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Meta-Analysis
. 2015 Dec 10;2015(12):CD011984.
doi: 10.1002/14651858.CD011984.

Urine tests for Down's syndrome screening

S Kate Alldred  1 , Boliang Guo, Yemisi Takwoingi, Mary Pennant, Susanna Wisniewski, Jonathan J Deeks, James P Neilson, Zarko Alfirevic
Affiliations
Meta-Analysis

Urine tests for Down's syndrome screening

S Kate Alldred et al. Cochrane Database Syst Rev. .

Abstract

Background: Down's syndrome occurs when a person has three copies of chromosome 21, or the specific area of chromosome 21 implicated in causing Down's syndrome, rather than two. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life. The risk of a Down's syndrome affected pregnancy increases with advancing maternal age.Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive and false negative screening tests (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have.

Objectives: To estimate and compare the accuracy of first and second trimester urine markers for the detection of Down's syndrome.

Search methods: We carried out a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), EMBASE (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2011, Issue 7), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (archived 2007), Health Services Research Projects in Progress database (25 August 2011). We studied reference lists and published review articles.

Selection criteria: Studies evaluating tests of maternal urine in women up to 24 weeks of gestation for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection.

Data collection and analysis: We extracted data as test positive or test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC (receiver operating characteristic) meta-analytical methods to analyse test performance and compare test accuracy. We performed analysis of studies allowing direct comparison between tests. We investigated the impact of maternal age on test performance in subgroup analyses.

Main results: We included 19 studies involving 18,013 pregnancies (including 527 with Down's syndrome). Studies were generally of high quality, although differential verification was common with invasive testing of only high-risk pregnancies. Twenty-four test combinations were evaluated formed from combinations of the following seven different markers with and without maternal age: AFP (alpha-fetoprotein), ITA (invasive trophoblast antigen), ß-core fragment, free ßhCG (beta human chorionic gonadotrophin), total hCG, oestriol, gonadotropin peptide and various marker ratios. The strategies evaluated included three double tests and seven single tests in combination with maternal age, and one triple test, two double tests and 11 single tests without maternal age. Twelve of the 19 studies only evaluated the performance of a single test strategy while the remaining seven evaluated at least two test strategies. Two marker combinations were evaluated in more than four studies; second trimester ß-core fragment (six studies), and second trimester ß-core fragment with maternal age (five studies).In direct test comparisons, for a 5% false positive rate (FPR), the diagnostic accuracy of the double marker second trimester ß-core fragment and oestriol with maternal age test combination was significantly better (ratio of diagnostic odds ratio (RDOR): 2.2 (95% confidence interval (CI) 1.1 to 4.5), P = 0.02) (summary sensitivity of 73% (CI 57 to 85) at a cut-point of 5% FPR) than that of the single marker test strategy of second trimester ß-core fragment and maternal age (summary sensitivity of 56% (CI 45 to 66) at a cut-point of 5% FPR), but was not significantly better (RDOR: 1.5 (0.8 to 2.8), P = 0.21) than that of the second trimester ß-core fragment to oestriol ratio and maternal age test strategy (summary sensitivity of 71% (CI 51 to 86) at a cut-point of 5% FPR).

Authors' conclusions: Tests involving second trimester ß-core fragment and oestriol with maternal age are significantly more sensitive than the single marker second trimester ß-core fragment and maternal age, however, there were few studies. There is a paucity of evidence available to support the use of urine testing for Down's syndrome screening in clinical practice where alternatives are available.

PubMed Disclaimer

Conflict of interest statement

S Kate Alldred: none known

Zarko Alfirevic: none known

Jonathan J Deeks: none known

James P Neilson: none known

Boliang Guo: none known

Mary Pennant: none known

Susanna Wisniewski: none known

Yemisi Takwoingi: none known

Figures

1
1
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
2
2
Detection rates (% sensitivity) at a 5% false positive rate for the five most evaluated or best performing test strategies. The estimates are shown with 95% confidence intervals. The test strategies are ordered on the plot according to decreasing detection rate. The number of studies, cases and women included for each test strategy are shown on the horizontal axis.
1
1. Test
Betacore, 1st trimester urine test, 5% FPR.
2
2. Test
Betacore, 2nd trimester urine test, 5% FPR.
3
3. Test
Betacore, 2nd trimester urine test, cutpoint mixed.
4
4. Test
Gonadotropin, 2nd trimester urine test, risk 1:100.
5
5. Test
Gonadotropin, 2nd trimester urine test, risk 1:384.
6
6. Test
Gonadotropin, 2nd trimester urine test, 95% percentile.
7
7. Test
ITA, 1st trimester urine test, 5% FPR.
8
8. Test
ITA, 2nd trimester urine test, 3.74MoM.
9
9. Test
ITA, 2nd trimester urine test, 5% FPR.
10
10. Test
Total hCG, 1st trimester urine test, 5% FPR.
11
11. Test
Total hCG, 2nd trimester urine test, 5% FPR.
12
12. Test
Free ßhCG, 1st trimester urine test, 5% FPR.
13
13. Test
Free ßhCG, 2nd trimester urine test, 5% FPR.
14
14. Test
Oestriol, 2nd trimester urine test, 5% FPR.
15
15. Test
Betacore to oestriol ratio, 2nd trimester urine test, 5% FPR.
16
16. Test
Betacore and oestriol, 2nd trimester 5% FPR.
17
17. Test
AFP and ITA, 2nd trimester urine test, 3% FPR.
18
18. Test
AFP and ITA, 2nd trimester urine test, 5% FPR.
19
19. Test
AFP and ITA, 2nd trimester urine test,10% FPR.
20
20. Test
AFP and ITA, 2nd trimester urine test, 15% FPR.
21
21. Test
AFP, uE3 and ITA, 2nd trimester urine test, 3% FPR.
22
22. Test
AFP, uE3 and ITA, 2nd trimester urine test, 5% FPR.
23
23. Test
AFP, uE3 and ITA, 2nd trimester urine test, 10% FPR.
24
24. Test
AFP, uE3 and ITA, 2nd trimester urine test, 15% FPR.
25
25. Test
Age, betacore, 2nd trimester urine test, 1% FPR.
26
26. Test
Age, betacore, 2nd trimester urine test, 3% FPR.
27
27. Test
Age, betacore, 2nd trimester urine test, 5% FPR.
28
28. Test
Age, betacore, 2nd trimester urine test, 10% FPR.
29
29. Test
Age, betacore, 2nd trimester urine test, 15% FPR.
30
30. Test
Age, betacore, 2nd trimester urine test, 20% FPR.
31
31. Test
Age, ITA, 2nd trimester urine test, 5% FPR.
32
32. Test
Age, oestriol, 2nd trimester urine test, 5% FPR.
33
33. Test
Age, free ßhCG, 2nd trimester urine test, 5% FPR.
34
34. Test
Age, betacore to oestriol ratio, 2nd trimester urine test, 1% FPR.
35
35. Test
Age, betacore to oestriol ratio, 2nd trimester urine test, 3% FPR.
36
36. Test
Age, betacore to oestriol ratio, 2nd trimester urine test, 5% FPR.
37
37. Test
Age, free ßhCG to oestriol ratio, 2nd trimester urine test, 5% FPR.
38
38. Test
Age, oestriol and free ßhCG, 2nd trimester, 5% FPR.
39
39. Test
Age, betacore to free ßhCG ratio, 2nd trimester, 5% FPR.
40
40. Test
Age, betacore and oestriol, 2nd trimester 1% FPR.
41
41. Test
Age, betacore and oestriol, 2nd trimester, 3% FPR.
42
42. Test
Age, betacore and oestriol, 2nd trimester, 5% FPR.
43
43. Test
Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:10.
44
44. Test
Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:20.
45
45. Test
Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:30.
46
46. Test
Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:58.
47
47. Test
Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:270.
48
48. Test
Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:526.
See this image and copyright information in PMC

References

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Benn 2005a {published data only}
    1. Benn P, Wright D, Cuckle H. Practical strategies in contingent sequential screening for Down syndrome. Prenatal Diagnosis 2005;25(8):645‐52. - PubMed
Benn 2005b {published data only}
    1. 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. - PubMed
Berry 1995 {published data only}
    1. 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. - PubMed
Berry 1997 {published data only}
    1. 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. - PubMed
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    1. 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. - PubMed
Bersinger 2000 {published data only}
    1. 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.
Bersinger 2001 {published data only}
    1. 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.
Bersinger 2003 {published data only}
    1. 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. - PubMed
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    1. 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. - PubMed
Bersinger 2005 {published data only}
    1. 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.
Biggio 2004 {published data only}
    1. Biggio JR 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. - PubMed
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Bradley 1994 {published data only}
    1. Bradley LA, Horwitz JA, Dowman AC, Ponting NR, Peterson LM. Triple marker screening for fetal Down syndrome. International Pediatrics 1994;9(3):168‐74.
Braithwaite 1996 {published data only}
    1. Braithwaite JM, Economides DL. Nuchal translucency and screening for Down's syndrome. Contemporary Reviews in Obstetrics and Gynaecology 1996;8(2):75‐81.
Brambati 1995 {published data only}
    1. 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. - PubMed
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    1. 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. - PubMed
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    1. 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. - PubMed
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    1. 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. - PubMed
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    1. Canick JA, Kellner LH, Saller DN 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. - PubMed
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    1. Canini S, Prefumo F, Famularo L, Venturini PL, Palazzese V, 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. - PubMed
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    1. 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. - PubMed
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    1. 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. - PubMed
Chen 2004 {published data only}
    1. 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. - PubMed
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    1. 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.
Cheng 1993 {published data only}
    1. 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. - PubMed
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    1. 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. - PubMed
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    1. 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. - PubMed
Cheng 2004b {published data only}
    1. 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. - PubMed
Chitayat 2002 {published data only}
    1. 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. - PubMed
Christiansen 2002 {published data only}
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    1. 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.
CNGOF 1996 {published data only}
    1. 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.
Cole 1996 {published data only}
    1. 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‐S8. - PubMed
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    1. 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.
Comas 2002a {published data only}
    1. 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. - PubMed
Comas 2002b {published data only}
    1. Comas C, Carrera JM. Early sonographic screening for chromosomal abnormalities. Ultrasound Review of Obstetrics and Gynecology 2002;2(2):88‐91.
Comstock 2006 {published data only}
    1. Comstock CH, Malone FD, Ball RH, Nyberg DA, Saade GR, Berkowitz RL, et al. FASTER Research Consortium. 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. - PubMed
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Crossley 1991 {published data only}
    1. 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. - PubMed
Crossley 1993 {published data only}
    1. 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. - PubMed
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Crossley 2002a {published data only}
    1. 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. - PubMed
Cuckle 1984 {published data only}
    1. Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha‐fetoprotein measurement: a screening test for Down syndrome. Lancet 1984;i(8383):926‐9. - PubMed
Cuckle 1987a {published data only}
    1. 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. - PubMed
Cuckle 1987b {published data only}
    1. Cuckle HS, Nanchahal K, Wald NJ. Maternal serum alpha‐fetoprotein and ethnic origin. British Journal of Obstetrics and Gynaecology 1987;94(11):1111‐2. - PubMed
Cuckle 1990 {published data only}
    1. 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. - PubMed
Cuckle 1996 {published data only}
    1. 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. - PubMed
Cuckle 1999b {published data only}
    1. 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. - PubMed
Cuckle 1999c {published data only}
    1. Cuckle HS, Lith JM. Appropriate biochemical parameters in first‐trimester screening for Down syndrome.[see comment]. Prenatal Diagnosis 1999;19(6):505‐12. - PubMed
Cullen 1990 {published data only}
    1. 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. - PubMed
Cusick 2004 {published data only}
    1. 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. - PubMed
D'Ottavio 1997 {published data only}
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Dancoine 2001 {published data only}
    1. 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.
De Biasio, 1999 {published data only}
    1. De Biasio, 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. - PubMed
De Biasio, 2001 {published data only}
    1. De Biasio, 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.
De Biasio 2000 {published data only}
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De Graaf 1991 {published data only}
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De Graaf 1999 {published data only}
    1. Graaf I, Pajkrt E, Bilardo CM, Leschot NJ, Cuckle HS, Lith JM. Early pregnancy screening for fetal aneuploidy with serum markers and nuchal translucency. Prenatal Diagnosis 1999;19(5):458‐62. - PubMed
DeVore 2001 {published data only}
    1. 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. - PubMed
Dickerson 1994 {published data only}
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Drugan 1996a {published data only}
    1. 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. - PubMed
Drugan 1996b {published data only}
    1. 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. - PubMed
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    1. 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 & Gynaecology 2002;22(2):159‐65. - PubMed
Ebell 1999 {published data only}
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Economides 1998 {published data only}
    1. 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. - PubMed
Erickson 2004 {published data only}
    1. 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. - PubMed
Evans 1996 {published data only}
    1. Evans MI, O'Brien JE, Dvorin E, Krivchenia EL, Drugan A, Hume RF Jr, 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. - PubMed
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    1. 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. - PubMed
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    1. 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. - PubMed
Ford 1998 {published data only}
    1. 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. - PubMed
Frishman 1997 {published data only}
    1. Frishman GN, Canick JA, Hogan JW, Hackett RJ, Kellner LH, Saller DN Jr. Serum triple‐marker screening in in vitro fertilization and naturally conceived pregnancies. Obstetrics & Gynecology 1997;90(1):98‐101. - PubMed
Fukada 2000 {published data only}
    1. 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. - PubMed
Ghidini 1998 {published data only}
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Goldie 1995 {published data only}
    1. 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. - PubMed
Gonçalves 2004 {published data only}
    1. 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. - PubMed
Goodburn 1994 {published data only}
    1. 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. - PubMed
Grozdea 2002 {published data only}
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Gyselaers 2004a {published data only}
    1. Gyselaers WJ, Vereecken AJ, Herck EJ, Straetmans DP, Martens GE, 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. - PubMed
Gyselaers 2004b {published data only}
    1. Gyselaers WJA, Vereecken AJ, Van Herck, Straetmans DPL, De Jonge, 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. - PubMed
Gyselaers 2006a {published data only}
    1. Gyselaers WJ, Vereecken AJ, 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. - PubMed
Gyselaers 2006b {published data only}
    1. Gyselaers WJ, Roets ER, Holsbeke CD, Vereecken AJ, 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. - PubMed
Hackshaw 1995 {published data only}
    1. 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. - PubMed
Hackshaw 2001 {published data only}
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Haddow 1992 {published data only}
    1. 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. - PubMed
Hafner 1995 {published data only}
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    1. 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. - PubMed
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    1. 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. - PubMed
Sonek 2003 {published data only}
    1. Sonek JD. Nasal bone evaluation with ultrasonography: a marker for fetal aneuploidy. Ultrasound in Obstetrics & Gynecology 2003;22(1):11‐5. - PubMed
Spencer 1985 {published data only}
    1. Spencer K, Carpenter P. Screening for Down's syndrome using serum alpha fetoprotein: a retrospective study indicating caution. BMJ (Clinical Research Ed.) 1985;290(6486):1940‐3. - PMC - PubMed
Spencer 1991a {published data only}
    1. 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. - PubMed
Spencer 1991b {published data only}
    1. Spencer K. Maternal serum CA125 is not a second trimester marker for Down's syndrome. Annals of Clinical Biochemistry 1991;28(3):299‐300. - PubMed
Spencer 1992 {published data only}
    1. 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. - PubMed
Spencer 1993a {published data only}
    1. 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. - PMC - PubMed
Spencer 1993b {published data only}
    1. 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. - PubMed
Spencer 1993c {published data only}
    1. Spencer K, Wood PJ, Anthony FW. Elevated levels of maternal serum inhibin immunoreactivity in second trimester pregnancies affected by Down's syndrome. Annals of Clinical Biochemistry 1993;30(Pt 2):219‐20. - PubMed
Spencer 1993d {published data only}
    1. 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. - PubMed
Spencer 1993e {published data only}
    1. Spencer K. Free alpha‐subunit of human chorionic gonadotropin in Down syndrome. American Journal of Obstetrics and Gynecology 1993;168(1):132‐5. - PubMed
Spencer 1995 {published data only}
    1. Spencer K. The influence of gravidity on Down's syndrome screening with free ß hCG. Prenatal Diagnosis 1995;15(1):87‐9. - PubMed
Spencer 1996a {published data only}
    1. Spencer K, Wallace EM, Ritoe S. Second‐trimester dimeric inhibin‐A in Down's syndrome screening. Prenatal Diagnosis 1996;16(12):1101‐10. - PubMed
Spencer 1997 {published data only}
    1. 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. - PubMed
Spencer 1998a {published data only}
    1. 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. - PubMed
Spencer 1998b {published data only}
    1. Spencer K, Carpenter P. Is prostate‐specific antigen a marker for pregnancies affected by Down syndrome?. Clinical Chemistry 1998;44(11):2362‐5. - PubMed
Spencer 1999a {published data only}
    1. 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. - PubMed
Spencer 1999b {published data only}
    1. Spencer K. Accuracy of Down's syndrome risks produced in a prenatal screening program. Annals of Clinical Biochemistry 1999;36(1):101‐3. - PubMed
Spencer 2000a {published data only}
    1. 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. - PubMed
Spencer 2000b {published data only}
    1. 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. - PubMed
Spencer 2000c {published data only}
    1. 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. - PubMed
Spencer 2000d {published data only}
    1. 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. - PubMed
Spencer 2000e {published data only}
    1. 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. - PubMed
Spencer 2000f {published data only}
    1. 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. - PubMed
Spencer 2000g {published data only}
    1. 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. - PubMed
Spencer 2000h {published data only}
    1. 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. - PubMed
Spencer 2000i {published data only}
    1. 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. - PubMed
Spencer 2001 {published data only}
    1. 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. - PubMed
Spencer 2001a {published data only}
    1. 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. - PubMed
Spencer 2001b {published data only}
    1. 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. - PubMed
Spencer 2001c {published data only}
    1. 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. - PubMed
Spencer 2001d {published data only}
    1. 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. - PubMed
Spencer 2002a {published data only}
    1. 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. - PubMed
Spencer 2002b {published data only}
    1. 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. - PubMed
Spencer 2002c {published data only}
    1. 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. - PubMed
Spencer 2002d {published data only}
    1. 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. - PubMed
Spencer 2003a {published data only}
    1. 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. - PubMed
Spencer 2003b {published data only}
    1. 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. - PubMed
Spencer 2003c {published data only}
    1. 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. - PubMed
Spencer 2003d {published data only}
    1. 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. - PubMed
Spencer 2004 {published data only}
    1. 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. - PubMed
Spencer 2005a {published data only}
    1. 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. - PubMed
Spencer 2005b {published data only}
    1. 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. - PubMed
Spencer 2005c {published data only}
    1. 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. - PubMed
Spong 1999 {published data only}
    1. 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. - PubMed
Stevens 1998 {published data only}
    1. 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.
Stoll 1992 {published data only}
    1. Stoll C. A new approach of prenatal prevention of constitutional disabilities ‐ the study of markers of maternal serum. Journal de Medecine de Strasbourg 1992;23(1):25‐7.
Su 2002a {published data only}
    1. 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. - PubMed
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    1. 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. - PubMed
Suchy 1990 {published data only}
    1. Suchy SF, Yeager MT. Down syndrome screening in women under 35 with maternal serum hCG. Obstetrics & Gynecology 1990;76(1):20‐4. - PubMed
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Summers 2003b {published data only}
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Tabor 1987 {published data only}
    1. 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. - PubMed
Tanski 1999 {published data only}
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    1. Lith JM, Mantingh A, Bruijn HW. Maternal serum CA 125 levels in pregnancies with chromosomally‐normal and ‐abnormal fetuses. Dutch Working Party on Prenatal Diagnosis. Prenatal Diagnosis 1993;13(12):1123‐31. - PubMed
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    1. Lith JM, Mantingh A, Pratt JJ. First‐trimester maternal serum immunoreactive inhibin in chromosomally normal and abnormal pregnancies. Dutch Working Party on Prenatal Diagnosis. Obstetrics and Gynecology 1994;83(5 Pt 1):661‐4. - PubMed
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    1. 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. - PubMed
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    1. 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. - PubMed
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    1. 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. - PMC - PubMed
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    1. 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. - PubMed
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    1. 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. - PubMed
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Wald 1996a {published data only}
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    1. 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. - PubMed
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Wald 1996e {published data only}
    1. 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. - PubMed
Wald 1997 {published data only}
    1. 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. - PubMed
Wald 1998 {published data only}
    1. Wald NJ, Watt HC, Haddow JE, Knight GJ. Screening for Down syndrome at 14 weeks of pregnancy. Prenatal Diagnosis 1998;18(3):291‐3. - PubMed
Wald 1999a {published data only}
    1. 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. - PubMed
Wald 1999b {published data only}
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    1. 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. - PubMed
Wald 1999d {published data only}
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Wald 2003b {published data only}
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Wald 2003c {published data only}
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Wald 2006 {published data only}
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Wenstrom 1995b {published data only}
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Whitlow 1998b {published data only}
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