First trimester ultrasound tests alone or in combination with first trimester serum tests for Down's syndrome screening

S Kate Alldred; Yemisi Takwoingi; Boliang Guo; Mary Pennant; Jonathan J Deeks; James P Neilson; Zarko Alfirevic

doi:10.1002/14651858.CD012600

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Figure 1

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 2

Study estimates of sensitivity and specificity with a summary ROC curve for the NT, PAPP‐A, free ßhCG and maternal age test combination at different cut‐points. Each symbol represents a pair of sensitivity and specificity at one cut‐point from each study.

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Figure 3

Study estimates of sensitivity and specificity with a summary ROC curve for NT and maternal age across different cut‐points. Each symbol represents a pair of sensitivity and specificity at one cut‐point from each study.

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Figure 4

Study estimates of sensitivity and specificity with a summary ROC curve for NT. Each symbol represents a pair of sensitivity and specificity at one cut‐point from each study.

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Figure 5

Detection rates (% sensitivity) at a 5% false positive rate for nine of the most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests. A = NT, PAPP‐A, free ßhCG and maternal age; B = NT, PAPP‐A, free ßhCG, ADAM 12 and maternal age; C = NT, PAPP‐A and maternal age; D = NT, nasal bone and maternal age; E= NT, free ßhCG and maternal age; F= NT and maternal age; G = NT; H = Nasal bone and maternal age; and I = Ductus and maternal age.

Each square represents the summary sensitivity for a test strategy at a 5% false positive rate. The size of each square is proportional to the number of Down's cases. The estimates are shown with 95% confidence intervals. The test strategies are ordered on the plot according to decreasing detection rate. For each test strategy, the number of included studies, Down's syndrome cases and pregnancies are shown on the horizontal axis.

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Figure 6

Forest plot of the NT, PAPP‐A, free ßhCG and maternal age test strategy by maternal age group (< 35 years versus ≥ 35 years).

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Figure 7

Summary ROC plot of the NT, PAPP‐A, free ßhCG and maternal age test strategy by maternal age group (< 35 years versus ≥ 35 years).

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Test 1

Aberrant right subclavian artery.

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Test 2

Frontomaxillary facial angle >95 percentile.

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Test 3

Presence of mitral gap.

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Test 4

Maxillary bone length, 5% percentile.

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Test 5

Tricuspid regurgitation.

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Test 6

Iliac angle 90 degrees.

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Test 7

Ductus venosus a‐wave reversed.

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Test 8

Ductus venosus pulsivity index > 95 percentile.

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Test 9

Nasal bone, mixed cut‐points.

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Test 10

NT, 2.5 mm.

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Test 11

NT, 3 mm.

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Test 12

NT, 5FPR.

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Test 13

NT, mixed cut‐points.

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Test 14

NT and age, risk 1:100.

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Test 15

NT and age, risk 1:250.

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Test 16

NT and age, risk 1:300.

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Test 17

NT and age, 1FPR.

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Test 18

NT and age, 3FPR.

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Test 19

NT and age, 5FPR.

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Test 20

NT and age, mixed cut‐points.

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Test 21

NT and nasal bone, Absent NB + NT ≥ 95th centile.

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Test 22

Ductus and age, risk 1:250.

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Test 23

Ductus and age, 5FPR.

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Test 24

Ductus and age, mixed cut‐points.

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Test 25

Ductus, NT and age, risk 1:100.

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Test 26

Ductus, NT and age, risk 1:250.

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Test 27

Ductus, NT and age, 5FPR.

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Test 28

Ductus, NT and age, mixed cut‐points.

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Test 29

Age and nasal bone, mixed cut‐points.

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Test 30

Age, NT and tricuspid blood flow, risk 1:100.

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Test 31

Age, NT and nasal bone, risk 1:100.

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Test 32

Age, NT and nasal bone, risk 1:300.

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Test 33

Age, NT and nasal bone, mixed cut‐points.

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Test 34

Age, NT, nasal bone and ductus, risk NT>1:300 AND abnormal DV flow AND absent NB.

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Test 35

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

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Test 36

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

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Test 37

Age, NT and free ßhCG, 1st trimester, 5FPR.

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Test 38

Age, NT and free ßhCG, 1st trimester, risk 1:240.

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Test 39

Age, NT and free ßhCG, 1st trimester, mixed cut‐points.

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Test 40

Age, NT and PAPP‐A, 1st trimester, risk 1:100.

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Test 41

Age, NT and PAPP‐A, 1st trimester, risk 1:185.

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Test 42

Age, NT and PAPP‐A, 1st trimester, 5FPR.

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Test 43

Age, NT and PAPP‐A, 1st trimester, mixed cut‐points.

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Test 44

Age, NT and total hCG, 1st trimester, 5FPR.

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Test 45

Age, NT and AFP, 1st trimester, 5FPR.

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Test 46

Age, NT and ITA, 1st trimester, 5FPR.

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Test 47

Age, NT and inhibin, 1st trimester, risk 1:100.

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Test 48

Age, NT and inhibin, 1st trimester, risk 1:250.

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Test 49

Age, NT and inhibin, 1st trimester, risk 1:400.

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Test 50

Age, NT and inhibin, 1st trimester, 5FPR.

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Test 51

Age, NT and inhibin, 1st trimester, mixed cut‐points.

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Test 52

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:100.

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Test 53

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:150.

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Test 54

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:200.

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Test 55

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:220.

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Test 56

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:250.

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Test 57

Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:300.

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Test 58

Age, NT, PAPP‐A and free ßhCG, 1st trimester, 1FPR.

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Test 59

Age, NT, PAPP‐A and free ßhCG, 1st trimester, 3FPR.

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Test 60

Age, NT, PAPP‐A and free ßhCG, 1st trimester, 5FPR.

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Test 61

Age, NT, PAPP‐A and free ßhCG, 1st trimester, mixed cut‐points.

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Test 62

Age, NT, PAPP‐A and uE3, 1st trimester, 5FPR.

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Test 63

Age, NT, PAPP‐A and ITA, 1st trimester, 5FPR.

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Test 64

Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:100.

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Test 65

Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:250.

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Test 66

Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:400.

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Test 67

Age, NT, PAPP‐A and inhibin, 1st trimester, 5FPR.

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Test 68

Age, NT, PAPP‐A and inhibin, 1st trimester, mixed cut‐points.

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Test 69

Age, NT, PAPP‐A and ADAM12, 1st trimester, 5FPR.

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Test 70

Age, NT, PAPP‐A and ADAM12, 1st trimester, risk 1:250.

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Test 71

Age, NT, free ßhCG and ADAM12, 1st trimester, 5FPR.

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Test 72

Age, NT, AFP and free ßhCG, 1st trimester, risk 1:250.

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Test 73

Age, NT, AFP and free ßhCG, 1st trimester, 5FPR.

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Test 74

Age, NT, AFP and free ßhCG, 1st trimester, mixed cut‐points.

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Test 75

Age, NT, AFP and PAPP‐A, 1st trimester, 5FPR.

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Test 76

Age, NT, total hCG and PAPP‐A, 1st trimester, 5FPR.

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Test 77

Age, NT, total hCG and inhibin, 1st trimester, 5FPR.

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Test 78

Age, NT, free ßhCG and inhibin, 1st trimester, 5FPR.

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Test 79

Age, NT, PAPP‐A, free ßhCG, 1st trimester serum, ductus venosus pulsivity index, 5FPR.

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Test 80

Age, free ßhCG and PAPP‐A, if risk 1:42‐1:1000, NT, final 1:250 risk.

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Test 81

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

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Test 82

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:250.

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Test 83

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

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Test 84

Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

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Test 85

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

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Test 86

Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:300.

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Test 87

Age, NT, tricuspid blood flow, free ßhCG and PAPP‐A, 1st trimester, risk 1:100.

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Test 88

Age, NT, fetal heart rate, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

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Test 89

Age, NT, fetal heart rate, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:200.

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Test 90

age, NT, fetal heart rate, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

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Test 91

Age, NT, fetal heart rate, tricuspid blood flow, free ßhCG and PAPP‐A,1st trimester, 5FPR.

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Test 92

Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, risk 1:250.

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Test 93

Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, 5FPR.

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Test 94

Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points.

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Test 95

Age, NT, total hCG, inhibin and PAPP‐A, 1st trimester, 5FPR.

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Test 96

Age, NT, PAPP‐A, free ßhCG and PGH, 1st trimester, 5FPR.

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Test 97

Age, NT, PAPP‐A, free ßhCG and GHBP, 1st trimester, 5FPR.

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Test 98

Age, NT, PAPP‐A, free ßhCG and PIGF, 1st trimester, 5FPR.

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Test 99

Age, NT, PAPP‐A, free ßhCG and total hCG, 1st trimester, 5FPR.

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Test 100

Age, NT, PAPP‐A, free ßhCG and PP13, 1st trimester, 5FPR.

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Test 101

Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, 5FPR.

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Test 102

Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, risk 1:250.

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Test 103

Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, mixed cut‐points.

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Test 104

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:100.

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Test 105

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:250.

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Test 106

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:400.

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Test 107

Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, 5FPR.

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Test 108

Age, NT, PAPP‐A, free ßhCG, ADAM12 and PlGH, 1st trimester, 5FPR.

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Test 109

Age, NT, total hCG, inhibin, PAPP‐A, AFP and uE3, 1st trimester, 5FPR.

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Test 110

Age, NT, free ßhCG, inhibin, PAPP‐A, AFP and uE3,1st trimester, 5FPR.

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Test 111

Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG and PlGF, 1st trimester, 5FPR.

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Test 112

Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG, PlGF and PP13, 1st trimester, 5FPR.

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Test 113

NT, free ßhCG and PAPP‐A, 1st trimester incidence rate 63.3%.

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Test 114

NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age < 35 years.

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Test 115

NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age ≥ 35 years.

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Summary of findings 1. Performance of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests

Review question	What is the accuracy of ultrasound based markers alone and in combination with maternal age and/or first trimester serum markers for screening for Down's syndrome?
Population	Pregnant women at less than 14 weeks' gestation confirmed by ultrasound, who had not undergone previous testing for Down’s syndrome. Some studies were undertaken in women identified to be at high risk based on maternal age.
Settings	All settings.
Numbers of studies, pregnancies and Down's syndrome cases	126 studies (reported in 152 publications) involving 1,604,040 fetuses of which 8454 were Down's syndrome cases
Index tests	Risk scores computed using maternal age and first trimester ultrasound and serum markers for ultrasound markers ‐ NT, nasal bone, ductus venosus Doppler, maxillary bone length, fetal heart rate, aberrant right subclavian artery, frontomaxillary facial angle, presence of mitral gap, tricuspid regurgitation, tricuspid blood flow and iliac angle 90 degrees ‐ and serum markers ‐ inhibin A, AFP, free ßhCG, total hCG, PAPP‐A, uE3, ADAM 12, PlGF, PGH, ITA (h‐hCG), GHBP and PP13.
Reference standards	Chromosomal verification (amniocentesis and CVS undertaken during pregnancy, and postnatal karyotyping) and postnatal macroscopic inspection.
Study limitations	116 studies only used selective chromosomal verification during pregnancy, and were at risk of under‐ascertainment of Down's syndrome cases due to pregnancy loss between administering the serum test and the reference standard.
Test strategy	Studies	Women (Down's cases)	Sensitivity (95% CI)	Specificity (95% CI)*	Consequences in a hypothetical cohort of 10,000 pregnant women assuming Down’s syndrome affects approximately one in 800 live‐born babies
Test strategy	Studies	Women (Down's cases)	Sensitivity (95% CI)	Specificity (95% CI)*	Missed cases	False positives
Nasal bone	11	48,279 (290)	49 (34, 64)	99 (99, 100)	7	100
NT	13	90,978 (593)	70 (61, 78)	95	4	500
NT and maternal age	50	530,874 (2701)	71 (66, 75)	95	4	500
Nasal bone and maternal age	4	25,303 (165)	68 (28, 92)	95	4	500
Ductus and maternal age	5	5331 (165)	68 (49, 83)	95	4	500
NT, nasal bone and maternal age	5	29,699 (221)	78 (55, 91)	95	3	500
NT, free ßhCG and maternal age	5	10,795 (421)	77 (72, 82)	95	3	500
NT, PAPP‐A and maternal age	5	9814 (372)	81 (75, 86)	95	3	500
NT, PAPP‐A, free ßhCG and maternal age	69	1,173,853 (6010)	87 (86, 89)	95	2	500
NT, PAPP‐A, free ßhCG, ADAM 12 and maternal age	4	2571 (256)	82 (75, 87)	95	3	500
*We estimated sensitivity (with a 95% confidence interval) at a 5% false positive rate from the summary ROC curve obtained for each test except nasal bone. For nasal bone, the pooled specificity is reported because the cut‐point was absence or presence of nasal bone, and all studies reported false positive rates below 5% so estimation of sensitivity at a fixed 5% FPR was not appropriate.

Summary of findings 1. Performance of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests

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Summary of findings 2. Performance of other first trimester ultrasound markers alone or in combination with first trimester serum tests

Test strategy	Studies	Women (Down's cases)	*Sensitivity (95% CI)**	*Specificity (95% CI)**	Threshold
Without maternal age
Ultrasound markers alone
Aberrant right subclavian artery	1	425 (51)	8 (2, 19)	99 (98, 100)	Feature
Frontomaxillary facial angle	1	242 (22)	18 (5, 40)	98 (95, 99)	> 95^th percentile
Presence of mitral gap	1	217 (20)	20 (6, 44)	87 (81, 91)	Feature
Maxillary bone length	1	927 (88)	24 (15, 34)	95 (93, 96)	5th centile
Tricuspid regurgitation	1	312 (20)	50 (27, 73)	98 (96, 99)	Feature
Iliac angle 90 degrees	1	2032 (52)	60 (45, 73)	98 (97, 98)	Feature
Ductus venosus a‐wave reversed	1	378 (72)	68 (56, 79)	70 (64, 75)	Feature
Ductus venosus pulsivity index	1	378 (72)	81 (70, 89)	58 (52, 63)	> 95^th percentile
NT and nasal bone	1	486 (38)	89 (75, 97)	93 (91, 95)	Absent nasal bone and NT ≥ 95th centile
Ultrasound and double serum markers
NT, free ßhCG and PAPP‐A	1	6508 (40)	90 (76, 97)	95 (95, 96)	First trimester incidence rate 63.3%
With maternal age
Ultrasound markers alone
NT‐adjusted risk > 1:300 and abnormal ductus venosus flow and absent nasal bones	1	544 (47)	21 (11, 36)	100 (99, 100)	1:300 risk
NT and ductus	3	23,697 (177)	76 to 93	73 to 99	5% FPR, 1:250 risk, feature
NT and tricuspid blood flow	1	19,736 (122)	85 (78, 91)	97 (97, 98)	1:100 risk
Ultrasound and single serum markers
NT and inhibin A	2	1150 (97)	61 to 75	95 to 96	5% FPR, 1:250 risk
NT and AFP	1	1110 (85)	61 (50, 72)	95 (94, 96)	5% FPR
NT and total hCG	1	1110 (85)	61 (50, 72)	95 (94, 96)	5% FPR
NT and ITA	1	278 (54)	80 (66, 89)	95 (91, 98)	5% FPR
Ultrasound and double serum markers
NT, AFP and free ßhCG	2	2766 (90)	66 to 100	93 to 95	5% FPR, 1:250 risk
NT, PAPP‐A and inhibin A	2	1150 (97)	80 to 83	95 to 96	5% FPR, 1:250 risk
NT, total hCG and inhibin A	1	1110 (85)	62 (51, 73)	95 (94, 96)	5% FPR
NT, free ßhCG and inhibin A	1	1110 (85)	66 (55, 76)	95 (94, 96)	5% FPR
NT, free ßhCG and ADAM 12	1	351 (31)	68 (49, 83)	95 (92, 97)	5% FPR
NT, PAPP‐A and uE3	1	576 (24)	79 (58, 93)	95 (93, 97)	5% FPR
NT, total hCG and PAPP‐A	1	1110 (85)	80 (70, 88)	95 (94, 96)	5% FPR
NT, AFP and PAPP‐A	1	1110 (85)	80 (70, 88)	95 (94, 96)	5% FPR
NT, PAPP‐A and ITA	2	11,053 (77)	83 (73, 90)	95	5% FPR
NT, PAPP‐A and ADAM 12	2	1042 (77)	83 (73, 90)	95	5% FPR
Free ßhCG and PAPP‐A, if risk between 1:42 and 1:1000 (intermediate risk), NToffered, final composite risk !:250	1	10,189 (44)	89 (75, 96)	94 (94, 95)	1:250 risk
NT, ductus, free ßhCG and PAPP‐A	3	30,061 (212)	83 to 96	97 to 99	1:100 risk, 1:250 risk
NT, nasal bone, free ßhCG and PAPP‐A	3	41,842 (271)	89 to 94	95 to 98	5% FPR, 1:100 risk, 1:300 risk
NT, PAPP‐A, free ßhCG and ductus venosus pulsivity index	1	7,250 (66)	89 (79, 96)	95 (94, 95)	5% FPR
NT, tricuspid blood flow, free ßhCG and PAPP‐A	1	19,736 (122)	91 (84, 95)	97 (97, 98)	1:100 risk
NT, fetal heart rate, free ßhCG and PAPP‐A	2	76,385 (517)	92 (89, 94)	95	5% FPR
NT, fetal heart rate, nasal bone, free ßhCG and PAPP‐A	1	19,736 (122)	95 (90, 98)	96 (95, 96)	1:200 risk
NT, fetal heart rate, tricuspid blood flow, free ßhCG and PAPP‐A	1	19,736 (122)	96 (91, 99)	95 (95, 95)	5% FPR
NT, fetal heart rate, ductus, free ßhCG and PAPP‐A	1	19,614 (122)	97 (92, 99)	95 (95, 95)	5% FPR
Ultrasound and triple serum markers
NT, AFP, free ßhCG and PAPP‐A	3	6789 (135)	73 to 84	95	5% FPR, 1:250 risk
NT, PAPP‐A, free ßhCG and PP13	1	998 (151)	77 (69, 83)	95 (93, 96)	5% FPR
NT, PAPP‐A, free ßhCG and total hCG	1	998 (151)	77 (69, 83)	95 (93, 96)	5% FPR
NT, total hCG, inhibin A and PAPP‐A	1	1110 (85)	81 (71, 89)	95 (94, 96)	5% FPR
NT, free ßhCG, inhibin A and PAPP‐A	1	1110 (85)	84 (74, 91)	95 (94, 96)	5% FPR
NT, PAPP‐A, free ßhCG and PGH	1	335 (74)	86 (77, 93)	95 (92, 97)	5% FPR
NT, PAPP‐A, free ßhCG and PIGF	2	1443 (221)	88 (70, 95)	95	5% FPR
NT, PAPP‐A, free ßhCG and GHBP	1	335 (74)	91 (81, 96)	95 (92, 97)	5% FPR
Ultrasound and quadruple serum markers
NT, PAPP‐A, free ßhCG, ADAM 12 and PlGF	1	998 (151)	79 (72, 86)	95 (93, 96)	5% FPR
Ultrasound and quintuple serum markers
NT, PAPP‐A, free ßhCG, ADAM 12, total hCG and PlGF	1	998 (151)	79 (72, 86)	95 (93, 96)	5% FPR
NT, total hCG, inhibin A, PAPP‐A, AFP and uE3	1	1110 (85)	84 (74, 91)	95 (94, 96)	5% FPR
NT, free ßhCG, inhibin A, PAPP‐A, AFP and uE3	1	1110 (85)	86 (77, 92)	95 (94, 96)	5% FPR
Ultrasound and sextuple serum markers
NT, PAPP‐A, free ßhCG, ADAM 12, total hCG, PlGF and PP13	1	998 (151)	80 (73, 86)	95 (93, 96)	5% FPR
*Tests evaluated by at least one study are presented in the table. Where there were two studies at the same threshold, estimates of summary sensitivity and summary specificity were obtained by using univariate fixed‐effect logistic regression models to pool sensitivities and specificities separately. If the threshold used was a 5% FPR, then only the sensitivities were pooled. The range of sensitivities and specificities are presented where meta‐analysis was not performed because there were only two or three studies and no common threshold.

Summary of findings 2. Performance of other first trimester ultrasound markers alone or in combination with first trimester serum tests

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Table 1. Direct (head‐to‐head) comparisons of the diagnostic accuracy of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests

Ratio of DORs (95% CI); P value (Studies)	Nasal bone	NT	Nasal bone and age	Ductus and age	NT and age	NT, nasal bone and age	NT, free ßhCG and age	NT, PAPP‐A and age	NT, PAPP‐A, free ßhCG and age
NT	–
Nasal bone and age	–	–
Ductus and age	1.19 (0.12, 11.4); P = 0.84 (K = 1)	–	0.85 (0.21, 3.41); P = 0.76 (K = 1)
NT and age	0.62 (0.13, 2.93); P = 0.50 (K = 2)	1.25 (0.90, 1.74); P = 0.17 (K = 3)	0.84 (0.48, 1.49); P = 0.52 (K = 3)	1.07 (0.51, 2.23); P = 0.85 (K = 3)
NT, nasal bone and age	0.61 (0.12, 3.10); P = 0.50 (K = 2)	–	4.01 (1.51, 10.6); P = 0.01 (K = 2)	0.95 (0.23, 3.97); P = 0.93 (K = 1)	1.05 (0.70, 1.56); P = 0.82 (K = 5)
NT, free ßhCG and age	–	2.15 (1.33, 3.50); P = 0.007 (K = 2)	–	–	1.47 (1.00, 2.15); P = 0.05 (K = 4)	–
NT, PAPP‐A and age	–	2.86 (1.73, 4.73); P = 0.001 (K = 2)	–	–	1.88 (1.27, 2.78); P = 0.004 (K = 4)	–	1.28 (0.84, 1.93); P = 0.23 (K = 4)
NT, PAPP‐A, free ßhCG and age	3.83 (0.89, 16.4); P = 0.07 (K = 2)	4.35 (2.00, 9.46); P = 0.015 (K = 4)	–	3.00 (0.42, 21.2); P = 0.19 (K = 1)	3.19 (2.19, 4.66); P < 0.0001 (K = 25)	1.23 (0.63, 2.40); P = 0.50 (K = 2)	2.06 (1.31, 3.22); P = 0.004 (K = 4)	1.61 (1.02, 2.55); P = 0.043 (K = 4)
NT, PAPP‐A, free ßhCG, ADAM 12 and age	–	–	–	–	–	–	–	–	0.87 (0.49, 1.52); P = 0.60 (K = 4)
– Indicates pairs of tests where there were no head‐to head comparisons of the two tests in a study. Direct comparisons were made using only data from studies that compared each pair of tests in the same population. Ratio of diagnostic odds ratios (DORs) were computed by division of the DOR for the test in the row by the DOR for the test in the column. If the ratio of DORs is greater than one, then the diagnostic accuracy of the test in the row is higher than that of the test in the column; if the ratio is less than one, the diagnostic accuracy of the test in the column is higher than that of the test in the row.

Table 1. Direct (head‐to‐head) comparisons of the diagnostic accuracy of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests

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Table 2. Indirect comparisons of the diagnostic accuracy of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests

Ratio of DORs (95% CI); P value		Nasal bone	NT	Nasal bone and age	Ductus and age	NT and age	NT, nasal bone and age	NT, free ßhCG and age	NT, PAPP‐A and age	NT, PAPP‐A, free ßhCG and age
	DOR (95% CI) Studies	132 (71, 245) K = 11	45 (31, 67) K = 13	40 (7, 224) K = 4	41 (18, 92) K = 5	46 (37, 57) K = 50	66 (24, 180) K = 5	65 (51, 84) K = 5	80 (59, 109) K = 5	133 (114, 155) K = 69
NT	45 (31, 67) K = 13	0.34 (0.16, 0.71); P = 0.006
Nasal bone and age	40 (7, 224) K = 4	0.31 (0.05, 1.90); P = 0.18	0.90 (0.16, 5.05); P = 0.89
Ductus and age	41 (18, 92) K = 5	0.31 (0.11, 0.87); P = 0.03	0.90 (0.37, 2.20); P = 0.80	1.00 (0.11, 9.34); P = 1.00
NT and age	46 (37, 57) K = 50	0.35 (0.19, 0.66); P = 0.002	1.02 (0.66, 1.58); P = 0.92	1.14 (0.23, 5.61); P = 0.87	1.14 (0.52, 2.49); P = 0.74
NT, nasal bone and age	66 (24, 180) K = 5	0.50 (0.14, 1.81); P = 0.26	1.47 (0.47, 4.58); P = 0.48	1.64 (0.12, 21.5); P = 0.62	1.64 (0.33, 8.08); P = 0.46	1.43 (0.52, 3.98); P = 0.48
NT, free ßhCG and age	65 (51, 84) K = 5	0.49 (0.25, 0.98); P = 0.04	1.44 (0.89, 2.34); P = 0.12	1.61 (0.26, 10.1); P = 0.56	1.61 (0.65, 3.99); P = 0.26	1.41 (1.02, 1.96); P = 0.04	0.98 (0.30, 3.19); P = 0.98
NT, PAPP‐A and age	80 (59, 109) K = 5	0.61 (0.29, 1.25); P = 0.16	1.77 (1.05, 3.00); P = 0.04	1.98 (0.30, 13.1); P = 0.42	1.98 (0.76, 5.15); P = 0.14	1.73 (1.19, 2.53); P = 0.005	1.21 (0.35, 4.13); P = 0.73	1.23 (0.74, 2.05); P = 0.35
NT, PAPP‐A, free ßhCG and age	133 (114, 155) K = 69	1.00 (0.55, 1.84); P = 1.00	2.93 (1.96, 4.40); P < 0.0001	3.27 (0.68, 15.8); P = 0.14	3.27 (1.53, 7.00); P = 0.003	2.87 (2.21, 3.72); P < 0.0001	2.00 (0.73, 5.45); P = 0.17	2.03 (1.52, 2.72) P < 0.0001	1.65 (1.17, 2.34) P = 0.005
NT, PAPP‐A, free ßhCG, ADAM 12 and age	85 (58, 124) K = 4	0.64 (0.30, 1.37); P = 0.23	1.88 (1.07, 3.32); P = 0.03	2.10 (0.31, 14.1); P = 0.39	2.10 (0.78, 5.63); P = 0.12	1.84 (1.19, 2.84); P = 0.007	1.28 (0.37, 4.47); P = 0.65	1.30 (0.81, 2.09) P = 0.26	1.06 (0.61, 1.86) P = 0.81	0.64 (0.43, 0.96) P = 0.03
Indirect comparisons were made using all available data for each pair of tests. Ratios of diagnostic odds ratios (DORs) were computed by division of the DOR for the test in the row by the DOR for the test in the column. If the ratio of DORs is greater than one, then the diagnostic accuracy of the test in the row is higher than that of the test in the column; if the ratio is less than one, the diagnostic accuracy of the test in the column is higher than that of the test in the row.

Table 2. Indirect comparisons of the diagnostic accuracy of the 10 most evaluated first trimester ultrasound markers alone or in combination with first trimester serum tests

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Table 3. Summary of study characteristics

Study	NT, PAPP‐A, free ßhCG and age	Nasal bone	NT and age	NT	Maternal age (range) in years	Reference standard	Population	Study design	Study location
Acacio 2001				X	Mean 35.8 (21‐45)	CVS biopsy, amniocentesis or blood or placenta used for fetal karyotyping	High‐risk referral for invasive testing	Retrospective study of patient notes	South America
Audibert 2001			X		Mean 30.1, all < 38, 86% < 35, 14% ≥ 35	Prenatal karyotype conducted (in 7.6% of patients) depending on presence of risk > 125, high maternal age, parental anxiety, history of chromosomal defects or parental translocation or abnormal second trimester scan age	Routine screening	Prospective consecutive series	France
Babbur 2005				X	Median 37 (19‐46)	Invasive testing offered to women with NT > 3 mm or risk > 1:250 as defined by combined NT and serum results (CVS from 11 weeks, amniocentesis from 15 weeks). Rapid in situ hybridisation test in patients with risk > 1:30. No details given of any follow‐up to birth	Women requesting screening (self‐paying service) and women attending on account of previous pregnancy history of fetal abnormality	Prospective cohort	UK
Barrett 2008	X				Mean 34.9 for screen positives, 30.5 for screen negatives	Karyotyping or follow‐up to birth	Routine screening	Cohort	Australia
Belics 2011					Mean 36.4 (15‐46) for Down's cases, 29.8 (15‐49) for unaffected pregnancies	Amniocentesis or CVS (85% of women) or follow‐up to birth	High‐risk referral for invasive testing	Cohort	Budapest
Benattar 1999			X		Mean 32 (16‐46), 8.3% > 35	Amniocentesis due to maternal age > 38 years (6.1% or women). Karyotyping encouraged for women with positive result on one or more index test. No details of reference standard for index test negative women	Routine screening	Prospective cohort	France
Bestwick 2010	X		X	X	Median 39 for Down's cases, 34 for unaffected pregnancies	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	UK
Biagiotti 1998	X		X		Unclear (maybe all ≥ 38)	Amniocentesis or CVS	High‐risk referral for invasive testing	Case control	Italy
Borenstein 2008					Median 35 (17‐49)	CVS	High‐risk referral for invasive testing	Prospective cohort	UK
Borrell 2005	X		X		Not reported	CVS (high‐risk women) or follow‐up to birth	Routine screening	Retrospective cohort	Spain
Borrell 2009	X				Mean 32	Karyotyping or follow‐up to birth	Routine screening and high‐risk referral	Prospective cohort	Spain
Brameld 2008	X				Median 31 (14‐47), 20% ≥ 35	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	Australia
Brizot 2001			X		Median 28 (13‐46), 19.4% ≥ 35	Antenatal karyotyping (5.9% of pregnancies: 62% of high‐risk, 29% of medium‐risk and 3% of the low‐risk women). Follow‐up to birth (85.3% of women)	Routine screening	Prospective cohort	Brazil
Centini 2005	X				≥ 35 (35‐44)	Amniocentesis in women high risk on screening (16.2%). Follow‐up at birth in women who were low risk on screening	High‐risk patients undergoing routine screening	Retrospective cohort	Italy
Chasen 2003			X		Median 33 (IQR 31‐36), 36.2% ≥ 35	Karyotyping or follow‐up to birth in 96.1% of patients	Routine screening	Prospective consecutive cohort	USA
Chen 2009					Median 30 (20‐44) for Down's cases, 32 (19‐40) for controls	Karyotyping or follow‐up to birth	Routine screening	Case control	China
Christiansen 2005	X				Not reported	Karyotyping	Screening programmes for syphilis and Down's syndrome	Case control	Denmark
Christiansen 2009	X				Median 37.5 for Down's cases, 36.4 for controls	Karyotyping or follow‐up to birth	Routine screening	Case control	Denmark
Christiansen 2010	X				Median 36 (25‐44) for Down's cases, 29 (17‐45) for controls	Karyotyping or follow‐up to birth	Routine screening	Case control	Denmark
Cicero 2004a					Median 37 (16‐48)	CVS	High‐risk referral for invasive testing	Prospective cohort	USA
Cicero 2006		X			Median 35 (18‐50)	CVS or amniocentesis (in high risk women) or follow‐up to birth	Routine screening	Prospective cohort	UK
Cocciolone 2008 (first trimester screening cohort)	X				Median 31.3	Karyotyping or follow‐up to birth	Routine screening	Cohort	Australia
Cowans 2009	X				Mean 38 (16‐49) for Down's cases, 29 (13‐56) for unaffected pregnancies	Karyotyping or follow‐up to birth	Routine screening	Cohort	UK
Cowans 2010	X				Mean 37.0 (IQR 32.9‐40.5) for Down's cases, 32.4 (IQR 29.0‐35.9) for controls	Karyotyping or follow‐up to birth	Routine screening	Case control	UK
Crossley 2002	X		X		Median 29.9, 15.4% ≥ 35	CVS (offered where women had high NT measurements), amniocentesis or follow‐up to birth	Routine screening	Prospective cohort	UK
De Graaf 1999	X		X		Not reported	CVS and amniocentesis	High‐risk referral for invasive testing	Case control	Netherlands
Ekelund 2008	X				Not reported	Karyotyping or follow‐up to birth	Routine screening	Cohort	Denmark
Gasiorek‐Wiens 2001			X		Median 33 (15‐49), 36.1% > 35	CVS, amniocentesis or follow‐up to birth	Routine screening	Prospective cohort	Germany, Switzerland and Austria
Gasiorek‐Wiens 2010			X		Median 35.1 (13.2‐46.7)	Karyotyping or follow‐up to birth	Routine screening	Cohort	Germany
Go 2005	X				49% ≤ 35, 51% ≥ 36	Invasive testing or follow‐up to birth	Routine screening	Retrospective cohort	Netherlands
Gyselaers 2005	X		X		Not reported	CVS, amniocentesis or follow‐up to birth	Routine screening	Prospective cohort	Belgium
Habayeb 2010					Median 35.4 (18‐49)	Karyotyping or follow‐up to birth	Routine screening	Cohort	UK
Hadlow 2005*	X				Mean 30.7, 21.2% ≥ 35	CVS, amniocentesis or follow‐up to birth	Routine screening	Prospective cohort	Australia
Hafner 1998*				X	Median 28 (15‐49) 6.9% ≥ 35	Amniocentesis or CVS in patients with previous Down’s pregnancy, > 35 years or with a positive biochemical test result. Other women underwent scan at 22 weeks and, if NT >2.5 mm special examination directed to examination of fetal heart. Follow‐up to birth	Routine screening	Prospective cohort	Austria
Has 2008	X	X	X		Median 28.3 (17‐45)	Karyotyping or follow‐up to birth	Routine screening	Cohort	Turkey
Hewitt 1996				X	Median 37 (21‐48)	CVS	High‐risk referral for invasive testing	Prospective cohort	Australia
Hormansdorfer 2011	X				Mean 31.1 (16‐46), 22% ≥ 35	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Germany
Huang 2010	X				Median 30 (15‐47), mean 29.8 (SD 3.3)	Karyotyping or follow‐up to birth	Routine screening	Cohort	Taiwan
Jaques 2007	X				Mean 33 (16‐51), 18.5% ≥ 37	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	Australia
Jaques 2010 FTS (first trimester screening)	X				Mean 16.3% ≥ 37	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	Australia
Kagan 2010	X		X		Mean 35.4 (14.1‐52.2)	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	UK
Kim 2006				X	Mean 29.9 (SD 3.3)	Amniocentesis or CVS in patients considered high risk (NT > 2.5, aged > 35 years, positive biochemical test result, history or chromosomal abnormality, fetal structural abnormality at ultrasound or other reason). Follow‐up to birth	Routine screening	Retrospective cohort	South Korea
Koster 2011	X				Median 37 (IQR 36‐39)	Karyotyping or follow‐up to birth	Routine screening	Case control	Netherlands
Kozlowski 2007 GC (Gynaecologists' practices)	X		X		Median 32 (15‐48), 26.4% ≥ 35	Karyotyping or follow‐up to birth	Routine screening	Cohort	Germany
Kozlowski 2007 PC (Prenatal centre)	X		X		Median 34 (14‐46), 43.2% ≥ 35	Karyotyping or follow‐up to birth	Routine screening	Cohort	Germany
Krantz 2000*	X		X		34.7% ≥ 35	Not reported	Routine screening	Prospective cohort	USA
Kublickas 2009	X				51% ≥ 35	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Sweden
Kuc 2010	X				Not reported	Karyotyping or follow‐up to birth	Routine screening	Case control	Netherlands
Lam 2002			X		Mean 30.5 (19% ≥ 35) for unaffected pregnancies	Women considered high risk offered CVS (0.7%) or amniocentesis (11.8%). Follow‐up to birth	Routine screening	Prospective cohort	Hong Kong
Leung 2009	X	X			Median 32 (IQR 30‐35), 27.4% ≥ 35	Amniocentesis or follow‐up to birth	Routine screening	Prospective cohort	China
MacRae 2008			X		Not reported	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	UK
Maiz 2007					Median 35 (17‐49)	CVS	High‐risk referral for invasive testing	Prospective cohort	UK
Maiz 2009					Median 34.5 (14.1‐50.1)	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	UK
Malone 2004		X			Mean 30.1 (16‐47), 22.1% ≥ 35	Amniocentesis (in women considered high risk, n = 510) or follow‐up to birth	Routine screening	Prospective cohort	USA
Malone 2005	X				21.6% ≥ 35	Amniocentesis offered to women with positive results from any screening test. Follow‐up to birth	Routine screening	Prospective cohort	USA
Marchini 2010*	X				Median 31.3 (18‐45), 19.7% ≥ 35	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	Italy
Marsis 2004				X	Mean 37.8 (35‐43)	Amniocentesis (unclear in which patients this was conducted) or follow‐up to birth	Screening of patients ≥ 35 years of age	Prospective cohort	Indonesia
Marsk 2006	X		X		Mean 38.5 (SD 4.0) for Down's cases, 35.5 (SD 4.0) for controls	Not reported	Routine screening	Case control	Sweden
Matias 1998					Median 35 (17‐46)	Fetal karyotyping. In cases where NT above 95th percentile or abnormal ductus venousus flow, follow‐up scan conducted at 14‐16 weeks	High‐risk referral for invasive testing	Prospective cohort	UK and Portugal
Matias 2001					Median 35 (17‐46)	Fetal karyotyping. In cases where NT above 95th percentile or abnormal ductus venousus flow, follow‐up scan conducted at 14‐16 weeks	High‐risk referral for invasive testing	Prospective cohort	Portugal
Mavrides 2002			X		Median 35 (15‐42)	CVS or follow‐up	High‐risk referral for invasive testing	Prospective cohort	UK
Maxwell 2011 FTS (first trimester screening cohort)	X				Median 31 (14‐48), 24.3% ≥ 35	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Australia
Maymon 2005					Mean 33.7 (SD 4.9) for Down's cases, 30.3 (SD 4.5) for controls	Amniocentesis (recommended for women with higher risk on first or second trimester testing) or follow‐up to birth	Routine screening	Case control	Israel
Maymon 2008	X		X		Not reported	Karyotyping or follow‐up to birth	Routine screening	Case control	USA
Merz 2011	X				Not reported	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	Germany
Michailidis 2001				X	Mean 30.1 (13‐50), 21.1% ≥ 35, 11.9% ≥ 37	Karyotyping in women considered at risk due to index test results, age or family history or those with considerable anxiety (632 women, 8.5%) or follow‐up to birth	Routine screening	Prospective cohort	UK
Molina 2010 high risk (High‐risk cohort)		X			Mean 32.7 (16.7‐47.5)	CVS	High‐risk referral for invasive testing	Cohort	Spain
Molina 2010 screening (Screening cohort)	X				Not reported	Karyotyping or follow‐up to birth	Routine screening	Cohort	Spain
Monni 2005			X		Median 32 (14‐49)	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Italy
Montalvo 2005	X				Mean 31.1 (14‐49), 25.9% ≥35	Invasive testing offered to women considered high risk from screening results or follow‐up to birth	Routine screening	Prospective cohort	Spain
Moon 2007		X			Mean 35.5 (SD 4.8) for Down's cases, 31.7 (SD 3.4) for unaffected pregnancies	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Korea
Muller 2003	X		X		Not reported	Invasive testing (offered to women with high NT measurement) or follow‐up to birth	Routine screening	Retrospective cohort	France
Nicolaides 1992				X	Median 38 (22‐47)	Fetal karyotyping by amniocentesis (52%) or CVS (48%)	High‐risk referral for invasive testing	Prospective cohort	UK
Nicolaides 2005	X				Median 31 (13‐49)	Amniocentesis or CVS (patients considered high risk based on screening). First trimester presence/absence of nasal bone, presence/absence of tricuspid regurgitation or normal/abnormal Doppler studies (patients of intermediate risk on first trimester screening and did not undergo CVS or amniocentesis. With the addition of information from these tests, if adjusted risk was high, CVS was performed). Follow‐up to birth	Routine screening	Prospective cohort	UK
Niemimaa 2001	X		X		17.5% ≥ 35	Invasive testing (patients considered high risk based on NT screening) or follow‐up to birth.	Routine screening	Prospective cohort	Finland
Noble 1995					Median 34 (15‐47), 47% ≥ 35	Karyotyping performed (27% of women) due to increased NT (14%), advanced maternal age (10%), previous chromosomally abnormal child (0.5%) or parental anxiety (2%). Ultrasound examination at 20 weeks (65% of patients). Follow‐up to birth (9% of women)	Routine screening in a high risk population	Prospective cohort	UK
O'Callaghan 2000			X		Median 32	CVS, amniocentesis or neonatal karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Australia
O'Leary 2006	X		X		Median 31 (14‐47), 20% ≥ 35	CVS or amniocentesis (women assessed to be high risk on screening) or follow‐up to birth	Routine screening	Prospective cohort	Australia
Okun 2008 FTS (first trimester screening cohort)	X				Mean 34	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Canada
Orlandi 1997	X		X		Range 15 to 46, 35% ≥ 35	Not reported	Routine screening	Prospective cohort	Italy
Orlandi 2003		X			Median 31.7 (SD 4.0) for Down's cases, 36.5 (SD 4.1) for unaffected pregnancies	CVS or amniocentesis (women considered high risk on screening on the basis of NT and biochemical results, but not on nasal bone screening, or if requested due to age or anxiety) or follow‐up to birth	Routine screening (2 centres) or in referred patients (1 centre)	Prospective cohort	Italy and Netherlands
Orlandi 2005		X			Median 30.5 (SD 8.2)	Not reported	Routine screening	Retrospective cohort	Italy
Otaño 2002		X			Median 36 (19‐44)	CVS	High‐risk referral for invasive testing	Prospective cohort	Argentina
Pajkrt 1998			X		Mean 31.4 (SD 5.7), 24% ≥ 35	Prenatal karyotyping offered to patients considered high risk or maternal anxiety (conducted in 24%) or follow‐up to birth	Routine screening	Prospective cohort	Netherlands
Pajkrt 1998a				X	Mean 37.6 (22‐46)	Prenatal karyotyping	High‐risk referral for invasive testing	Consecutive cohort	Netherlands
Palomaki 2007 FTS (first trimester screening cohort)					Mean 32.3 (SD 4.6)	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Canada
Perni 2006	X				Median 33.0 (IQR 31.0‐36.0)	CVS or amniocentesis. Cytogenetic testing in cases of miscarriage. Follow‐up to birth.	Routine screening	Retrospective cohort	USA
Prefumo 2005			X		Median 37 (19‐46)	CVS	High‐risk referral for invasive testing	Prospective cohort	UK
Prefumo 2006			X		Mean 31.4 (14.5‐50.2)	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	UK
Ramos‐Corpas 2006		X			Mean 30.1 (15‐46) (SD 5.37), 18% ≥ 35	Invasive testing offered to patients considered high risk at screening (> 1:300) or follow‐up to birth	Routine screening	Prospective cohort	Spain
Rissanen 2007	X				29.5, 17.7% ≥35	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Finland
Rozenberg 2002			X		Median 30.5 (18‐37)	Amniocentesis offered to patients with NT >3mm or serum marker risk was > 1:250, or follow‐up to birth	Routine screening	Prospective cohort	France
Rozenberg 2007	X				Mean 30.9 (SD 4.5)	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Canada
Sahota 2010	X		X		Median 33.1, 30.1% ≥ 35	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	China
Salomon 2010	X				Median 30.7 (18.0‐46.3)	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	France
Santiago 2007	X		X		Mean 30.6 (14‐46)	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	Spain
Sau 2001			X		Mean 28 (SD 5)	Invasive testing (women with high risk on screening) or follow‐up to birth	Routine screening	Prospective cohort	UK
Schaelike 2009	X		X		31.0% ≥35	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Germany
Schielen 2006*	X				Median 36.5 (18‐47)	Invasive testing or follow‐up to birth	Routine screening	Retrospective cohort	Netherlands
Schuchter 2001			X		Mean 28 (15‐46), 10.7% ≥ 35	CVS (offered to patients with first trimester NT > 3.5 mm), amniocentesis (offered to patients with first trimester NT 2.5‐3.4 mm, high risk on second trimester serum testing (> 1:250) and those > 35 years) or follow‐up to birth	Routine screening	Retrospective cohort	Austria
Schuchter 2002	X			X	13% > 35	CVS and amniocentesis (offered to patients with increased risk (> 1:400) at first trimester screening. CVS recommended when NT > 3.5 or when women did not want to wait until the 15^th week for amniocentesis), or follow‐up to birth	Routine screening	Prospective cohort	Austria
Schwarzler 1999			X		Mean 29.4 (16‐47)	Invasive testing (women considered high risk on screening) or follow‐up to birth	Routine screening	Prospective consecutive cohort	UK
Scott 2004	X		X		Median 32 (15‐44), 29% ≥ 35	Invasive testing or follow‐up to birth	Routine screening	Prospective cohort	Australia
Sepulveda 2007		X	X		Median 33 (14‐47), 35.4% ≥ 35	CVS, amniocentesis, cordocentesis or follow‐up to birth	Routine screening	Prospective cohort	Chile
Snijders 1998			X		Median 31 (14‐49)	CVS and amniocentesis (9.6% of women) or follow‐up to birth	Routine screening	Prospective cohort	UK
Sorensen 2011	X				Median 34 (23‐44) for Down's cases; mean 30.4 (16‐45), 16.5% ≥ 35 for unaffected pregnancies	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	Denmark
Spencer 1999	X		X	X	Median 38 (19‐46) for Down's cases, 36 (15‐47) for controls	Invasive testing (high‐risk women) or follow‐up to birth	Routine screening	Case control	UK
Spencer 2002					Median 36 (20‐44) for Down's cases, 30 (16‐41) for controls	Not reported	Routine screening	Case control	UK
Spencer 2008	X				Median 35.8 for Down's cases, 29.3 for controls	Karyotyping or follow‐up to birth	Routine screening	Case control	Denmark
Stenhouse 2004	X				Median 32 (14‐45), 27% ≥ 35	Invasive testing offered to women with screening risk of > 1:250 or follow‐up to birth	Routine screening	Prospective cohort	UK
Strah 2008			X		Median 28.6 (15‐42)	Karyotyping or follow‐up to birth	Routine screening	Cohort	Slovenia
Theodoropoulos 1998			X		Median 29 (16‐48), 7.8% ≥ 37	CVS or amniocentesis or follow‐up to birth. Unclear reference standard in cases of intrauterine death, miscarriages and terminations.	Routine screening	Prospective cohort	Greece
Thilaganathan 1999			X		Mean 29 (15‐45)	CVS (offered to patients considered high risk on screening) or follow‐up to birth	Routine screening	Prospective cohort	UK
Timmerman 2010					Mean 34.5 (19‐45)	Karyotyping or follow‐up to birth	Routine screening	Prospective cohort	Netherlands
Torring 2010	X				Mean 35 for Down's cases, 31 for controls	Karyotyping or follow‐up to birth	Routine screening	Case control	Denmark
Vadiveloo 2009	X				Median 33.1, 36.9% ≥ 35	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	UK
Valinen 2007	X				Mean 29.6, 18.6% ≥ 35	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	Finland
Viora 2003					Median 32 (18‐47)	CVS or follow‐up to birth	Routine screening	Prospective cohort	Italy
Wald 2003	X		X	X	Not reported	Invasive testing (following second trimester screening) or follow‐up to birth	Routine screening	Case control	UK and Austria
Wapner 2003*	X		X		Mean 35 (SD 4.6), 50% ≥ 35	Invasive testing. Miscarriage with cytogenetic testing. Follow‐up to birth	Routine screening	Prospective cohort	USA
Wax 2009	X				Mean 36.7 (SD 3.2)	Karyotyping or follow‐up to birth	Routine screening	Retrospective cohort	USA
Wojdemann 2005	X		X		Mean 29, 10.8% ≥ 35	Invasive testing (in cases of increased risk) or follow‐up to birth	Referrals for screening	Prospective cohort	Denmark
Wortelboer 2009	X				Median 34.9 (15‐48)	Karyotyping or follow‐up to birth	Routine screening	Cohort	Netherlands
Wright 2008			X		Median 35.2 (16‐52)	Karyotyping or follow‐up to birth	Routine screening	Cohort	UK
Wright 2010	X				Median 31.9 (IQR 27.7‐35.8)	Karyotyping or follow‐up to birth	Routine screening	Cohort	UK, Denmark and Cyprus
Zoppi 2001			X		Median 33 (14‐48)	Amniocentesis, CVS or follow‐up to birth	Routine screening	Prospective cohort	Italy
*The study provided data for the subset of women with maternal age of 35 or more. X indicates that the test was evaluated in the study. CVS = chorionic villus sampling; IQR = interquartile range; SD = standard deviation.

Table 3. Summary of study characteristics

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Table 4. Investigation of the effect of type of population

Correction made for missing false negatives in studies with delayed verification of test negatives	NT			NT and maternal age			NT, PAPP‐A, free ßhCG and maternal age
	Ratio of DORs (95% CI); P value	Sensitivity at 5% FPR (95% CI) (studies)		Ratio of DORs (95% CI); P value	Sensitivity at 5% FPR (95% CI) (studies)		Ratio of DORs (95% CI); P value	Sensitivity at 5% FPR (95% CI) (studies)
	Ratio of DORs (95% CI); P value	Screening (n = 9)	High risk (n = 4)	Ratio of DORs (95% CI); P value	Screening (n = 46)	High risk (n = 4)	Ratio of DORs (95% CI); P value	Screening (n = 66)	High risk (n =3)
No FN correction	0.68 (0.26, 1.77); P = 0.40	73 (62, 81)	64 (45, 80)	0.34 (0.17, 0.69); P = 0.003	72 (68, 76)	47 (31, 63)	0.41 (0.16, 1.00); P = 0.05	88 (86, 89)	74 (54, 88)
FN increased +10%	0.69 (0.27, 1.78); P = 0.40	70 (59, 79)	62 (42, 78)	0.40 (0.20, 0.82); P = 0.01	69 (64, 73)	47 (31, 64)	0.48 (0.19, 1.20); P = 0.11	86 (84, 87)	74 (53, 88)
FN increased +20%	0.74 (0.29, 1.92); P = 0.50	69 (57, 78)	62 (42, 78)	0.43 (0.21, 0.89); P = 0.02	67 (63, 71)	47 (31, 64)	0.51 (0.20, 1.28); P = 0.15	85 (83, 87)	74 (54, 88)
FN increased +30%	0.81 (0.31, 2.09); P = 0.63	67 (55, 76)	62 (42, 78)	0.46 (0.22, 0.97); P = 0.04	66 (61, 70)	47 (30, 64)	0.55 (0.22, 1.38); P = 0.20	84 (82, 86)	74 (54, 88)
FN increased +40%	0.76 (0.29, 2.02); P = 0.55	66 (53, 76)	59 (39, 77)	0.50 (0.24, 1.02); P = 0.06	64 (60, 68)	47 (31, 64)	0.59 (0.24, 1.48); P = 0.26	83 (81, 85)	74 (54, 88)
FN increased +50%	0.81 (0.30, 2.15): P = 0.65	64 (52, 75)	59 (39, 77)	0.52 (0.25, 1.08); P = 0.08	63 (58, 67)	47 (30, 64)	0.62 (0.25, 1.56); P = 0.31	82 (80, 84)	74 (54, 88)
DOR = diagnostic odds ratio

Table 4. Investigation of the effect of type of population

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Table Tests. Data tables by test

Test	No. of studies	No. of participants
1 Aberrant right subclavian artery Show forest plot	1	425

2 Frontomaxillary facial angle >95 percentile Show forest plot	1	242

3 Presence of mitral gap Show forest plot	1	217

4 Maxillary bone length, 5% percentile Show forest plot	1	927

5 Tricuspid regurgitation Show forest plot	1	312

6 Iliac angle 90 degrees Show forest plot	1	2032

7 Ductus venosus a‐wave reversed Show forest plot	1	378

8 Ductus venosus pulsivity index > 95 percentile Show forest plot	1	378

9 Nasal bone, mixed cut‐points Show forest plot	11	48279

10 NT, 2.5 mm Show forest plot	4	11835

11 NT, 3 mm Show forest plot	6	10381

12 NT, 5FPR Show forest plot	3	63885

13 NT, mixed cut‐points Show forest plot	13	90978

14 NT and age, risk 1:100 Show forest plot	1	10668

15 NT and age, risk 1:250 Show forest plot	10	79412

16 NT and age, risk 1:300 Show forest plot	23	252811

17 NT and age, 1FPR Show forest plot	4	98453

18 NT and age, 3FPR Show forest plot	4	98453

19 NT and age, 5FPR Show forest plot	22	288853

20 NT and age, mixed cut‐points Show forest plot	50	530874

21 NT and nasal bone, Absent NB + NT ≥ 95th centile Show forest plot	1	486

22 Ductus and age, risk 1:250 Show forest plot	1	3731

23 Ductus and age, 5FPR Show forest plot	2	3965

24 Ductus and age, mixed cut‐points Show forest plot	5	5331

25 Ductus, NT and age, risk 1:100 Show forest plot	1	19736

26 Ductus, NT and age, risk 1:250 Show forest plot	1	3727

27 Ductus, NT and age, 5FPR Show forest plot	2	3961

28 Ductus, NT and age, mixed cut‐points Show forest plot	3	23697

29 Age and nasal bone, mixed cut‐points Show forest plot	4	25303

30 Age, NT and tricuspid blood flow, risk 1:100 Show forest plot	1	19736

31 Age, NT and nasal bone, risk 1:100 Show forest plot	1	19736

32 Age, NT and nasal bone, risk 1:300 Show forest plot	4	9963

33 Age, NT and nasal bone, mixed cut‐points Show forest plot	5	29699

34 Age, NT, nasal bone and ductus, risk NT>1:300 AND abnormal DV flow AND absent NB Show forest plot	1	544

35 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot	1	20305

36 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot	3	41842

37 Age, NT and free ßhCG, 1st trimester, 5FPR Show forest plot	4	4986

38 Age, NT and free ßhCG, 1st trimester, risk 1:240 Show forest plot	1	5809

39 Age, NT and free ßhCG, 1st trimester, mixed cut‐points Show forest plot	5	10795

40 Age, NT and PAPP‐A, 1st trimester, risk 1:100 Show forest plot	1	1507

41 Age, NT and PAPP‐A, 1st trimester, risk 1:185 Show forest plot	1	5809

42 Age, NT and PAPP‐A, 1st trimester, 5FPR Show forest plot	3	2498

43 Age, NT and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot	5	9814

44 Age, NT and total hCG, 1st trimester, 5FPR Show forest plot	1	1110

45 Age, NT and AFP, 1st trimester, 5FPR Show forest plot	1	1110

46 Age, NT and ITA, 1st trimester, 5FPR Show forest plot	1	278

47 Age, NT and inhibin, 1st trimester, risk 1:100 Show forest plot	1	40

48 Age, NT and inhibin, 1st trimester, risk 1:250 Show forest plot	1	40

49 Age, NT and inhibin, 1st trimester, risk 1:400 Show forest plot	1	40

50 Age, NT and inhibin, 1st trimester, 5FPR Show forest plot	1	1110

51 Age, NT and inhibin, 1st trimester, mixed cut‐points Show forest plot	2	1150

52 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:100 Show forest plot	10	102332

53 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:150 Show forest plot	5	177643

54 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:200 Show forest plot	8	135768

55 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:220 Show forest plot	1	2231

56 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:250 Show forest plot	25	174712

57 Age, NT, PAPP‐A and free ßhCG, 1st trimester, risk 1:300 Show forest plot	29	544681

58 Age, NT, PAPP‐A and free ßhCG, 1st trimester, 1FPR Show forest plot	7	88874

59 Age, NT, PAPP‐A and free ßhCG, 1st trimester, 3FPR Show forest plot	9	312680

60 Age, NT, PAPP‐A and free ßhCG, 1st trimester, 5FPR Show forest plot	24	391874

61 Age, NT, PAPP‐A and free ßhCG, 1st trimester, mixed cut‐points Show forest plot	69	1173853

62 Age, NT, PAPP‐A and uE3, 1st trimester, 5FPR Show forest plot	1	576

63 Age, NT, PAPP‐A and ITA, 1st trimester, 5FPR Show forest plot	2	11053

64 Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:100 Show forest plot	1	40

65 Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:250 Show forest plot	1	40

66 Age, NT, PAPP‐A and inhibin, 1st trimester, risk 1:400 Show forest plot	1	40

67 Age, NT, PAPP‐A and inhibin, 1st trimester, 5FPR Show forest plot	1	1110

68 Age, NT, PAPP‐A and inhibin, 1st trimester, mixed cut‐points Show forest plot	2	1150

69 Age, NT, PAPP‐A and ADAM12, 1st trimester, 5FPR Show forest plot	2	1042

70 Age, NT, PAPP‐A and ADAM12, 1st trimester, risk 1:250 Show forest plot	1	691

71 Age, NT, free ßhCG and ADAM12, 1st trimester, 5FPR Show forest plot	1	351

72 Age, NT, AFP and free ßhCG, 1st trimester, risk 1:250 Show forest plot	1	1656

73 Age, NT, AFP and free ßhCG, 1st trimester, 5FPR Show forest plot	1	1110

74 Age, NT, AFP and free ßhCG, 1st trimester, mixed cut‐points Show forest plot	2	2766

75 Age, NT, AFP and PAPP‐A, 1st trimester, 5FPR Show forest plot	1	1110

76 Age, NT, total hCG and PAPP‐A, 1st trimester, 5FPR Show forest plot	1	1110

77 Age, NT, total hCG and inhibin, 1st trimester, 5FPR Show forest plot	1	1110

78 Age, NT, free ßhCG and inhibin, 1st trimester, 5FPR Show forest plot	1	1110

79 Age, NT, PAPP‐A, free ßhCG, 1st trimester serum, ductus venosus pulsivity index, 5FPR Show forest plot	1	7250

80 Age, free ßhCG and PAPP‐A, if risk 1:42‐1:1000, NT, final 1:250 risk Show forest plot	1	10189

81 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:100 Show forest plot	2	26986

82 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, risk 1:250 Show forest plot	2	10325

83 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot	2	10325

84 Age, NT, ductus, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot	3	30061

85 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:100 Show forest plot	1	19736

86 Age, NT, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:300 Show forest plot	1	1801

87 Age, NT, tricuspid blood flow, free ßhCG and PAPP‐A, 1st trimester, risk 1:100 Show forest plot	1	19736

88 Age, NT, fetal heart rate, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot	2	76385

89 Age, NT, fetal heart rate, nasal bone, free ßhCG and PAPP‐A, 1st trimester, risk 1:200 Show forest plot	1	19736

90 age, NT, fetal heart rate, ductus, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot	1	19614

91 Age, NT, fetal heart rate, tricuspid blood flow, free ßhCG and PAPP‐A,1st trimester, 5FPR Show forest plot	1	19736

92 Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, risk 1:250 Show forest plot	1	5483

93 Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, 5FPR Show forest plot	2	1306

94 Age, NT, AFP, free ßhCG and PAPP‐A, 1st trimester, mixed cut‐points Show forest plot	3	6789

95 Age, NT, total hCG, inhibin and PAPP‐A, 1st trimester, 5FPR Show forest plot	1	1110

96 Age, NT, PAPP‐A, free ßhCG and PGH, 1st trimester, 5FPR Show forest plot	1	335

97 Age, NT, PAPP‐A, free ßhCG and GHBP, 1st trimester, 5FPR Show forest plot	1	335

98 Age, NT, PAPP‐A, free ßhCG and PIGF, 1st trimester, 5FPR Show forest plot	2	1443

99 Age, NT, PAPP‐A, free ßhCG and total hCG, 1st trimester, 5FPR Show forest plot	1	998

100 Age, NT, PAPP‐A, free ßhCG and PP13, 1st trimester, 5FPR Show forest plot	1	998

101 Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, 5FPR Show forest plot	4	2571

102 Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, risk 1:250 Show forest plot	2	1222

103 Age, NT, PAPP‐A, free ßhCG and ADAM12, 1st trimester, mixed cut‐points Show forest plot	4	2571

104 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:100 Show forest plot	1	40

105 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:250 Show forest plot	1	40

106 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, risk 1:400 Show forest plot	1	40

107 Age, NT, free ßhCG, PAPP‐A and inhibin, 1st trimester, 5FPR Show forest plot	1	1110

108 Age, NT, PAPP‐A, free ßhCG, ADAM12 and PlGH, 1st trimester, 5FPR Show forest plot	1	998

109 Age, NT, total hCG, inhibin, PAPP‐A, AFP and uE3, 1st trimester, 5FPR Show forest plot	1	1110

110 Age, NT, free ßhCG, inhibin, PAPP‐A, AFP and uE3,1st trimester, 5FPR Show forest plot	1	1110

111 Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG and PlGF, 1st trimester, 5FPR Show forest plot	1	998

112 Age, NT, PAPP‐A, free ßhCG, ADAM12, total hCG, PlGF and PP13, 1st trimester, 5FPR Show forest plot	1	998

113 NT, free ßhCG and PAPP‐A, 1st trimester incidence rate 63.3% Show forest plot	1	6508

114 NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age < 35 years Show forest plot	5	19057

115 NT, PAPP‐A, free ßhCG and maternal age ‐ maternal age ≥ 35 years Show forest plot	5	10980

Table Tests. Data tables by test

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