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Meta-Analysis
. 2015 Nov 30;2015(11):CD011975.
doi: 10.1002/14651858.CD011975.

First trimester serum tests for Down's syndrome screening

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

First trimester serum 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, rather than two copies of chromosome 21; or the specific area of chromosome 21 implicated in causing Down's syndrome. 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.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. However, no test can predict the severity of problems a person with Down's syndrome will have.

Objectives: The aim of this review was to estimate and compare the accuracy of first trimester serum markers for the detection of Down's syndrome in the antenatal period, both as individual markers and as combinations of markers. Accuracy is described by the proportion of fetuses with Down's syndrome detected by screening before birth (sensitivity or detection rate) and the proportion of women with a low risk (normal) screening test result who subsequently had a baby unaffected by Down's syndrome (specificity).

Search methods: We conducted 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 25 August 2011), 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 did forward citation searching ISI citation indices, Google Scholar and PubMed 'related articles'. We did not apply a diagnostic test search filter. We also searched reference lists and published review articles.

Selection criteria: We included studies in which all women from a given population had one or more index test(s) compared to a reference standard (either chromosomal verification or macroscopic postnatal inspection). Both consecutive series and diagnostic case-control study designs were included. Randomised trials where individuals were randomised to different screening strategies and all verified using a reference standard were also eligible for inclusion. Studies in which test strategies were compared head-to-head either in the same women, or between randomised groups were identified for inclusion in separate comparisons of test strategies. We excluded studies if they included less than five Down's syndrome cases, or more than 20% of participants were not followed up.

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 meta-analytical methods or random-effects logistic regression methods to analyse test performance and compare test accuracy as appropriate. Analyses of studies allowing direct and indirect comparisons between tests were undertaken.

Main results: We included 56 studies (reported in 68 publications) involving 204,759 pregnancies (including 2113 with Down's syndrome). Studies were generally of good quality, although differential verification was common with invasive testing of only high-risk pregnancies. We evaluated 78 test combinations formed from combinations of 18 different tests, with or without maternal age; ADAM12 (a disintegrin and metalloprotease), AFP (alpha-fetoprotein), inhibin, PAPP-A (pregnancy-associated plasma protein A, ITA (invasive trophoblast antigen), free βhCG (beta human chorionic gonadotrophin), PlGF (placental growth factor), SP1 (Schwangerschafts protein 1), total hCG, progesterone, uE3 (unconjugated oestriol), GHBP (growth hormone binding protein), PGH (placental growth hormone), hyperglycosylated hCG, ProMBP (proform of eosinophil major basic protein), hPL (human placental lactogen), (free αhCG, and free ßhCG to AFP ratio. Direct comparisons between two or more tests were made in 27 studies.Meta-analysis of the nine best performing or frequently evaluated test combinations showed that a test strategy involving maternal age and a double marker combination of PAPP-A and free ßhCG significantly outperformed the individual markers (with or without maternal age) detecting about seven out of every 10 Down's syndrome pregnancies at a 5% false positive rate (FPR). Limited evidence suggested that marker combinations involving PAPP-A may be more sensitive than those without PAPP-A.

Authors' conclusions: Tests involving two markers in combination with maternal age, specifically PAPP-A, free βhCG and maternal age are significantly better than those involving single markers with and without age. They detect seven out of 10 Down's affected pregnancies for a fixed 5% FPR. The addition of further markers (triple tests) has not been shown to be statistically superior; the studies included are small with limited power to detect a difference.The screening blood tests themselves have no adverse effects for the woman, over and above the risks of a routine blood test. However some women who have a 'high risk' screening test result, and are given amniocentesis or chorionic villus sampling (CVS) have a risk of miscarrying a baby unaffected by Down's. Parents will need to weigh up this risk when deciding whether or not to have an amniocentesis or CVS following a 'high risk' screening test result.

PubMed Disclaimer

Conflict of interest statement

KA: None known.

ZA: None known.

JD: None known.

JN: None known.

BG: None known.

MP: None known.

YT: None known.

Figures

1
1
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
2
2
Detection rates (sensitivity) at a 5% false positive rate for the nine selected test strategies. Each circle represents the summary sensitivity for a test strategy and the size of each circle 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. The number of studies, cases and women included for each test strategy are shown on the horizontal axis. A = Age, PlGF, PAPP‐A and free ßhCG; B = Age, PAPP‐A, free ßhCG and AFP; C = Age, ADAM 12, PAPP‐A and free ßhCG; D = Age, PAPP‐A and free ßhCG ; E = Age, PAPP‐A; F = PAPP‐A; G = Age, free ßhCG and AFP ; H = Age, free ßhCG; I = Free ßhCG
1
1. Test
1T PAPP‐A, 5% FPR.
2
2. Test
1T PAPP‐A, ≤5th percentile.
3
3. Test
1T PAPP‐A, mixed cut‐points.
4
4. Test
1T free ßhCG, 5% FPR.
5
5. Test
1T total hCG, 5FPR.
6
6. Test
1T AFP, 5% FPR.
10
10. Test
1T AFP, mixed cut‐points.
11
11. Test
1T Inhibin, 5FPR.
12
12. Test
1T ADAM 12, 5FPR.
13
13. Test
1T SP1, 5% FPR.
17
17. Test
ba_hcg_ratio, 0.25MoM.
18
18. Test
1T uE3, 5% FPR.
19
19. Test
1T PlGF, 5FPR.
20
20. Test
1T PAPP‐A and 1T free ßhCG, 5% FPR.
21
21. Test
1T PAPP‐A and 1T free ßhCG, mixed cut‐points.
22
22. Test
1T PAPP‐A and 1T AFP, 5% FPR.
23
23. Test
1T PAPP‐A and 1T ITA, 3% FPR.
24
24. Test
1T PAPP‐A and 1T ITA, 5% FPR.
25
25. Test
1T free ßhCG and 1T Inhibin, 5% FPR.
26
26. Test
1T free ßhCG and 1T AFP, 5% FPR.
27
27. Test
1T PAPP‐A and 1T ITA, 10% FPR.
28
28. Test
1T PAPP‐A, 1T free ßhCG and 1T ITA, 5% FPR.
29
29. Test
1T PAPP‐A, 1T free ßhCG and 1T ITA,3% FPR.
30
30. Test
1T PAPP‐A, 1T free ßhCG and 1T ITA, 10% FPR.
31
31. Test
1T total hCG, 1T free αhCG and 1T progesterone, 0.34 MoM.
32
32. Test
Age, 1T Inhibin, risk 1:100.
33
33. Test
Age, 1T Inhibin, risk 1:250.
34
34. Test
Age, 1T Inhibin, risk 1:400.
35
35. Test
Age, 1T Inhibin, 5FPR.
36
36. Test
Age, 1T Inhibin, mixed cut‐points.
37
37. Test
Age, 1T PAPP‐A, 5FPR.
38
38. Test
Age, 1T PAPP‐A, mixed cut‐points.
39
39. Test
Age, 1T free ßhCG, 5FPR.
40
40. Test
Age, 1T free ßhCG, risk 1:384.
41
41. Test
Age, 1T free ßhCG, mixed cut‐points.
42
42. Test
Age, 1T total hCG,risk 1:384.
43
43. Test
Age, 1T total hCG, mixed cut‐points.
44
44. Test
Age, 1T AFP, 5FPR.
45
45. Test
Age, 1T AFP, risk1:384.
46
46. Test
Age, 1T AFP,mixed cut‐points.
47
47. Test
Age, 1T uE3, risk 1:384.
48
48. Test
Age, 1T uE3, mixed cut‐points.
49
49. Test
Age, 1T free αhCG, risk 1:384.
50
50. Test
Age, 1T SP1, 5FPR.
51
51. Test
Age, 1T ProMBP, risk 1:250.
52
52. Test
Age, 1T ITA, 5FPR.
53
53. Test
Age, 1T ADAM 12, risk 1:400.
54
54. Test
Age, 1T PAPP‐A and 1T free ßhCG, risk 1:250.
55
55. Test
Age, 1T PAPP‐A and 1T free ßhCG, 5FPR.
56
56. Test
Age, 1T PAPP‐A and 1T free ßhCG, mixed cut‐points.
57
57. Test
Age, 1T PAPP‐A and 1T free ßhCG, mixed cut‐points without 5FPR.
58
58. Test
Age, 1T total hCG and 1T PAPP‐A, 5FPR.
59
59. Test
Age, 1T PAPP‐A and 1T Inhibin, risk 1:100.
60
60. Test
Age, 1T PAPP‐A and 1T Inhibin, risk 1:250.
61
61. Test
Age, 1T PAPP‐A and 1T Inhibin, risk 1:400.
62
62. Test
Age, 1T PAPP‐A and 1T Inhibin, 5FPR.
63
63. Test
Age, 1T PAPP‐A and 1T Inhibin, mixed cut‐points.
64
64. Test
Age, 1T PAPP‐A and 1T ITA, 5FPR.
65
65. Test
Age, 1T PAPP‐A and 1T AFP, 5FPR.
66
66. Test
Age, 1T free ßhCG and 1T Inhibin, risk 1:100.
67
67. Test
Age, 1T free ßhCG and 1T Inhibin, risk 1:250.
68
68. Test
Age, 1T free ßhCG and 1T Inhibin, risk 1:400.
69
69. Test
Age, 1T free ßhCG and 1T Inhibin, 5FPR.
70
70. Test
Age, 1T free ßhCG and 1T Inhibin, mixed cut‐points.
71
71. Test
Age, 1T free ßhCG and 1T AFP, 5FPR.
72
72. Test
Age, 1T free ßhCG and 1T AFP, risk 1:250.
73
73. Test
Age, 1T free ßhCG and 1T AFP, risk 1:384.
74
74. Test
Age, 1T free ßhCG and 1T AFP, mixed cut‐points.
75
75. Test
Age, 1T AFP and 1T uE3, risk 1:384.
76
76. Test
Age, 1T AFP and 1T free αhCG, risk 1:384.
77
77. Test
Age, 1T free ßhCG and 1T total hCG, risk 1:384.
78
78. Test
Age, 1T free ßhCG and 1T uE3, risk 1:384.
79
79. Test
Age, 1T free ßhCG and 1T uE3, 5FPR.
80
80. Test
Age, 1T free ßhCG and 1T uE3, mixed cut‐points.
81
81. Test
Age, 1T free ßhCG and 1T SP1, 5FPR.
82
82. Test
Age, 1T free ßhCG and 1T SP1 risk 1:250.
83
83. Test
Age, 1T AFP and 1T total hCG, 1:384.
84
84. Test
Age, 1T free ßhCG and 1T free αhCG, risk 1:384.
85
85. Test
Age, 1T total hCG and 1T uE3, risk 1:384.
86
86. Test
Age, 1T total hCG and 1T Inhibin, 5FPR.
87
87. Test
Age, 1T total hCG and 1T free αhCG, risk 1:384.
88
88. Test
Age, 1T uE3 and 1T free αhCG, risk 1:384.
89
89. Test
Age, 1T PAPP‐A, 1T free ßhCG and 1T AFP, 5FPR.
90
90. Test
Age, 1T PAPP‐A, 1T free ßhCG and 1T AFP, mixed cut‐points.
91
91. Test
Age, 1T free ßhCG, 1T AFP and 1T uE3, 5FPR.
92
92. Test
Age, 1T free ßhCG, 1T AFP and 1T uE3, risk 1:384.
93
93. Test
Age, 1T free ßhCG, 1T AFP and 1T uE3, mixed cut‐points.
94
94. Test
Age, 1T total hCG, 1T AFP and 1T uE3, risk 1:384.
95
95. Test
Age, 1T total hCG, 1T AFP and 1T uE3, mixed cut‐points.
96
96. Test
Age, 1T AFP, free αhCG and 1T uE3, risk 1:384.
97
97. Test
Age, 1T PAPP‐A, 1T free ßhCG and 1T Inhibin, 5FPR.
98
98. Test
Age, 1T PAPP‐A, 1T total hCG and 1T Inhibin, 5FPR.
99
99. Test
Age, 1T PAPP‐A, sp1 and 1T ProMBP, 5FPR.
100
100. Test
Age, 1T PAPP‐A, sp1 and 1T ProMBP, risk 1:250.
101
101. Test
Age, 1T free ßhCG, 1T total hCG, 1T AFP and 1T uE3, risk 1:384.
102
102. Test
Age, 1T total hCG, 1T AFP, 1T uE3 and 1T free αhCG, risk 1:384.
103
103. Test
Age, 1T PAPP‐A, 1T free ßhCG, 1T AFP, 1T uE3 and 1T Inhibin, 5FPR.
104
104. Test
Age, 1T PAPP‐A, 1T total hCG, 1T AFP, 1T uE3 and 1T Inhibin, 5FPR.
105
105. Test
Age, 1T free ßhCG, 1T total hCG, 1T AFP, 1T uE3 and 1T free αhCG, risk 1:384.
106
106. Test
Age, 1T hPL, risk 1:250.
107
107. Test
Age, 1T hPL, 1T PAPP‐A, risk 1:250.
108
108. Test
Age, 1T hPL, 1T free ßhCG, risk 1:250.
109
109. Test
Age, 1T hPL, 1T PAPP‐A, 1T free ßhCG, risk 1:250.
110
110. Test
Age, 1T PGH, risk 1:250.
111
111. Test
Age, 1T PGH, 1T PAPP‐A , risk 1:250.
112
112. Test
Age, 1T PGH, 1T free ßhCG , risk 1:250.
113
113. Test
Age, 1T PGH, 1T PAPP‐A, 1T free ßhCG , risk 1:250.
114
114. Test
Age, 1T GHBP, risk 1:250.
115
115. Test
Age, 1T GHBP, 1T PAPP‐A, risk 1:250.
116
116. Test
Age, 1T GHBP, 1T free ßhCG, risk 1:250.
117
117. Test
Age, 1T GHBP, 1T PGH, risk 1:250.
118
118. Test
Age, 1T GHBP, 1T PAPP‐A, 1T free ßhCG , risk 1:250.
119
119. Test
Age, 1T GHBP, 1T PGH, 1T PAPP‐A, 1T free ßhCG , risk 1:250.
120
120. Test
Age, 1T ADAM 12, risk 1:250.
121
121. Test
Age, 1T ADAM 12, 1T PAPP‐A, 1T free ßhCG, risk 1:250.
122
122. Test
Age, PlGF, 1T PAPP‐A, 1T free ßhCG, 5FPR.
123
123. Test
Age, 1T PAPP‐A and 1T free ßhCG, risk 1:300.
124
124. Test
Age, 1T PAPP‐A, 1T Hyperglycosylated hCG, 5FPR.
128
128. Test
Age, ADAM 12, 1T PAPP‐A, 5FPR.
129
129. Test
Age, ADAM 12, 1T PAPP‐A, 1T free ßhCG, 5FPR.
130
130. Test
Age, 1T PlGF, 5FPR.
131
131. Test
1T PlGF, 1T PAPP‐A, 1T free ßhCG, 5FPR.
132
132. Test
Age, 1T ADAM 12, 1T PAPP‐A, 1T free ßhCG, mixed cut‐points.
133
133. Test
Age, 1T PAPP‐A, 1T free ßhCG and 1T Inhibin, risk 1:250.
134
134. Test
Age, 1T PAPP‐A, 1T free ßhCG, and 1T Inhibin, mixed cut‐points.
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References

References to studies included in this review

Baviera 2010 {published data only}
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Christiansen 2007a {published data only}
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Crossley 2002a {published data only}
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Forest 1997 {published data only}
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Haddow 1998 {published data only}
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Kagan 2009 {published data only}
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Kornman 1998 {published data only}
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Kozlowski 2007 GC {published data only}
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Kozlowski 2007 PC {published data only}
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Krantz 2000 {published data only}
    1. Krantz DA, Hallahan TW, Orlandi F, Buchanan P, Larsen JW Jr, Macri JN. First‐trimester Down syndrome screening using dried blood biochemistry and nuchal translucency. Obstetrics and Gynecology 2000;96(2):207‐13. - PubMed
Kratzer 1991 {published data only}
    1. Kratzer PG, Golbus MS, Monroe SE, Finkelstein DE, Taylor RN. First‐trimester uneuploidy screening using serum human chorionic gonadotropin (hCG), free alphahCG, and progesterone. Prenatal Diagnosis 1991;11(10):751‐63. - PubMed
Laigaard 2003 {published data only}
    1. Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM12: a novel first‐trimester maternal serum marker for Down syndrome. Prenatal Diagnosis 2003;23(13):1086‐91. - PubMed
Macintosh 1993 {published data only}
    1. Macintosh MC, Brambati B, Chard T, Grudzinskas JG. First‐trimester maternal serum Schwangerschafts protein 1 (SP1) in pregnancies associated with chromosomal anomalies. Prenatal Diagnosis 1993;13(7):563‐8. - PubMed
Muller 2003a {published data only}
    1. 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. - PubMed
Nebiolo 1990 {published data only}
    1. Milunsky A, Wands J, Brambati B, Bonacchi I, Currie K. First‐trimester maternal serum alpha‐fetoprotein screening for chromosome defects. American Journal of Obstetrics and Gynecology 1988;159(5):1209‐13. - PubMed
    1. Nebiolo L, Ozturk M, Brambati B, Miller S, Wands J, Milunsky A. First‐trimester maternal serum alpha‐fetoprotein and human chorionic gonadotropin screening for chromosome defects. Prenatal Diagnosis 1990;10(9):575‐81. - PubMed
Niemimaa 2001a {published data only}
    1. 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. - PubMed
Noble 1995 {published data only}
    1. 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. - PubMed
    1. 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. - PubMed
Noble 1997 {published data only}
    1. Noble PL, Wallace EM, Snijders RJ, Groome NP, Nicolaides KH. Maternal serum 1T Inhibin‐A and free beta‐hCG concentrations in trisomy 21 pregnancies at 10 to 14 weeks of gestation. British Journal of Obstetrics and Gynaecology 1997;104(3):367‐71. - PubMed
O'Leary 2006 {published data only}
    1. 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 and Gynecology 2006;107(4):869‐76. - PubMed
Orlandi 1997 {published data only}
    1. 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. - PubMed
Palomaki 2007 {published data only}
    1. 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. - PubMed
Qin 1997 {published data only}
    1. Qin QP, Christiansen M, Nguyen TH, Sorensen S, Larsen SO, Norgaard‐Pedersen B. Schwangerschaftsprotein 1 (SP1) as a maternal serum marker for Down syndrome in the first and second trimesters. Prenatal Diagnosis 1997;17(2):101‐8. - PubMed
Sahota 2010 {published data only}
    1. 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. - PubMed
    1. 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. - PubMed
Schaelike 2009 {published data only}
    1. 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, and Reproductive Biology 2009;144(2):140‐5. - PubMed
Scott 2004 {published data only}
    1. 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. - PubMed
Spencer 1999a {published data only}
    1. 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. - PubMed
Spencer 2002a {published data only}
    1. 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. - PubMed
Torring 2010 {published data only}
    1. 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. - PMC - PubMed
Tsukerman 1999 {published data only}
    1. Tsukerman GL, Gusina NB, Cuckle HS. Maternal serum screening for Down syndrome in the first trimester: experience from Belarus. Prenatal Diagnosis 1999;19(6):499‐504. - PubMed
Valinen 2007 {published data only}
    1. 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. - PubMed
Valinen 2009 {published data only}
    1. Valinen Y, Laitinen P, Ranta J, Ignatius J, Jarvela I, Ryynanen M. Effect of a new marker, ADAM12, on Down risk figures in first trimester screening. Journal of Maternal‐fetal & Neonatal Medicine 2009;22(7):602‐7. - PubMed
Van Lith 1992 {published data only}
    1. Lith JM, Mantingh A, Kloosterman MD, Kanhai HHH, Wolf H, Everhardt E, et al. First‐trimester maternal serum human chorionic gonadotrophin as a marker for fetal chromosomal disorders. Prenatal Diagnosis 1992;12(6):495‐504. - PubMed
Wald 2003a {published data only}
    1. Wald NJ, Rodeck C, Hackshaw AK, Rudnicka A. SURUSS in perspective. Seminars in Perinatology 2005;29(4):225‐35. - PubMed
    1. 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. - PubMed
    1. 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. - PubMed
    1. 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. - PubMed
Wallace 1995 {published data only}
    1. Wallace EM, Grant VE, Swanston IA, Groome NP. Evaluation of maternal serum dimeric 1T Inhibin A as a first‐trimester marker of Down's syndrome. Prenatal Diagnosis 1995;15(4):359‐62. - PubMed
Wapner 2003 {published data only}
    1. 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. - PubMed
    1. Wapner RJ. First trimester screening: the BUN study. Seminars in Perinatology 2005;29(4):236‐9. - PubMed
Weinans 2005 {published data only}
    1. Weinans MJ, Sancken U, Pandian R, Ouweland JM, Bruijn HW, Holm JP, et al. Invasive trophoblast antigen (hyperglycosylated human chorionic gonadotropin) as a first‐trimester serum marker for Down syndrome. Clinical Chemistry 2005;51(7):1276‐9. - PubMed
Wojdemann 2005 {published data only}
    1. 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. - PubMed
Zaragoza 2009 {published data only}
    1. Zaragoza E, Akolekar R, Poon LC, Pepes S, Nicolaides KH. Maternal serum placental growth factor at 11‐13 weeks in chromosomally abnormal pregnancies. Ultrasound in Obstetrics & Gynecology 2009;33(4):382‐6. - PubMed

References to studies excluded from this review

Abbas 1995 {published data only}
    1. 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. - PubMed
Abdul‐Hamid 2004 {published data only}
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Abraha 1999 {published data only}
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Abu‐Rustum 2010 {published data only}
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Adekunle 1999 {published data only}
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Agaard‐Tillery 2010 {published data only}
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Aitken 1993 {published data only}
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Aitken 1996a {published data only}
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Aitken 1996b {published data only}
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Ajayi 2011 {published data only}
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American College 2009 {published data only}
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Antona 1998 {published data only}
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Antsaklis 1999 {published data only}
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Anuwutnavin 2009 {published data only}
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Ashwood 1987 {published data only}
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Asrani 2005 {published data only}
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Audibert 2001 {published data only}
    1. 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. - PubMed
Axt‐Fleidner 2006 {published data only}
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Azuma 2002 {published data only}
    1. 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. - PubMed
Baghagho 2004 {published data only}
    1. 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. - PubMed
Bahado‐Singh 1995 {published data only}
    1. Bahado‐Singh RO, 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. - PubMed
Bahado‐Singh 1996 {published data only}
    1. Bahado‐Singh RO, 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. - PubMed
Bahado‐Singh 1999 {published data only}
    1. Bahado‐Singh RO, 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. - PubMed
Bahado‐Singh 2002 {published data only}
    1. 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. - PubMed
Bahado‐Singh 2003 {published data only}
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Ball 2007 {published data only}
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Bar‐Hava 2001 {published data only}
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Barkai 1996 {published data only}
    1. 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. - PubMed
Barnabei 1995 {published data only}
    1. Barnabei VM, Krantz DA, Macri JN, Larsen JW Jr. 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. - PubMed
Bartels 1988 {published data only}
    1. 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. - PubMed
Bartels 1993 {published data only}
    1. 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. - PubMed
Barth 1991 {published data only}
    1. Barth WH Jr, Frigoletto FD Jr, Krauss CM, MacMillin MD, Stryker JM, Benacerraf BR. Ultrasound detection of fetal aneuploidy in women with elevated maternal serum alpha‐fetoprotein. Obstetrics and Gynecology 1991;77(6):897‐900. - PubMed
Bas‐Budecka 2007 {published data only}
    1. 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. - PubMed
Baviera 2004 {published data only}
    1. 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. - PubMed
Bazzett 1998 {published data only}
    1. 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. - PubMed
Beke 2008 {published data only}
    1. 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. - PubMed
Bellver 2005 {published data only}
    1. 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. - PubMed
Benn 1995 {published data only}
    1. 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. - PubMed
Benn 1996 {published data only}
    1. 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. - PubMed
Benn 1997 {published data only}
    1. 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. - PubMed
Benn 1998 {published data only}
    1. 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. - PubMed
Benn 2001 {published data only}
    1. 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. - PubMed
Benn 2002 {published data only}
    1. Benn PA, Kaminsky LM, Ying J, Borgida AF, Egan JF. Combined second‐trimester biochemical and ultrasound screening for Down syndrome. Obstetrics and Gynecology 2002;100(6):1168‐76. - PubMed
Benn 2003a {published data only}
    1. 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. - PubMed
Benn 2003b {published data only}
    1. Benn P. Improved antenatal screening for Down's syndrome. Lancet 2003;361(9360):794‐5. - PubMed
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
Benn 2007 {published data only}
    1. 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. - 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
Bersinger 1994 {published data only}
    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
Bersinger 2004 {published data only}
    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.
Bestwick 2008 {published data only}
    1. 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. - PubMed
Biggio 2004 {published data only}
    1. 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. - PubMed
Bilardo 2011 {published data only}
    1. Bilardo CM, Timmerman E, 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. - PubMed
Bindra 2002 {published data only}
    1. 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. - PubMed
Blundell 1999 {published data only}
    1. 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. - PubMed
Boormans 2010 {published data only}
    1. Boormans EM, Birnie E, Oepkes D, Galjaard RJ, Schuring‐Blom GH, Lith JM, et al. Comparison of multiplex ligation‐dependent probe amplification and karyotyping in prenatal diagnosis. Obstetrics and Gynecology 2010;115(2 Pt 1):297‐303. - PubMed
Boots 1989 {published data only}
    1. Boots LR, Davis RO, Foster JM, Goldenberg RL. Maternal serum alpha‐fetoprotein prenatal screening for Down syndrome. Alabama Medicine 1989;59(1):25‐7. - PubMed
Bornstein 2009a {published data only}
    1. 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. - PubMed
Bornstein 2009b {published data only}
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Bornstein 2010 {published data only}
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Braithwaite 1996 {published data only}
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Chen 2008 {published data only}
    1. 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. - PubMed
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    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}
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    1. 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. - PubMed
Christiansen 2002 {published data only}
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CNGOF 1996 {published data only}
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Cole 1996 {published data only}
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Cuckle 1996 {published data only}
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De Biasio 2000 {published data only}
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Del Carmen Saucedo 2009 {published data only}
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Dhallan 2007 {published data only}
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Dickerson 1994 {published data only}
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Drugan 1996a {published data only}
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Ebell 1999 {published data only}
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Economides 1998 {published data only}
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Erickson 2004 {published data only}
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Goetzinger 2010 {published data only}
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Gonçalves 2004 {published data only}
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Gray 2009 {published data only}
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Grether 2009 {published data only}
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Hogdall 1992 {published data only}
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Hong Kong Practitioner {published data only}
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Huang 2007a {published data only}
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Hultén 2004 {published data only}
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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 1996 {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 1999b {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 1999c {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 2001a {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 2001b {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 2001c {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 2001d {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 2001e {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 2002b {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 2002c {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 2002d {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 2002e {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
Spencer 2008 {published data only}
    1. 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. - 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
Staboulidou 2009 {published data only}
    1. 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. - 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.
Stressig 2011 {published data only}
    1. 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. - PubMed
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Summers 2003b {published data only}
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Tabor 1987 {published data only}
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Thilaganathan 1999 {published data only}
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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, 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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Wald 1996d {published data only}
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Wald 1997 {published data only}
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Wald 1998 {published data only}
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Wald 1999a {published data only}
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Wald 1999b {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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