective cohort study

Target condition and reference standard(s)

Down's syndrome: 140 cases

Reference standards: CVS or amniocentesis in high‐risk women, or follow‐up to birth

Index and comparator tests

Maternal age

Presence of nasal Bone (FMF methods)

First trimester NT (FMF methods)

First trimester serum free ßhCG (Kryptor analyser, Brahms AG)

First trimester serum PAPP‐A (Kryptor analyser, Brahms AG)

Follow‐up

Data on pregnancy outcome from cytogenetics laboratory and by letters and telephone calls to patients, GPs and maternity units

656 patients excluded because karyotype was not known due to miscarriage (n = 185), termination of pregnancy (n = 85) or loss to follow‐up (n = 386)

Aim of study

To investigate the impact of incorporating assessment of the nasal bone into first trimester combined screening by fetal nuchal translucency thickness and maternal serum biochemistry

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Reported that fetal NT and serum markers were successfully measured in all cases

Withdrawals explained?
All tests

Yes

Patients lost to follow‐up reported
Cocciolone 2008 FTS

Clinical features and settings

Routine screening  

Participants

18,901 participants

Australia ‐ South Australian Maternal Serum Antenatal Screening Program

Dates not reported

Pregnant women

Median age 31.3 years

Maternal and gestational age not reported

Study design

Cohort study

Target condition and reference standard(s)

Down's syndrome: 66 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT PAPP‐A and free ßhCG (details not reported)

Follow‐up

Details not reported

Aim of study

To compare different screening strategies for the detection of Down's syndrome and to consider the practical implications of using multiple screening protocols

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Cowans 2009

Clinical features and settings

Routine screening  

Participants

57,057 participants

June 1998 ‐ July 2007

UK ‐ 6 Hospitals

Pregnant women

Singleton pregnancies

Mean age: Down's syndrome 38 years (range 16‐49 years) and healthy 29 years (range 13‐56 years)

10‐14 weeks' gestation

Study design

Cohort study

Target condition and reference standard(s)

Down's syndrome: 723 cases (307 from original cohort and 416 supplemented cases screened at the Fetal Medicine centre or Harris Birthright Research Centre for Fetal Medicine)

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF certified sonographers)

First trimester PAPP‐A and free ßhCG (Kryptor analyser, Brahms)

Rick cut‐point 1:300

Follow‐up

Birth data collected at birth by the delivering hospital and stored in several databases which were merged. Only women with full records for screening and birth outcome included in the study

Aim of study

To investigate if fetal sex has an impact on first trimester combined screening for aenuploidy

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Cowans 2010

Clinical features and settings

Routine screening  

Participants

445 participants: 70 cases and 375 controls matched for storage time and gestational age

January 2007 ‐ October 2008

UK

Pregnant women

Singleton pregnancies

Mean maternal age cases 37.0 years (IQR 32.9 to 40.5 years) and controls 32.4 years (IQR 29.0 to 35.9 years)

11‐13 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 70 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF certified sonographers)

Fresh serum samples tested for:

First trimester PAPP‐A and free ßhCG (Kryptor analyser, Brahms)

Frozen serum samples tested for:

First trimester placental growth factor (Solid‐phase, 2‐site fluoroimmunometric research assay (4083‐0010) on 6000 DELFIA Xpress random access platform, PerkinElmer)

Follow‐up

Karyotype and results for pregnancy outcome received from cytogenetics laboratories and maternity units where deliveries took place

Aim of study

To examine placental growth factor levels in first trimester maternal serum in trisomy 21 pregnancies and to investigate the potential value of PIGF in a first trimester screening test

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of some index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Crossley 2002

Clinical features and settings

Routine screening

Participants

17,229 participants

UK ‐ 15 centres

Dates not specified

Pregnant women

Median age 29.9 years, 15.4% ≥ 35 years

10‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down’s syndrome: 45 cases

Reference standards: CVS (offered where women had high NT measurements), amniocentesis or follow‐up to birth

Index and comparator tests

Maternal age

NT (FMF method) in 73% of patients

Clotted blood samples tested for:

Free ßhCG and PAPP‐A (Kryptor analyser) in 98.4% of patients

Follow‐up

Reported that the outcome of all pregnancies was followed up

Aim of study

To evaluate the use of NT measurement in combination with biochemical markers as a first trimester test for Down's syndrome in routine antenatal setting

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Report average success rate of NT (72.9%)

Withdrawals explained?
All tests

Yes

Numbers of patients not undergoing NT and biochemical testing given
De Graaf 1999

Clinical features and settings

High‐risk referral for invasive testing

Participants

292 participants (207 participants before 14 weeks' gestation)

The Netherlands ‐ single centre

19 84‐1997

Pregnant women

Cases: 37 with Down's syndrome

Controls: 255 matched 5:1 with cases for maternal age (within 2 years), gestational age (within 2 weeks) and duration of sample storage (within 2 months)

9‐15 weeks' gestation (in a few cases, blood samples for serum testing taken at 15‐19 weeks)

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 37 cases (24 affected pregnancies in women with NT testing enrolled before 14 weeks' gestation)

Reference standards: CVS and amniocentesis

Index and comparator tests

Maternal age

NT (FMF methods) with cut‐off > 3 mm

Frozen serum samples tested for:

First trimester free ßhCG and AFP (DELFIA dual labelled time resolved fluorescent assay)

First trimester serum PAPP‐A (DELFIA research assay (CR61‐105))

First trimester serum AFP

Follow‐up

100% karyotyping

Aim of study

To determine the expected detection rate and false positive rate for Down's syndrome achievable by early pregnancy screening with combined measurements of serum PAPP‐A, free ßhCG and fetal nuchal translucency, with the addition of AFP

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

 Selective testing of high‐risk women as done in practice

Acceptable reference standard?
All tests

Yes

Karyotyping

Partial verification avoided?
All tests

Yes

All women had a reference standard

Differential verification avoided?
All tests

Yes

All women had karyotyping

Incorporation avoided?
All tests

Yes

Index test did not form part of the reference standard

Reference standard results blinded?
All tests

No

Reference standard interpreted without knowledge of index test results

Index test results blinded?
All tests

Unclear

Unclear if index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

In 11 controls, failed to measure NT

Withdrawals explained?
All tests

No

No details of withdrawals given
Ekelund 2008

Clinical features and settings

Routine screening  

Participants

95,645 participants (40,815 in 2005 and 54,830 in 2006)

Denmark ‐ 19 obstetrics and gynaecology departments

January 2005 ‐ December 2006

Pregnant women

Maternal and gestational age not reported

First trimester

Study design

Cohort

Target condition and reference standard(s)

Down's syndrome: 225 cases (121 in 2005 and 104 in 2006)

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (by nurses, midwives and doctors in accordance with FMF guidelines)

First trimester PAPP‐A and free ßhCG (Brahms Kryptor, Brahms Immunodiagnostic Systems or Delfia Xpress, PerkinElmer)

Risk cut‐point 1:300

Follow‐up

Information obtained from the Danish central cytogenetic registry. No details of follow‐up for women without pre or post‐natal chromosome analysis

Aim of study

To evaluate the impact of a screening strategy in the first trimester, introduced in Denmark during 2004 to 2006, on the number of infants born with Down's syndrome and the number of CVS and amniocentesis, and to determine detection and false positive rates in the screened population in 2005 and 2006

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

Yes

Information given on the proportion of women not undergoing screening
Gasiorek‐Wiens 2001

Clinical features and settings

Routine screening

Participants

21,959 participants

Germany, Switzerland and Austria ‐ multicentre study

June 1995‐May 2000

Pregnant women

Median age 33 years (15‐49 years), 36.1% > 35 years

Singleton pregnancies

10‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 210 cases

Reference standards: CVS, amniocentesis or follow‐up to birth

Index and comparator tests

Maternal age

NT (FMF methods)

Risk cut‐points of 1:100 and 1:300

Follow‐up

Follow‐up in 92.2% of women. Loss to follow‐up was due to miscarriage (n = 258), termination of pregnancy (n = 125) or absence of antenatal karyotyping (n = 1463). Only those with follow‐up information included in the study

Aim of study

To examine the effectiveness of screening for Down's syndrome using age and NT at 10‐14 weeks of gestation

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Reported that NT successfully measured in all cases

Withdrawals explained?
All tests

No

No details of withdrawals given
Gasiorek‐Wiens 2010

Clinical features and settings

Routine screening

Participants

4097 participants with complete data on pregnancy outcome

Germany ‐ single examiner

December 1997 ‐ November 2006

Pregnant women

Singleton pregnancies

Median age 35.1 years (range 13.2‐46.7 years)

11‐13 weeks' gestation

Study design

Cohort study

Target condition and reference standard(s)

Down's syndrome: 34 cases

Reference standards: Karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

Mixture model, Delta NT and multiple of the median methods

Follow‐up

Patient history and ultrasound results were entered into a database and pregnancy outcome or chromosomal results added as they became available

74 (1.8%) of women were excluded from the study because of incomplete follow‐up information

Aim of study

To validate the mixture model in a single operator dataset and to compare the detection rates for fetal chromosomal defects obtained from the mixture model with those obtained from either the delta NT or log multiple of the median approach

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Go 2005

Clinical features and settings

Routine screening

Participants

1759 participants

The Netherlands ‐ private practice (VU medical centre)

May 2001‐October 2003

Pregnant women

49% ≤ 35 years, 51% ≥ 36 years

9‐14 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 21 cases

Reference standards: Invasive testing or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods using own medians)

First trimester PAPP‐A and free ßhCG (ELIPS Perkin Elmer, Finland)

Follow‐up

Follow‐up data from medical records and patient reports. Data from 242 patients (12%) were not available and these patients were excluded from the study.

Aim of study

To determine the diagnostic value of the combination screening test for Down's syndrome in the first trimester of pregnancy

Notes

Dutch language

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Incomplete investigation reported in 25 patients (1.2%)

Withdrawals explained?
All tests

No

No details of withdrawals given
Gyselaers 2005

Clinical features and settings

Routine screening

Participants

13,267 participants (13,207 participant received both NT test and serum testing)

Belgium ‐ multicentre study (35 centres)

Data from January 2004‐April 2004 added to previous database from before 2003

Pregnant women

First and second trimester testing

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 26 cases

Reference standards: CVS, amniocentesis or follow‐up to birth 

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

First trimester PAPP‐A (ELISA 2397, DRG International Inc) and free ßhCG (IRMA K1P1001)

Second trimester PAPP‐A and free ßhCG

Risk cut‐points of 1:200 and 1:300

Follow‐up

Follow‐up to birth reported by mail by obstetricians. Non‐responding obstetricians contacted personally to obtain missing data. Results of follow‐up reported by mail by obstetricians. Non‐responding obstetricians contacted personally to obtain missing data

Cases of miscarriages (n = 49) and other fetal chromosomal abnormalities excluded from the study. Unclear if other patients lost to follow‐up

Aim of study

To evaluate the performance of a first trimester fetal aneuploidy screening programme

Notes

Women with miscarriages or cases of other chromosomal defects were excluded from the study. 9 live births of babies with Down's syndrome

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

Yes

Numbers of women excluded due to miscarriage or other chromosomal defects and numbers not undergoing NT and biochemical testing reported.

Habayeb 2010

Clinical features and settings

Routine screening

Participants

1507 participants

UK ‐ fetal medicine unit

September 2007 ‐ December 2008

Pregnant women

Median maternal age 35.4 years (range 18‐49 years)

9‐10, 11‐13 and > 14 weeks' gestation

Study design

Cohort study

Target condition and reference standard(s)

Down's syndrome: 12 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

Early first trimester PAPP‐A (9 weeks' gestation) (AutoDELFIA PAPP‐A kit, PerkinElmer LAS (UK) Ltd)

First trimester NT (11‐13 weeks' gestation) (General Electric E8, Voluson 730 Pro, GE Healthcare)

Second trimester AFP, free ßhCG and uE3 (at or after 14 weeks' gestation) (AutoDELFIA(TM) time‐resolved fluorimmunoassay, PerkinElmer Life Sciences)

Second trimester tests given if first trimester risk low (< 1:100) or invasive testing declined

Cut‐point for second‐stage risk 1:250

Follow‐up

Data recorded on a fetal medicine database and combined with data held on separate databases for pregnancy outcome and the regional cytogenetic laboratory. Cytogenetic test results available for all women delivering in the region

Aim of study

To audit a model combining early PAPP‐A with NT and early triple test

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Hadlow 2005

Clinical features and settings

Routine screening

Participants

10,436 participants receiving both NT and serum testing and with complete follow‐up data

Australia

Data from 2‐year period (dates not specified)

Pregnant women

Mean age 30.7 years, 21.2% ≥ 35 years

Singleton pregnancies

11‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 32 cases

Reference standards: CVS, amniocentesis or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

Clotted blood samples tested for:

First trimester PAPP‐A (Kryptor random access immunoassay analyser or manual Ortho Clinical Diagnostics Immunometric I125 immunoassay)

First trimester free ßhCG (Kryptor random access immunoassay analyser or Ortho Clinical Diagnostics Vitros ECi automated analyser)

Risk cut‐point 1:300

Follow‐up

Data obtained from WA Midwives notification system and WA Birth defects registry. Missing information sought from referring doctor and ultrasound practice. Data linkage achieved in 10,436 (99.6%) of patients

In index test negative patients, outcome for 160 women not known

In index test positive patients, outcome in 2 women not known

Aim of study

To audit the initial 2 years of conduct of the combined first trimester screening

Notes

Women with miscarriages or multiple pregnancies were excluded from the study

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Hafner 1998

Clinical features and settings

Routine screening

Participants

4233 participants

Austria ‐ single hospital

June 1993 to July 1996

Pregnant women

Median age 28 years (15‐49 years), 6.9% ≥ 35 years

10‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down’s syndrome: 7 cases

Reference standards: amniocentesis or CVS in patients with previous Down’s pregnancy, > 35 years or with a positive biochemical test result. Other women underwent scan at 22 weeks and, if NT > 2.5 mm special examination directed to examination of fetal heart. Follow‐up to birth

Index and comparator tests

First trimester NT (cut‐off 2.5 mm)

NT taken in saggital section. Distance between the end of the echogenic muscles of the c spine and the inner layer of echogenic skin with callipers on the line

Follow‐up

No details given of methods of follow‐up. 138 women lost to follow‐up

Aim of study

To determine the value of NT measurement for the detection of aneuploidies and other malformations in a low‐risk population

Notes

It appears that Down’s syndrome was only picked up in cases where CVS or amniocentesis had been conducted and it s not clear if patients were followed up to birth

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Unclear

Amniocentesis or anomalies scan at 22 weeks. Unclear if women were also followed up to birth.

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

NT measurement was not possible in 2% of cases

Withdrawals explained?
All tests

No

No details of withdrawals given
Has 2008

Clinical features and settings

Routine screening

Participants

1807 participants with successful scans

Turkey

September 2003 ‐ December 2005

Pregnant women

Singleton pregnancies

Median maternal age 28.3 years (range 17‐45 years)

11‐14 weeks' gestation

Study design

Cohort study

Target condition and reference standard(s)

Down's syndrome: 9 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

First trimester fetal nasal bone (experienced maternal fetal specialists)

First trimester  PAPP‐A and free ßhCG (details not reported)

Combined cut‐point 1:300

Follow‐up

Findings recorded in a computer database. Karyotype results obtained directly from the genetics department. Pregnancy outcomes obtained from hospital records or from parents via telephone interview. 110 women (5%) with terminations, miscarriages or malformations and unknown outcome were excluded from the study

Aim of study

To evaluate the contribution of nasal bone assessment in first trimester Down's syndrome screening

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Evaluation of nasal bone was not possible in 9 (0.5%) cases

Withdrawals explained?
All tests

No

No details of withdrawals given
Hewitt 1996

Clinical features and settings

High‐risk referral for invasive testing

Participants

1306 women with 1317 fetuses (11 sets of twins)

Australia ‐ 2 hospitals and 2 private practices

September 1993 to September 1994

Pegnant women

Singleton or multifetal pregnancies

Median age 37 years (21‐48 years)

10 to 14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down’s syndrome: 21 cases

Reference standard: CVS

Index and comparator tests

First trimester NT (ATL HDI ESP Diagnostic Ultrasound system), cut‐point 3 mm or more

Follow‐up

100% karyotyping

Aim of study

To evaluate the accuracy of ultrasound measurement of nuchal thickness in first trimester fetuses for predicting fetal karyotype

Notes

No measurement of NT was recorded in 126 cases (9.6%). All down’s syndrome fetuses terminated

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice 

Acceptable reference standard?
All tests

Yes

CVS

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

Yes

All women had the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

No measurement of NT was recorded in 126 cases (9.6%)

Withdrawals explained?
All tests

No

No details of withdrawals given
Hormansdorfer 2011

Clinical features and settings

Routine screening

Participants

6508 participants with known fetal outcome

Germany ‐ 3 prenatal health centres

August 1999 ‐ May 2007

Pregnant women

Mean maternal age 31.1 years (16‐46 years), 22% ≥ 35 years

First trimester

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 40 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF standards)

First trimester PAPP‐A and free ßhCG (no details given)

Different software programmes used with and without modification to exclude the role of maternal age

Follow‐up

Methods of follow‐up not reported. Stated that only women with known fetal outcome were included in the study

Aim of study

To analyse the impact in test performance of 3 widely used first trimester screening software programs if the maternal age was excluded from their calculation algorithm

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Huang 2010

Clinical features and settings

Routine screening

Participants

7118 participants undergoing combined first trimester screening and a fetal abnormality scan

Taiwan ‐ single hospital

January 2004 ‐ December 2007

Pregnant women

Median maternal age 30 years (range 15‐47 years)

8‐13 weeks' gestation

Study design

Cohort study

Target condition and reference standard(s)

Down's syndrome: 25 cases  

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (11‐13 weeks' gestation) (FMF accredited obstetricians)

First trimester free ßhCG and PAPP‐A (8‐12 weeks' gestation) (time resolved amplified cryptate emission, automated Kryptor Analyser, Brahms)

Combined cut‐point 1:300

Second trimester fetal abnormality scan (18‐22 weeks' gestation) for intracardiac echogenic focus (ICEF) (In accordance with the American Institute of Ultrasound in Medicine Practice Guideline)

Follow‐up

All neonates examined postnatally and Hospital records reviewed

Aim of study

To determine the relation between intracardiac echogenic focus and trisomy 21 in a population of fetuses previously evaluated by first trimester combined screening

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Jaques 2007

Clinical features and settings

Routine screening

Participants

16,153 participants

Australia ‐ State screening programme

February 2000 ‐ June 2002

Pregnant women

Mean maternal age 33 years (range 16‐51 years), 18.5% ≥ 37 years

10‐13 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 63 cases  

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF accredited ultrasonologists)

First trimester PAPP‐A and free ßhCG (details not reported)

First trimester AFP, inhibin A and uE3 added to first trimester results for women who were screened at 13 weeks' gestation (augmented screening, number not reported)

Follow‐up

Probabilistic record linkage was used to link health records from the Genetic Health prenatal screening database, Perinatal Data Collection Unit and the Birth Defects Register. Written requests for pregnancy outcome were sent to referring health professionals. Pathology and cytogenetics reports were collected for confirmation of birth defects and/or karyotype

151 women were lost to follow‐up and these were excluded in the analysis

Of the 16,003 women, pregnancy loss in 71 due to miscarriage (n = 68), stillbirth (n = 1) and neonatal death (n = 2)

Aim of study

To follow up and evaluate the state‐wide first trimester combined screening programme for Down's syndrome and trisomy 18 at Genetic Health Services Victoria, Australia

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Jaques 2010 FTS

Clinical features and settings

Routine screening

Participants

38,584 participants

Australia ‐ State screening programme

2003 ‐ 2004

Pregnant women

Maternal age ≥ 37 years in 16.3% of women

First and second trimester

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 110 cases

Reference standards: karyotyping (CVS = 774, amniocentesis =1644) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT, PAPP‐A and free ßhCG (n = 38,584) (details not reported)

Follow‐up

Probabilistic record linkage was used to link health records from the Prenatal Screening Database, prenatal diagnostic data from cytogenetic laboratories, the Victoria Birth Register (Perinatal Data collection Unit) and the Victoria Birth Defects Register

Aim of study

To map prenatal screening and diagnostic testing pathways in Victorian pregnant women during 2003‐2004; measure the impact of prenatal diagnostic testing uptake on the effectiveness of prenatal screening for Down's syndrome; and assess factors influencing uptake of diagnostic testing following screening

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Invalid results obtained for 7.4% of first and 0.1% of second trimester screenings

Withdrawals explained?
All tests

Yes

48% of pregnant women in the state did not undergo prenatal testing
Kagan 2010

Clinical features and settings

Routine screening

Participants

56,954 participants with available outcome data  

UK ‐ multicentre  

July 1999 ‐ April 2007

Pregnant women

Singleton pregnancies

Mean maternal age 35.4 years (range 14.1 to 52.2 years)

11‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 395 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT

First trimester fetal heart rate (pulsed‐wave Doppler)

First trimester nasal bone (FMF certified sonographers)

First trimester ductus venous flow (FMF certified sonographers)

First trimester flow across tricuspid valve (FMF certified sonographers)

First trimester PAPP‐A and free ßhCG (Kryptor, Brahms AG or Delfia Express, Perkin Elmer) 

Multiple publications with different test evaluations

Follow‐up

Karyotype results and details of pregnancy outcome added to databases as they became available. Women without complete screening and outcome data (n = 3053, 5.1%) were excluded from the study

Aim of study

To examine the performance of first‐trimester screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency thickness, fetal heart rate and maternal serum free ßhCG and PAPP‐A

Other objectives in related publications

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Kim 2006

Clinical features and settings

Routine screening

Participants

2570 participants with available outcome data

Korea ‐ hospital and womens healthcare centre

January 2001 to December 2001

Pregnant women

Mean age 29.9 years (SD 3.3 years)

Singleton pregnancies

10‐14 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 31 cases

Reference standard: amniocentesis or CVS in 419 patients considered high risk (NT > 2.5, aged > 35 years, positive biochemical test result, history of chromosomal abnormality, fetal structural abnormality at ultrasound or other reason). Follow‐up to birth

Index and comparator tests

First trimester NT (FMF methods) (HDI 3000, ATL, Bothell, WA, USA)

3 measurements taken, largest one used for risk calculation

Cut‐off 2.5 mm, 3.0 mm or 95th percentile of each CRL

Follow‐up

Pregnancy outcomes ascertained from obstetric and neonatal medical records of live or stillborn babies

Only patients with known pregnancy outcome included in the study

8 patients who terminated their pregnancies because of structural abnormalities on ultrasound with no karyotyping results were excluded. Karyotyping was performed in intrauterine fetal death (n = 4) cases

Aim of study

To determine the value of NT with different cut‐offs for the detection of chromosomal aberrations

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Koster 2011

Clinical features and settings

Routine screening

Participants

998 participants: 151 cases and 847 controls matched for gestational age, maternal weight, maternal age and storage time

The Netherlands ‐ National institute for Public Health and the Environment

2004 ‐ 2006

Pregnant women

Singleton pregnancies

Median maternal age 37 years (interquartile range 36‐39 years)

8‐13 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 151 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT

Fresh serum samples tested for:

First trimester free ßhCG and PAPP‐A (AutoDELFIA, PerkinElmer)

Frozen serum samples tested for:

First trimester ADAM 12s, total hCG, placental protein 13 (PP13) and placental growth factor (PlGF) (AutoDELFIA or DelfiaXpress, PerkinElmer)

Follow‐up

Pregnancy outcome was recorded via questionnaires and self‐reporting by the participating women. Only samples for pregnancies with known outcome were selected as controls

Aim of study

To evaluate the modelled predictive value of 3 current screening markers (PAPP‐A, free ßhCG and NT) and 4 potential screening markers (ADAM 12, total hCG, PP13 and PIGF) for Down's syndrome using different screening strategies

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of some index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Kozlowski 2007 GC

Clinical features and settings

Routine referral

Participants

6906 participants with complete outcome data

Germany ‐ gynaecologists practices

January 2000 ‐ December 2003

Pregnant women

Median maternal age 32 years (15‐48 years), 26.4% ≥ 35 years

11‐14 weeks' gestation

Study design

Cohort study

Target condition and reference standard(s)

Down's syndrome: 19 cases in gynaecologists practices

Reference standard: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF certified gynaecologists)

First trimester free ßhCG and PAPP‐A (Kryptor analyser, Brahms)

Risk cut‐point 1:300

Follow‐up

Data on pregnancy outcome were obtained by contacting the patient or their general gynaecologist. Women without complete outcome data (36%) were excluded from the study

Aim of study

To evaluate and compare the screening performance for fetal trisomy 21 in the first trimester of pregnancy in general gynaecologists practices and specialised centres for prenatal care in Germany

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

Yes

146 women (including 11 with down's syndrome) excluded as results could not be assigned to gynaecologists' or prenatal centre group 

Kozlowski 2007 PC

Clinical features and settings

Routine referral

Participants

3862 participants with complete outcome data

Germany ‐ tertiary level prenatal centres

January 2000 ‐ December 2003

Pregnant women

Median maternal age 34 years (range 14‐46 years), 43.2% ≥ 35 years

11‐14 weeks' gestation

Study design

Cohort study

Target condition and reference standard(s)

Down's syndrome: 26 cases

Reference standard: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF certified sonographers)

First trimester free ßhCG and PAPP‐A (Kryptor analyser, Brahms)

Risk cut‐point 1:300

Follow‐up

Data on pregnancy outcome were obtained by contacting the patient or their general gynaecologist. Women without complete outcome data (8%) were excluded from the study

Aim of study

To evaluate and compare the screening performance for fetal trisomy 21 in the first trimester of pregnancy in general gynaecologists practices and specialised centres for prenatal care in Germany

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

Yes

146 women (including 11 with down's syndrome) excluded as results could not be assigned to gynaecologists' or prenatal centre group 

Krantz 2000

Clinical features and settings

Routine screening

Participants

10,251 participants

USA

September 1995 to June 1998

Pregnant women

34.7% ≥ 35 years

Singleton pregnancies

No diabetes

9‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 50 cases (33 had undergone biochemical testing)

Reference standards: not reported

Index and comparator tests

Maternal age

First trimester NT in 5,809 (2018 ≥ 35 years).patients (FMF methods)

Dried blood samples tested for:

First trimester free ßhCG and PAPP‐A in 10,251 patients (enzyme‐linked immunosorbent asay procedures)

Follow‐up

No details of follow‐up reported

Aim of study

To assess the effectiveness of free ßhCG, PAPP‐A and NT for first trimester screening for Down's syndrome and trisomy 18

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Unclear

Unclear reference standard

Partial verification avoided?
All tests

Unclear

Unclear if all patients had a reference standard

Differential verification avoided?
All tests

Unclear

Unclear if choice of reference depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Kublickas 2009

Clinical features and settings

Routine screening

Participants

3907 participants

Sweden

2005 ‐ 2006

Pregnant women

51% of women aged ≥ 35 years

9‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 29 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF trained sonographers)

First trimester free ßhCG and PAPP‐A (AutoDELFIA, PerkinElmer)

Follow‐up

The dataset used contained outcomes for all pregnancies

Aim of study

To provide the necessary mathematical formulae to construct a risk calculation package for Down's syndrome using maternal serum free ßhCG, PAPP‐A and NT measurements in the first trimester for use in a web‐based system

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Kuc 2010

Clinical features and settings

Routine screening

Participants

27,291 participants: 223 cases and 22,157 controls (not matched)

The Netherlands ‐ The Dutch National Institute for Public Health and the Environment

Dates not specified

Pregnant women

Maternal age not reported

8‐13 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 223 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF trained sonographers)

First trimester free ßhCG and PAPP‐A (automated dissociation‐enhanced lanthanide fluorescent immunoassay, AutoDELFIA, PerkinElmer)

Follow‐up

Known outcomes for cases and controls

Aim of study

To estimate the effect of timing of serum collection on screening performance

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Lam 2002

Clinical features and settings

Routine screening

Participants

16,237 participants

Hong Kong ‐ multicentre study

1997 to 2000

Pregnant women

Mean age 30.5 years (19% ≥ 35 years) (unaffected pregnancies)

10‐14 weeks and 15‐18 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 35 cases

Reference standards: women considered high risk offered CVS (0.7%) or amniocentesis (11.8%). Follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

Second trimester free ßhCG and AFP (methods not stated)

(All women underwent both NT and biochemical testing)

Follow‐up

By review of hospital and laboratory records and by directly telephoning women.  

Participants who defaulted the second trimester serum tests (n = 1015) and those who miscarried after NT but before serum testing (n = 91) were excluded from the study. Outcome obtained in only 15,253 patients (93.9%)

Aim of study

To report data on participants undergoing both first and second trimester methods of screening to assess the relative efficacy of different methods of screening

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

No

Not all women received a reference standard (6.1% had no ascertainment of pregnancy outcome)

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

NT successful in 99.8% of cases

Withdrawals explained?
All tests

No

No details of withdrawals given
Leung 2009

Clinical features and settings

Routine screening

Participants

10,185 participants (178 twin pregnancies; 10,363 fetuses)

Hong Kong ‐ University Hospital

June 2003 ‐ March 2007

Pregnant women

Singleton or multifetal pregnancies

Median maternal age 32 years (IQR 30‐35 years), 27.4% of women aged ≥ 35 years

11‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 34 cases

Reference standards: amniocentesis or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF accredited doctors, HDI 5000 or HDI 3000, Philips Medical System)

First trimester nasal bone assessment (7925 women) (FMF accredited doctors, HDI 5000 or HDI 3000, Philips Medical System)

First trimester PAPP‐A and free ßhCG (Kryptor analyser, Brahms Diagnostica GmbH)

Risk cut‐point 1:300

For twin pregnancies, a risk was calculated for each fetus based on the individual NT and maternal serum biochemistry corrected for twin pregnancies

Follow‐up

Specific staff were allocated to contact all women for pregnancy and fetal outcome. Women were contacted by phone and mail. 5 screen positive and 50 screen negative cases had unknown outcome.

Aim of study

To examine the effectiveness of first trimester fetal trisomy 21 screening using a combination of maternal age, NT and maternal serum free ßhCG and PAPP‐A levels in a predominantly Chinese population in Hong Kong

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Nasal bone status could not be determined in 176 women (2.2%) (2 with Down's syndrome)

Withdrawals explained?
All tests

No

No details of withdrawals given
MacRae 2008

Clinical features and settings

Routine screening

Participants

18,965 pregnancies

UK ‐ University Hospital

July 1998 ‐ January 2004

Maternal age not reported

10‐13 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 37 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (trained sonographers)

Risk cut‐point 1:300

Follow‐up

Information on birth outcome from Harris birthright Research Centre database, the North East Regional Cytogenetic Laboratory, the National Down's syndrome register and the Basildon and Thurrock University Hospital database and, in some cases, maternal and paediatric records. For each case, screening results were linked to cytogenetic results/pregnancy outcome

Aim of study

To evaluate NT scans with a view to comparing findings with other research centres

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Index tests did not form part of the reference standard

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Maiz 2007

Clinical features and settings

High‐risk referral for invasive testing

Participants

227 participants

UK ‐ single centre

Pregnant women

Singleton pregnancies

Median maternal age 35 years (17‐49 years)

11‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 20 cases

Reference standard: CVS

Index and comparator tests

First trimester presence of mitral gap (Doppler flow traces)

Follow‐up

100% karyotyping 

Aim of study

To investigate the possible association between a particular pulsed Doppler waveform pattern, mitral gap and trisomy 21 at 11 + 0 to 13 + 6 weeks

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

Yes

Choice of reference standard did not depend on index test results

Incorporation avoided?
All tests

Yes

Index tests did not form part of the reference standard

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Maiz 2009

Clinical features and settings

Routine screening

Participants

19,614 participants with complete screening and outcome data

UK ‐ multicentre

January 2006 ‐ May 2007

Pregnant women

Singleton pregnancies

Median maternal age 34.5 years (14.1‐50.1 years)

11‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 122 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT and fetal heart rate

First trimester ductus venous blood flow velocity waveforms (FMF certified sonographers)

First trimester PAPP‐A and free ßhCG (Delfia Xpress, PerkinElmer)

Follow‐up

Karyotype results and details on pregnancy outcome were added to the database as soon as they became available. Women without complete outcome data (5.3%) were excluded from the study

Aim of study

To investigate the performance of first trimester screening for aneuploidies by including assessment of ductus venosus flow in the combined test of maternal age, fetal NT thickness, fetal heart rate and serum free ßhCG and PAPP‐A  

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Malone 2004

Clinical features and settings

Routine screening

Participants

6324 participants

USA ‐ multicentre study (15 centres)

May 2002 to December 2002

Pregnant women

Mean age 30.1 years (16‐47 years), 22.1% ≥ 35 years

Singleton pregnancies

10‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 11 cases

Reference standards: karyotyping in 587 (amniocentesis n = 510; neonatal cord blood n = 41; products of conception and autopsy material n = 31), or follow‐up to birth

Index and comparator tests

Nasal bone imaging

Fetal image in a perfect saggital plane with fetal spine down. Angle of insonation of ultrasound beam with fetal profile close to 45 degrees. Image magnified significantly until 2 echogenic lines are visible in region of fetal nose. Transducer tilted from side to side to distinguish fetal skin from nasal bone. Deeper echogenic line noted to become more echolucent at its distal end

Follow‐up

A tracking programme with up to 10 contact options for each patient used for follow‐up

Follow‐up to birth in 6228 patients (98.5%) and adequate nasal bone imaging in 4801 (75.9%)

Aim of study

To evaluate first trimester nasal bone imaging as a screening tool for aneuploidy

Notes

Only 17% of patients who had miscarriage or termination of pregnancy had karyotype information available

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

No

Not all women received a reference standard (1.5% had no ascertainment of pregnancy outcome)

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Nasal bone screening successful in 4801 cases (75.9%)

Withdrawals explained?
All tests

No

No details of withdrawals given
Malone 2005

Clinical features and settings

Routine screening

Participants

38,033 participants

USA ‐ multicentre study (15 centres)

October 1999 to December 2002

Pregnant women

Mean maternal age 30.1 years (SD 5.8 years.); 8199 (21.6%) aged ≥ 35 years

Singleton pregnancies

Live fetuses

10‐13 and 15‐18 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down’s syndrome: 92 cases

Reference standards: amniocentesis offered to women with positive results from any screening test or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT in 36,306 patients (92.9%)

First trimester PAPP‐A and free ßhCG in 37,843 patients (99.5%)

Second trimester AFP, total hCG, uE3 and inhibin A in 35,236 patients (92.6%)

All data in 33,546 patients (88.2%)

Follow‐up

Follow‐up with computerised tracking system. Medical records were reviewed in cases of 1) possible medical problem suspected 2) positive screening test results with no karyotype data, 3) 10% random sample of all enrolled patients

Follow‐up to birth in 36,378 patients (97%)

Aim of study

To evaluate first trimester and/or second trimester screening tool for Down's syndrome

Notes

Unclear which types of patients did not have follow‐up data. Appears that aborted/miscarried fetuses did not have follow‐up

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

No

Not all women received a reference standard (3% had no ascertainment of pregnancy outcome, patients not excluded from study)

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

NT failed or rejected at review in only 7.1%

Withdrawals explained?
All tests

Yes

Details given for patients who did not undergo different index tests
Marchini 2010

Clinical features and settings

Routine screening

Participants

1521 participants (18 twin and 2 triplet pregnancies; 1543 fetuses)

Italy

Pregnant women

Singleton or multifetal pregnancies

Median maternal age 31.3 years (range 18‐45 years), 19.7% ≥ 35 years

11‐14 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 8 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF accredited sonographers)

First trimester serum free ßhCG and PAPP‐A (Kryptor analyser, Brahms)

Risk cut‐point 1:300

Follow‐up

Follow‐up obtained by analysis of fetal karyotype, from patient notes and by telephoning patients

Aim of study

To evaluate the performance of the combined test compared to the NT measurement alone, in fetal aneuploidy screening in the general population and in pregnant women aged 35 years and over

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Marsis 2004

Clinical features and settings

Screening of patients ≥ 35 years of age

Participants

262 participants

Indonesia ‐ 4 hospitals

January 2001 to January 2003

Pregnant women

Mean age 37.7 years (35‐43 years)

Singleton pregnancies

11‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 8 cases

Reference standards: amniocentesis (unclear in which patients this was conducted) or follow‐up to birth

Index and comparator tests

First trimester NT (all patients) with > 3.0 mm cut‐off (FMF methods, Apoge 800‐ATL, SSD 680‐Aloka, Logic alpha 200 GE, Veluson 730 Pro GE)

First trimester nasal bone assessment (97 (55%) patients who also had NT)

Follow‐up

Follow‐up to birth in patients with no nasal bone and NT > 3 mm. Unclear if screen‐negative patients had follow‐up to birth

Aim of study

Evaluation of a non‐invasive method to screen for Down's syndrome at a maternal age of 35 years or more

Notes

No cases of Down’s detected that were not picked up in screening tests

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Marsk 2006

Clinical features and settings

Routine screening

Participants

139 participants: 31 cases and 108 controls (3:1 with cases, matched for time of study, geographic location and to be within 5‐year age interval)

Sweden ‐ data from Swedish Nuchal Translucency Trial

Dates not reported

Pregnant women

Mean age cases 38.5 years (SD 4.0 years) and controls 35.5 years (SD 4.0 years)

Singleton pregnancies

8‐14 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 31 cases

Reference standards: not reported

Index and comparator tests

Maternal age

First trimester NT (12‐14 weeks) (method not specified)

Frozen serum samples

PAPP‐A and free ßhCG in sample taken at 8‐14 weeks (Auto Delfia Instrument)

Risk cut‐points of 1:250 and 1:350 (Lifecycle software used to calculate risk)

Follow‐up

No details of methods used to follow women‐up

Aim of study

To determine to what extent adding first trimester serum screening to NT would change the detection rate and test positive rate for Down's syndrome

Notes

Part of NUPP trial

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

Yes

Details given for women who did not agree to take part
Matias 1998

Clinical features and settings

High‐risk referral for invasive testing

Participants

486 participants

UK and Portugal

Dates not reported

Pregnant women

Singleton pregnancies

Median age 35 years (17‐46 years)

10‐14 weeks' gestation

Study design

Prospective cohort study

Target condition and reference standard(s)

Down's syndrome: 38 cases

Reference standard: fetal karyotyping. In cases where NT above 95th percentile or abnormal ductus venousus flow, follow‐up scan conducted at 14‐16 weeks

Index and comparator tests

Maternal age

First trimester NT (SSD, Aloka)

First trimester ductus venosus flow velocity: measured transabdominally (5‐MHz curvilinear probe, Ecocee, Toshiba) or transvaginally (SSD 2000, Aloka)

Follow‐up

100% karyotyping

Aim of study

To assess the possible role of Doppler ultrasound assessment of ductus venous blood flow in screening for chromosomal abnormalities at 11 to 14 weeks of gestation

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice 

Acceptable reference standard?
All tests

Yes

Karyotyping

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

Yes

All women had the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Reported that measurements made successfully in all cases

Withdrawals explained?
All tests

No

No details of withdrawals given
Matias 2001

Clinical features and settings

High‐risk referral for invasive testing

Participants

515 participants

Portugal

Dates not reported

Pregnant women

Median age 35 years (17‐46 years)

Singleton pregnancies

11‐14 weeks' gestation

Study design

Prospective cohort study

Target condition and reference standard(s)

Down's syndrome: 43 cases

Reference standards: fetal karyotyping. In cases where NT above 95th percentile, follow‐up scan conducted at 14‐16 weeks

Index and comparator tests

Maternal age

First trimester NT (SSD, Aloka)

First trimester ductus venous Doppler evaluation ‐ ductus venosus flow velocity ‐ abnormal flow is defined as absent or reversed flow of blood in the ductus venosus, normal flow defined as presence. Measurement made by obtaining the right ventral midsaggital plane of the fetal trunk in fetal quiescence. Pulsed Doppler gate placed in distal portion of umbilical sinus. 5 consecutive high‐quality waveforms used to measure peak velocity during ventricular systole and diastole, the lowest forward velocity during atrial contraction in late diastole and the pulsatility index. Up to 10 minutes allowed for measurements

Follow‐up

All women received karyotyping. Unclear if patients followed up to birth

Aim of study

To review the role of Doppler ultrasound in screening for chromosomal abnormalities at 11 to 14 weeks of gestation

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice

Acceptable reference standard?
All tests

Yes

Karyotyping

Partial verification avoided?
All tests

Yes

All women had a reference standard

Differential verification avoided?
All tests

Yes

All women had the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Reported that Doppler measurements made successfully in all cases

Withdrawals explained?
All tests

No

No details of withdrawals given
Mavrides 2002

Clinical features and settings

High‐risk referral for invasive testing

Participants

256 participants who were referred to unit for fetal karyotyping and had NT and Doppler studies

UK ‐ tertiary referral fetal medicine unit

Conducted over 18 months, dates not reported

Pregnant women

Median age 35 years (15‐42 years)

11‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 30 cases

Reference standard: CVS or follow‐up

Index and comparator tests

Maternal age

First trimester NT

First trimester ductus venous Doppler studies (ATI HDL 5000 US machine with curvilinear TV probe)

Follow‐up

Follow‐up based on ultrasounds findings, examination at birth, postmortem examination in cases of intrauterine death or termination of pregnancy and by telephone interviews with parents

Aim of study

To assess the role of first trimester Doppler assessment of the ductus venosus in screening for fetal aneuploidy in pregnancies at 11‐14 weeks of gestation

Notes

2 live births with Down’s syndrome. Appears to be a high‐risk invasive testing study but some people did not appear to get karyotyping but were followed up. Probably the majority got karyotyping

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice 

Acceptable reference standard?
All tests

Yes

Karyotyping

Partial verification avoided?
All tests

Yes

All participants had a reference standard

Differential verification avoided?
All tests

Yes

All participants had the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Doppler studies failed in 4 cases (1.5%)

Withdrawals explained?
All tests

No

No details of withdrawals given
Maxwell 2011 FTS

Clinical features and settings

Routine screening

Participants

32,478 participants with available outcome data

Australia ‐ screening programme

2005 ‐ 2006

Pregnant women

Singleton pregnancies

Median maternal age 31 years (14‐48 years), 24.3% of women aged ≥ 35 years

10‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 94 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT PAPP‐A and free ßhCG (details not reported)

Risk cut‐point 1:300

Follow‐up

Diagnostic data collected from cytogenetic laboratories. Screening data linked to Western Australia diagnostic data, hospital morbidity and mortality data, midwives notification data and the Birth Defects Registry data through the Department of Health Western Australias Data Linkage Branch. Outcome data available for 92.3% of screened women

Aim of study

To investigate socio‐demographic characteristics in the uptake of prenatal aneuploidy screening in Western Australia and to identify potential barriers to screening access

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Maymon 2005

Clinical features and settings

Routine screening

Participants

595 participants

Israel

January 1999 ‐ January 2004

Pregnant women

Mean age, healthy 30.3 years (SD 4.5), Down's syndrome 33.7 years (SD 4.9)

Singleton pregnancies

11‐14 weeks' gestation and second trimester screening

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 24 cases

Reference standards: amniocentesis (recommended for women with higher risk on first or second trimester testing) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (11‐14 weeks)

First trimester PAPP‐A and free ßhCG (methods detailed in Maymon 2001) (some analysed retrospectively from banked samples)

Second trimester PAPP‐A and free ßhCG (methods detailed in Maymon 2001)

Follow‐up

Delivery outcome obtained by telephone interview or medical records. Information was available for all uneventful pregnancies and delivery outcomes. It is unclear whether information on terminations of pregnancy or miscarriages was available.   

Aim of study

To evaluate the cross‐trimester multiple marker correlation and the minimum marker combination needed for detecting various chromosomal aneuploides

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard 

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Maymon 2008

Clinical features and settings

Routine screening

Participants

243 participants: 19 cases and 224 consecutive controls

USA ‐ antenatal sonographic unit

October 2005 ‐ May 2007

Pregnant women

Singleton pregnancies

11‐13 and 14‐28 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 19 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (according to FMF criteria)

Second trimester nuchal skin‐fold (according to published criteria)

First trimester free ßhCG and PAPP‐A (details not reported)

Follow‐up

Cases detected through karyotyping. Stated that controls had normal pregnancies

Aim of study

To assess whether there is a correlation between nuchal translucency and nuchal skin‐fold measurements in Down's syndrome and in normal pregnancies

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Different reference standards used

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of some index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Merz 2011

Clinical features and settings

Routine referral

Participants

124,205 participants

Germany

Dates not reported

Pregnant women

Maternal age not reported

Singleton pregnancies

First trimester

Study design

Retrospective cohort study

Target condition and reference standard(s)

Down's syndrome: 500 cases

Reference standard: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (only data obtained by level II or III certified sonographers included)

First trimester free ßhCG and PAPP‐A (Brahms Kryptor system)

FMF Germany risk calculation

Risk cut‐point 1:150

Follow‐up

Details not reported

Aim of study

To demonstrate that the variability of the FPR can be reduced through adjusting the concentrations of free ßhCG and PAPP‐A measured in the maternal serum by meaning of a nonlinear regression function modelling the dependence of these variables on maternal weight

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Michailidis 2001

Clinical features and settings

Routine screening

Participants

7447 participants

UK ‐ hospital maternity unit

January 1995 to January 2000

Pregnant women

Mean age 30.1 years (13‐50 years), 21.1% ≥ 35 years, 11.9% ≥ 37 years

10‐14 weeks' gestation

Study design

Prospective cohort study

Target condition and reference standard(s)

Down’s syndrome: 23 cases

Reference standards: karyotyping in women considered at risk due to index test results, age or family history or those with considerable anxiety (632 women, 8.5%). Follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT in all patients (fetus in mid‐sagittal section. Maximum thickness of subcutaneous translucency between skin and soft tissue overlying the C‐spine with the fetus in the ventral position)

Second trimester AFP, free ßhCG in 65% of patients with NT (radio‐immunoassay and immunoradiometric assays)

Follow‐up

Outcome at birth assess from hospital database, labour ward records or directly from patients.

Follow‐up data in 7447 patients (87% of initial patient cohort). Patients without follow‐up excluded

Aim of study

To asses the effectiveness of antenatal screening for trisomy 21 by first trimester sonography followed by second trimester biochemical screening

Notes

2nd trimester data not analysed

4 live births: 1 diagnosed before birth and chose not to abort. 3 diagnosed after birth (no invasive testing was conducted)

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Molina 2010 high risk

Clinical features and settings

High‐risk referral for invasive testing

Participants

333 participants

Spain ‐ fetal medicine unit

February 2007 ‐ January 2009

Pregnant women

Singleton pregnancies

Mean maternal age 32.7 years (range 16.7‐47.5 years)

11‐14 weeks' gestation

Study design

Cohort

Target condition and reference standard(s)

Down's syndrome: 20 cases

Reference standard: CVS

Index and comparator tests

First trimester nasal bone (FMF certified sonographer)

First trimester ductus venosus (FMF certified sonographer)

First trimester tricuspid regurgitation (FMF certified sonographer)

Follow‐up

100% karyotyping

Aim of study

To evaluate detection and false positive rates of the ultrasound markers ‐ nasal bone, ductus venosus flow and tricuspid regurgitation, during the first trimester in a population at high‐genetic risk and to study the influence of a 2‐stage screening policy after previous combined screening on the rate of invasive procedures

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice

Acceptable reference standard?
All tests

Yes

Karyotyping

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

Yes

Choice of reference standard did not depend on index test results

Incorporation avoided?
All tests

Yes

Index tests did not form part of the reference standard

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

5 (1.5%) women did not have measurements obtained for nasal bone and tricuspid regurgitation and 10 (3%) did not have measurements obtained for ductus venosus

Withdrawals explained?
All tests

No

No details of withdrawals given
Molina 2010 screening

Clinical features and settings

Routine screening

Participants

6831 participants

Spain ‐ fetal medicine unit

February 2007 ‐ January 2009

Pregnant women

Maternal age not reported

9‐11 weeks' gestation

Study design

Cohort

Target condition and reference standard(s)

Down's syndrome: 23 cases

Reference standard: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF certified sonographer)

First trimester PAPP‐A and free ßhCG (DELFIA Xpress random access platform, PerkinElmer)

Follow‐up

Details not reported

Aim of study

To evaluate detection and false positive rates of the ultrasound markers ‐ nasal bone, ductus venosus flow and tricuspid regurgitation, during the first trimester in a population at high‐genetic risk and to study the influence of a 2‐stage screening policy after previous combined screening on the rate of invasive procedures

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Index tests did not form part of the reference standard

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Monni 2005

Clinical features and settings

Routine screening

Participants

16,654 participants

Italy ‐ single centre

2001‐2004

Pregnant women

Median age 32 years (14‐49 years)

Singleton pregnancies

10‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 96 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods, No information given regarding machines used)

First trimester nasal bone examination (transabdominal ultrasound in mid‐sagittal view)

Annual audit of screening performance (medians)

Follow‐up

Outcome at birth as recorded in hospital database (provided by outcome sheets or telephone interviews). Of 32,000 cases in the database, 16,654 (52%) patients had NT, nasal bone assessment and follow‐up data available. Patients without follow‐up data were excluded from the study

Aim of study

To evaluate the feasibility and diagnostic accuracy of fetal NT and nasal bone assessment at 11‐14 weeks for screening of trisomy 21

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

In 13 cases (1.3%) not possible to ascertain if nasal bone was visible

Withdrawals explained?
All tests

No

No details of withdrawals given
Montalvo 2005

Clinical features and settings

Routine screening

Participants

4538 participants who had follow‐up data available

Spain ‐ tertiary hospital

July 1999 ‐ October 2004

Pregnant women

Mean age 31.1 years (14‐49 years), 25.9% of patients ≥ 35 years

Singleton pregnancies

10‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 19 cases

Reference standards: invasive testing offered to women considered high risk from screening results or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (Methods described by Nicholaides)

First trimester PAPP‐A and free ßhCG (Kryptor Trace system, CIS Bio International)

Risk cut‐point 1:270

Follow‐up

Only patients with postnatal results available are included in the study

Aim of study

To report the experience of using of use of the combined first trimester screening test

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Moon 2007

Clinical features and settings

Routine screening

Participants

6471 fetuses with available outcome data

Korea

July 2004 ‐ March 2006

Pregnant women

Singleton or multifetal pregnancies

Mean maternal age: Down's syndrome 35.5 years (SD 4.8 years), non‐Down's syndrome 31.7 years (SD 3.4 years)

11‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 15 cases

Reference standard: karyotyping or follow‐up to birth

Index and comparator tests

First trimester fetal nasal bone assessment (Voluson 730, LOGIQ 400 or 5, GE Medical Systems or HDI 500, Philips Medical systems) (American Registry of Diagnostic Medical Sonographers certified Sonographers)

Follow‐up

Obstetric and neonatal outcome obtained from medical records, karyotyping reports and, when needed, telephone conversations with parents or physicians. A total of 7834 fetuses were included in the study but 1047 fetuses (13.4%) without available outcome data were excluded. The remaining 6787 fetuses included 154 twin pregnancies. Assessment of fetal nasal bone was possible in 6490 (95.6%) of the 6787 fetuses. Comparison of nasal assessments between the control population and Down's cases was performed in 6471 fetuses

Aim of study

To evaluate the role of nasal bone assessment in first‐trimester screening for Down's syndrome in the Korean population

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Index tests did not form part of the reference standard

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Assessment of fetal nasal bone was not possible in 297 women (4.4%)

Withdrawals explained?
All tests

No

No details of withdrawals given
Muller 2003

Clinical features and settings

Routine screening

Participants

5694 participants who had first trimester NT and biochemical testing

France ‐ 9 centres serving 12 maternity units

January 1998 ‐ June 2001

Pregnant women

Singleton pregnancies

Maternal age not reported

11‐13 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 26 cases

Reference standards: invasive testing (offered to women with high NT measurement) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester nuchal translucency in 98% of patients (methods not specified. 60 sonographers ‐ 2 trained by Fetal Medicine Foundation, who trained 30 in turn. 8 received specific training in France, and 20 were self‐taught. Machines not specified)

Frozen serum tested for:

First trimester PAPP‐A (99% of patients), free ßhCG 99% of patients and AFP (93% of patients) (time‐resolved fluorescent assay, Perkin‐Elmer Life sciences)

Risk cut‐point 1:250

Follow‐up

Data from the French national screening programme used for follow‐up at birth. 211 women (3.7%) who did not return after NT or were found to be > 14 weeks were excluded. It is unclear how many patients had follow‐up to birth

Aim of study

Prospective study of NT and retrospective evaluation of serum (in same patient population) to evaluate whether or not to move the national French Down's screening programme to a first trimester programme

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Women with NT too small to measure assumed to have NT of < 0.5 mm.

Withdrawals explained?
All tests

Yes

Women failing to return or who more than 14 weeks pregnant were excluded (214).
Nicolaides 1992

Clinical features and settings

High‐risk referral for invasive testing

Participants

827 participants

UK ‐ research centre for fetal medicine

January 1990 ‐ October 1991

Pregnant women

Median age 38 years (22‐47 years)

10‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 13 cases

Reference standards: fetal karyotyping by amniocentesis (52%) or CVS (48%)

Index and comparator tests

Maternal age

First trimester NT (curvilinear 5MHz transducer, Aloka 650 CO Limited)

Follow‐up

100% karyotyping

Aim of study

To examine the significance of fetal NT at 10‐14 weeks' gestation in the prediction of abnormal fetal karyotype

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice 

Acceptable reference standard?
All tests

Yes

Amniocentesis or CVS

Partial verification avoided?
All tests

Yes

All women had a reference standard

Differential verification avoided?
All tests

No

Women had different reference standards

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Nicolaides 2005

Clinical features and settings

Routine screening

Participants

75,821 participants with available information on outcome

UK ‐ Various hospitals and a fetal medicine centre

June 1998 ‐ December 2003

Pregnant women

Median age 31 years (13‐49 years)

Singleton pregnancies

11‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 325 cases

Reference standards: amniocentesis or CVS (patients considered high risk based on screening). First trimester presence/absence of nasal bone, presence/absence of tricuspid regurgitation or normal/abnormal Doppler studies (patients of intermediate risk on first trimester screening and did not undergo CVS or amniocentesis. With the addition of information from these tests, if adjusted risk was high, CVS was performed). Follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

First trimester free ßhCG and PAPP‐A (Kryptor analyser, Brahms AG)

Risk cut‐point 1:300

Follow‐up

Follow‐up data from cytogenetics laboratories, patients, GPs or maternity units where they delivered. Patients without follow‐up information due to miscarriage or termination (n = 490) or loss to follow‐up (n = 2117) were excluded from the study.

Aim of study

To evaluate the performance of first trimester screening for trisomy 21 by a combination of maternal age, fetal NT and maternal serum free ßhCG and PAPP‐A. In addition, the impact of a new individual risk orientated 2‐stage approach to first trimester screening was examined

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

Yes

Exclusions due to loss to follow‐up and missing information for women with miscarriages or terminations of pregnancy explained

Niemimaa 2001

Clinical features and settings

Routine screening

Participants

2515 participants

Finland ‐ primary care centres and maternity clinics of hospitals

During 1999

Pregnant women

17.5% aged ≥ 35 years

10‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 8 cases

Reference standards: invasive testing (patients considered high risk based on NT screening) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (≥ 3 mm) (64% of women) (method not described)

Fresh serum tested for:

First trimester free ßhCG and PAPP‐A (Wallac analytes and 1st trimester risk calculation programme maternal weight correction)

Risk cut‐point 1:250

Follow‐up

Follow‐up data from maternity clinics and the National Research and Development Centre for Welfare and Health. Test negative patients followed up by contacting all maternity clinics and the National Research and Development Centre for Welfare and Health. Unclear if follow‐up information was obtained in all cases

Aim of study

To evaluate efficacy of combining first trimester maternal serum and fetal NT measurement in screening for Down's syndrome in Finland

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Noble 1995

Clinical features and settings

Routine screening in a high‐risk population

Participants

2529 participants

UK

October 1994 to April 1995

Pregnant women

Singleton pregnancies

Median age 34 years (15‐47 years), 47% ≥ 35 years

10‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 61 cases

Reference standards: karyotyping performed (27% of women) due to increased NT (14%), advanced maternal age (10%), previous chromosomally abnormal child (0.5%) or parental anxiety (2%). Ultrasound examination at 20 weeks (65% of patients). Follow‐up to birth (9% of women)

Index and comparator tests

Maternal age

First trimester NT (methods not stated)

Fresh serum (or serum frozen over a weekend) tested for:

First trimester free ßhCG (immunoradiometric assay, CIS)

Follow‐up

Pregnancy outcome obtained from maternity units or the patients themselves. Follow‐up information only appears to have been obtained in 9% of cases (second trimester ultrasound used as reference standard for other women)

Aim of study

To measure the contribution of maternal serum free beta hCG in a screening programme for fetal trisomy 21 based on fetal NT in the first trimester of pregnancy

Notes

No proper results data are presented for this study

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

No

Invasive testing, ultrasound at 20 weeks or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
O'Callaghan 2000

Clinical features and settings

Routine screening

Participants

1000 participants

Australia ‐ public and private sector venues

September 1997 to September 1999

Pregnant women

Singleton or multifetal pregnancies (2000 fetuses including 25 sets of dichorionic twins, 7 sets of monochorionic twins and 4 sets of triplets but the numbers amongst the 1000 fetuses reported in the paper were not stated)

Median age 32 years

11‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down’s syndrome: 8 cases

Reference standards: CVS, amniocentesis, neonatal karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

NT (FMF methods)

Follow‐up

Follow‐up from cytogenetics laboratory records but the completeness of follow‐up is not reported

Aim of study

To evaluate a risk assessment tool based on first trimester NT

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women had a reference standard

Differential verification avoided?
All tests

Unclear

Unclear if the choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
O'Leary 2006

Clinical features and settings

Routine screening

Participants

22,340 participants

Australia ‐ 13 ultrasound practices

August 2001 to October 2003

Singleton pregnancies

Pregnant women

Median age 31 years (14‐47 years), 20% ≥ 35 years

11‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 60 cases

Reference standards: CVS or amniocentesis (women assessed to be high risk on screening) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

First trimester free ßhCG and PAPP‐A (machine not stated)

All study participants underwent all tests

Risk cut‐point 1:300

Follow‐up

Follow‐up data obtained by review of the Midwives Notification System and the Birth Defects Registry. 415 patients (1.8%) excluded due to no follow‐up data. Patients with multiple pregnancies or incomplete screens (n = 3946) were also excluded from the study

Aim of study

To assess fetal outcomes for pregnancies identified at increase risk for Down's syndrome by first trimester combined ultrasound examination and maternal serum biochemistry

Notes

Appears likely that patients with miscarriages and terminations excluded

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

Yes

Details given of patients excluded due to incomplete screening data or loss to follow‐up
Okun 2008 FTS

Clinical features and settings

Routine screening

Participants

14,487 participants undergoing first trimester screening (a separate cohort of 30,792 pregnancies were evaluated for integrated screening)

November 2002 ‐ December 2005

Canada ‐ 2 hospitals

Pregnant women

Singleton pregnancies

Mean maternal age 34 years

11‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 62 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (most sonographers had FMF certification)

First trimester free ßhCG and PAPP‐A (DSX Four Plate Automated ELISA Processing system, Dynex Technologies and DPC Immulite 2000 automated immunoassay analyser, Siemens Medical Solutions Diagnostics)

Risk cut‐point 1:200 or NT ≥ 3.5 mm

Results presented with and without adjustment for bias due to miscarriages (viability bias)

Follow‐up

From cytogenetics databases in both Hospitals, the Canadian Institute for Health Information, labour and delivery databases, written and phone follow‐up with care providers and phone follow‐up with women after birth

Aim of study

To evaluate the performance of integrated prenatal screening and first trimester combined screening for trisomy 21 in a large Canadian urban centre

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Orlandi 1997

Clinical features and settings

Routine screening of general and high‐risk women

Participants

2010 participants (744 in subgroup undergoing NT testing)

Italy

Dates not reported

Recruited through private physician or genetic counselling program for women of advanced maternal age

Pregnant women

Aged 15‐46 years, 35% ≥ 35 years

Singleton pregnancies

9‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 11 cases (7 in subgroup with NT testing)

Reference standards: not reported  

Index and comparator tests

Maternal age

First trimester NT (37% of patients) (FMF methods, Toshiba SSA 250A or Acuson XP 10)

First trimester free ßhCG and PAPP‐A (all patients) (dried blood samples, enzyme‐linked immunosorbent assays)

Risk cut‐point 1:380

Follow‐up

Not reported

Aim of study

To evaluate first trimester combined screening for Down's syndrome

Notes

Unclear as to what reference standard (if any) was used. All cases of Down's syndrome identified had been picked up by screening

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Unclear

Reference standard not reported

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

Unclear

Unclear if the choice of reference standard depended on screening results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

Yes

Details given of women undergoing NT but not biochemical testing
Orlandi 2003

Clinical features and settings

Routine screening (2 centres) or in referred patients (1 centre)

Participants

1089 participants undergoing fetal nasal bone assessment

Italy/The Netherlands ‐ 3 centres

February 2002 to April 2002

Pregnant women

Singleton pregnancies

Median age 31.7 years (SD 4.0) in unaffected cases and 36.5 years (SD 4.1) in affected cases

11‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 15 cases

Reference standards: CVS or amniocentesis (women considered high risk on screening on the basis of NT and biochemical results, but not on nasal bone screening, or if requested due to age or anxiety), or follow‐up to birth

Index and comparator tests

Maternal age

First trimester nasal bone assessment

First trimester NT

First trimester free ßhCG

First trimester PAPP‐A

Follow‐up

Reported that karyotyping was performed postnatally. It is unclear in which cases this was conducted

Aim of study

To assess the feasibility of measuring nasal bone length in first trimester pregnancy and to confirm if the absence of fetal nasal bone is a marker for Down's syndrome

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Nasal bone assessment was successfully conducted in 94.3% of women

Withdrawals explained?
All tests

No

No details of withdrawals given
Orlandi 2005

Clinical features and settings

Routine screening

Participants

2411 participants

Italy

Dates not reported

Pregnant women

Median age 30.5 years (SD 8.2)

First trimester (gestational weeks not reported)

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 15 cases

Reference standard: not reported

Index and comparator tests

Maternal age

First trimester nasal bone assessment (FMF methods)

First trimester NT, free ßhCG and PAPP‐A

Data from other studies used to generate statistical parameters to estimate performance of first trimester screening with and without nasal bone evaluation)

Risk cut‐point 1:250

Follow‐up

No details reported for any follow‐up to birth

Aim of study

To determine the benefit of including nasal bone assessment in addition to standard first trimester markers as a screening test for Down's syndrome  

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

Unclear

Unclear if the choice of reference standard depended on screening results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

Unclear

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Otaño 2002

Clinical features and settings

High‐risk referral for invasive testing

Participants

194 participants

Argentina

October 2001 ‐ January 2002

Pregnant women

Median age 36 years (19‐44 years)

Singleton pregnancies

11‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 5 cases

Reference standard: CVS

Index and comparator tests

First trimester nasal bone assessment (frontal saggital section of the fetal face. Angle of insonation of fetal nose close to 90 degree angle)

Follow‐up

100% karyotyping

Aim of study

To evaluate the association of nasal bone on ultrasound and Down's syndrome fetuses at 11‐14 weeks' gestation

Notes

States in text that there were 6 cases of trisomy 21

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice 

Acceptable reference standard?
All tests

Yes

CVS

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

Yes

All women had the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

Unclear

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Unsuccessful nasal bone assessment in 6%

Withdrawals explained?
All tests

No

No details of withdrawals given  
Pajkrt 1998

Clinical features and settings

Routine screening

Participants

1473 participants

The Netherlands tertiary maternity unit

June 1994 to March 1997

Pregnant women

Mean age 31.4 years (SD 5.7), 24% ≥ 35 years

Singleton pregnancies

10‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 9 cases

Reference standards: prenatal karyotyping offered to patients considered high risk or maternal anxiety (conducted in 24%) or follow‐up to birth

Index and comparator tests

Maternal age

NT (FMF method, Hitachi machines, 6 sonographers instructed to take 'sufficient time')

Risk cut‐point ≥ 3 mm

Follow‐up

Follow‐up to outcome assessment in the delivery room. 68 women (4.4%) were excluded from the study due to loss to follow‐up

Aim of study

To evaluate the effectiveness of NT measurement in the detection of trisomy 21 in a low‐risk population

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

Unclear

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Unsuccessful NT measurement in 4.3%

Withdrawals explained?
All tests

No

No details of withdrawals given
Pajkrt 1998a

Clinical features and settings

High‐risk referral for invasive testing

Participants

2247 participants undergoing NT and fetal karyotyping

The Netherlands ‐ prenatal diagnostic centre

February 1994 to July 1997

Singleton pregnancies

Pregnant women

Mean age 37.6 years (22‐46 years)

10‐14 weeks' gestation

Study design

Consecutive cohort

Target condition and reference standard(s)

Down's syndrome: 36 cases

Reference standard: prenatal karyotyping

Index and comparator tests

Maternal age

FT NT (maximal saggital thickness of NT, corrected for gestational age)

Follow‐up

100% karyotyping

Aim of study

To examine the discriminatory capacity of NT measurement in the detection of trisomy 21 and other chromosomal anomalies

Notes

No follow‐up information on 12 miscarriages

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice 

Acceptable reference standard?
All tests

Yes

Karyotyping

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

Yes

All women had the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Unsuccessful NT measurement in 2.4%

Withdrawals explained?
All tests

Yes

Patients excluded due to sonographically detected fetal abnormalities at NT measurement, no karyotyping or miscarriages

Palomaki 2007 FTS

Clinical features and settings

Routine screening

Participants

10,775 participants

Canada ‐ General Hospital

October 2003 ‐ November 2004

Pregnant women

Mean maternal age 32.3 years (SD 4.6 years)

10‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 23 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

FT NT (encouraged to only accept measurements from sonographers with FMF certification)

FT PAPP‐A (AutoDELFIA, PerkinElmer)

FT hyperglycosylated‐hCG (Nichols Advantage Specialty system, Nochols Institute Diagnosics)

Follow‐up

From electronic record searches of local patient and cytogenetic records and case finding of local and regional birth records

Aim of study

To validate Down's syndrome screening protocols that include hyperglycosylated‐hCG measurements

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Perni 2006

Clinical features and settings

Routine screening

Participants

4615 participants

USA ‐ single institution

January 2003 to September 2004

Pregnant women

Singleton pregnancies

Mean age 33.0 years (IQR 31.0‐36.0)

10‐13 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 22 cases

Reference standards: CVS or amniocentesis. Cytogenetic testing in cases of miscarriage. Follow‐up to birth.

Index and comparator tests

Maternal

First trimester NT (FMF methods)

First trimester PAPP‐A and free ßhCG (dried blood spots, methodology described elsewhere)

Follow‐up

Outcome information from computerised medical record review. Numbers of patients lost to follow‐up not reported

Aim of study

To evaluate the performance of maternal age, fetal NT, PAPP‐A and free ßhCG for aneuploidy screening

Notes

Appears that all cases of Down’s were diagnosed prenatally by karyotyping

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Prefumo 2005

Clinical features and settings

High‐risk referral for invasive testing

Participants

544 participants

UK ‐ tertiary referral fetal medicine unit

December 2001 to November 2003

Pregnant women

Median age 37 years (19‐46 years)

Singleton pregnancies

11‐14 weeks' gestation

Study design

Prospective cohort study

Target condition and reference standard(s)

Down’s syndrome: 47 cases

Reference standard: CVS

Index and comparator tests

Maternal age

First trimester NT (methods not reported), risk cut‐point 1:300

First trimester nasal bone examination (mid‐sagittal view with beam of the ultrasound transducer being parallel to the nasal bones, previously described)

First trimester ductus venous flow (abnormal defined as absent or reversed flow. Angle of insonation < 30 degrees. 3 minutes allotted time. NB previously described)

Follow‐up

100% karyotyping

Aim of study

To assess the role of fetal ductus venous and nasal bone evaluation in first trimester screening for Down’s syndrome

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice 

Acceptable reference standard?
All tests

Yes

CVS

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

Yes

All women had the same reference standard

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Not possible to satisfactorily assess ductus venous flow in 4 cases (0.6%) and nasal bones in 52 cases (8.3%)

Withdrawals explained?
All tests

Yes

158 patients not included in the study due to time restrictions or due to the patient declining taking part

Prefumo 2006

Clinical features and settings

Routine screening

Participants

7116 participants

UK ‐ single institution

December 2001 to November 2003

Pregnant women

Singleton pregnancies

Mean age 31.4 years (14.5‐50.2 years)

10‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 12 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (all patients) (mid‐sagittal view)

First trimester nasal bone assessment

Follow‐up

Outcome information from computerised hospital records. Results cross‐matched with the registry of the Regional Genetics Service. No report of how many patients lost to follow‐up

Aim of study

To assess the role of fetal nasal bone evaluation in first trimester screening for trisomy 21 in selected and unselected pregnancies

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Nasal bones could not be satisfactorily assessed in 9.9% of fetuses

Withdrawals explained?
All tests

No

No details of withdrawals given
Ramos‐Corpas 2006

Clinical features and settings

Routine screening

Participants

1800 participants

Spain ‐ hospital fetal medicine department

June 2003 to April 2004

Pregnant women

Singleton pregnancies

Mean age 30.1 years (15‐46 years) (SD 5.37), 18% ≥ 35 years

First trimester (before week 14)

Study design

Prospective cohort

Target condition and reference standard(s)

Down’s syndrome: 7 cases

Reference standards: invasive testing offered to patients considered high risk at screening (> 1:300) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF method (Accuson XP10, Mountain View, California) Maximum allotted time of 20 minutes)

First trimester nasal bone assessment (in 93.4% of patients)

Risk cut‐point 1:300

PAPP‐A and free ßhCG (Delfia Xpress 6000 immunoanalyzer, Perkin Elmer) ‐ not used in study

Published population parameters used (Wald 2003)

Follow‐up

Follow‐up in all patients without invasive testing by 1) monitoring all births and miscarriages at the hospital, 2) continued contact with the genetics departments and 3) telephone follow‐up. States in abstract that only fetuses with complete follow‐up results included in the study

Aim of study

To evaluate the utility of determining the presence or absence of nasal bone in a low‐risk fetal population

Notes

5 cases diagnosed by invasive testing, 2 by follow‐up

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Nasal bones could not be satisfactorily assessed in 6.6% of fetuses

Withdrawals explained?
All tests

No

No details of withdrawals given
Rissanen 2007

Clinical features and settings

Routine screening

Participants

4776 participants undergoing NT and/or biochemical screening

Finland ‐ hospitals or health care centres

1999 ‐ 2000

Pregnant women

Singleton pregnancies

Mean maternal age 29.5 years, 17.7% ≥ 35 years

10‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 13 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (Trained personnel)

First trimester PAPP‐A and free ßhCG (AutoDelfia kits, PerkinElmer)

Risk cut‐point 1:250

Follow‐up

Outcomes obtained from all maternity clinics, the Finnish Register of Congenital Malformations and the National Research and Development Centre for Welfare and Health. Follow‐up was complete in 99% of live‐born infants. Data on miscarriages (n = 68) received from the National Research and Development Centre for Welfare and Health

Aim of study

To evaluate whether first trimester screening markers are altered in pregnancies affected both by other chromosomal defects than trisomy 21 and structural anomalies and whether it is possible to detect these pregnancies by combined ultrasound and biochemical screening

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Rozenberg 2002

Clinical features and settings

Routine screening

Participants

9118 participants

France ‐ 2 tertiary and 4 primary referral centres

March 1994 to December 1997

Pregnant women

Median age 30.5 years (18‐37 years)

Singleton pregnancies

12‐14 and 14‐17 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down’s syndrome: 21 cases

Reference standards: amniocentesis offered to patients with NT > 3 mm or serum marker risk was > 1:250, or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT in 98.6% of women (FMF methods)

Second trimester free ßhCG (beta hCG ELISA immunoradiometric assay) and AFP (AFP ELISA immunoradiometric assay) in 91.1% of women

Both NT and biochemical testing in 60.4% of women

Follow‐up

Details of the method of follow‐up not given. 3.4% of patients were lost to follow‐up and were excluded from the study. This included 113 women (1.2%) with miscarriages

Aim of study

To assess the performance of combined first trimester sonographic screening and second trimester serum screening

Notes

Includes cost‐effectiveness analysis

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women had a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

NT was not able to be measured in 93 women (1.5%)

Withdrawals explained?
All tests

No

No details of withdrawals given
Rozenberg 2007

Clinical features and settings

Routine screening

Participants

14,934 participants

Canada ‐ multicentre study

Pregnant women

Singleton pregnancies

Mean maternal age 30.9 (SD 4.5) years

11‐13 weeks' gestation

Study design

Prospective cohort study

Target condition and reference standard(s)

Down's syndrome: 51 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (trained assessors following protocol)

First trimester PAPP‐A and free ßhCG (PerkinElmer Life Sciences)

Second trimester ultrasound and/or serum markers (free ßhCG and AFP or total hCG, AFP and uE3) performed in some cases

Risk cut‐point 1:250

Follow‐up

Notebooks in maternity hospitals used to record information on patient characteristics, screening and outcome at birth. Data obtained from cytogenetic laboratories and DASDY database (contains results of birth examinations). Letters sent to women with missing outcome information and, after 3 months, if there was no response, they were contacted by telephone

Aim of study

To evaluate the performance, acceptability and cost‐effectiveness ratio of a pragmatic approach to screening for Down's syndrome based on the combined first trimester test supplemented by routine ultrasound at 20‐22 weeks in the general population

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

Yes

554 women (3.7%) did not undergo screening
Sahota 2010

Clinical features and settings

Routine screening

Participants

10,854 pregnancies with complete outcome data

China ‐ University Hospital

January 2005 ‐ May 2008

Pregnant women

Singleton pregnancies

Median maternal age 33.1 years, 30.1% of women aged ≥ 35 years

10‐13 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 32 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF accredited sonographers, HDI 5000, Philips Medical System)

First trimester PAPP‐A and free ßhCG (kryptor analyser, Brahms Diagnostica GmbH)

Contingent screening strategies

  • Strategy‐NT‐BC: combined screening and if risk intermediate, nasal bone assessment added

  • Strategy‐BC: screening with PAPP‐A and free ßhCG and if intermediate risk, NT added. If risk still intermediate, nasal bone assessment added

  • Strategy‐NT: screening with NT and if intermediate risk, PAPP‐A and free ßhCG added. If risk still intermediate, nasal bone assessment added

Intermediate risk cut‐points 1:50 to 1:1000

Follow‐up

Fetal karyotypes entered into database when available. Data on pregnancy outcomes obtained either from local maternity database for those who delivered in the unit or via telephone calls to patients

Aim of study

To assess the relative performance of a multi‐stage first trimester screening protocol for fetal Down's syndrome

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Salomon 2010

Clinical features and settings

Routine screening

Participants

21,492 participants

France ‐ Single Health Authority district

January 2001 ‐ December 2003

Pregnant women

Median maternal age 30.7 years (18.0‐46.3 years)

11‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 80 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (sonographers trained to FMF standards)

First trimester PAPP‐A and free ßhCG (time resolved fluorescent assay, PerkinElmer Life Sciences)

Routine abnormality scan for structural malformations (20‐24 weeks)

Femur length at routine abnormality scan

Follow‐up

Case report forms completed by attending obstetrician or midwife throughout pregnancy and delivery. Databases of certified laboratories cross‐checked with delivery and outcome data in all maternity units, the databases of all cytogenetic laboratories, the database of the health authority (DASDY), contact with women by mail 3 months after expected delivery and direct telephone with women.

Aim of study

To evaluate the performance of the contingent use of femur length at routine mid‐trimester scan in screening for Down's syndrome in women having previously undergone first trimester screening with disclosure of risk estimates

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Santiago 2007

Clinical features and settings

Routine screening

Participants

4248 participants

Spain ‐ Screening database managed by the Fetaltest project

To December 2005

Pregnant women

Singleton pregnancies

Mean maternal age 30.6 years (14‐46 years)

11‐13 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 13 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (trained sonographers)

First trimester PAPP‐A and free ßhCG (details not reported)

Cut‐point 1:300 and detection rate at 5% FPR

Follow‐up

Follow‐up by supervising the live births and miscarriages at the Hospital together with continuous contact with the genetics department. 24 pregnancies ended in miscarriage and were lost to follow‐up. In 269 women not giving birth at that Hospital, only those karyotyped were followed up. In total, 287 women (6.8%) were lost to follow‐up

Aim of study

To determine whether delta‐NT could be extrapolated successfully from 1 centre‐specific NT reference curve to another and thus to empirically calculate the likelihood ratios of delta‐NT

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Sau 2001

Clinical features and settings

Routine screening

Participants

3185 participants

UK ‐ single hospital

November 1996 to November 1998

Pregnant women

Mean age 28 years (SD 5)

11‐14 and 6‐20 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down’s syndrome: 8 cases

Reference standards: invasive testing (women with high risk on screening) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods, transabdominal route) in 84% of women. NT risk cut‐point of 1:100 or if NT measurement > 95th centile for that particular CRL considered screen positive. Confirmatory NT test conducted in all women positive on first NT screening

Second trimester AFP, ßhCG and uE3 in 49% of women. Serum risk cut‐point 1:250

Follow‐up

Follow‐up from computerised maternity records, the neonatal database and the hospital termination of pregnancy and miscarriage record books

Aim of study

To present data on the performance of biochemical screening in a population with a prior low‐risk screening result

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

In 122 (4.3%) of women, a second NT scan was needed since the first 1 failed to obtain a measurement

Withdrawals explained?
All tests

Yes

Of 3704 women booked for hospital delivery, 3185 had at least 1 screening test and were included in the study

Schaelike 2009

Clinical features and settings

Routine screening

Participants

10,668 participants with complete outcome data

Germany ‐ private centre

November 2000 ‐ December 2006

Pregnant women

Singleton pregnancies

Maternal age ≥ 35 years in 31.0% of women

11‐13 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 59 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF certified physicians)

First trimester PAPP‐A and free ßhCG (Kryptor analyser, Brahms GmbH)

Cut‐point 1:300

Follow‐up

Information provided by either obstetric departments or obstetricians. Results from CVS and amniocentesis, as well as karyotypes from aborted fetal tissue or from postnatal investigations were used. 3.9% of women were lost to follow‐up and were excluded from the study

Aim of study

To assess the performance of a combined first trimester screening concept for trisomies 21, 18 and 13 applied to a low‐ and high‐risk patient sample in a specialised private centre for prenatal medicine  

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Schielen 2006

Clinical features and settings

Routine screening

Participants

4033 participants

The Netherlands ‐ multicentre (44 centres) study

July 2002 to May 2004

Singleton pregnancies

Pregnant women aged 18‐47 years (median 36.5 years)

10‐14 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 21 cases

Reference standards: invasive testing or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

First trimester free ßhCG and PAPP‐A (AutoDELFIA analyser)

Follow‐up

Women were asked to fill in a questionnaire about outcome of pregnancy. A second request was sent by mail if necessary

784 patients were lost to follow‐up (16.2%) and were excluded from the study

Aim of study

To report the results of a first trimester combined‐test screening programme in a multicentre routine clinical setting

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Schuchter 2001

Clinical features and settings

Routine screening

Participants

9342 participants

Austria ‐ single institution

January 1994 to December 1998

Pregnant women

Singleton pregnancies

Mean age 28 years (15‐46 years), 10.7% ≥ 35 years

10‐13 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 19 cases

Reference standards: CVS (offered to patients with first trimester NT > 3.5 mm), amniocentesis (offered to patients with first trimester NT 2.5‐3.4 mm, high risk on second trimester serum testing (> 1:250) and those > 35 years) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (5‐MHz transducer, Acuson Corp)

Second trimester AFP, uE3 and hGC (triple test) offered to patients not undergoing first trimester invasive testing (99.7% of women) (AMERLEX‐M 2nd Trimester kits, Ortho Clinical Diagnostics)

Follow‐up

Patients included in study if they were delivered in the same hospital where they were screened. All newborns were examined for malformations by a paediatrician after delivery.

Aim of study

To evaluate screening for trisomy 21 in a low‐risk population utilising a combination of NT measurement in the first trimester and the triple test in the second trimester

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Schuchter 2002

Clinical features and settings

Routine screening

Participants

4802 participants

Austria ‐ single institution

December 1997 to April 2000

Singleton pregnancies

Pregnant women

13.0% > 35 years

10‐12 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 14 cases

Reference standards: CVS and amniocentesis (offered to patients with increased risk (> 1:400) at first trimester screening. CVS recommended when NT > 3.5 or when women did not want to wait until the 15th week for amniocentesis), or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (transabdominal transducer, 5‐MHz curvilinear Transducer, Acuson, Mountain View), cut‐point 2.5 mm

First trimester PAPP‐A and free ßhCG (done radioimmunologically, kits by Ortho Clinical Diagnostics)

Combined risk cut‐point 1:250

Follow‐up

Patients without follow‐up information (n = 92, 2%) were excluded from the study. 27 women with spontaneous abortions were also excluded from the study

Aim of study

To determine the detection rate of the combined test, NT alone and maternal age alone in a non‐selected population at a false positive rate of about 5%

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All patients received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

Yes

Women not attending visits were excluded from the study
Schwarzler 1999

Clinical features and settings

Routine screening

Participants

4523 participants

UK ‐ single institution

July 1996 to November 1997

Pregnant women

Mean age 29.4 years (16‐47 years)

10‐14 weeks' gestation

Study design

Prospective consecutive cohort

Target condition and reference standard(s)

Down's syndrome: 12 cases

Reference standards: invasive testing (women considered high risk on screening) or follow‐up to birth

Index and comparator tests

Maternal age

NT (Sagittal plane by transabdominal (92.7%) and transvaginal (7.3%) sonography)

Adjusted risk cut‐point 1:270

Follow‐up

Pregnancy outcome obtained via questionnaires, examination by neonatologist and outcome cross‐referenced with regional cytogenetics registry. 26 test‐negative patients lost to follow‐up and excluded from the study

Aim of study

To evaluate first trimester pregnancy screening for fetal aneuploidy and congenital heart defects by maternal age and NT measurement in an unselected population

Notes

3 live births, 9 termination of pregnancy

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard 

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Scott 2004

Clinical features and settings

Routine screening

Participants

2053 participants

Australia ‐ private practice (Sydney Ultrasound for Women)

July 2000 to May 2002

Pregnant women

Median age 32 years (15‐44 years), 29% ≥ 35 years

Singleton pregnancies

11‐14 weeks' gestation

Study design

Prospective cohort study

Target condition and reference standard(s)

Down’s syndrome: 5 affected cases

Reference standards: invasive testing or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods, sagittal plane, ATL 5000; Philips)

First trimester free ßhCG and PAPP‐A (kryptor analyser, Brahms Diagnostics)

All participants had all tests

Risk cut‐point 1:300

Follow‐up

Data obtained from referring doctors or patients via letter, phone or completed feedback form given at the time of consultation. Only cases of known outcome included in the study. 68 (1.3%) lost to follow‐up, largely due to miscarriage (n = 20) and loss to follow‐up (n = 40).

Aim of study

To report the sensitivity of combined first trimester biochemistry and ultrasound screening for Down's syndrome in an Australian private practice specialising in obstetric ultrasound

Notes

Only women having biochemical testing before NT were included in the study. This was done to avoid bias from women declining biochemical testing following negative NT. 

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Sepulveda 2007

Clinical features and settings

Routine screening

Participants

1287 participants

Chile ‐ fetal medicine centre

January 2003 ‐ January 2006

Pregnant women

Median maternal age 33 years (range 14‐47 years), 35.4% ≥ 35 years

Singleton pregnancies

11‐14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 31 cases

Reference standards: CVS, amniocentesis, cordocentesis or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT and nasal bone assessment (Accuvix XQ, Medison or Voluson 730, GE Healthcare) (only included in study if scanned by 1 of 2 fetal medicine specialists following FMF guidelines)

Follow‐up

Cases of chromosomal abnormality were identified from the cytogenetics laboratory logbook, which recorded all the cytogenetic studies performed prenatally, after a spontaneous abortion or fetal death, or in neonates with physical abnormalities. Information from the remaining cases was obtained from the delivery records and neonatal discharge summaries, which recorded the condition of the neonate at birth and the physical examination performed by a neonatologist

Aim of study

To report their experience with first trimester screening for trisomy 21 by using the combination of NT thickness and nasal bone assessment

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Snijders 1998

Clinical features and settings

Routine screening

Participants

96,127 participants

UK ‐ multicentre study (22 centres)

Women due to deliver before June 1997

Pregnant women

Median age 31 years (14‐49 years)

Singleton pregnancies

10 to 14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 326 cases

Reference standards: CVS and amniocentesis (9.6% of women) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (sagittal section)

Risk cut‐point 1:300

Follow‐up

Each women given a request form to complete about the outcome of pregnancy. 4184 women (4.2%) were excluded due to loss to follow‐up or due to miscarriages that were not karyotyped

Aim of study

To investigate the assessment of risk by a combination of maternal age and fetal NT thickness, measured by ultrasonography at 10‐14 weeks of gestation

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Sorensen 2011

Clinical features and settings

Routine screening

Participants

19,694 participants

Denmark ‐ 2 centres

July 2005 ‐ June 2007

Pregnant women

Singleton pregnancies

Maternal age: healthy mean age 30.4 years (16‐45 years), 16.5% ≥ 35 years, Down's syndrome median age 34 years (23‐44 years)

8‐13 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 100 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF certified sonographers)

First trimester PAPP‐A and free ßhCG (TRACE technology, Kryptor instrument, Brahms AG)

Follow‐up

Details not reported. It was stated that, for non‐Down's syndrome pregnancies, only those with known healthy fetus were included

Aim of study

To develop 2 alternative risk calculation programmes to assess whether the screening efficacies for T13, T18 and T21 could be improved by using our locally estimated medians

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Spencer 1999

Clinical features and settings

Women referred for invasive testing or self‐referred for screening

Participants

1156 participants: 210 cases and 946 controls matched for gestational and maternal age

UK ‐ fetal medicine research centre

Dates not specified

Pregnant women

Median maternal age 38 years (19‐46 years) (cases) and 36 years (15‐47 years) (controls)

10‐14 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 210 cases

Reference standards: invasive testing (high‐risk women) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (methods not reported)

Frozen serum samples tested for:

First trimester free ßhCG and PAPP‐A (Kryptor analyser, time resolved amplified cryptate emission (TRACE))

Follow‐up

Stated that pregnancy outcome was ascertained in all women

Aim of study

To examine the potential impact of combining maternal age with fetal NT thickness and maternal serum free ßhCG and PAPP‐A in screening for trisomy 21 at 10‐14 weeks of gestation

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements 

Withdrawals explained?
All tests

No

No details of withdrawals given
Spencer 2002

Clinical features and settings

Routine screening

Participants

278 participants: 54 cases and 224 controls (no details of how selected)

UK ‐ OSCAR screening program

Samples collected since 1998

Pregnant women

Median maternal age 36 years (20‐44 years) (cases) and 30 years (16‐41 years) (controls)

11‐13 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 54 cases

Reference standards: details not reported

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

Frozen serum samples tested for:

First trimester free ßhCG, PAPP‐A and ThCG (Kryptor Analyser (TRACE) and automated immunofluorescent assays)

Follow‐up

Methods for follow‐up to birth not reported

Aim of study

To assess serum hyperglycosylated hCG for use in the first trimester of pregnancy as a marker of Down's syndrome

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth (Nicolaides 2005(OSCAR screening program))  

Partial verification avoided?
All tests

Yes

All women received a reference standard 

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Unclear

Unclear of all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Spencer 2008

Clinical features and settings

Routine screening

Participants

622 participants: 55 cases and 567 controls matched for gestational age

Denmark ‐ screening programme

Dates not reported

Pregnant women

Median maternal age cases 35.8 years, controls 29.3 years

8‐13 weeks' gestation (results modelled on only cases where testing conducted before 10 weeks' gestation)

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 55 cases (31 tested before 10 weeks' gestation)

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (details not reported)

Fresh serum samples tested for:

First trimester PAPP‐A and free ßhCG (Kryptor analyser, Brahms)

Frozen samples tested for:

First trimester ADAM 12 (measured blind to clinical outcome) (manual DELFIA assay, PerkinElmer Life & Analytical Sciences)

Follow‐up

Details not reported

Aim of study

To establish the effectiveness or otherwise of ADAM 12 as an early screening marker

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Stenhouse 2004

Clinical features and settings

Routine screening

Participants

5000 participants

UK ‐ maternity clinic

Over a 3 year period ‐ dates not specified

Pregnant women

Singleton pregnancies

Median age 32 years (14‐45 years), 27% ≥ 35 years

11 to 14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 15 cases

Reference standards: invasive testing offered to women with screening risk of > 1:250 or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods, ATL HDI 3500, ATL HDI 3000, Toshiba SSA‐340A and Kretz Voluson)

First trimester free ßhCG and PAPP‐A (Clotted venous blood samples, AutoDELFIA immunoassy, Perkin Elmer)

Follow‐up

Details not reported

Aim of study

To assess the effectiveness of combined ultrasound and biochemical screening for chromosomal abnormalities in singleton pregnancies in a routine antenatal clinic and laboratory setting

Notes

Fetal loss rate for invasive testing was 1.4% (3/212)

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

NT not successfully measured in 25 patients (0.5%)

Withdrawals explained?
All tests

No

No details of withdrawals given
Strah 2008

Clinical features and settings

Routine screening

Participants

7096 participants with information available on pregnancy outcome

Slovenia ‐ 2 outpatient clinics

November 1999 ‐ May 2006

Pregnant women

Singleton pregnancies

Median maternal age 28.6 years (range 15‐42 years), 2.5% ≥ 36 years

11‐14 weeks' gestation

Study design

Cohort

Target condition and reference standard(s)

Down's syndrome: 12 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (2 FMF certified sonographers) (3.5‐5 MHz and 8‐4 MHz transducers Toshiba Corevision Pro and 2‐5 MHz and 9.3‐3.7 MHz transducers GE Healthcare Voluson 730 Pro)

Cut‐off 1/300

Follow‐up

Pregnancy outcomes were obtained from participating women, referring gynaecologists, paediatricians and maternity units and were missing in 3% (n = 225) of cases. Karyotype results were reported from the cytogenetics laboratory. Only women with known outcome were included in the study analysis

Aim of study

To evaluate screening for trisomy 21 by maternal age and NT in a low‐risk population

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Theodoropoulos 1998

Clinical features and settings

Routine screening

Participants

4611 women due to deliver before July 1996

Greece ‐ 4 medical centres

Dates not specified

Singleton pregnancies

Median maternal age 29 years (16‐48 years), 7.8% ≥ 37 years

10 to 14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 10 cases

Reference standards: CVS or amniocentesis or follow‐up to birth. Unclear reference standard in cases of intrauterine death, miscarriages and terminations

Index and comparator tests

Maternal age

First trimester NT (FMF methods, transabdominally with 5 or 3.5 MHz curvilinear translucer or transvaginally with 5 MHz transducer)

Pandya's risk criteria

Follow‐up

Results of fetal karyotyping and pregnancy outcome were entered into the database when they became available

Aim of study

To evaluate first trimester screening for chromosomal defects by fetal NT thickness at 10‐14 weeks of gestation in 4 medical centres in Greece

Notes

1 set of parents continued with diagnosed Down’s pregnancy to birth, 9 terminated. 1 case of Down’s syndrome only detected at birth.

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given  
Thilaganathan 1999

Clinical features and settings

Routine screening

Participants

9802 participants

UK ‐ district general hospital

November 1994 to November 1998

Pregnant women

Singleton pregnancies

Mean age 29 years (15‐45 years)

10 to 14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 21 cases

Reference standards: CVS (offered to patients considered high risk on screening) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (transabdominally, Toshiba SSA‐250, Accuson 128XP/4 or Aloka 650CL with 3.5‐7.5 curvilinear transducers)

Follow‐up

Pregnancy outcomes from hospital records and general practitioners. Karyotype results or postnatal tests were provided by the local Regional Cytoenetics laboratory. The proportion of patients who were followed up is not reported (49 patients had not given birth at the time of analysis of outcomes)

Aim of study

To evaluate the effectiveness of 10‐14 week NT measurement in routine ultrasounds screening for Down's syndrome

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

Unsuccessful NT in 10.1% of patients

Withdrawals explained?
All tests

Yes

Patients not included due to ineligibility described
Timmerman 2010

Clinical features and settings

High‐risk referral

Participants

445 fetuses with increased risk based on NT or biochemical testing and information available on pregnancy outcome

The Netherlands ‐ fetal medicine unit

September 1996 ‐ March 2008

Mean maternal age 34.5 years (19‐45 years)

First trimester

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 72 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

First trimester ductus venosus pulsatility index and Ductus venosus a‐wave (methods reported elsewhere)

Follow‐up

Pregnancy outcome was obtained from standard follow‐up forms filled in and returned by patients, maternity wards or midwife practices and by reviewing neonatal, pathology and clinical paediatric notes. When the baby was born without structural defects or dysmorphic features, the chromosomes were assumed to be normal. In all cases of enlarged NT or antenatal suspicion of abnormal development, the infant was investigated by a neonatologist, paediatric cardiologist or geneticist.  

Aim of study

To investigate if ductus venosus pulsatility index for veins and a‐wave measurements can increase the accuracy of first trimester Down's syndrome screening in a high‐risk population

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Selective testing of high‐risk women as done in practice

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Satisfactory waveform measurements made in 98% of cases

Withdrawals explained?
All tests

No

No details of withdrawals given
Torring 2010

Clinical features and settings

Routine screening

Participants

691 participants: 46 cases and 645 controls

Denmark ‐ nationwide screening programme

Dates not reported

Pregnant women

Singleton pregnancies

Mean maternal age cases 35 years, controls 31 years

8‐11 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 46 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (11‐13 weeks' gestation) (FMF certified sonographers)

First trimester PAPP‐A and free ßhCG (fresh serum, 8‐11 weeks' gestation) (Kryptor analyser, Brahms)

First trimester ADAM 12 (frozen serum, 8‐11 weeks' gestation) (Kyptor analyser, assay by Cezanne SAS, TRACE technology)

Follow‐up

Not reported  

Aim of study

To determine whether ADAM 12 is a useful serum marker for fetal trisomy 21 using the mixture model

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of some index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Vadiveloo 2009

Clinical features and settings

Routine screening

Participants

10,189 participants

UK ‐ screening programme

July 2000 ‐ October 2005

Pregnant women

Median maternal age 33.1 years, 36.9% ≥ 35 years

9‐14 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 44 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (trained sonographers)

First trimester PAPP‐A and free ßhCG (DELFIA fluoroimmunoassay, PerkinElmer LAS)

Contingent: biochemistry high risk cut‐off 1:42, low risk cut‐off 1:1000. If biochemical/maternal age risk between 1:42 and 1:1000, NT results added and combined risk calculated. Final cut‐point 1:250

Follow‐up

Not reported  

Aim of study

To assess the performance of a 2‐stage screening protocol for Down's syndrome based on initial serum marker analysis for all women and NT measurement only in women with intermediate risks

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Valinen 2007

Clinical features and settings

Routine screening

Participants

7534 participants

Finland ‐ screening programme

2002‐2004

Pregnant women

Singleton pregnancies

Mean maternal age 29.6 years, 18.6% ≥ 35 years

10‐12 weeks' gestation

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 30 cases (24 underwent NT as well as biochemical testing)

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (trained nurses, midwives and doctors) (4765 women)

First trimester PAPP‐A and free ßhCG (details not reported) (all women)

Cut‐point 1:250

Follow‐up

Contacted chromosome laboratory at the department of clinical genetics in the Oulu university clinic and the Finish Register of Congenital Malformation and the National Research and Development Centre for Welfare and Health  

Aim of study

To compare the efficacy of both separate and combined maternal serum testing and fetal NT measurement in the first trimester screening for Down's syndrome in northern Finland

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Viora 2003

Clinical features and settings

Routine screening

Participants

1752 participants

Italy ‐ ultrasound and prenatal diagnosis unit

December 2001 to June 2002

Pregnant women

Median age 32 years (18‐47 years)

11 to 14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 10 cases

Reference standards: CVS or follow‐up to birth

Index and comparator tests

Maternal age

Nasal bone assessment (ultrasound examinations with Aloka SSD‐1700 or ATL‐Philips 5000 HCD)

Follow‐up

Follow‐up to birth in all cases of abnormalities. Not reported if there was follow‐up in screen‐negative patients

Aim of study

To evaluate the significance of nasal bone ossification as a marker fir trisomy 21 at 11 to 14 weeks' gestation in an unselected population

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

In 154 cases (8.1%) fetal profile was not obtained

Withdrawals explained?
All tests

No

No details of withdrawals given
Wald 2003

Clinical features and settings

Routine screening

Participants

39,983 participants

UK and Austria ‐ multicentre trial

September 1996 to April 2000

Pregnant women

9‐13 and 14‐20 weeks' gestation

Study design

Case‐control study

Target condition and reference standard(s)

Down's syndrome: 85 cases

Reference standards: invasive testing (following second trimester screening) or follow‐up to birth

Index and comparator tests

First trimester NT (midsaggital section, optimal magnification of thickness of translucent space between inner skin surface and fascia covering cervical spine (white black interface (oute) ‐ black white interface (inner), 41 models of ultrasound machine, 20 minutes allotted scanning time)

First and second trimester serum AFP, hCG, uE3, PAPP‐A, free ßhCG (time resolved fluoroimmunoassay, AutoDELFIA)

First and second trimester inhibin A (Sandwich enzyme linked immunosorbent assay, Oxford bioinnovation)

First and second trimester urinary beta core fragment, total hCG, ITA and free ßhCG (ITA and beta core fragment, Quest diagnostics USA)

Follow‐up

Follow‐up by: 1) staff at local hospitals completed a study outcome form at, or just after delivery, 2) study records of CVS, amniocentesis or karyotype at birth linked to information from cytogenic laboratories, 3) study records linked to records of cases of Down's syndrome from the National Down's Syndrome Cytogenetic Register, 4) information obtained from local obstetrical outcome records, 5) forms sent to all women with a request to return details of the outcome of their pregnancy, 6) individual searches in respect of women whose outcomes of pregnancy had not been obtained by any of the previous methods. 4% of total patient cohort did not have a documented outcome of pregnancy. Unclear if any of these were included in the nested case‐control study

Aim of study

To identify the most effective, safe and cost‐effective strategy for antenatal screening for Down's syndrome using NT, maternal serum and urine markers in the first and second trimesters of pregnancy and maternal age in various combinations

Notes

Performance of screening assessed at 17 weeks' gestation. Study tried to be non‐interventional in the first trimester ‐ second trimester testing was aimed to be used as the basis for any referral for invasive testing

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Unclear

Unclear if all index tests interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

Yes

Rates of NT failure on average 9%. Pre‐10 weeks' gestation, > 33% failure rate, declined to 7% at 12 weeks

Withdrawals explained?
All tests

No

No details of withdrawals given
Wapner 2003

Clinical features and settings

Routine screening

Participants

8216 participants

USA multicentre study (12 prenatal diagnostic centres)

Dates not specified

Singleton pregnancies

Pregnant women

Mean age 35 years (SD 4.6), 50% ≥ 35 years

11 to 14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 61 cases

Reference standards: invasive testing. Miscarriage with cytogenetic testing. Follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

Dried blood samples tested for:

First trimester free ßhCG and PAPP‐A (dried blood samples, enzyme‐linked immunoadsorbent assay as previously described)

Risk cut‐point 1:270

Follow‐up

Follow‐up to birth by directly following up women and reviewing delivery records. An effort was also made to obtain information on terminated or miscarried pregnancies. 196 (2.3%) of patients without follow‐up information were excluded and women with a previous trisomy 18 or 21 pregnancy were also excluded

Aim of study

To evaluate the use of combined first trimester markers for aneuploidy in clinical practice

Notes

16 live Down’s syndrome births

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population 

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Wax 2009

Clinical features and settings

Routine screening

Participants

2231 participants

USA

January 2005 ‐ January 2008

Pregnant women

Singleton pregnancies

Mean maternal age 36.7 years (SD 3.2 years)

First and second trimester

Study design

Retrospective cohort

Target condition and reference standard(s)

Down's syndrome: 8 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (Sonographers credited by FMF or Nuchal Translucency Quality Review Program)

First trimester PAPP‐A and free ßhCG (details not reported)

Second trimester ultrasound (in 884 women)

Cut‐point for combined test 1:220

Follow‐up

Down's syndrome cases ascertained from pre‐natal genetic database, including prenatal and newborn testing or physical examination at birth   

Aim of study

To evaluate the trisomy 21 screening performance of the first trimester combined test followed by second trimester genetic sonography

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Wojdemann 2005

Clinical features and settings

Referrals for screening

Participants

8622 participants

Denmark ‐ 3 obstetrics departments

March 1998 to June 2001

Pregnant women

Mean age 29 years, 10.8% ≥ 35 years

Singleton pregnancies

11 to 14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 12 cases

Reference standards: invasive testing (in cases of increased risk) or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods, Logic 700 MR machine) (all women)

First trimester free ßhCCG (AFP/ßhCG Auto Delfia kit) and PAPP‐A (In‐house ELISA (Sandwich)) in 6,441 women (75%)

Risk cut‐point 1:250

Follow‐up

Cross‐checking with all the chromosome laboratories in Denmark. Follow‐up in 96.2% of pregnancies through patients records

Aim of study

To determine the performance of screening for Down's syndrome and other major chromosomal abnormalities using NT, free ßhCG and PAPP‐A in a prospective study of a non‐selected population

Notes

Uptake of screening was 73% (9,941 accepted out of 13,621 offered screening)

Women with miscarriages excluded from the study

3 live Down’s syndrome births

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

NT could not be measured in 2.5% of cases

Withdrawals explained?
All tests

No

No details of withdrawals given
Wortelboer 2009

Clinical features and settings

Routine screening

Participants

20,293 participants with complete outcome data

The Netherlands ‐ nationwide screening programme

May 2004 ‐ July 2006

Pregnant women

Singleton pregnancies

Median maternal age 34.9 years (15‐48 years)

8‐14 weeks' gestation

Study design

Cohort

Target condition and reference standard(s)

Down's syndrome: 87 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF protocols)

First trimester PAPP‐A and free ßhCG (AutoDELFIA analyser, PerkinElmer, Turku)

Cut‐point for combined test 1:250

Follow‐up

Pregnancy outcome was evaluated by questionnaire and collected through self‐reporting of the participating women. Due to strict privacy rules of the Dutch Personal Data Protection Act, the researchers were allowed to send a reminder letter to collect missing data only once. Women without complete information on outcome were excluded from the study

Aim of study

To study the performance of the first‐trimester combined test between 2004 and 2006 compared to a previous period to investigate changes in time and identify reasons for sub‐optimal performance

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

Yes

Only 65% of biochemistry screened women (n = 41,782) had NT results 
Wright 2008

Clinical features and settings

Routine screening

Participants

37,488 participants with complete outcome data

UK ‐ single centre

July 1999 ‐ July 2005

Pregnant women

Singleton pregnancies

Median maternal age 35.2 years (16‐52 years)

11‐13 weeks' gestation

Study design

Cohort

Target condition and reference standard(s)

Down's syndrome: 264 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT

First trimester PAPP‐A and free ßhCG (Kryptor system, Brahms AG)

Follow‐up

Maternal characteristics and test results were recorded in a computer database and karyotype results and details on pregnancy outcomes added as they became available. Women without complete outcome data (n = 1231, 3.2%) were excluded from the study

Aim of study

To examine the validity of methods used to derive patient‐specific risks form NT measurements

Notes

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Yes

All women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

No details given for test failures/uninterpretable measurements

Withdrawals explained?
All tests

No

No details of withdrawals given
Wright 2010

Clinical features and settings

Routine screening

Participants

223,361 pregnant women

UK, Denmark and Cyprus – multicentre

Some data from UK and Denmark in previous publications

Dates not reported

Singleton pregnancies

Median maternal age 31.9 years (IQR 27.7‐35.8 years)

7‐14 weeks' gestation

Study design

Cohort

Target condition and reference standard(s)

Down’s syndrome: 886 cases

Reference standards: karyotyping or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (details not reported)

First trimester PAPP‐A and free βhCG (Kryptor system, Brahms AG or Delfia Express sustem, PerkinElmer, Waltham)

Follow‐up

Karyotype results and details on pregnancy outcomes were added to databases as soon as they became available

Aim of study

To establish an algorithm for first trimester combined screening for trisomy 21 with biochemical testing from 7 to 14 weeks’ gestation and ultrasound testing at 11‐13 weeks

Notes

Taken results modelled for PAPP‐A and free ßhcg at 12 weeks as that was most common time for testing (44% of women)

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice

Uninterpretable results reported?
All tests

No

Withdrawals explained?
All tests

No
Zoppi 2001

Clinical features and settings

Routine screening

Participants

10,001 participants

Italy ‐ genetic diagnosis centre

May 1996 to unspecified date

Pregnant women

Median age 33 years (14‐48 years)

Singleton pregnancies

10 to 14 weeks' gestation

Study design

Prospective cohort

Target condition and reference standard(s)

Down's syndrome: 64 cases

Reference standards: amniocentesis, CVS or follow‐up to birth

Index and comparator tests

Maternal age

First trimester NT (FMF methods)

Risk cut‐points of 1:100, 1:200 and 1:300

Follow‐up

Outcome obtained from women themselves. 1422 patients (11%) with no data on follow‐up outcome and 202 patients with miscarriages were excluded from the study

Aim of study

To examine the distribution of fetal NT thickness in normal and abnormal fetuses in Sardinia and to determine its effectiveness as a screening tool

Notes

Study design unclear (maybe a case‐control study)

Table of Methodological Quality

Item

Authors' judgement

Description

Representative spectrum?
All tests

Yes

Routine screening of typical pregnant population

Acceptable reference standard?
All tests

Yes

Karyotyping or follow‐up to birth

Partial verification avoided?
All tests

Unclear

Unclear if all women received a reference standard

Differential verification avoided?
All tests

No

Choice of reference standard depended on index test results

Incorporation avoided?
All tests

Yes

Reference standard was independent of the index test

Reference standard results blinded?
All tests

No

Reference standard interpreted with knowledge of index test results

Index test results blinded?
All tests

Yes

Index test interpreted without knowledge of reference standard results

Relevant clinical information?
All tests

Yes

Information available as would be in standard clinical practice 

Uninterpretable results reported?
All tests

Yes

NT could not be measured in 25 (0.2%) of cases

Withdrawals explained?
All tests

No

No details of withdrawals given

AFP:alpha‐fetoprotein
ßhCG: beta human chorionic gonadotrophin
CVS: chorionic villus sampling
DELFIA: dual labelled time resolved fluorescent assay
DVPI: ductus venosus pulsivity index
FMF: frontomaxillary facial
hCG: human chorionic gonadotrophin
NT: nuchal translucency
PAPP‐A: pregnancy‐associated plasma protein A
PIGF: placental growth factor
uE3: unconjugated oestriol

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Abbas 1995

Unable to extract useful data

Abdul‐Hamid 2004

No Down's syndrome pregnancies

Abraha 1999

Unable to extract useful data

Abu‐Rustum 2010

Not Down’s syndrome specific

Achiron 2010

Study only includes cases of Down’s syndrome

Adekunle 1999

Unable to extract useful information

Agaard‐Tillery 2010

Results presented in another study

Aitken 1993

Unable to extract useful data

Aitken 1996

Fewer than 80% of pregnancies had gestational age confirmed by USS

Aitken 1996a

Fewer than 80% of pregnancies had gestational age confirmed by USS

Ajayi 2011

No diagnostic data

Akbas 2001

Less than 5 Down's syndrome pregnancies

Alexioy 2009

Study only includes test‐positives

Allingham‐Hawkins 2011

Quantitative fluorescent polymerase chain reaction study

American College 2009

Discussion article

Antona 1998

Likely fewer than 80% of pregnancies dated by USS

Antsaklis 1999

Women screened at greater than 24 weeks' gestation

Anuwutnavin 2009

Second trimester ultrasound

Ashwood 1987

Unable to extract useful data

Asrani 2005

Review article

Audibert 2001b

Unable to ascertain whether part of screening population in Rozenberg et al. No response from authors, therefore excluded to reduce risk of data replication.

Axt‐Fleidner 2006

Unable to extract useful data

Azuma 2002

Unable to extract useful data

Baghagho 2004

Unable to obtain paper

Bahado‐Singh 1995

USS markers greater than 14 weeks' gestation

Bahado‐Singh 1996

USS markers greater than 14 weeks' gestation

Bahado‐Singh 1999b

USS markers greater than 14 weeks' gestation

Bahado‐Singh 2002

USS markers greater than 14 weeks' gestation

Bahado‐Singh 2003

Review article

Ball 2007

Data from the FASTER trial

Bar‐Hava 2001

No Down's pregnancies in study population

Barkai 1996

No Down's pregnancies in study population

Barnabei 1995

No Down's pregnancies in study population

Bartels 1988

Unable to extract useful data

Bartels 1993

No Down's pregnancies in study population

Barth 1991

Second trimester ultrasound study

Bas‐Budecka 2007

No diagnostic data

Baviera 2004

Unclear method of confirmation of gestational age

Bazzett 1998

Male versus female fetuses

Beke 2008

Results are not specific to Down’s syndrome

Bellver 2005

No Down's syndrome pregnancies in study

Benn 1995

Less than 80% follow‐up

Benn 1996

Less than 80% follow‐up

Benn 1997

No Down's pregnancies in study population

Benn 1998

Less than 80% follow‐up

Benn 2001

Statistical modelling (computer simulation)

Benn 2002

Modelled data

Benn 2003

Less than 80% of pregnancies dated by USS

Benn 2003a

Editorial

Benn 2005

No Down's pregnancies included

Benn 2005a

Mathematical model

Benn 2007

No follow‐up information

Berry 1995

Less than 80% of pregnancies USS dated

Berry 1997

Less than 80% of pregnancies USS dated

Bersinger 1994

Gestational age not USS estimated

Bersinger 2000

Unable to extract useful data

Bersinger 2001

No Down's syndrome pregnancies in study population

Bersinger 2003

Unable to extract useful data

Bersinger 2004

No Down's syndrome pregnancies in study population

Bersinger 2005

No Down's syndrome pregnancies in study population

Bestwick 2008

All healthy pregnancies

Biggio 2004

Cost‐effectiveness analysis

Bilardo 2011

Not a proper sample ‐ most had elevated NT

Bindra 2002

Review article

Blundell 1999

Unable to extract useful data

Boormans 2010

Study of testing on amniocentesis samples

Boots 1989

Population risk factor calculations

Bornstein 2009

No diagnostic data

Bornstein 2009a

No diagnostic data

Bornstein 2010

No diagnostic data

Borowski 2007

No diagnostic data

Borrell 2007

No follow‐up data

Borrell 2009a

Based on SURUSS data ‐ second trimester serum parameters not actually measured

Borruto 2002

Unable to extract useful data

Bottalico 2009

Second trimester ultrasound

Boue 1990

Review article

Bradley 1994

Screen‐negative population gestations not confirmed by ultrasound

Braithwaite 1996

Review article

Brambati 1995

USS screening inclusive of women greater than 14 weeks' gestation

Brambati 1996

Review article

Brizot 1995

Unable to extract useful data

Brizot 1995a

Unable to extract useful data

Brizzi 1989a

Second trimester ultrasound

Brock 1990

Unable to extract useful data

Calda 2010

No data for false positive rates

Campogrande 2001

Unable to extract useful data

Canick 1988

Unable to extract useful data

Canick 1995b

Unable to extract useful data

Canini 2002

No Down's syndrome pregnancies in study population

Cans 1998

Second trimester ultrasound

Carreras 1991

Second trimester ultrasound

Caughey 2007

No diagnostic data

Cebesoy 2008

No diagnostic data

Chelli 2008

No follow‐up for false negatives

Chen 1999

Review article

Chen 2002

No Down's syndrome pregnancies in study population

Chen 2004

Less than 5 Down's cases in study population

Chen 2005

Unable to extract useful data

Chen 2008

No diagnostic data

Cheng 1993

Likely that fewer than 80% of gestational age confirmed by USS

Cheng 1999

Case series

No Down's syndrome pregnancies in study population

Cheng 2004

No Down's syndrome pregnancies in study population

Cheng 2004a

No Down's syndrome pregnancies in study population

Chitayat 2002

Less than 5 Down's cases in study population

Chiu 2011

Study of maternal DNA testing

Cho 2009

Study of testing amniotic fluid

Chou 2009

Not possible to calculate specificity

Christiansen 2002

Unable to extract useful data

Christiansen 2007a

Unable to extract useful data

Christiansen 2008

No diagnostic data

Chung 2000

Less than 5 Down's syndrome pregnancies in study population

CNGOF 1996

Unable to obtain translation

Cocciolone 2008

Unable to extract useful data ‐ attempted to contact author

Cole 1996

Review article

Comas 2001

USS at greater than 14 weeks

Comas 2002

USS at greater than 14 weeks

Comas 2002a

USS at greater than 14 weeks

Comstock 2006

Unable to extract useful data

Conde‐Agudelo 1998

Review article

Cowans 2011

No diagnostic data

Crossley 1991

Less than 80% of pregnancies had gestational age confirmation by ultrasound

Crossley 1993

Less than 80% of pregnancies had gestational age confirmation by ultrasound

Crossley 1996

No Down's syndrome pregnancies in study population

Crossley 2002a

Adjustment factors for smokers

Cuckle 1984

Gestational age not confirmed by USS

Cuckle 1987

Gestational age not confirmed by USS

Cuckle 1987a

No gestational age limits given

Cuckle 1990

Paper presenting adjustment factors

Cuckle 1996

Data modelled on 4 meta‐analysed studies

Cuckle 1999b

Unable to extract useful data

Cuckle 1999c

Review article

Cullen 1990

Abnormal scans only in study population

Cusick 2004

Less than 5 Down's syndrome pregnancies in study population

Cusick 2007

ST ultrasound

Dancoine 2001

No Down's syndrome pregnancies in study population

Dane 2008

Not specific to Down’s syndrome

De Biasio 2000

Unable to extract useful information

De Biasio, 1999

Unable to ascertain whether overlapping populations between several papers ‐ attempted to contact author with no response

De Biasio, 2001

Unable to ascertain whether overlapping populations between several papers ‐ attempted to contact author with no response

De Graaf 1991

Unable to extract useful data

Del Carmen Saucedo 2009

No follow‐up information

DeVore 2001

Second trimester ultrasound

Dhaifalah 2007

Unable to obtain translation

Dhaifalah 2007a

Unable to obtain translation

Dhallan 2007

DNA testing of blood samples from parents

Dickerson 1994

Comment

Dimaio 1987

Gestational age by USS only in screen‐positive population

Doran 1986

Ultrasound confirmation of gestational age performed in screen‐positive women only

Dreux 2008

No information for specificity

Drugan 1996

Second trimester ultrasound

Drugan 1996a

Unable to extract useful data

Drysdale 2002

Fewer than 5 Down's syndrome pregnancies in population

Dugoff 2008

Not specific to Down’s syndrome

Ebell 1999

Review article

Economides 1998

Unable to extract useful data

Erickson 2004

No Down's syndrome pregnancies in population

Evans 1996

No Down's syndrome pregnancies in population

Evans 2007

Data previously presented in another study

Falcon 2005

Unable to extract useful data

Falcon 2006

Unable to extract useful data

Ford 1998

Audit

Frishman 1997

No Down's syndrome pregnancies in population

Fukada 2000

Unable to extract useful data

Gaudry 2009

Study of karyotyping

Gebb 2009

Study only examines screen‐positives

Geerts 2008

Study only examines abnormal fetuses

Geipel 2010

ST ultrasound

Gekas 2009

Diagnostic data from other studies

Gekas 2011

Diagnostic data from other studies

Gekas 2011a

Diagnostic parameters from other studies

Gerovassili 2007

No diagnostic data

Ghidini 1998

Comparison of male versus female fetuses

Goetzinger 2010

Second trimester ultrasound

Goldie 1995

Fewer than 80% of study population had gestational age confirmed by USS

Gollo 2008

Only 1 case of Down’s syndrome

Gonçalves 2004

Greater than 14 weeks USS screening

Goodburn 1994

Likely that fewer than 80% of pregnancies had gestational age estimated by USS

Gorduza 2007

Study of FISH technique

Grace 2010

ST ultrasound

Grati 2010

No diagnostic data

Gray 2009

ST ultrasound

Gregor 2007

Unable to obtain translation

Gregor 2009

Unable to obtain translation

Grether 2009

Systematic review and guidelines

Grozdea 2002

Unable to extract useful data

Guo 2010

Study of fetal samples

Gyselaers 2004

Less than 80% follow‐up

Gyselaers 2004a

Less than 80% follow‐up

Gyselaers 2006

Unaffected pregnancies only

Gyselaers 2006a

Unable to extract useful data

Hackshaw 1995

No Down's syndrome pregnancies in population

Hackshaw 2001

No Down's syndrome pregnancies in population

Haddow 1992

Less than 80% of pregnancies had gestational age confirmed by ultrasound scan

Hadzsiev 2007

Study of FISH technique

Hafner 1995

Less than 5 Down's pregnancies in study population

Hallahan 1998

Gestational age greater than 24 weeks

Han 2008

Study of findings on amniocentesis

Harper 2010

Second trimester ultrasound

Harrison 2006

Less than 80% of pregnancies had gestational age confirmed by ultrasound scan

Harry 2006

Editorial

Hayashi 1995

Unable to extract useful data

Hayashi 1996

Less than 5 Down's pregnancies in study population

Heikkila 1997

Fewer than 80% of pregnancies had gestational age confirmed by USS

Heinig 2007

No Down’s syndrome data

Heinonen 1996

No Down's syndrome pregnancies in population

Herman 2000

No Down's syndrome pregnancies in study population

Herman 2003

Correlation between markers, not evaluation of screening tests

Herrou 1992

Unable to extract useful data

Hershey 1985

Gestation unclear

Hershey 1986

Gestation based on LMP

Hewitt 1993

Unable to extract useful data

Hills 2010

Study of testing on CVS and amniocentesis samples

Ho 2010

Study of FISH diagnosis

Hogdall 1992

Unclear method of determination of gestational age

Unable to extract useful data

Hong Kong Practitioner

CME

Hoogendoorn 2008

Diagnostic data from other studies used

Howe 2000

Second trimester ultrasound scans

Hsiao 1991

Unable to obtain translation

Hsieh 1999

No Down's syndrome pregnancies in study population

Hsu 1997a

Adjustment factors

Hsu 1998a

No Down's syndrome pregnancies in study population

Hsu 1999b

No Down's pregnancies

Hu 2007

Same data as Liu 2010

Huang 2003

No Down's syndrome pregnancies in study population

Huang 2007

Not possible to obtain detection rate

Huang 2007a

No diagnostic data

Huggon 2004

Study of cardiac function in pregnancies with normal and abnormal NT results

Hui 2003

No Down's syndrome pregnancies in population

Hui 2005

No Down's syndrome pregnancies in population

Hultén 2004

Editorial/commentary

Hung 2003

Modelling

Hung 2008

Second trimester ultrasound

Hurley 1993

Unable to extract useful data

Huttly 2004

No Down's syndrome pregnancies in population

Hwa 2004

Less than 5 Down's pregnancies in population

Iles 1996

Review

Ind 1994

Unable to extract useful data

Ivorra‐Deleuze 2010

No diagnostic data

Jakobsen 2011

Not Down’s syndrome specific

Jean‐Pierre 2005

Review article

Johnson 1991

Gestational age estimated by USS in fewer than 80% of cases

Johnson 1993

Normal pregnancies only

Jorgensen 1999

Gestation greater than 14 weeks for USS

Jorgez 2007

Study of DNA testing on maternal blood

Josefsson 1998

No Down's syndrome pregnancies in study population

Jou 2001

Less than 5 Down's syndrome pregnancies in study population

Jun‐Tao 2003

Unable to obtain translation

Jung 2007

ST ultrasound

Kagan 2006

Screen‐positive pregnancies only

Kagan 2007

No diagnostic data

Kagan 2008

Not Down’s syndrome detection

Kalelioglu 2007

ST ultrasound

Kautzmann 1995

Fewer than 80% pregnancies had gestational age estimated by USS

Kazerouni 2009

Not possible to obtain complete diagnostic data

Keith 1992

Summary article

Kelekci 2004

Less than 5 Down's syndrome pregnancies in population

Kellner 1995

Less than 5 Down's syndrome pregnancies in population

Kellner 1995a

Less than 80% follow‐up

Unable to ascertain proportion of population with gestational age confirmed by USS

Kellner 1997

Assumption of normal karyotype without reference standard in significant proportion of control pregnancies

Kirkegaard 2008

FPR only calculated for subset of the cohort

Kjaergaard 2008

Unable to obtain translation

Knight 1990

Review article

Knight 2001

Validation of a specific assay

Knight 2005

Less than 80% of pregnancies had gestational age confirmed by ultrasound scan

Koos 2006

Review article

Kornman 1996

Less than 5 Down's syndrome pregnancies in population

Kornman 1997

Unable to extract useful information

Kotaska 2007

No new data

Kramer 1998

No Down's syndrome pregnancies in study population

Krantz 1996

Modelled data

Krantz 2005

Adjustment factor

Krantz 2007

Uses data from other published studies

Kulch 1993

No Down's cases in population

Lai 1998

Modelled population

Lai 2003

No Down's syndrome pregnancies in study population

Laigaard 2006

Unable to extract useful data

Laigaard 2006b

Simulation

Lam 1997

Unable to extract useful data

Lam 1998

Fewer than 80% pregnancies had gestational age estimated by USS

Lam 1999

No Down's syndrome pregnancies in population

Lam 1999a

Unable to extract useful data

Lam 2000

Study of women's decisions about screening

Lam 2001

Male versus female fetuses

Lambert‐Messerlian 1996

Fewer than 80% of pregnancies USS dated

Lambert‐Messerlian 1998

Unable to extract useful data

Lauria 2007

No diagnostic data

Lehavi 2005

Down's syndrome pregnancies only

Leung 2006

Unable to separate twins from singletons therefore unable to extract useful data

Leymarie 1993

Appears to be a review article (French)

Li 1998

Unable to obtain translation

Li 1999

Unable to obtain translation

Li 2010

No diagnostic data

Liao 1997

Unable to obtain translation

Liao 2001

Unable to extract useful data

Lim 2002

Second trimester ultrasound

Lippman 1987

Editorial

Liu 2010

Not possible to separate out data for cases of Down’s syndrome

Lo 2010

Pooled test results

Lustig 1988

Gestational age by LMP only

Luthgens 2008

FPR and DR obtained from different cohorts

MacDonald 1991

Fewer than 80% of gestational ages estimated by USS

Macintosh 1994

Unable to extract useful data

Macintosh 1997

Unable to extract useful data

MacRae 2010

Pooled test results

Macri 1994

Likely fewer than 80% evaluated for gestational age by ultrasound examination

Macri 1996

Likely fewer than 80% evaluated for gestational age by ultrasound examination

Malone 1998

Review article

Malone 2003

Review article

Mandryka‐Stankewycz 2009

No diagnostic data

Mangione 2001

Abnormal screening results only

Markov 2008

Unable to obtain paper

Maymon 2001

No Down's syndrome pregnancies in study population

Maymon 2001a

No normal test results included therefore unable to extract meaningful data

Maymon 2002

No Down's syndrome pregnancies in study population

Maymon 2004a

No Down's syndrome pregnancies in study population

Maymon 2005a

Modelled data

McDuffie 1996

USS dating on screen positive women only

Meier 2002

Observed versus expected cases of Down's syndrome in a population

Merkatz 1984

Gestational age not confirmed by ultrasound scan

Merz 2005

Editorial

Merz 2008

Part of Merz 2011 cohort

Metzenbauer 2001

Normal pregnancies only

Metzenbauer 2002

Unable to extract useful data

Mikic 1999

No Down's syndrome pregnancies in study population

Miller 1991

Unable to extract useful data

Milunsky 1989

Fewer than 80% gestational age estimated by USS

Milunsky 1996

Fewer than 80% gestational age estimated by USS

Minobe 2002

Gestational age greater than specified limits

Miron 2008

No diagnostic data

Miron 2009

No diagnostic data

Miron 2010

No diagnostic data

Miyamura 1999

Unable to extract useful data

Moghadam 1998

Unable to extract useful data

Monni 2000

Less than 5 Down's syndrome pregnancies

Monni 2002

Review article

Mooney 1994

Greater than 24 weeks' gestation

Muhcu 2008

No diagnostic data

Muller 1994

No Down's syndrome pregnancies in study population

Muller 1996a

Unable to extract useful data

Muller 1999

Unable to extract useful data

Muller 2002

Gestational age greater than 24 weeks

Muller 2002a

Unable to extract meaningful data ‐ unable to separate double and triple test data

Muller 2003b

No Down's syndrome pregnancies in study population

Murta 2002

Unable to extract useful data

Musone 2000

Unable to extract useful data

Musto 1986

Fewer than 80% USS dated

Myrick 1990

Unable to extract useful data

Naidoo 2008

Not specific Down’s syndrome results

Nau 2009

No diagnostic data

Nau 2009a

No diagnostic data

Neveux 1996

No Down's syndrome pregnancies in population

Neveux 1996a

Unable to extract useful data

Ng 2004

Unable to extract useful data

Nicolaides 1992a

Study of outcomes of abnormal NT results

Nicolaides 2000

Review article

Nicolaides 2004

Review article

Nicolaides 2005a

Unable to obtain translation ‐ appears to be a review article

Nicolaides 2005b

Unable to obtain translation ‐ appears to be a review article

Nicolaides 2005c

Unable to obtain translation ‐ appears to be a review article

Nicolaides 2005d

Unable to obtain translation ‐ appears to be a review article

Nicolaides 2005e

Unable to obtain translation ‐ appears to be a review article

Nicolaides 2005f

Review article

Niemimaa 2001b

No Down's pregnancies in study population

Niemimaa 2002

No Down's syndrome pregnancies in population

Niemimaa 2003

No Down's syndrome pregnancies in population

Noble 1997b

Unable to extract useful data

Norgaard 1990

Less than 80% of gestational ages confirmed by USS

Norton 1992

Unable to extract useful data

Novakov‐Mikic 2007

Out of FT screening time frame

O'Brien 1997a

No Down's syndrome pregnancies in population

O'Brien 1997b

No Down's syndrome pregnancies in population

Odibo 2004

Gestational age of greater than 14 weeks in USS population

Odibo 2007

ST ultrasound

Odibo 2008

ST ultrasound

Odibo 2009

No results presented

Offerdal 2008

ST ultrasound

Ognibene 1999

Unable to extract useful data

Oh 2007

No diagnostic data

Olajide 1989

Unable to extract useful data

Onda 1996

Unable to extract useful data

Onda 1998

Unable to extract useful data

Onda 2000

Less than 80% follow‐up

Orlandi 2002

No Down's syndrome pregnancies in study population

Ottavio 1997

Second trimester USS

Ozkaya 2010

Only healthy pregnancies

Paladini 2007

No diagnostic data

Palka 1998

Twin data used in calculation of the median

Palomaki 1989

Fewer than 80% USS dated

Palomaki 1993

No Down's syndrome pregnancies in population

Palomaki 1994

No Down's syndrome pregnancies in population

Palomaki 1996

Meta‐analysis

Palomaki 2005

Unable to extract meaningful data

Panburana 2001

Less than 5 Down's syndrome pregnancies in population

Pandya 1994

Study of outcomes of abnormal NT results

Pandya 1995b

Review article

Papadopoulou 2008

No diagnostic data

Parra‐Cordero 2007

ST ultrasound

Paterlini‐Brechot 2007

Editorial, no new data

Paul 2001

Unable to extract useful data

Peralta 2005

Unable to extract useful data

Perenc 1998

No Down's syndrome pregnancies in study population

Perheentupa 2002

No Down's syndrome pregnancies in population

Perona 1998

Smokers versus non smokers

Persico 2008

ST ultrasound

Petervari 2000

Unable to extract useful data

Petrocik 1989

Likely fewer than 80% USS dated

Phillips 1992

Gestational age confirmed by USS in less than 80% of population

Phillips 1993

Gestational age confirmed by USS in less than 80% of population

Pihl 2008

Only 2 cases of Down's syndrome

Pinette 2003

Women screened prior to recruitment

Platt 2004

Unable to extract useful data

Podobnik 1995

Abnormal results only

Poon 2009

No diagnostic data

Prefumo 2002

Comparison of prevalence and predicition

Prefumo 2004

Comparison of a marker in women of different ethnic origins

Price 1998

Unable to extract useful data

Páez 2004

Unable to obtain translation

Raty 2000

No Down's syndrome pregnancies in population

Rembouskos 2004

Unable to extract useful data

Ren 1992

Review article

Renier 1998

Method of ascertainment of gestational age unclear

Twin gestations included in general population

Resta 1990

Second trimester USS

Reynders 1997

Fewer than 5 Down's cases

Reynolds 1989

Explanation of mathematical techniques

Reynolds 1999

Unable to extract useful data

Reynolds 2008

Not full diagnostic data

Ribbert 1996

No Down's syndrome pregnancies in study population

Rice 2005

Down's syndrome pregnancies excluded from study

Rich 1991

Unable to extract useful data

Roberts 1995

No Down's syndrome pregnancies in study population

Robertson 1991

Editorial

Rode 2003

No Down's pregnancies

Ronge 2006

Editorial ‐ summary of FASTER results

Rose 1995

Review article

Ross 1997

Review article

Rotmensch 1996

Unable to extract useful data

Rotmensch 1999

No Down's syndrome pregnancies in study population

Rozenberg 2006

USS greater than 14 weeks' gestation

Rudnicka 2002

No Down's syndrome pregnancies in population

Ryall 1992

Unable to determine method of confirmation of gestational age

Ryall 2001

High‐risk results only included (i.e. no screen‐negative group for comparison)

Räty 2002

No Down's pregnancies in population

Sabriá 2002

Unable to ascertain how numbers calculated and from which populations

Sacchini 2003

Unable to extract useful data

Sahota 2009

No diagnostic data

Sahota 2010a

Included in Sahota 2010

Salazar 2007

Unable to obtain paper

Salazar 2008

Only 1 case of Down’s syndrome

Saller 1997

Down's syndrome secondary to Robertsonian translocation only. No controls

Salomon 2001

No Down's syndrome pregnancies in population

Salonen 1997

Fewer than 80% had gestational age estimated by USS

Saltvedt 2005

Gestation greater than 14 weeks for nuchal scanning

Saridogan 1996

Down's syndrome and Edward's syndrome affected pregnancies only

Savoldelli 1993

Unable to extract useful data

Schielen 2009

Full study information not given

Schiott 2006

Unable to extract useful data

Schmidt 2007a

Not specific to Down’s syndrome

Schmidt 2007b

No separate Down’s syndrome data

Schmidt 2007c

No diagnostic data

Schmidt 2008a

Not specific to Down’s syndrome

Schmidt 2008b

Not specific to Down’s syndrome

Schmidt 2008c

Not specific to Down’s syndrome

Schmidt 2010

No follow‐up data for test negatives

Schuchter 1998

No Down's pregnancies in study population

Scott 1995

Less than 5 Down's syndrome pregnancies in study population

Seeds 1990

Review article

Seki 1995

No Down's syndrome pregnancies in study population

Shenhav 2003

No Down's syndrome pregnancies

Shintaku 1989

Unable to extract useful data

Shulman 2003

No Down's syndrome pregnancies in population

Sieroszewski 2008

No Down’s syndrome specific information for specificity

Simon‐Bouy 1999

Review article

Simpson 1986

Gestational age confirmed by USS in less than 80% of population

Smith 1990

Analysis of screen‐positive results

Smith 1996

Review/meta‐analysis

Smith 1999

Unable to extract useful data

Smith‐Bindman 2001

Meta‐analysis of second trimester ultrasound markers

Smith‐Bindman 2003

Population study, not examining DTA

Snijders 1995

Study of prevalence, not screening

Snijders 1999

Study of prevalence, not screening

Soergel 2006

Less than 80% follow‐up

Sokol 1998

Observation of Down's prevalence stratified by age

Sonek 2003

Editorial

Sonek 2007

ST ultrasound

Sood 2010

No diagnostic data

Sooklim 2010

ST ultrasound

Spencer 1985

Fewer than 80% USS dated

Spencer 1991a

Likely fewer than 80% USS dated

Spencer 1991b

Unable to extract useful data

Spencer 1992

Unable to extract useful data

Spencer 1993a

Fewer than 80% USS dated

Spencer 1993b

No Down's pregnancies in study population

Spencer 1993c

Unable to extract useful data

Spencer 1993d

Fewer than 80% of pregnancies had gestational age confirmed by USS

Spencer 1993e

Unable to extract useful data

Spencer 1995a

No Down's pregnancies in population

Spencer 1996b

Fewer than 80% of pregnancies had gestational age confirmed by USS

Spencer 1997

Statistical modelling, aneuploid pregnancies only in study population

Spencer 1998a

No Down's pregnancies in population

Spencer 1998b

Unable to extract useful data

Spencer 1999a

Review

Spencer 1999b

Statistical methods paper

Spencer 2000a

Examination of median shifts rather than an evaluation of screening

Spencer 2000b

No Down's syndrome pregnancies in population

Spencer 2000c

No Down's syndrome pregnancies in population

Spencer 2000d

No Down's cases

Spencer 2000e

Male versus female fetuses

Spencer 2000f

No Down's cases in population

Spencer 2000g

No Down's pregnancies in population

Spencer 2000h

No Down's pregnancies in population

Spencer 2000i

Comparsison of fetal sex

Spencer 2001a

No Down's syndrome pregnancies in population

Spencer 2001b

Unable to extract useful data

Spencer 2001c

Unable to extract useful data

Spencer 2001d

Unable to extract useful data

Spencer 2001e

No Down's syndrome pregnancies in population

Spencer 2002a

No Down's pregnancies

Spencer 2002b

Risk validation study

Spencer 2002c

No Down's syndrome pregnancies in population

Spencer 2002d

Demonstration of median changes with time, rather than evaluation of screening

Spencer 2003a

No Down's pregnancies in population

Spencer 2003b

No Down's pregnancies in population

Spencer 2003c

Calculation of weight correction factor

Spencer 2003d

Fewer than 5 Down's syndrome pregnancies

Spencer 2004

Calculation of smoking correction factor

Spencer 2005a

No Down's pregnancies

Spencer 2005b

No Down's pregnancies

Spencer 2005c

Comparison of 2 different assays ‐ not actual screening evaluation

Spencer 2008a

Unable to extract appropriate data for unaffected pregnancies

Spong 1999

Comparison of male and female fetuses

Staboulidou 2009

No diagnostic data

Stevens 1998

Literature review

Stoll 1992

Review article

Stressig 2011

ST ultrasound

Su 2002a

Unable to extract useful data

Suchet 1995

Review article

Suchy 1990

Unable to ascertain method of confirmation of gestational age

Summers 2003a

Only 55% gestational ages estimated by USS

Summers 2003b

No Down's syndrome pregnancies in study population

Suntharasaj 2005

Examination of inter‐observer variation in NT scanning

Susman 2010

No diagnostic data

Sutton 2004

Unable to extract useful data

Suzuki 1998

Unable to extract useful data

Tabor 1987

Gestational age not confirmed by USS

Tanski 1999

Information on screen‐positive pregnancies only

Thilaganathan 1998

No Down's syndrome pregnancies in study population

Thilaganathan 1999b

Editorial

Tislaric 2002

No Down's syndrome pregnancies in population

Torok 1997

Unable to extract useful data

Torring 2009

Not possible to obtain full diagnostic data

Trninic‐Pjevic 2007

Unable to obtain translation

Tsai 2001

Less than 5 Down's syndrome pregnancies in study population

Valerio 1996

Fewer than 80% pregnancies had gestational age estimated by USS

Van Blerk 1992

Unable to extract useful data

Van Dyke 2007

Not possible to obtain full diagnostic data

Van Heesch, 2006

No Down's syndrome pregnancies in study population

Software comparison study

Van Lith 1991

Unable to extract useful data

Van Lith, 1993

Unable to extract useful data

Van Lith, 1994

Unable to extract useful data

Veress 1986

Unable to extract useful data

Veress 1988

Unable to extract useful data

Vergani 2008

ST ultrasound

Vintzileos 2003

Second trimester USS

Wald 1988a

Less than 80% had gestational age confirmed by ultrasound

Wald 1988b

Gestational age not confirmed by USS

Wald 1991

No Down's pregnancies in study

Wald 1992a

Less than 80% had gestational age confirmed by ultrasound

Wald 1992b

No Down's pregnancies in study

Wald 1992c

No Down's pregnancies in study

Wald 1993

No USS dating

Wald 1994a

No Down's syndrome pregnancies in population

Wald 1994b

Review article

Wald 1996a

No Down's pregnancies

Wald 1996b

Dated by LMP

Wald 1996c

No Down's syndrome pregnancies in population

Wald 1996d

Gestational age greater than 24 weeks

Wald 1997

Data modelled on 3 separate populations of women

Wald 1998

Unable to extract useful data

Wald 1999a

Unable to extract useful data

Wald 1999b

Gestational age not confirmed by USS

Wald 1999c

No Down's syndrome pregnancies

Wald 1999d

Modelled on several studies, some of which have no USS dating

Wald 2003b

No cases

Wald 2003c

Less than 80% had gestational age confirmed by USS

Wald 2006

Modelled on SURRUS data

Wallace 1994

Unable to extract useful data

Wallace 1997

No Down's syndrome pregnancies in study population

Wang 2010

ST ultrasound

Ward 2005

Review article

Watt 1996a

No Down's syndrome pregnancies in study population

Watt 1996b

No Down's syndrome pregnancies in study population

Wax 2007

No diagnostic data

Weinans 2001

Unable to extract useful data

Weinans 2004

Study of women's views on screening

Weisz 2007

Cohort split into people having different tests and non‐representative samples of women assessed for each test

Welborn 1994

Abnormal results only (cystic hygroma)

Wenstrom 1993

Less than 80% of pregnancies had gestational age confirmed by USS

Wenstrom 1995a

Adjustment factors

Wenstrom 1995b

Less than 80% of pregnancies had gestational age confirmed by USS

Wetta 2011

No diagnostic data

Whitlow 1998a

Unable to extract useful data

Whitlow 1998b

Unable to extract useful data

Whitlow 1999

Unable to extract useful data

Williamson 1994

Likely fewer than 80% USS dated

Wilson 2000

Review

Wojdemann 2001

No Down's syndrome pregnancies in study population

Wong 2003

Less than 5 Down's syndrome pregnancies in population

Wright 2006

Mathematical model

Wright 2007

Simulation study, no new data

Xie 2010

Only cases of false negatives and true negatives included

Yagel 1998

Second trimester USS

Yamamoto 2001a

Unable to extract useful data

Yamamoto 2001b

Method of determination of gestational age unclear

Yamamoto 2001c

Unable to extract useful data

Yaron 2001

Male versus female fetuses

Ye 1995

Unable to obtain translation

Yoshida 2000

Fewer than 80% pregnancies had gestational age estimated by USS

Zalel 2008

No diagnostic data

Zeitune 1991

Only aneuploid pregnancies included in study

Zelop 2005

No Down's cases in population

Zhang 2011

No diagnostic data

Zhao 1998

Unable to obtain translation

Zhong 2011

Second trimester ultrasound

Zoppi 2003a

Inappropriate study design

CVS: chorionic villus sampling
DR: detection rate
FPR: false positive rate
LMP: last menstrual period
NT: nuchal translucency
USS: ultrasound scan

Data

Presented below are all the data for all of the tests entered into the review.

Open in table viewer
Tests. Data tables by test

Test

No. of studies

No. of participants

1 Aberrant right subclavian artery Show forest plot

1

425
Test 1
Aberrant right subclavian artery.

Aberrant right subclavian artery.

2 Frontomaxillary facial angle >95 percentile Show forest plot

1

242
Test 2
Frontomaxillary facial angle >95 percentile.

Frontomaxillary facial angle >95 percentile.

3 Presence of mitral gap Show forest plot

1

217
Test 3
Presence of mitral gap.

Presence of mitral gap.

4 Maxillary bone length, 5% percentile Show forest plot

1

927
Test 4
Maxillary bone length, 5% percentile.

Maxillary bone length, 5% percentile.

5 Tricuspid regurgitation Show forest plot

1

312
Test 5
Tricuspid regurgitation.

Tricuspid regurgitation.

6 Iliac angle 90 degrees Show forest plot

1

2032
Test 6
Iliac angle 90 degrees.

Iliac angle 90 degrees.

7 Ductus venosus a‐wave reversed Show forest plot

1

378
Test 7
Ductus venosus a‐wave reversed.

Ductus venosus a‐wave reversed.

8 Ductus venosus pulsivity index > 95 percentile Show forest plot

1

378
Test 8
Ductus venosus pulsivity index > 95 percentile.

Ductus venosus pulsivity index > 95 percentile.

9 Nasal bone, mixed cut‐points Show forest plot

11

48279
Test 9
Nasal bone, mixed cut‐points.

Nasal bone, mixed cut‐points.

10 NT, 2.5 mm Show forest plot

4

11835
Test 10
NT, 2.5 mm.

NT, 2.5 mm.

11 NT, 3 mm Show forest plot

6

10381
Test 11
NT, 3 mm.

NT, 3 mm.

12 NT, 5FPR Show forest plot

3

63885
Test 12
NT, 5FPR.

NT, 5FPR.

13 NT, mixed cut‐points Show forest plot

13

90978
Test 13
NT, mixed cut‐points.

NT, mixed cut‐points.

14 NT and age, risk 1:100 Show forest plot

1

10668
Test 14
NT and age, risk 1:100.

NT and age, risk 1:100.

15 NT and age, risk 1:250 Show forest plot

10

79412
Test 15
NT and age, risk 1:250.

NT and age, risk 1:250.

16 NT and age, risk 1:300 Show forest plot

23

252811
Test 16
NT and age, risk 1:300.

NT and age, risk 1:300.

17 NT and age, 1FPR Show forest plot

4

98453
Test 17
NT and age, 1FPR.

NT and age, 1FPR.

18 NT and age, 3FPR Show forest plot

4

98453
Test 18
NT and age, 3FPR.

NT and age, 3FPR.

19 NT and age, 5FPR Show forest plot

22

288853
Test 19
NT and age, 5FPR.

NT and age, 5FPR.

20 NT and age, mixed cut‐points Show forest plot

50

530874
Test 20
NT and age, mixed cut‐points.

NT and age, mixed cut‐points.

21 NT and nasal bone, Absent NB + NT ≥ 95th centile Show forest plot

1

486
Test 21
NT and nasal bone, Absent NB + NT ≥ 95th centile.

NT and nasal bone, Absent NB + NT ≥ 95th centile.

22 Ductus and age, risk 1:250 Show forest plot

1

3731
Test 22
Ductus and age, risk 1:250.

Ductus and age, risk 1:250.

23 Ductus and age, 5FPR Show forest plot

2

3965
Test 23
Ductus and age, 5FPR.

Ductus and age, 5FPR.

24 Ductus and age, mixed cut‐points Show forest plot

5

5331
Test 24
Ductus and age, mixed cut‐points.

Ductus and age, mixed cut‐points.

25 Ductus, NT and age, risk 1:100 Show forest plot

1

19736
Test 25
Ductus, NT and age, risk 1:100.

Ductus, NT and age, risk 1:100.

26 Ductus, NT and age, risk 1:250 Show forest plot

1

3727
Test 26
Ductus, NT and age, risk 1:250.

Ductus, NT and age, risk 1:250.

27 Ductus, NT and age, 5FPR Show forest plot

2

3961
Test 27
Ductus, NT and age, 5FPR.

Ductus, NT and age, 5FPR.

28 Ductus, NT and age, mixed cut‐points Show forest plot

3

23697
Test 28
Ductus, NT and age, mixed cut‐points.

Ductus, NT and age, mixed cut‐points.

29 Age and nasal bone, mixed cut‐points Show forest plot

4

25303
Test 29
Age and nasal bone, mixed cut‐points.

Age and nasal bone, mixed cut‐points.

30 Age, NT and tricuspid blood flow, risk 1:100 Show forest plot

1

19736
Test 30
Age, NT and tricuspid blood flow, risk 1:100.

Age, NT and tricuspid blood flow, risk 1:100.

31 Age, NT and nasal bone, risk 1:100 Show forest plot

1

19736
Test 31
Age, NT and nasal bone, risk 1:100.

Age, NT and nasal bone, risk 1:100.

32 Age, NT and nasal bone, risk 1:300 Show forest plot

4

9963
Test 32
Age, NT and nasal bone, risk 1:300.

Age, NT and nasal bone, risk 1:300.

33 Age, NT and nasal bone, mixed cut‐points Show forest plot

5

29699
Test 33
Age, NT and nasal bone, mixed cut‐points.

Age, NT and nasal bone, mixed cut‐points.

34 Age, NT, nasal bone and ductus, risk NT>1:300 AND abnormal DV flow AND absent NB Show forest plot

1

544
Test 34
Age, NT, nasal bone and ductus, risk NT>1:300 AND abnormal DV flow AND absent NB.

Age, NT, nasal bone and ductus, risk NT>1:300 AND abnormal DV flow AND absent NB.

35 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

1

20305
Test 35
Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

36 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot

3

41842
Test 36
Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

37 Age, NT and free ßhCG, 1st trimester, 5FPR Show forest plot

4

4986
Test 37
Age, NT and free ßhCG, 1st trimester, 5FPR.

Age, NT and free ßhCG, 1st trimester, 5FPR.

38 Age, NT and free ßhCG, 1st trimester, risk 1:240 Show forest plot

1

5809
Test 38
Age, NT and free ßhCG, 1st trimester, risk 1:240.

Age, NT and free ßhCG, 1st trimester, risk 1:240.

39 Age, NT and free ßhCG, 1st trimester, mixed cut‐points Show forest plot

5

10795
Test 39
Age, NT and free ßhCG, 1st trimester, mixed cut‐points.

Age, NT and free ßhCG, 1st trimester, mixed cut‐points.

40 Age, NT and PAPP‐A, 1st trimester, risk 1:100 Show forest plot

1

1507
Test 40
Age, NT and PAPP‐A, 1st trimester, risk 1:100.

Age, NT and PAPP‐A, 1st trimester, risk 1:100.

41 Age, NT and PAPP‐A, 1st trimester, risk 1:185 Show forest plot

1

5809
Test 41
Age, NT and PAPP‐A, 1st trimester, risk 1:185.

Age, NT and PAPP‐A, 1st trimester, risk 1:185.

42 Age, NT and PAPP‐A, 1st trimester, 5FPR Show forest plot

3

2498
Test 42
Age, NT and PAPP‐A, 1st trimester, 5FPR.

Age, NT and PAPP‐A, 1st trimester, 5FPR.

43 Age, NT and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot

5

9814
Test 43
Age, NT and PAPP‐A, 1st trimester, mixed cut‐points.

Age, NT and PAPP‐A, 1st trimester, mixed cut‐points.

44 Age, NT and total hCG, 1st trimester, 5FPR Show forest plot

1

1110
Test 44
Age, NT and total hCG, 1st trimester, 5FPR.

Age, NT and total hCG, 1st trimester, 5FPR.

45 Age, NT and AFP, 1st trimester, 5FPR Show forest plot

1

1110
Test 45
Age, NT and AFP, 1st trimester, 5FPR.

Age, NT and AFP, 1st trimester, 5FPR.

46 Age, NT and ITA, 1st trimester, 5FPR Show forest plot

1

278
Test 46
Age, NT and ITA, 1st trimester, 5FPR.

Age, NT and ITA, 1st trimester, 5FPR.

47 Age, NT and inhibin, 1st trimester, risk 1:100 Show forest plot

1

40
Test 47
Age, NT and inhibin, 1st trimester, risk 1:100.

Age, NT and inhibin, 1st trimester, risk 1:100.

48 Age, NT and inhibin, 1st trimester, risk 1:250 Show forest plot

1

40
Test 48
Age, NT and inhibin, 1st trimester, risk 1:250.

Age, NT and inhibin, 1st trimester, risk 1:250.

49 Age, NT and inhibin, 1st trimester, risk 1:400 Show forest plot

1

40
Test 49
Age, NT and inhibin, 1st trimester, risk 1:400.

Age, NT and inhibin, 1st trimester, risk 1:400.

50 Age, NT and inhibin, 1st trimester, 5FPR Show forest plot

1

1110
Test 50
Age, NT and inhibin, 1st trimester, 5FPR.

Age, NT and inhibin, 1st trimester, 5FPR.

51 Age, NT and inhibin, 1st trimester, mixed cut‐points Show forest plot

2

1150
Test 51
Age, NT and inhibin, 1st trimester, mixed cut‐points.

Age, NT and inhibin, 1st trimester, mixed cut‐points.

52 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:100 Show forest plot

10

102332
Test 52
Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:100.

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:100.

53 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:150 Show forest plot

5

177643
Test 53
Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:150.

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:150.

54 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:200 Show forest plot

8

135768
Test 54
Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:200.

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:200.

55 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:220 Show forest plot

1

2231
Test 55
Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:220.

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:220.

56 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:250 Show forest plot

25

174712
Test 56
Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:250.

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:250.

57 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:300 Show forest plot

29

544681
Test 57
Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:300.

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:300.

58 Age, NT, PAPP‐A and free ßhCG, 1st trimester, 1FPR Show forest plot

7

88874
Test 58
Age, NT, PAPP‐A and free ßhCG, 1st trimester, 1FPR.

Age, NT, PAPP‐A and free ßhCG, 1st trimester, 1FPR.

59 Age, NT, PAPP‐A and free ßhCG, 1st trimester, 3FPR Show forest plot

9

312680
Test 59
Age, NT, PAPP‐A and free ßhCG, 1st trimester, 3FPR.

Age, NT, PAPP‐A and free ßhCG, 1st trimester, 3FPR.

60 Age, NT, PAPP‐A and free ßhCG, 1st trimester, 5FPR Show forest plot

24

391874
Test 60
Age, NT, PAPP‐A and free ßhCG, 1st trimester, 5FPR.

Age, NT, PAPP‐A and free ßhCG, 1st trimester, 5FPR.

61 Age, NT, PAPP‐A and free ßhCG, 1st trimester, mixed cut‐points Show forest plot

69

1173853
Test 61
Age, NT, PAPP‐A and free ßhCG, 1st trimester, mixed cut‐points.

Age, NT, PAPP‐A and free ßhCG, 1st trimester, mixed cut‐points.

62 Age, NT, PAPP‐A and uE3, 1st trimester, 5FPR Show forest plot

1

576
Test 62
Age, NT, PAPP‐A and uE3, 1st trimester, 5FPR.

Age, NT, PAPP‐A and uE3, 1st trimester, 5FPR.

63 Age, NT, PAPP‐A and ITA, 1st trimester, 5FPR Show forest plot

2

11053
Test 63
Age, NT, PAPP‐A and ITA, 1st trimester, 5FPR.

Age, NT, PAPP‐A and ITA, 1st trimester, 5FPR.

64 Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:100 Show forest plot

1

40
Test 64
Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:100.

Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:100.

65 Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:250 Show forest plot

1

40
Test 65
Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:250.

Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:250.

66 Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:400 Show forest plot

1

40
Test 66
Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:400.

Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:400.

67 Age, NT, PAPP‐A and inhibin, 1st trimester, 5FPR Show forest plot

1

1110
Test 67
Age, NT, PAPP‐A and inhibin, 1st trimester, 5FPR.

Age, NT, PAPP‐A and inhibin, 1st trimester, 5FPR.

68 Age, NT, PAPP‐A and inhibin, 1st trimester, mixed cut‐points Show forest plot

2

1150
Test 68
Age, NT, PAPP‐A and inhibin, 1st trimester, mixed cut‐points.

Age, NT, PAPP‐A and inhibin, 1st trimester, mixed cut‐points.

69 Age, NT, PAPP‐A and ADAM12, 1st trimester, 5FPR Show forest plot

2

1042
Test 69
Age, NT, PAPP‐A and ADAM12, 1st trimester, 5FPR.

Age, NT, PAPP‐A and ADAM12, 1st trimester, 5FPR.

70 Age, NT, PAPP‐A and ADAM12, 1st trimester, risk 1:250 Show forest plot

1

691
Test 70
Age, NT, PAPP‐A and ADAM12, 1st trimester, risk 1:250.

Age, NT, PAPP‐A and ADAM12, 1st trimester, risk 1:250.

71 Age, NT, free ßhCG and ADAM12, 1st trimester, 5FPR Show forest plot

1

351
Test 71
Age, NT, free ßhCG and ADAM12, 1st trimester, 5FPR.

Age, NT, free ßhCG and ADAM12, 1st trimester, 5FPR.

72 Age, NT, AFP and free ßhCG, 1st trimester, risk 1:250 Show forest plot

1

1656
Test 72
Age, NT, AFP and free ßhCG, 1st trimester, risk 1:250.

Age, NT, AFP and free ßhCG, 1st trimester, risk 1:250.

73 Age, NT, AFP and free ßhCG, 1st trimester, 5FPR Show forest plot

1

1110
Test 73
Age, NT, AFP and free ßhCG, 1st trimester, 5FPR.

Age, NT, AFP and free ßhCG, 1st trimester, 5FPR.

74 Age, NT, AFP and free ßhCG, 1st trimester, mixed cut‐points Show forest plot

2

2766
Test 74
Age, NT, AFP and free ßhCG, 1st trimester, mixed cut‐points.

Age, NT, AFP and free ßhCG, 1st trimester, mixed cut‐points.

75 Age, NT, AFP and PAPP‐A, 1st trimester, 5FPR Show forest plot

1

1110
Test 75
Age, NT, AFP and PAPP‐A, 1st trimester, 5FPR.

Age, NT, AFP and PAPP‐A, 1st trimester, 5FPR.

76 Age, NT, total hCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

1

1110
Test 76
Age, NT, total hCG and PAPP‐A, 1st trimester, 5FPR.

Age, NT, total hCG and PAPP‐A, 1st trimester, 5FPR.

77 Age, NT, total hCG and inhibin, 1st trimester, 5FPR Show forest plot

1

1110
Test 77
Age, NT, total hCG and inhibin, 1st trimester, 5FPR.

Age, NT, total hCG and inhibin, 1st trimester, 5FPR.

78 Age, NT, free ßhCG and inhibin, 1st trimester, 5FPR Show forest plot

1

1110
Test 78
Age, NT, free ßhCG and inhibin, 1st trimester, 5FPR.

Age, NT, free ßhCG and inhibin, 1st trimester, 5FPR.

79 Age, NT, PAPP‐A, free ßhCG, 1st trimester serum, ductus venosus pulsivity index, 5FPR Show forest plot

1

7250
Test 79
Age, NT, PAPP‐A, free ßhCG, 1st trimester serum, ductus venosus pulsivity index, 5FPR.

Age, NT, PAPP‐A, free ßhCG, 1st trimester serum, ductus venosus pulsivity index, 5FPR.

80 Age, free ßhCG and PAPP‐A, if risk 1:42‐1:1000, NT, final 1:250 risk Show forest plot

1

10189
Test 80
Age, free ßhCG and PAPP‐A, if risk 1:42‐1:1000, NT, final 1:250 risk.

Age, free ßhCG and PAPP‐A, if risk 1:42‐1:1000, NT, final 1:250 risk.

81 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:100 Show forest plot

2

26986
Test 81
Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

82 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:250 Show forest plot

2

10325
Test 82
Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:250.

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:250.

83 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

2

10325
Test 83
Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

84 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot

3

30061
Test 84
Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

85 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:100 Show forest plot

1

19736
Test 85
Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

86 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:300 Show forest plot

1

1801
Test 86
Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:300.

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:300.

87 Age, NT, tricuspid blood flow, free ßhCG and PAPP‐A, 1st trimester, risk 1:100 Show forest plot

1

19736
Test 87
Age, NT, tricuspid blood flow, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

Age, NT, tricuspid blood flow, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

88 Age, NT, fetal heart rate, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

2

76385
Test 88
Age, NT, fetal heart rate, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

Age, NT, fetal heart rate, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

89 Age, NT, fetal heart rate, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:200 Show forest plot

1

19736
Test 89
Age, NT, fetal heart rate, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:200.

Age, NT, fetal heart rate, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:200.

90 age, NT, fetal heart rate, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

1

19614
Test 90
age, NT, fetal heart rate, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

age, NT, fetal heart rate, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

91 Age, NT, fetal heart rate, tricuspid blood flow, free ßhCG and PAPP‐A,1st trimester, 5FPR Show forest plot

1

19736
Test 91
Age, NT, fetal heart rate, tricuspid blood flow, free ßhCG and PAPP‐A,1st trimester, 5FPR.

Age, NT, fetal heart rate, tricuspid blood flow, free ßhCG and PAPP‐A,1st trimester, 5FPR.

92 Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, risk 1:250 Show forest plot

1

5483
Test 92
Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, risk 1:250.

Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, risk 1:250.

93 Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

2

1306
Test 93
Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

94 Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot

3

6789
Test 94
Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

95 Age, NT, total hCG, inhibin and PAPP‐A, 1st trimester, 5FPR Show forest plot

1

1110
Test 95
Age, NT, total hCG, inhibin and PAPP‐A, 1st trimester, 5FPR.

Age, NT, total hCG, inhibin and PAPP‐A, 1st trimester, 5FPR.

96 Age, NT, PAPP‐A, free ßhCG and PGH, 1st trimester, 5FPR Show forest plot

1

335
Test 96
Age, NT, PAPP‐A, free ßhCG and PGH, 1st trimester, 5FPR.

Age, NT, PAPP‐A, free ßhCG and PGH, 1st trimester, 5FPR.

97 Age, NT, PAPP‐A, free ßhCG and GHBP, 1st trimester, 5FPR Show forest plot

1

335
Test 97
Age, NT, PAPP‐A, free ßhCG and GHBP, 1st trimester, 5FPR.

Age, NT, PAPP‐A, free ßhCG and GHBP, 1st trimester, 5FPR.

98 Age, NT, PAPP‐A, free ßhCG and PIGF, 1st trimester, 5FPR Show forest plot

2

1443
Test 98
Age, NT, PAPP‐A, free ßhCG and PIGF, 1st trimester, 5FPR.

Age, NT, PAPP‐A, free ßhCG and PIGF, 1st trimester, 5FPR.

99 Age, NT, PAPP‐A, free ßhCG and total hCG, 1st trimester, 5FPR Show forest plot

1

998
Test 99
Age, NT, PAPP‐A, free ßhCG and total hCG, 1st trimester, 5FPR.

Age, NT, PAPP‐A, free ßhCG and total hCG, 1st trimester, 5FPR.

100 Age, NT, PAPP‐A, free ßhCG and PP13, 1st trimester, 5FPR Show forest plot

1

998
Test 100
Age, NT, PAPP‐A, free ßhCG and PP13, 1st trimester, 5FPR.

Age, NT, PAPP‐A, free ßhCG and PP13, 1st trimester, 5FPR.

101 Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, 5FPR Show forest plot

4

2571
Test 101
Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, 5FPR.

Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, 5FPR.

102 Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, risk 1:250 Show forest plot

2

1222
Test 102
Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, risk 1:250.

Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, risk 1:250.

103 Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, mixed cut‐points Show forest plot

4

2571
Test 103
Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, mixed cut‐points.

Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, mixed cut‐points.

104 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:100 Show forest plot

1

40
Test 104
Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:100.

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:100.

105 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:250 Show forest plot

1

40
Test 105
Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:250.

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:250.

106 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:400 Show forest plot

1

40
Test 106
Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:400.

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:400.

107 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, 5FPR Show forest plot

1

1110
Test 107
Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, 5FPR.

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, 5FPR.

108 Age, NT, PAPP‐A, free ßhCG, ADAM12 and PlGH, 1st trimester, 5FPR Show forest plot

1

998
Test 108
Age, NT, PAPP‐A, free ßhCG, ADAM12 and PlGH, 1st trimester, 5FPR.

Age, NT, PAPP‐A, free ßhCG, ADAM12 and PlGH, 1st trimester, 5FPR.

109 Age, NT, total hCG, inhibin, PAPP‐A, AFP and uE3, 1st trimester, 5FPR Show forest plot

1

1110
Test 109
Age, NT, total hCG, inhibin, PAPP‐A, AFP and uE3, 1st trimester, 5FPR.

Age, NT, total hCG, inhibin, PAPP‐A, AFP and uE3, 1st trimester, 5FPR.

110 Age, NT, free ßhCG, inhibin, PAPP‐A, AFP and uE3,1st trimester, 5FPR Show forest plot

1

1110
Test 110
Age, NT, free ßhCG, inhibin, PAPP‐A, AFP and uE3,1st trimester, 5FPR.

Age, NT, free ßhCG, inhibin, PAPP‐A, AFP and uE3,1st trimester, 5FPR.

111 Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG and PlGF, 1st trimester, 5FPR Show forest plot

1

998
Test 111
Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG and PlGF, 1st trimester, 5FPR.

Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG and PlGF, 1st trimester, 5FPR.

112 Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG, PlGF and PP13, 1st trimester, 5FPR Show forest plot

1

998
Test 112
Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG, PlGF and PP13, 1st trimester, 5FPR.

Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG, PlGF and PP13, 1st trimester, 5FPR.

113 NT, free ßhCG and PAPP‐A, 1st trimester incidence rate 63.3% Show forest plot

1

6508
Test 113
NT, free ßhCG and PAPP‐A, 1st trimester incidence rate 63.3%.

NT, free ßhCG and PAPP‐A, 1st trimester incidence rate 63.3%.

114 NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age < 35 years Show forest plot

5

19057
Test 114
NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age < 35 years.

NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age < 35 years.

115 NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age ≥ 35 years Show forest plot

5

10980
Test 115
NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age ≥ 35 years.

NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age ≥ 35 years.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
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Figure 1

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Study estimates of sensitivity and specificity with a summary ROC curve for the NT, PAPP‐A, free ßhCG and maternal age test combination at different cut‐points. Each symbol represents a pair of sensitivity and specificity at one cut‐point from each study.
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Figure 2

Study estimates of sensitivity and specificity with a summary ROC curve for the NT, PAPP‐A, free ßhCG and maternal age test combination at different cut‐points. Each symbol represents a pair of sensitivity and specificity at one cut‐point from each study.

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Study estimates of sensitivity and specificity with a summary ROC curve for NT and maternal age across different cut‐points. Each symbol represents a pair of sensitivity and specificity at one cut‐point from each study.
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Figure 3

Study estimates of sensitivity and specificity with a summary ROC curve for NT and maternal age across different cut‐points. Each symbol represents a pair of sensitivity and specificity at one cut‐point from each study.

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Study estimates of sensitivity and specificity with a summary ROC curve for NT. Each symbol represents a pair of sensitivity and specificity at one cut‐point from each study.
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Figure 4

Study estimates of sensitivity and specificity with a summary ROC curve for NT. Each symbol represents a pair of sensitivity and specificity at one cut‐point from each study.

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Detection rates (% sensitivity) at a 5% false positive rate for nine of the most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests. A = NT, PAPP‐A, free ßhCG and maternal age; B = NT, PAPP‐A, free ßhCG, ADAM 12 and maternal age; C = NT, PAPP‐A and maternal age; D = NT, nasal bone and maternal age; E= NT, free ßhCG and maternal age; F= NT and maternal age; G = NT; H = Nasal bone and maternal age; and I = Ductus and maternal age.Each square represents the summary sensitivity for a test strategy at a 5% false positive rate. The size of each square is proportional to the number of Down's cases. The estimates are shown with 95% confidence intervals. The test strategies are ordered on the plot according to decreasing detection rate. For each test strategy, the number of included studies, Down's syndrome cases and pregnancies are shown on the horizontal axis.
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Figure 5

Detection rates (% sensitivity) at a 5% false positive rate for nine of the most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests. A = NT, PAPP‐A, free ßhCG and maternal age; B = NT, PAPP‐A, free ßhCG, ADAM 12 and maternal age; C = NT, PAPP‐A and maternal age; D = NT, nasal bone and maternal age; E= NT, free ßhCG and maternal age; F= NT and maternal age; G = NT; H = Nasal bone and maternal age; and I = Ductus and maternal age.

Each square represents the summary sensitivity for a test strategy at a 5% false positive rate. The size of each square is proportional to the number of Down's cases. The estimates are shown with 95% confidence intervals. The test strategies are ordered on the plot according to decreasing detection rate. For each test strategy, the number of included studies, Down's syndrome cases and pregnancies are shown on the horizontal axis.

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Forest plot of the NT, PAPP‐A, free ßhCG and maternal age test strategy by maternal age group (< 35 years versus ≥ 35 years).
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Figure 6

Forest plot of the NT, PAPP‐A, free ßhCG and maternal age test strategy by maternal age group (< 35 years versus ≥ 35 years).

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Summary ROC plot of the NT, PAPP‐A, free ßhCG and maternal age test strategy by maternal age group (< 35 years versus ≥ 35 years).
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Figure 7

Summary ROC plot of the NT, PAPP‐A, free ßhCG and maternal age test strategy by maternal age group (< 35 years versus ≥ 35 years).

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Aberrant right subclavian artery.
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Test 1

Aberrant right subclavian artery.

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Frontomaxillary facial angle >95 percentile.
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Test 2

Frontomaxillary facial angle >95 percentile.

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Presence of mitral gap.
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Test 3

Presence of mitral gap.

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Maxillary bone length, 5% percentile.
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Test 4

Maxillary bone length, 5% percentile.

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Tricuspid regurgitation.
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Test 5

Tricuspid regurgitation.

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Iliac angle 90 degrees.
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Test 6

Iliac angle 90 degrees.

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Ductus venosus a‐wave reversed.
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Test 7

Ductus venosus a‐wave reversed.

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Ductus venosus pulsivity index > 95 percentile.
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Test 8

Ductus venosus pulsivity index > 95 percentile.

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Nasal bone, mixed cut‐points.
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Test 9

Nasal bone, mixed cut‐points.

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NT, 2.5 mm.
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Test 10

NT, 2.5 mm.

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NT, 3 mm.
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Test 11

NT, 3 mm.

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NT, 5FPR.
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Test 12

NT, 5FPR.

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NT, mixed cut‐points.
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Test 13

NT, mixed cut‐points.

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NT and age, risk 1:100.
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Test 14

NT and age, risk 1:100.

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NT and age, risk 1:250.
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Test 15

NT and age, risk 1:250.

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NT and age, risk 1:300.
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Test 16

NT and age, risk 1:300.

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NT and age, 1FPR.
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Test 17

NT and age, 1FPR.

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NT and age, 3FPR.
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Test 18

NT and age, 3FPR.

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NT and age, 5FPR.
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Test 19

NT and age, 5FPR.

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NT and age, mixed cut‐points.
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Test 20

NT and age, mixed cut‐points.

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NT and nasal bone, Absent NB + NT ≥ 95th centile.
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Test 21

NT and nasal bone, Absent NB + NT ≥ 95th centile.

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Ductus and age, risk 1:250.
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Test 22

Ductus and age, risk 1:250.

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Ductus and age, 5FPR.
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Test 23

Ductus and age, 5FPR.

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Ductus and age, mixed cut‐points.
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Test 24

Ductus and age, mixed cut‐points.

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Ductus, NT and age, risk 1:100.
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Test 25

Ductus, NT and age, risk 1:100.

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Ductus, NT and age, risk 1:250.
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Test 26

Ductus, NT and age, risk 1:250.

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Ductus, NT and age, 5FPR.
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Test 27

Ductus, NT and age, 5FPR.

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Ductus, NT and age, mixed cut‐points.
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Test 28

Ductus, NT and age, mixed cut‐points.

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Age and nasal bone, mixed cut‐points.
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Test 29

Age and nasal bone, mixed cut‐points.

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Age, NT and tricuspid blood flow, risk 1:100.
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Test 30

Age, NT and tricuspid blood flow, risk 1:100.

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Age, NT and nasal bone, risk 1:100.
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Test 31

Age, NT and nasal bone, risk 1:100.

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Age, NT and nasal bone, risk 1:300.
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Test 32

Age, NT and nasal bone, risk 1:300.

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Age, NT and nasal bone, mixed cut‐points.
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Test 33

Age, NT and nasal bone, mixed cut‐points.

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Age, NT, nasal bone and ductus, risk NT>1:300 AND abnormal DV flow AND absent NB.
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Test 34

Age, NT, nasal bone and ductus, risk NT>1:300 AND abnormal DV flow AND absent NB.

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Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, 5FPR.
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Test 35

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

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Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.
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Test 36

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

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Age, NT and free ßhCG, 1st trimester, 5FPR.
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Test 37

Age, NT and free ßhCG, 1st trimester, 5FPR.

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Age, NT and free ßhCG, 1st trimester, risk 1:240.
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Test 38

Age, NT and free ßhCG, 1st trimester, risk 1:240.

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Age, NT and free ßhCG, 1st trimester, mixed cut‐points.
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Test 39

Age, NT and free ßhCG, 1st trimester, mixed cut‐points.

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Age, NT and PAPP‐A, 1st trimester, risk 1:100.
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Test 40

Age, NT and PAPP‐A, 1st trimester, risk 1:100.

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Age, NT and PAPP‐A, 1st trimester, risk 1:185.
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Test 41

Age, NT and PAPP‐A, 1st trimester, risk 1:185.

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Age, NT and PAPP‐A, 1st trimester, 5FPR.
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Test 42

Age, NT and PAPP‐A, 1st trimester, 5FPR.

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Age, NT and PAPP‐A, 1st trimester, mixed cut‐points.
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Test 43

Age, NT and PAPP‐A, 1st trimester, mixed cut‐points.

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Age, NT and total hCG, 1st trimester, 5FPR.
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Test 44

Age, NT and total hCG, 1st trimester, 5FPR.

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Age, NT and AFP, 1st trimester, 5FPR.
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Test 45

Age, NT and AFP, 1st trimester, 5FPR.

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Age, NT and ITA, 1st trimester, 5FPR.
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Test 46

Age, NT and ITA, 1st trimester, 5FPR.

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Age, NT and inhibin, 1st trimester, risk 1:100.
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Test 47

Age, NT and inhibin, 1st trimester, risk 1:100.

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Age, NT and inhibin, 1st trimester, risk 1:250.
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Test 48

Age, NT and inhibin, 1st trimester, risk 1:250.

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Age, NT and inhibin, 1st trimester, risk 1:400.
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Test 49

Age, NT and inhibin, 1st trimester, risk 1:400.

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Age, NT and inhibin, 1st trimester, 5FPR.
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Test 50

Age, NT and inhibin, 1st trimester, 5FPR.

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Age, NT and inhibin, 1st trimester, mixed cut‐points.
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Test 51

Age, NT and inhibin, 1st trimester, mixed cut‐points.

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Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:100.
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Test 52

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:100.

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Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:150.
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Test 53

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:150.

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Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:200.
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Test 54

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:200.

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Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:220.
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Test 55

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:220.

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Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:250.
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Test 56

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:250.

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Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:300.
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Test 57

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:300.

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Age, NT, PAPP‐A and free ßhCG, 1st trimester, 1FPR.
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Test 58

Age, NT, PAPP‐A and free ßhCG, 1st trimester, 1FPR.

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Age, NT, PAPP‐A and free ßhCG, 1st trimester, 3FPR.
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Test 59

Age, NT, PAPP‐A and free ßhCG, 1st trimester, 3FPR.

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Age, NT, PAPP‐A and free ßhCG, 1st trimester, 5FPR.
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Test 60

Age, NT, PAPP‐A and free ßhCG, 1st trimester, 5FPR.

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Age, NT, PAPP‐A and free ßhCG, 1st trimester, mixed cut‐points.
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Test 61

Age, NT, PAPP‐A and free ßhCG, 1st trimester, mixed cut‐points.

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Age, NT, PAPP‐A and uE3, 1st trimester, 5FPR.
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Test 62

Age, NT, PAPP‐A and uE3, 1st trimester, 5FPR.

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Age, NT, PAPP‐A and ITA, 1st trimester, 5FPR.
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Test 63

Age, NT, PAPP‐A and ITA, 1st trimester, 5FPR.

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Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:100.
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Test 64

Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:100.

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Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:250.
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Test 65

Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:250.

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Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:400.
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Test 66

Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:400.

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Age, NT, PAPP‐A and inhibin, 1st trimester, 5FPR.
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Test 67

Age, NT, PAPP‐A and inhibin, 1st trimester, 5FPR.

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Age, NT, PAPP‐A and inhibin, 1st trimester, mixed cut‐points.
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Test 68

Age, NT, PAPP‐A and inhibin, 1st trimester, mixed cut‐points.

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Age, NT, PAPP‐A and ADAM12, 1st trimester, 5FPR.
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Test 69

Age, NT, PAPP‐A and ADAM12, 1st trimester, 5FPR.

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Age, NT, PAPP‐A and ADAM12, 1st trimester, risk 1:250.
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Test 70

Age, NT, PAPP‐A and ADAM12, 1st trimester, risk 1:250.

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Age, NT, free ßhCG and ADAM12, 1st trimester, 5FPR.
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Test 71

Age, NT, free ßhCG and ADAM12, 1st trimester, 5FPR.

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Age, NT, AFP and free ßhCG, 1st trimester, risk 1:250.
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Test 72

Age, NT, AFP and free ßhCG, 1st trimester, risk 1:250.

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Age, NT, AFP and free ßhCG, 1st trimester, 5FPR.
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Test 73

Age, NT, AFP and free ßhCG, 1st trimester, 5FPR.

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Age, NT, AFP and free ßhCG, 1st trimester, mixed cut‐points.
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Test 74

Age, NT, AFP and free ßhCG, 1st trimester, mixed cut‐points.

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Age, NT, AFP and PAPP‐A, 1st trimester, 5FPR.
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Test 75

Age, NT, AFP and PAPP‐A, 1st trimester, 5FPR.

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Age, NT, total hCG and PAPP‐A, 1st trimester, 5FPR.
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Test 76

Age, NT, total hCG and PAPP‐A, 1st trimester, 5FPR.

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Age, NT, total hCG and inhibin, 1st trimester, 5FPR.
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Test 77

Age, NT, total hCG and inhibin, 1st trimester, 5FPR.

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Age, NT, free ßhCG and inhibin, 1st trimester, 5FPR.
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Test 78

Age, NT, free ßhCG and inhibin, 1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG, 1st trimester serum, ductus venosus pulsivity index, 5FPR.
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Test 79

Age, NT, PAPP‐A, free ßhCG, 1st trimester serum, ductus venosus pulsivity index, 5FPR.

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Age, free ßhCG and PAPP‐A, if risk 1:42‐1:1000, NT, final 1:250 risk.
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Test 80

Age, free ßhCG and PAPP‐A, if risk 1:42‐1:1000, NT, final 1:250 risk.

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Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.
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Test 81

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

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Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:250.
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Test 82

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:250.

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Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR.
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Test 83

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

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Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.
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Test 84

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

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Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.
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Test 85

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

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Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:300.
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Test 86

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:300.

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Age, NT, tricuspid blood flow, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.
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Test 87

Age, NT, tricuspid blood flow, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

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Age, NT, fetal heart rate, free ßhCG and PAPP‐A, 1st trimester, 5FPR.
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Test 88

Age, NT, fetal heart rate, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

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Age, NT, fetal heart rate, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:200.
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Test 89

Age, NT, fetal heart rate, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:200.

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age, NT, fetal heart rate, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR.
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Test 90

age, NT, fetal heart rate, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

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Age, NT, fetal heart rate, tricuspid blood flow, free ßhCG and PAPP‐A,1st trimester, 5FPR.
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Test 91

Age, NT, fetal heart rate, tricuspid blood flow, free ßhCG and PAPP‐A,1st trimester, 5FPR.

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Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, risk 1:250.
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Test 92

Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, risk 1:250.

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Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, 5FPR.
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Test 93

Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

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Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.
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Test 94

Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

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Age, NT, total hCG, inhibin and PAPP‐A, 1st trimester, 5FPR.
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Test 95

Age, NT, total hCG, inhibin and PAPP‐A, 1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG and PGH, 1st trimester, 5FPR.
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Test 96

Age, NT, PAPP‐A, free ßhCG and PGH, 1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG and GHBP, 1st trimester, 5FPR.
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Test 97

Age, NT, PAPP‐A, free ßhCG and GHBP, 1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG and PIGF, 1st trimester, 5FPR.
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Test 98

Age, NT, PAPP‐A, free ßhCG and PIGF, 1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG and total hCG, 1st trimester, 5FPR.
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Test 99

Age, NT, PAPP‐A, free ßhCG and total hCG, 1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG and PP13, 1st trimester, 5FPR.
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Test 100

Age, NT, PAPP‐A, free ßhCG and PP13, 1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, 5FPR.
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Test 101

Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, risk 1:250.
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Test 102

Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, risk 1:250.

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Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, mixed cut‐points.
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Test 103

Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, mixed cut‐points.

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Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:100.
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Test 104

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:100.

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Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:250.
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Test 105

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:250.

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Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:400.
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Test 106

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:400.

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Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, 5FPR.
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Test 107

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG, ADAM12 and PlGH, 1st trimester, 5FPR.
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Test 108

Age, NT, PAPP‐A, free ßhCG, ADAM12 and PlGH, 1st trimester, 5FPR.

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Age, NT, total hCG, inhibin, PAPP‐A, AFP and uE3, 1st trimester, 5FPR.
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Test 109

Age, NT, total hCG, inhibin, PAPP‐A, AFP and uE3, 1st trimester, 5FPR.

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Age, NT, free ßhCG, inhibin, PAPP‐A, AFP and uE3,1st trimester, 5FPR.
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Test 110

Age, NT, free ßhCG, inhibin, PAPP‐A, AFP and uE3,1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG and PlGF, 1st trimester, 5FPR.
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Test 111

Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG and PlGF, 1st trimester, 5FPR.

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Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG, PlGF and PP13, 1st trimester, 5FPR.
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Test 112

Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG, PlGF and PP13, 1st trimester, 5FPR.

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NT, free ßhCG and PAPP‐A, 1st trimester incidence rate 63.3%.
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Test 113

NT, free ßhCG and PAPP‐A, 1st trimester incidence rate 63.3%.

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NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age < 35 years.
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Test 114

NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age < 35 years.

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NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age ≥ 35 years.
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Test 115

NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age ≥ 35 years.

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Summary of findings 1. Performance of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests

Review question

What is the accuracy of ultrasound based markers alone and in combination with maternal age and/or first trimester serum markers for screening for Down's syndrome?

Population

Pregnant women at less than 14 weeks' gestation confirmed by ultrasound, who had not undergone previous testing for Down’s syndrome. Some studies were undertaken in women identified to be at high risk based on maternal age.

Settings

All settings.

Numbers of studies, pregnancies and Down's syndrome cases

126 studies (reported in 152 publications) involving 1,604,040 fetuses of which 8454 were Down's syndrome cases

Index tests

Risk scores computed using maternal age and first trimester ultrasound and serum markers for ultrasound markers ‐ NT, nasal bone, ductus venosus Doppler, maxillary bone length, fetal heart rate, aberrant right subclavian artery, frontomaxillary facial angle, presence of mitral gap, tricuspid regurgitation, tricuspid blood flow and iliac angle 90 degrees ‐ and serum markers ‐ inhibin A, AFP, free ßhCG, total hCG, PAPP‐A, uE3, ADAM 12, PlGF, PGH, ITA (h‐hCG), GHBP and PP13.

Reference standards

Chromosomal verification (amniocentesis and CVS undertaken during pregnancy, and postnatal karyotyping) and postnatal macroscopic inspection.

Study limitations

116 studies only used selective chromosomal verification during pregnancy, and were at risk of under‐ascertainment of Down's syndrome cases due to pregnancy loss between administering the serum test and the reference standard.

Test strategy

Studies

Women (Down's cases)

Sensitivity (95% CI)

Specificity

(95% CI)*

Consequences in a hypothetical cohort of 10,000 pregnant women assuming Down’s syndrome affects approximately one in 800 live‐born babies

Missed cases

False positives

Nasal bone

11

48,279 (290)

49 (34, 64)

99 (99, 100)

7

100

NT

13

90,978 (593)

70 (61, 78)

95

4

500

NT and maternal age

50

530,874 (2701)

71 (66, 75)

95

4

500

Nasal bone and maternal age

4

25,303 (165)

68 (28, 92)

95

4

500

Ductus and maternal age

5

5331 (165)

68 (49, 83)

95

4

500

NT, nasal bone and maternal age

5

29,699 (221)

78 (55, 91)

95

3

500

NT, free ßhCG and maternal age

5

10,795 (421)

77 (72, 82)

95

3

500

NT, PAPP‐A and maternal age

5

9814 (372)

81 (75, 86)

95

3

500

NT, PAPP‐A, free ßhCG and maternal age

69

1,173,853 (6010)

87 (86, 89)

95

2

500

NT, PAPP‐A, free ßhCG, ADAM 12 and maternal age

4

2571 (256)

82 (75, 87)

95

3

500

*We estimated sensitivity (with a 95% confidence interval) at a 5% false positive rate from the summary ROC curve obtained for each test except nasal bone. For nasal bone, the pooled specificity is reported because the cut‐point was absence or presence of nasal bone, and all studies reported false positive rates below 5% so estimation of sensitivity at a fixed 5% FPR was not appropriate.

Figures and Tables -
Summary of findings 1. Performance of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests
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Summary of findings 2. Performance of other first trimester ultrasound markers alone or in combination with first trimester serum tests

Test strategy

Studies

Women (Down's cases)

Sensitivity* (95% CI)

Specificity* (95% CI)

Threshold

Without maternal age

Ultrasound markers alone

Aberrant right subclavian artery

1

425 (51)

8 (2, 19)

99 (98, 100)

Feature

Frontomaxillary facial angle

1

242 (22)

18 (5, 40)

98 (95, 99)

> 95th percentile

Presence of mitral gap

1

217 (20)

20 (6, 44)

87 (81, 91)

Feature

Maxillary bone length

1

927 (88)

24 (15, 34)

95 (93, 96)

5th centile

Tricuspid regurgitation

1

312 (20)

50 (27, 73)

98 (96, 99)

Feature

Iliac angle 90 degrees

1

2032 (52)

60 (45, 73)

98 (97, 98)

Feature

Ductus venosus a‐wave reversed

1

378 (72)

68 (56, 79)

70 (64, 75)

Feature

Ductus venosus pulsivity index

1

378 (72)

81 (70, 89)

58 (52, 63)

> 95th percentile

NT and nasal bone

1

486 (38)

89 (75, 97)

93 (91, 95)

Absent nasal bone and NT ≥ 95th centile

Ultrasound and double serum markers

NT, free ßhCG and PAPP‐A

1

6508 (40)

90 (76, 97)

95 (95, 96)

First trimester incidence rate 63.3%

With maternal age

Ultrasound markers alone

NT‐adjusted risk > 1:300 and abnormal ductus venosus flow and absent nasal bones

1

544 (47)

21 (11, 36)

100 (99, 100)

1:300 risk

NT and ductus

3

23,697 (177)

76 to 93

73 to 99

5% FPR, 1:250 risk, feature

NT and tricuspid blood flow

1

19,736 (122)

85 (78, 91)

97 (97, 98)

1:100 risk

Ultrasound and single serum markers

NT and inhibin A

2

1150 (97)

61 to 75

95 to 96

5% FPR, 1:250 risk

NT and AFP

1

1110 (85)

61 (50, 72)

95 (94, 96)

5% FPR

NT and total hCG

1

1110 (85)

61 (50, 72)

95 (94, 96)

5% FPR

NT and ITA

1

278 (54)

80 (66, 89)

95 (91, 98)

5% FPR

Ultrasound and double serum markers

NT, AFP and free ßhCG

2

2766 (90)

66 to 100

93 to 95

5% FPR, 1:250 risk

NT, PAPP‐A and inhibin A

2

1150 (97)

80 to 83

95 to 96

5% FPR, 1:250 risk

NT, total hCG and inhibin A

1

1110 (85)

62 (51, 73)

95 (94, 96)

5% FPR

NT, free ßhCG and inhibin A

1

1110 (85)

66 (55, 76)

95 (94, 96)

5% FPR

NT, free ßhCG and ADAM 12

1

351 (31)

68 (49, 83)

95 (92, 97)

5% FPR

NT, PAPP‐A and uE3

1

576 (24)

79 (58, 93)

95 (93, 97)

5% FPR

NT, total hCG and PAPP‐A

1

1110 (85)

80 (70, 88)

95 (94, 96)

5% FPR

NT, AFP and PAPP‐A

1

1110 (85)

80 (70, 88)

95 (94, 96)

5% FPR

NT, PAPP‐A and ITA

2

11,053 (77)

83 (73, 90)

95

5% FPR

NT, PAPP‐A and ADAM 12

2

1042 (77)

83 (73, 90)

95

5% FPR

Free ßhCG and PAPP‐A, if risk between 1:42 and 1:1000 (intermediate risk), NToffered, final composite risk !:250

1

10,189 (44)

89 (75, 96)

94 (94, 95)

1:250 risk

NT, ductus, free ßhCG and PAPP‐A

3

30,061 (212)

83 to 96

97 to 99

1:100 risk, 1:250 risk

NT, nasal bone, free ßhCG and PAPP‐A

3

41,842 (271)

89 to 94

95 to 98

5% FPR, 1:100 risk, 1:300 risk

NT, PAPP‐A, free ßhCG and ductus venosus pulsivity index

1

7,250 (66)

89 (79, 96)

95 (94, 95)

5% FPR

NT, tricuspid blood flow, free ßhCG and PAPP‐A

1

19,736 (122)

91 (84, 95)

97 (97, 98)

1:100 risk

NT, fetal heart rate, free ßhCG and PAPP‐A

2

76,385 (517)

92 (89, 94)

95

5% FPR

NT, fetal heart rate, nasal bone, free ßhCG and PAPP‐A

1

19,736 (122)

95 (90, 98)

96 (95, 96)

1:200 risk

NT, fetal heart rate, tricuspid blood flow, free ßhCG and PAPP‐A

1

19,736 (122)

96 (91, 99)

95 (95, 95)

5% FPR

NT, fetal heart rate, ductus, free ßhCG and PAPP‐A

1

19,614 (122)

97 (92, 99)

95 (95, 95)

5% FPR

Ultrasound and triple serum markers

NT, AFP, free ßhCG and PAPP‐A

3

6789 (135)

73 to 84

95

5% FPR, 1:250 risk

NT, PAPP‐A, free ßhCG and PP13

1

998 (151)

77 (69, 83)

95 (93, 96)

5% FPR

NT, PAPP‐A, free ßhCG and total hCG

1

998 (151)

77 (69, 83)

95 (93, 96)

5% FPR

NT, total hCG, inhibin A and PAPP‐A

1

1110 (85)

81 (71, 89)

95 (94, 96)

5% FPR

NT, free ßhCG, inhibin A and PAPP‐A

1

1110 (85)

84 (74, 91)

95 (94, 96)

5% FPR

NT, PAPP‐A, free ßhCG and PGH

1

335 (74)

86 (77, 93)

95 (92, 97)

5% FPR

NT, PAPP‐A, free ßhCG and PIGF

2

1443 (221)

88 (70, 95)

95

5% FPR

NT, PAPP‐A, free ßhCG and GHBP

1

335 (74)

91 (81, 96)

95 (92, 97)

5% FPR

Ultrasound and quadruple serum markers

NT, PAPP‐A, free ßhCG, ADAM 12 and PlGF

1

998 (151)

79 (72, 86)

95 (93, 96)

5% FPR

Ultrasound and quintuple serum markers

NT, PAPP‐A, free ßhCG, ADAM 12, total hCG and PlGF

1

998 (151)

79 (72, 86)

95 (93, 96)

5% FPR

NT, total hCG, inhibin A, PAPP‐A, AFP and uE3

1

1110 (85)

84 (74, 91)

95 (94, 96)

5% FPR

NT, free ßhCG, inhibin A, PAPP‐A, AFP and uE3

1

1110 (85)

86 (77, 92)

95 (94, 96)

5% FPR

Ultrasound and sextuple serum markers

NT, PAPP‐A, free ßhCG, ADAM 12, total hCG, PlGF and PP13

1

998 (151)

80 (73, 86)

95 (93, 96)

5% FPR

*Tests evaluated by at least one study are presented in the table. Where there were two studies at the same threshold, estimates of summary sensitivity and summary specificity were obtained by using univariate fixed‐effect logistic regression models to pool sensitivities and specificities separately. If the threshold used was a 5% FPR, then only the sensitivities were pooled. The range of sensitivities and specificities are presented where meta‐analysis was not performed because there were only two or three studies and no common threshold.

Figures and Tables -
Summary of findings 2. Performance of other first trimester ultrasound markers alone or in combination with first trimester serum tests
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Table 1. Direct (head‐to‐head) comparisons of the diagnostic accuracy of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests

Ratio of DORs

(95% CI); P value

(Studies)

Nasal bone

NT

Nasal bone and age

Ductus and age

NT and age

NT, nasal bone and age

NT, free ßhCG and age

NT, PAPP‐A and age

NT, PAPP‐A, free ßhCG and age

NT

–

Nasal bone and age

–

–

Ductus and age

1.19 (0.12, 11.4); P = 0.84

(K = 1)

–

0.85 (0.21, 3.41); P = 0.76

(K = 1)

NT and age

0.62 (0.13, 2.93); P = 0.50

(K = 2)

1.25 (0.90, 1.74); P = 0.17

(K = 3)

0.84 (0.48, 1.49); P = 0.52

(K = 3)

1.07 (0.51, 2.23); P = 0.85

(K = 3)

NT, nasal bone and age

0.61 (0.12, 3.10); P = 0.50

(K = 2)

–

4.01 (1.51, 10.6); P = 0.01

(K = 2)

0.95 (0.23, 3.97); P = 0.93

(K = 1)

1.05 (0.70, 1.56); P = 0.82

(K = 5)

NT, free ßhCG and age

–

2.15 (1.33, 3.50); P = 0.007

(K = 2)

–

–

1.47 (1.00, 2.15); P = 0.05

(K = 4)

–

NT, PAPP‐A and age

–

2.86 (1.73, 4.73); P = 0.001

(K = 2)

–

–

1.88 (1.27, 2.78); P = 0.004

(K = 4)

–

1.28 (0.84, 1.93); P = 0.23

(K = 4)

NT, PAPP‐A, free ßhCG and age

3.83 (0.89, 16.4); P = 0.07

(K = 2)

4.35 (2.00, 9.46); P = 0.015

(K = 4)

–

3.00 (0.42, 21.2); P = 0.19

(K = 1)

3.19 (2.19, 4.66); P < 0.0001

(K = 25)

1.23 (0.63, 2.40); P = 0.50

(K = 2)

2.06 (1.31, 3.22); P = 0.004

(K = 4)

1.61 (1.02, 2.55); P = 0.043

(K = 4)

NT, PAPP‐A, free ßhCG, ADAM 12 and age

–

–

–

–

–

–

–

–

0.87 (0.49, 1.52); P = 0.60

(K = 4)

– Indicates pairs of tests where there were no head‐to head comparisons of the two tests in a study. Direct comparisons were made using only data from studies that compared each pair of tests in the same population. Ratio of diagnostic odds ratios (DORs) were computed by division of the DOR for the test in the row by the DOR for the test in the column. If the ratio of DORs is greater than one, then the diagnostic accuracy of the test in the row is higher than that of the test in the column; if the ratio is less than one, the diagnostic accuracy of the test in the column is higher than that of the test in the row.

Figures and Tables -
Table 1. Direct (head‐to‐head) comparisons of the diagnostic accuracy of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests
Navigate to table in Review
Table 2. Indirect comparisons of the diagnostic accuracy of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests

Ratio of DORs

(95% CI); P value

Nasal bone

NT

Nasal bone and age

Ductus and age

NT and age

NT, nasal bone and age

NT, free ßhCG and age

NT, PAPP‐A and age

NT, PAPP‐A, free ßhCG and age

DOR (95% CI)

Studies

132 (71, 245) K = 11

45 (31, 67) K = 13

40 (7, 224) K = 4

41 (18, 92) K = 5

46 (37, 57) K = 50

66 (24, 180) K = 5

65 (51, 84)

K = 5

80 (59, 109)

K = 5

133 (114, 155)

K = 69

NT

45 (31, 67) K = 13

0.34 (0.16, 0.71); P = 0.006

Nasal bone and age

40 (7, 224) K = 4

0.31 (0.05, 1.90); P = 0.18

0.90 (0.16, 5.05); P = 0.89

Ductus and age

41 (18, 92) K = 5

0.31 (0.11, 0.87); P = 0.03

0.90 (0.37, 2.20); P = 0.80

1.00 (0.11, 9.34); P = 1.00

NT and age

46 (37, 57) K = 50

0.35 (0.19, 0.66); P = 0.002

1.02 (0.66, 1.58); P = 0.92

1.14 (0.23, 5.61); P = 0.87

1.14 (0.52, 2.49); P = 0.74

NT, nasal bone and age

66 (24, 180) K = 5

0.50 (0.14, 1.81); P = 0.26

1.47 (0.47, 4.58); P = 0.48

1.64 (0.12, 21.5); P = 0.62

1.64 (0.33, 8.08); P = 0.46

1.43 (0.52, 3.98); P = 0.48

NT, free ßhCG and age

65 (51, 84)

K = 5

0.49 (0.25, 0.98); P = 0.04

1.44 (0.89, 2.34); P = 0.12

1.61 (0.26, 10.1); P = 0.56

1.61 (0.65, 3.99); P = 0.26

1.41 (1.02, 1.96); P = 0.04

0.98 (0.30, 3.19); P = 0.98

NT, PAPP‐A and age

80 (59, 109) K = 5

0.61 (0.29, 1.25); P = 0.16

1.77 (1.05, 3.00); P = 0.04

1.98 (0.30, 13.1); P = 0.42

1.98 (0.76, 5.15); P = 0.14

1.73 (1.19, 2.53); P = 0.005

1.21 (0.35, 4.13); P = 0.73

1.23 (0.74, 2.05); P = 0.35

NT, PAPP‐A, free ßhCG and age

133 (114, 155)

K = 69

1.00 (0.55, 1.84); P = 1.00

2.93 (1.96, 4.40); P < 0.0001

3.27 (0.68, 15.8); P = 0.14

3.27 (1.53, 7.00); P = 0.003

2.87 (2.21, 3.72); P < 0.0001

2.00 (0.73, 5.45); P = 0.17

2.03 (1.52, 2.72)

P < 0.0001

1.65 (1.17, 2.34)

P = 0.005

NT, PAPP‐A, free ßhCG, ADAM 12 and age

85 (58, 124) K = 4

0.64 (0.30, 1.37); P = 0.23

1.88 (1.07, 3.32); P = 0.03

2.10 (0.31, 14.1); P = 0.39

2.10 (0.78, 5.63); P = 0.12

1.84 (1.19, 2.84); P = 0.007

1.28 (0.37, 4.47); P = 0.65

1.30 (0.81, 2.09)

P = 0.26

1.06 (0.61, 1.86)

P = 0.81

0.64 (0.43, 0.96)

P = 0.03

Indirect comparisons were made using all available data for each pair of tests. Ratios of diagnostic odds ratios (DORs) were computed by division of the DOR for the test in the row by the DOR for the test in the column. If the ratio of DORs is greater than one, then the diagnostic accuracy of the test in the row is higher than that of the test in the column; if the ratio is less than one, the diagnostic accuracy of the test in the column is higher than that of the test in the row.

Figures and Tables -
Table 2. Indirect comparisons of the diagnostic accuracy of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests
Navigate to table in Review
Table 3. Summary of study characteristics

Study

NT, PAPP‐A, free ßhCG and age

Nasal bone

NT and age

NT

Maternal age (range) in years

Reference standard

Population

Study design

Study location

Acacio 2001

X

Mean 35.8 (21‐45)

CVS biopsy, amniocentesis or blood or placenta used for fetal karyotyping

High‐risk referral for invasive testing

Retrospective study of patient notes

South America

Audibert 2001

X

Mean 30.1, all < 38, 86% < 35, 14% ≥ 35

Prenatal karyotype conducted (in 7.6% of patients) depending on presence of risk > 125, high maternal age, parental anxiety, history of chromosomal defects or parental translocation or abnormal second trimester scan age

Routine screening

Prospective consecutive series

France

Babbur 2005

X

Median 37 (19‐46)

Invasive testing offered to women with NT > 3 mm or risk > 1:250 as defined by combined NT and serum results (CVS from 11 weeks, amniocentesis from 15 weeks). Rapid in situ hybridisation test in patients with risk > 1:30. No details given of any follow‐up to birth

Women requesting screening (self‐paying service) and women attending on account of previous pregnancy history of fetal abnormality

Prospective cohort

UK

Barrett 2008

X

Mean 34.9 for screen positives, 30.5 for screen negatives

Karyotyping or follow‐up to birth

Routine screening

Cohort

Australia

Belics 2011

Mean 36.4 (15‐46) for Down's cases, 29.8 (15‐49) for unaffected pregnancies

Amniocentesis or CVS (85% of women) or follow‐up to birth

High‐risk referral for invasive testing

Cohort

Budapest

Benattar 1999

X

Mean 32 (16‐46), 8.3% > 35

Amniocentesis due to maternal age > 38 years (6.1% or women). Karyotyping encouraged for women with positive result on one or more index test. No details of reference standard for index test negative women

Routine screening

Prospective cohort

France

Bestwick 2010

X

X

X

Median 39 for Down's cases, 34 for unaffected pregnancies

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

UK

Biagiotti 1998

X

X

Unclear (maybe all ≥ 38)

Amniocentesis or CVS

High‐risk referral for invasive testing

Case control

Italy

Borenstein 2008

Median 35 (17‐49)

CVS

High‐risk referral for invasive testing

Prospective cohort

UK

Borrell 2005

X

X

Not reported

CVS (high‐risk women) or follow‐up to birth

Routine screening

Retrospective cohort

Spain

Borrell 2009

X

Mean 32

Karyotyping or follow‐up to birth

Routine screening and high‐risk referral

Prospective cohort

Spain

Brameld 2008

X

Median 31 (14‐47), 20% ≥ 35

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

Australia

Brizot 2001

X

Median 28 (13‐46), 19.4% ≥ 35

Antenatal karyotyping (5.9% of pregnancies: 62% of high‐risk, 29% of medium‐risk and 3% of the low‐risk women). Follow‐up to birth (85.3% of women)

Routine screening

Prospective cohort

Brazil

Centini 2005

X

≥ 35 (35‐44)

Amniocentesis in women high risk on screening (16.2%). Follow‐up at birth in women who were low risk on screening

High‐risk patients undergoing routine screening

Retrospective cohort

Italy

Chasen 2003

X

Median 33 (IQR 31‐36), 36.2% ≥ 35

Karyotyping or follow‐up to birth in 96.1% of patients

Routine screening

Prospective consecutive cohort

USA

Chen 2009

Median 30 (20‐44) for Down's cases, 32 (19‐40) for controls

Karyotyping or follow‐up to birth

Routine screening

Case control

China

Christiansen 2005

X

Not reported

Karyotyping

Screening programmes for syphilis and Down's syndrome

Case control

Denmark

Christiansen 2009

X

Median 37.5 for Down's cases, 36.4 for controls

Karyotyping or follow‐up to birth

Routine screening

Case control

Denmark

Christiansen 2010

X

Median 36 (25‐44) for Down's cases, 29 (17‐45) for controls

Karyotyping or follow‐up to birth

Routine screening

Case control

Denmark

Cicero 2004a

Median 37 (16‐48)

CVS

High‐risk referral for invasive testing

Prospective cohort

USA

Cicero 2006

X

Median 35 (18‐50)

CVS or amniocentesis (in high risk women) or follow‐up to birth

Routine screening

Prospective cohort

UK

Cocciolone 2008 (first trimester screening cohort)

X

Median 31.3

Karyotyping or follow‐up to birth

Routine screening

Cohort

Australia

Cowans 2009

X

Mean 38 (16‐49) for Down's cases, 29 (13‐56) for unaffected pregnancies

Karyotyping or follow‐up to birth

Routine screening

Cohort

UK

Cowans 2010

X

Mean 37.0 (IQR 32.9‐40.5) for Down's cases, 32.4 (IQR 29.0‐35.9) for controls

Karyotyping or follow‐up to birth

Routine screening

Case control

UK

Crossley 2002

X

X

Median 29.9, 15.4% ≥ 35

CVS (offered where women had high NT measurements), amniocentesis or follow‐up to birth

Routine screening

Prospective cohort

UK

De Graaf 1999

X

X

Not reported

CVS and amniocentesis

High‐risk referral for invasive testing

Case control

Netherlands

Ekelund 2008

X

Not reported

Karyotyping or follow‐up to birth

Routine screening

Cohort

Denmark

Gasiorek‐Wiens 2001

X

Median 33 (15‐49), 36.1% > 35

CVS, amniocentesis or follow‐up to birth

Routine screening

Prospective cohort

Germany, Switzerland and Austria

Gasiorek‐Wiens 2010

X

Median 35.1 (13.2‐46.7)

Karyotyping or follow‐up to birth

Routine screening

Cohort

Germany

Go 2005

X

49% ≤ 35, 51% ≥ 36

Invasive testing or follow‐up to birth

Routine screening

Retrospective cohort

Netherlands

Gyselaers 2005

X

X

Not reported

CVS, amniocentesis or follow‐up to birth

Routine screening

Prospective cohort

Belgium

Habayeb 2010

Median 35.4 (18‐49)

Karyotyping or follow‐up to birth

Routine screening

Cohort

UK

Hadlow 2005*

X

Mean 30.7, 21.2% ≥ 35

CVS, amniocentesis or follow‐up to birth

Routine screening

Prospective cohort

Australia

Hafner 1998*

X

Median 28 (15‐49) 6.9% ≥ 35

Amniocentesis or CVS in patients with previous Down’s pregnancy, > 35 years or with a positive biochemical test result. Other women underwent scan at 22 weeks and, if NT >2.5 mm special examination directed to examination of fetal heart. Follow‐up to birth

Routine screening

Prospective cohort

Austria

Has 2008

X

X

X

Median 28.3 (17‐45)

Karyotyping or follow‐up to birth

Routine screening

Cohort

Turkey

Hewitt 1996

X

Median 37 (21‐48)

CVS

High‐risk referral for invasive testing

Prospective cohort

Australia

Hormansdorfer 2011

X

Mean 31.1 (16‐46), 22% ≥ 35

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Germany

Huang 2010

X

Median 30 (15‐47), mean 29.8 (SD 3.3)

Karyotyping or follow‐up to birth

Routine screening

Cohort

Taiwan

Jaques 2007

X

Mean 33 (16‐51), 18.5% ≥ 37

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

Australia

Jaques 2010 FTS (first trimester screening)

X

Mean 16.3% ≥ 37

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

Australia

Kagan 2010

X

X

Mean 35.4 (14.1‐52.2)

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

UK

Kim 2006

X

Mean 29.9 (SD 3.3)

Amniocentesis or CVS in patients considered high risk (NT > 2.5, aged > 35 years, positive biochemical test result, history or chromosomal abnormality, fetal structural abnormality at ultrasound or other reason). Follow‐up to birth

Routine screening

Retrospective cohort

South Korea

Koster 2011

X

Median 37 (IQR 36‐39)

Karyotyping or follow‐up to birth

Routine screening

Case control

Netherlands

Kozlowski 2007 GC (Gynaecologists' practices)

X

X

Median 32 (15‐48), 26.4% ≥ 35

Karyotyping or follow‐up to birth

Routine screening

Cohort

Germany

Kozlowski 2007 PC (Prenatal centre)

X

X

Median 34 (14‐46), 43.2% ≥ 35

Karyotyping or follow‐up to birth

Routine screening

Cohort

Germany

Krantz 2000*

X

X

34.7% ≥ 35

Not reported

Routine screening

Prospective cohort

USA

Kublickas 2009

X

51% ≥ 35

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Sweden

Kuc 2010

X

Not reported

Karyotyping or follow‐up to birth

Routine screening

Case control

Netherlands

Lam 2002

X

Mean 30.5 (19% ≥ 35) for unaffected pregnancies

Women considered high risk offered CVS (0.7%) or amniocentesis (11.8%).

Follow‐up to birth

Routine screening

Prospective cohort

Hong Kong

Leung 2009

X

X

Median 32 (IQR 30‐35), 27.4% ≥ 35

Amniocentesis or follow‐up to birth

Routine screening

Prospective cohort

China

MacRae 2008

X

Not reported

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

UK

Maiz 2007

Median 35 (17‐49)

CVS

High‐risk referral for invasive testing

Prospective cohort

UK

Maiz 2009

Median 34.5 (14.1‐50.1)

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

UK

Malone 2004

X

Mean 30.1 (16‐47), 22.1% ≥ 35

Amniocentesis (in women considered high risk, n = 510) or follow‐up to birth

Routine screening

Prospective cohort

USA

Malone 2005

X

21.6% ≥ 35

Amniocentesis offered to women with positive results from any screening test. Follow‐up to birth

Routine screening

Prospective cohort

USA

Marchini 2010*

X

Median 31.3 (18‐45), 19.7% ≥ 35

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

Italy

Marsis 2004

X

Mean 37.8 (35‐43)

Amniocentesis (unclear in which patients this was conducted) or follow‐up to birth

Screening of patients ≥ 35 years of age

Prospective cohort

Indonesia

Marsk 2006

X

X

Mean 38.5 (SD 4.0) for Down's cases, 35.5 (SD 4.0) for controls

Not reported

Routine screening

Case control

Sweden

Matias 1998

Median 35 (17‐46)

Fetal karyotyping. In cases where NT above 95th percentile or abnormal ductus venousus flow, follow‐up scan conducted at 14‐16 weeks

High‐risk referral for invasive testing

Prospective cohort

UK and Portugal

Matias 2001

Median 35 (17‐46)

Fetal karyotyping. In cases where NT above 95th percentile or abnormal ductus venousus flow, follow‐up scan conducted at 14‐16 weeks

High‐risk referral for invasive testing

Prospective cohort

Portugal

Mavrides 2002

X

Median 35 (15‐42)

CVS or follow‐up

High‐risk referral for invasive testing

Prospective cohort

UK

Maxwell 2011 FTS (first trimester screening cohort)

X

Median 31 (14‐48), 24.3% ≥ 35

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Australia

Maymon 2005

Mean 33.7 (SD 4.9) for Down's cases, 30.3 (SD 4.5) for controls

Amniocentesis (recommended for women with higher risk on first or second trimester testing) or follow‐up to birth

Routine screening

Case control

Israel

Maymon 2008

X

X

Not reported

Karyotyping or follow‐up to birth

Routine screening

Case control

USA

Merz 2011

X

Not reported

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

Germany

Michailidis 2001

X

Mean 30.1 (13‐50), 21.1% ≥ 35, 11.9% ≥ 37

Karyotyping in women considered at risk due to index test results, age or family history or those with considerable anxiety (632 women, 8.5%) or follow‐up to birth

Routine screening

Prospective cohort

UK

Molina 2010 high risk (High‐risk cohort)

X

Mean 32.7 (16.7‐47.5)

CVS

High‐risk referral for invasive testing

Cohort

Spain

Molina 2010 screening (Screening cohort)

X

Not reported

Karyotyping or follow‐up to birth

Routine screening

Cohort

Spain

Monni 2005

X

Median 32 (14‐49)

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Italy

Montalvo 2005

X

Mean 31.1 (14‐49), 25.9% ≥35

Invasive testing offered to women considered high risk from screening results or follow‐up to birth

Routine screening

Prospective cohort

Spain

Moon 2007

X

Mean 35.5 (SD 4.8) for Down's cases, 31.7 (SD 3.4) for unaffected pregnancies

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Korea

Muller 2003

X

X

Not reported

Invasive testing (offered to women with high NT measurement) or follow‐up to birth

Routine screening

Retrospective cohort

France

Nicolaides 1992

X

Median 38 (22‐47)

Fetal karyotyping by amniocentesis (52%) or CVS (48%)

High‐risk referral for invasive testing

Prospective cohort

UK

Nicolaides 2005

X

Median 31 (13‐49)

Amniocentesis or CVS (patients considered high risk based on screening). First trimester presence/absence of nasal bone, presence/absence of tricuspid regurgitation or normal/abnormal Doppler studies (patients of intermediate risk on first trimester screening and did not undergo CVS or amniocentesis. With the addition of information from these tests, if adjusted risk was high, CVS was performed). Follow‐up to birth

Routine screening

Prospective cohort

UK

Niemimaa 2001

X

X

17.5% ≥ 35

Invasive testing (patients considered high risk based on NT screening) or follow‐up to birth.

Routine screening

Prospective cohort

Finland

Noble 1995

Median 34 (15‐47), 47% ≥ 35

Karyotyping performed (27% of women) due to increased NT (14%), advanced maternal age (10%), previous chromosomally abnormal child (0.5%) or parental anxiety (2%).
Ultrasound examination at 20 weeks (65% of patients). Follow‐up to birth (9% of women)

Routine screening in a high risk population

Prospective cohort

UK

O'Callaghan 2000

X

Median 32

CVS, amniocentesis or neonatal karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Australia

O'Leary 2006

X

X

Median 31 (14‐47), 20% ≥ 35

CVS or amniocentesis (women assessed to be high risk on screening) or follow‐up to birth

Routine screening

Prospective cohort

Australia

Okun 2008 FTS (first trimester screening cohort)

X

Mean 34

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Canada

Orlandi 1997

X

X

Range 15 to 46, 35% ≥ 35

Not reported

Routine screening

Prospective cohort

Italy

Orlandi 2003

X

Median 31.7 (SD 4.0) for Down's cases, 36.5 (SD 4.1) for unaffected pregnancies

CVS or amniocentesis (women considered high risk on screening on the basis of NT and biochemical results, but not on nasal bone screening, or if requested due to age or anxiety) or follow‐up to birth

Routine screening (2 centres) or in referred patients (1 centre)

Prospective cohort

Italy and Netherlands

Orlandi 2005

X

Median 30.5 (SD 8.2)

Not reported

Routine screening

Retrospective cohort

Italy

Otaño 2002

X

Median 36 (19‐44)

CVS

High‐risk referral for invasive testing

Prospective cohort

Argentina

Pajkrt 1998

X

Mean 31.4 (SD 5.7), 24% ≥ 35

Prenatal karyotyping offered to patients considered high risk or maternal anxiety (conducted in 24%) or follow‐up to birth

Routine screening

Prospective cohort

Netherlands

Pajkrt 1998a

X

Mean 37.6 (22‐46)

Prenatal karyotyping

High‐risk referral for invasive testing

Consecutive cohort

Netherlands

Palomaki 2007 FTS (first trimester screening cohort)

Mean 32.3 (SD 4.6)

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Canada

Perni 2006

X

Median 33.0 (IQR 31.0‐36.0)

CVS or amniocentesis. Cytogenetic testing in cases of miscarriage. Follow‐up to birth.

Routine screening

Retrospective cohort

USA

Prefumo 2005

X

Median 37 (19‐46)

CVS

High‐risk referral for invasive testing

Prospective cohort

UK

Prefumo 2006

X

Mean 31.4 (14.5‐50.2)

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

UK

Ramos‐Corpas 2006

X

Mean 30.1 (15‐46) (SD 5.37), 18% ≥ 35

Invasive testing offered to patients considered high risk at screening (> 1:300) or follow‐up to birth

Routine screening

Prospective cohort

Spain

Rissanen 2007

X

29.5, 17.7% ≥35

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Finland

Rozenberg 2002

X

Median 30.5 (18‐37)

Amniocentesis offered to patients with NT >3mm or serum marker risk was > 1:250, or follow‐up to birth

Routine screening

Prospective cohort

France

Rozenberg 2007

X

Mean 30.9 (SD 4.5)

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Canada

Sahota 2010

X

X

Median 33.1, 30.1% ≥ 35

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

China

Salomon 2010

X

Median 30.7 (18.0‐46.3)

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

France

Santiago 2007

X

X

Mean 30.6 (14‐46)

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

Spain

Sau 2001

X

Mean 28 (SD 5)

Invasive testing (women with high risk on screening) or follow‐up to birth

Routine screening

Prospective cohort

UK

Schaelike 2009

X

X

31.0% ≥35

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Germany

Schielen 2006*

X

Median 36.5 (18‐47)

Invasive testing or follow‐up to birth

Routine screening

Retrospective cohort

Netherlands

Schuchter 2001

X

Mean 28 (15‐46), 10.7% ≥ 35

CVS (offered to patients with first trimester NT > 3.5 mm), amniocentesis (offered to patients with first trimester NT 2.5‐3.4 mm, high risk on second trimester serum testing (> 1:250) and those > 35 years) or follow‐up to birth

Routine screening

Retrospective cohort

Austria

Schuchter 2002

X

X

13% > 35

CVS and amniocentesis (offered to patients with increased risk (> 1:400) at first trimester screening. CVS recommended when NT > 3.5 or when women did not want to wait until the 15th week for amniocentesis), or follow‐up to birth

Routine screening

Prospective cohort

Austria

Schwarzler 1999

X

Mean 29.4 (16‐47)

Invasive testing (women considered high risk on screening) or follow‐up to birth

Routine screening

Prospective consecutive cohort

UK

Scott 2004

X

X

Median 32 (15‐44), 29% ≥ 35

Invasive testing or follow‐up to birth

Routine screening

Prospective cohort

Australia

Sepulveda 2007

X

X

Median 33 (14‐47), 35.4% ≥ 35

CVS, amniocentesis, cordocentesis or follow‐up to birth

Routine screening

Prospective cohort

Chile

Snijders 1998

X

Median 31 (14‐49)

CVS and amniocentesis (9.6% of women) or follow‐up to birth

Routine screening

Prospective cohort

UK

Sorensen 2011

X

Median 34 (23‐44) for Down's cases; mean 30.4 (16‐45), 16.5% ≥ 35 for unaffected pregnancies

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

Denmark

Spencer 1999

X

X

X

Median 38 (19‐46) for Down's cases, 36 (15‐47) for controls

Invasive testing (high‐risk women) or follow‐up to birth

Routine screening

Case control

UK

Spencer 2002

Median 36 (20‐44) for Down's cases, 30 (16‐41) for controls

Not reported

Routine screening

Case control

UK

Spencer 2008

X

Median 35.8 for Down's cases, 29.3 for controls

Karyotyping or follow‐up to birth

Routine screening

Case control

Denmark

Stenhouse 2004

X

Median 32 (14‐45), 27% ≥ 35

Invasive testing offered to women with screening risk of > 1:250 or follow‐up to birth

Routine screening

Prospective cohort

UK

Strah 2008

X

Median 28.6 (15‐42)

Karyotyping or follow‐up to birth

Routine screening

Cohort

Slovenia

Theodoropoulos 1998

X

Median 29 (16‐48), 7.8% ≥ 37

CVS or amniocentesis or follow‐up to birth. Unclear reference standard in cases of intrauterine death, miscarriages and terminations.

Routine screening

Prospective cohort

Greece

Thilaganathan 1999

X

Mean 29 (15‐45)

CVS (offered to patients considered high risk on screening) or follow‐up to birth

Routine screening

Prospective cohort

UK

Timmerman 2010

Mean 34.5 (19‐45)

Karyotyping or follow‐up to birth

Routine screening

Prospective cohort

Netherlands

Torring 2010

X

Mean 35 for Down's cases, 31 for controls

Karyotyping or follow‐up to birth

Routine screening

Case control

Denmark

Vadiveloo 2009

X

Median 33.1, 36.9% ≥ 35

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

UK

Valinen 2007

X

Mean 29.6, 18.6% ≥ 35

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

Finland

Viora 2003

Median 32 (18‐47)

CVS or follow‐up to birth

Routine screening

Prospective cohort

Italy

Wald 2003

X

X

X

Not reported

Invasive testing (following second trimester screening) or follow‐up to birth

Routine screening

Case control

UK and Austria

Wapner 2003*

X

X

Mean 35 (SD 4.6), 50% ≥ 35

Invasive testing. Miscarriage with cytogenetic testing. Follow‐up to birth

Routine screening

Prospective cohort

USA

Wax 2009

X

Mean 36.7 (SD 3.2)

Karyotyping or follow‐up to birth

Routine screening

Retrospective cohort

USA

Wojdemann 2005

X

X

Mean 29, 10.8% ≥ 35

Invasive testing (in cases of increased risk) or follow‐up to birth

Referrals for screening

Prospective cohort

Denmark

Wortelboer 2009

X

Median 34.9 (15‐48)

Karyotyping or follow‐up to birth

Routine screening

Cohort

Netherlands

Wright 2008

X

Median 35.2 (16‐52)

Karyotyping or follow‐up to birth

Routine screening

Cohort

UK

Wright 2010

X

Median 31.9 (IQR 27.7‐35.8)

Karyotyping or follow‐up to birth

Routine screening

Cohort

UK, Denmark and Cyprus

Zoppi 2001

X

Median 33 (14‐48)

Amniocentesis, CVS or follow‐up to birth

Routine screening

Prospective cohort

Italy

*The study provided data for the subset of women with maternal age of 35 or more.

X indicates that the test was evaluated in the study.

CVS = chorionic villus sampling; IQR = interquartile range; SD = standard deviation.
Figures and Tables -
Table 3. Summary of study characteristics
Navigate to table in Review
Table 4. Investigation of the effect of type of population

Correction made for missing false negatives in studies with delayed verification of test negatives

NT

NT and maternal age

NT, PAPP‐A, free ßhCG and maternal age

Ratio of DORs (95% CI);

P value

Sensitivity at 5% FPR (95% CI) (studies)

Ratio of DORs (95% CI);

P value

Sensitivity at 5% FPR (95% CI) (studies)

Ratio of DORs (95% CI);

P value

Sensitivity at 5% FPR (95% CI) (studies)

Screening (n = 9)

High risk (n = 4)

Screening (n = 46)

High risk (n = 4)

Screening (n = 66)

High risk (n =3)

No FN correction

0.68 (0.26, 1.77);

P = 0.40

73 (62, 81)

64 (45, 80)

0.34 (0.17, 0.69);

P = 0.003

72 (68, 76)

47 (31, 63)

0.41 (0.16, 1.00); P = 0.05

88 (86, 89)

74 (54, 88)

FN increased +10%

0.69 (0.27, 1.78);

P = 0.40

70 (59, 79)

62 (42, 78)

0.40 (0.20, 0.82);

P = 0.01

69 (64, 73)

47 (31, 64)

0.48 (0.19, 1.20); P = 0.11

86 (84, 87)

74 (53, 88)

FN increased +20%

0.74 (0.29, 1.92);

P = 0.50

69 (57, 78)

62 (42, 78)

0.43 (0.21, 0.89);

P = 0.02

67 (63, 71)

47 (31, 64)

0.51 (0.20, 1.28); P = 0.15

85 (83, 87)

74 (54, 88)

FN increased +30%

0.81 (0.31, 2.09);

P = 0.63

67 (55, 76)

62 (42, 78)

0.46 (0.22, 0.97);

P = 0.04

66 (61, 70)

47 (30, 64)

0.55 (0.22, 1.38); P = 0.20

84 (82, 86)

74 (54, 88)

FN increased +40%

0.76 (0.29, 2.02);

P = 0.55

66 (53, 76)

59 (39, 77)

0.50 (0.24, 1.02);

P = 0.06

64 (60, 68)

47 (31, 64)

0.59 (0.24, 1.48); P = 0.26

83 (81, 85)

74 (54, 88)

FN increased +50%

0.81 (0.30, 2.15): P = 0.65

64 (52, 75)

59 (39, 77)

0.52 (0.25, 1.08);

P = 0.08

63 (58, 67)

47 (30, 64)

0.62 (0.25, 1.56); P = 0.31

82 (80, 84)

74 (54, 88)

DOR = diagnostic odds ratio
Figures and Tables -
Table 4. Investigation of the effect of type of population
Navigate to table in Review
Table Tests. Data tables by test

Test

No. of studies

No. of participants

1 Aberrant right subclavian artery Show forest plot

1

425

2 Frontomaxillary facial angle >95 percentile Show forest plot

1

242

3 Presence of mitral gap Show forest plot

1

217

4 Maxillary bone length, 5% percentile Show forest plot

1

927

5 Tricuspid regurgitation Show forest plot

1

312

6 Iliac angle 90 degrees Show forest plot

1

2032

7 Ductus venosus a‐wave reversed Show forest plot

1

378

8 Ductus venosus pulsivity index > 95 percentile Show forest plot

1

378

9 Nasal bone, mixed cut‐points Show forest plot

11

48279

10 NT, 2.5 mm Show forest plot

4

11835

11 NT, 3 mm Show forest plot

6

10381

12 NT, 5FPR Show forest plot

3

63885

13 NT, mixed cut‐points Show forest plot

13

90978

14 NT and age, risk 1:100 Show forest plot

1

10668

15 NT and age, risk 1:250 Show forest plot

10

79412

16 NT and age, risk 1:300 Show forest plot

23

252811

17 NT and age, 1FPR Show forest plot

4

98453

18 NT and age, 3FPR Show forest plot

4

98453

19 NT and age, 5FPR Show forest plot

22

288853

20 NT and age, mixed cut‐points Show forest plot

50

530874

21 NT and nasal bone, Absent NB + NT ≥ 95th centile Show forest plot

1

486

22 Ductus and age, risk 1:250 Show forest plot

1

3731

23 Ductus and age, 5FPR Show forest plot

2

3965

24 Ductus and age, mixed cut‐points Show forest plot

5

5331

25 Ductus, NT and age, risk 1:100 Show forest plot

1

19736

26 Ductus, NT and age, risk 1:250 Show forest plot

1

3727

27 Ductus, NT and age, 5FPR Show forest plot

2

3961

28 Ductus, NT and age, mixed cut‐points Show forest plot

3

23697

29 Age and nasal bone, mixed cut‐points Show forest plot

4

25303

30 Age, NT and tricuspid blood flow, risk 1:100 Show forest plot

1

19736

31 Age, NT and nasal bone, risk 1:100 Show forest plot

1

19736

32 Age, NT and nasal bone, risk 1:300 Show forest plot

4

9963

33 Age, NT and nasal bone, mixed cut‐points Show forest plot

5

29699

34 Age, NT, nasal bone and ductus, risk NT>1:300 AND abnormal DV flow AND absent NB Show forest plot

1

544

35 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

1

20305

36 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot

3

41842

37 Age, NT and free ßhCG, 1st trimester, 5FPR Show forest plot

4

4986

38 Age, NT and free ßhCG, 1st trimester, risk 1:240 Show forest plot

1

5809

39 Age, NT and free ßhCG, 1st trimester, mixed cut‐points Show forest plot

5

10795

40 Age, NT and PAPP‐A, 1st trimester, risk 1:100 Show forest plot

1

1507

41 Age, NT and PAPP‐A, 1st trimester, risk 1:185 Show forest plot

1

5809

42 Age, NT and PAPP‐A, 1st trimester, 5FPR Show forest plot

3

2498

43 Age, NT and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot

5

9814

44 Age, NT and total hCG, 1st trimester, 5FPR Show forest plot

1

1110

45 Age, NT and AFP, 1st trimester, 5FPR Show forest plot

1

1110

46 Age, NT and ITA, 1st trimester, 5FPR Show forest plot

1

278

47 Age, NT and inhibin, 1st trimester, risk 1:100 Show forest plot

1

40

48 Age, NT and inhibin, 1st trimester, risk 1:250 Show forest plot

1

40

49 Age, NT and inhibin, 1st trimester, risk 1:400 Show forest plot

1

40

50 Age, NT and inhibin, 1st trimester, 5FPR Show forest plot

1

1110

51 Age, NT and inhibin, 1st trimester, mixed cut‐points Show forest plot

2

1150

52 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:100 Show forest plot

10

102332

53 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:150 Show forest plot

5

177643

54 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:200 Show forest plot

8

135768

55 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:220 Show forest plot

1

2231

56 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:250 Show forest plot

25

174712

57 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:300 Show forest plot

29

544681

58 Age, NT, PAPP‐A and free ßhCG, 1st trimester, 1FPR Show forest plot

7

88874

59 Age, NT, PAPP‐A and free ßhCG, 1st trimester, 3FPR Show forest plot

9

312680

60 Age, NT, PAPP‐A and free ßhCG, 1st trimester, 5FPR Show forest plot

24

391874

61 Age, NT, PAPP‐A and free ßhCG, 1st trimester, mixed cut‐points Show forest plot

69

1173853

62 Age, NT, PAPP‐A and uE3, 1st trimester, 5FPR Show forest plot

1

576

63 Age, NT, PAPP‐A and ITA, 1st trimester, 5FPR Show forest plot

2

11053

64 Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:100 Show forest plot

1

40

65 Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:250 Show forest plot

1

40

66 Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:400 Show forest plot

1

40

67 Age, NT, PAPP‐A and inhibin, 1st trimester, 5FPR Show forest plot

1

1110

68 Age, NT, PAPP‐A and inhibin, 1st trimester, mixed cut‐points Show forest plot

2

1150

69 Age, NT, PAPP‐A and ADAM12, 1st trimester, 5FPR Show forest plot

2

1042

70 Age, NT, PAPP‐A and ADAM12, 1st trimester, risk 1:250 Show forest plot

1

691

71 Age, NT, free ßhCG and ADAM12, 1st trimester, 5FPR Show forest plot

1

351

72 Age, NT, AFP and free ßhCG, 1st trimester, risk 1:250 Show forest plot

1

1656

73 Age, NT, AFP and free ßhCG, 1st trimester, 5FPR Show forest plot

1

1110

74 Age, NT, AFP and free ßhCG, 1st trimester, mixed cut‐points Show forest plot

2

2766

75 Age, NT, AFP and PAPP‐A, 1st trimester, 5FPR Show forest plot

1

1110

76 Age, NT, total hCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

1

1110

77 Age, NT, total hCG and inhibin, 1st trimester, 5FPR Show forest plot

1

1110

78 Age, NT, free ßhCG and inhibin, 1st trimester, 5FPR Show forest plot

1

1110

79 Age, NT, PAPP‐A, free ßhCG, 1st trimester serum, ductus venosus pulsivity index, 5FPR Show forest plot

1

7250

80 Age, free ßhCG and PAPP‐A, if risk 1:42‐1:1000, NT, final 1:250 risk Show forest plot

1

10189

81 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:100 Show forest plot

2

26986

82 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:250 Show forest plot

2

10325

83 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

2

10325

84 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot

3

30061

85 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:100 Show forest plot

1

19736

86 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:300 Show forest plot

1

1801

87 Age, NT, tricuspid blood flow, free ßhCG and PAPP‐A, 1st trimester, risk 1:100 Show forest plot

1

19736

88 Age, NT, fetal heart rate, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

2

76385

89 Age, NT, fetal heart rate, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:200 Show forest plot

1

19736

90 age, NT, fetal heart rate, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

1

19614

91 Age, NT, fetal heart rate, tricuspid blood flow, free ßhCG and PAPP‐A,1st trimester, 5FPR Show forest plot

1

19736

92 Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, risk 1:250 Show forest plot

1

5483

93 Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot

2

1306

94 Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot

3

6789

95 Age, NT, total hCG, inhibin and PAPP‐A, 1st trimester, 5FPR Show forest plot

1

1110

96 Age, NT, PAPP‐A, free ßhCG and PGH, 1st trimester, 5FPR Show forest plot

1

335

97 Age, NT, PAPP‐A, free ßhCG and GHBP, 1st trimester, 5FPR Show forest plot

1

335

98 Age, NT, PAPP‐A, free ßhCG and PIGF, 1st trimester, 5FPR Show forest plot

2

1443

99 Age, NT, PAPP‐A, free ßhCG and total hCG, 1st trimester, 5FPR Show forest plot

1

998

100 Age, NT, PAPP‐A, free ßhCG and PP13, 1st trimester, 5FPR Show forest plot

1

998

101 Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, 5FPR Show forest plot

4

2571

102 Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, risk 1:250 Show forest plot

2

1222

103 Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, mixed cut‐points Show forest plot

4

2571

104 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:100 Show forest plot

1

40

105 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:250 Show forest plot

1

40

106 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:400 Show forest plot

1

40

107 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, 5FPR Show forest plot

1

1110

108 Age, NT, PAPP‐A, free ßhCG, ADAM12 and PlGH, 1st trimester, 5FPR Show forest plot

1

998

109 Age, NT, total hCG, inhibin, PAPP‐A, AFP and uE3, 1st trimester, 5FPR Show forest plot

1

1110

110 Age, NT, free ßhCG, inhibin, PAPP‐A, AFP and uE3,1st trimester, 5FPR Show forest plot

1

1110

111 Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG and PlGF, 1st trimester, 5FPR Show forest plot

1

998

112 Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG, PlGF and PP13, 1st trimester, 5FPR Show forest plot

1

998

113 NT, free ßhCG and PAPP‐A, 1st trimester incidence rate 63.3% Show forest plot

1

6508

114 NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age < 35 years Show forest plot

5

19057

115 NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age ≥ 35 years Show forest plot

5

10980
Figures and Tables -
Table Tests. Data tables by test
Navigate to table in Review