Urine tests for Down's syndrome screening

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

doi:10.1002/14651858.CD011984

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Figure 1

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 2

Detection rates (% sensitivity) at a 5% false positive rate for the five most evaluated or best performing test strategies. The estimates are shown with 95% confidence intervals. The test strategies are ordered on the plot according to decreasing detection rate. The number of studies, cases and women included for each test strategy are shown on the horizontal axis.

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Test 1

Betacore, 1st trimester urine test, 5% FPR.

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Test 2

Betacore, 2nd trimester urine test, 5% FPR.

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Test 3

Betacore, 2nd trimester urine test, cutpoint mixed.

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Test 4

Gonadotropin, 2nd trimester urine test, risk 1:100.

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Test 5

Gonadotropin, 2nd trimester urine test, risk 1:384.

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Test 6

Gonadotropin, 2nd trimester urine test, 95% percentile.

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Test 7

ITA, 1st trimester urine test, 5% FPR.

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Test 8

ITA, 2nd trimester urine test, 3.74MoM.

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Test 9

ITA, 2nd trimester urine test, 5% FPR.

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Test 10

Total hCG, 1st trimester urine test, 5% FPR.

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Test 11

Total hCG, 2nd trimester urine test, 5% FPR.

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Test 12

Free ßhCG, 1st trimester urine test, 5% FPR.

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Test 13

Free ßhCG, 2nd trimester urine test, 5% FPR.

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Test 14

Oestriol, 2nd trimester urine test, 5% FPR.

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Test 15

Betacore to oestriol ratio, 2nd trimester urine test, 5% FPR.

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Test 16

Betacore and oestriol, 2nd trimester 5% FPR.

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Test 17

AFP and ITA, 2nd trimester urine test, 3% FPR.

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Test 18

AFP and ITA, 2nd trimester urine test, 5% FPR.

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Test 19

AFP and ITA, 2nd trimester urine test,10% FPR.

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Test 20

AFP and ITA, 2nd trimester urine test, 15% FPR.

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Test 21

AFP, uE3 and ITA, 2nd trimester urine test, 3% FPR.

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Test 22

AFP, uE3 and ITA, 2nd trimester urine test, 5% FPR.

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Test 23

AFP, uE3 and ITA, 2nd trimester urine test, 10% FPR.

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Test 24

AFP, uE3 and ITA, 2nd trimester urine test, 15% FPR.

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Test 25

Age, betacore, 2nd trimester urine test, 1% FPR.

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Test 26

Age, betacore, 2nd trimester urine test, 3% FPR.

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Test 27

Age, betacore, 2nd trimester urine test, 5% FPR.

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Test 28

Age, betacore, 2nd trimester urine test, 10% FPR.

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Test 29

Age, betacore, 2nd trimester urine test, 15% FPR.

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Test 30

Age, betacore, 2nd trimester urine test, 20% FPR.

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Test 31

Age, ITA, 2nd trimester urine test, 5% FPR.

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Test 32

Age, oestriol, 2nd trimester urine test, 5% FPR.

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Test 33

Age, free ßhCG, 2nd trimester urine test, 5% FPR.

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Test 34

Age, betacore to oestriol ratio, 2nd trimester urine test, 1% FPR.

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Test 35

Age, betacore to oestriol ratio, 2nd trimester urine test, 3% FPR.

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Test 36

Age, betacore to oestriol ratio, 2nd trimester urine test, 5% FPR.

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Test 37

Age, free ßhCG to oestriol ratio, 2nd trimester urine test, 5% FPR.

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Test 38

Age, oestriol and free ßhCG, 2nd trimester, 5% FPR.

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Test 39

Age, betacore to free ßhCG ratio, 2nd trimester, 5% FPR.

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Test 40

Age, betacore and oestriol, 2nd trimester 1% FPR.

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Test 41

Age, betacore and oestriol, 2nd trimester, 3% FPR.

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Test 42

Age, betacore and oestriol, 2nd trimester, 5% FPR.

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Test 43

Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:10.

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Test 44

Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:20.

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Test 45

Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:30.

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Test 46

Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:58.

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Test 47

Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:270.

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Test 48

Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:526.

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Summary of findings Performance of urine tests with or without maternal age

Review Question	What is the accuracy of urine based markers for screening for Down's syndrome?
Population	Pregnant women at less than 24 weeks' gestation confirmed by ultrasound, who had not undergone previous testing for Down’s syndrome. Most studies were undertaken in women identified to be high risk based on maternal age
Settings	All settings
Numbers of studies, pregnancies and Down's syndrome cases	19 studies (reported in 29 publications) involving 18,013 pregnancies of which 527 were Down's syndrome pregnancies.
Index tests	Risk scores computed using maternal age and first and second trimester urine markers for AFP; ITA; ß‐core fragment; free ßhCG; total hCG; oestriol (also termed as uE3); gonadotropin peptide.
Reference standards	Chromosomal verification (amniocentesis and CVS undertaken during pregnancy, and postnatal karyotyping) and postnatal macroscopic inspection.
Study limitations	Seven studies only used selective chromosomal verification during pregnancy, and were at risk of under‐ascertainment of Down's syndrome cases due loss of the pregnancy to miscarriage between the serum test and the reference standard.

Test	Studies	Women (Cases)	*Sensitivity (95% CI)**	*Specificity (95% CI)**	Threshold
Test without maternal age
Single tests
First trimester free ßhCG	1	516 (86)	5 (1 to 11)	95 (92 to 97)	5% FPR
First trimester ß‐core fragment	1	516 (86)	10 (5 to 19)	95 (92 to 97)	5% FPR
First trimester ITA	2	579 (94)	15 (2 to 62)	95	5% FPR
First trimester total hCG	1	516 (86)	17 (10 to 27)	95 (92 to 97)	5% FPR
Second trimester oestriol	2	1472 (47)	23 (8 to 49)	95	5% FPR
Second trimester total hCG	1	390 (65)	31 (20 to 43)	95 (92 to 97)	5% FPR
Second trimester free ßhCG	3	1517 (107)	32 (12 to 63)	95	5% FPR
Second trimester ß‐core fragment	6	9613 (193)	41 (20 to 66)	95	5% FPR
Second trimester ITA	3	2748 (131)	43 (35 to 51)	95	5% FPR
Second trimester ß‐core fragment to oestriol ratio	2	1649 (35)	74 (58 to 86)	95	5% FPR
Second trimester gonadotropin test	1	105 (14)	93 (66 to 100)	95 (88 to 98)	1:384 risk
Double tests
Second trimester AFP and ITA	1	524 (24)	79 (58 to 93)	95 (93 to 97)	5% FPR
Second trimester ß‐core fragment and oestriol	1	315 (24)	83 (63 to 95)	95 (92 to 97)	5% FPR
Triple tests
Second trimester AFP, uE3 and ITA	1	524 (24)	79 (58 to 93)	95 (93 to 97)	5% FPR
Test with maternal age
Single tests
Second trimester oestriol	1	474 (69)	49 (37 to 62)	95 (92 to 97)	5% FPR
Second trimester ß‐core fragment	5	3419 (155)	56 (45 to 66)	95	5% FPR
Second trimester free ßhCG	2	879 (98)	57 (47 to 67)	95	5% FPR
Second trimester free ßhCG to oestriol ratio	1	474 (69)	64 (51 to 75)	95 (92 to 97)	5% FPR
Second trimester ß‐core fragment to free ßhCG	1	474 (69)	67 (54 to 78)	95 (92 to 97)	5% FPR
Second trimester ITA	1	1016 (23)	70 (47 to 87)	95 (93 to 96)	5% FPR
Second trimester ß‐core fragment to oestriol ratio	3	2088 (105)	71 (51 to 86)	95	5% FPR
Double tests
Second trimester oestriol and free ßhCG	1	474 (69)	68 (56 to 79)	95 (92 to 97)	5% FPR
Second trimester ß‐core fragment and oestriol	2	1631 (92)	73 (57 to 85)	95	5% FPR
Second trimester AFP and ß‐core fragment to oestriol ratio	1	356 (10)	90 (55 to 100)	95 (93 to 97)	1:58 risk
Tests evaluated by at least one study are presented in the table. Where two studies reported the same threshold, estimates of summary sensitivity and summary specificity were obtained by using univariate fixed effects logistic regression models to pool sensitivities and specificities separately. if the threshold used was a 5% FPR, then only the sensitivities were pooled. AFP:* alpha‐fetoprotein; ßhCG: beta human chorionic gonadotrophin;CI: confidence interval; CVS: chorionic villus sampling; FPR: false positive rate; hCG: beta human chorionic gonadotrophin;ITA: invasive trophoblast antigen; uE3: unconjugated oestriol

Summary of findings Performance of urine tests with or without maternal age

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Table 1. Direct comparisons of the diagnostic accuracy of five urine tests in combination with maternal age

Ratio of DORs (95% CI); P values (studies)	Second trimester AFP and ß‐core fragment to oestriol ratio, risk 1:58	Second trimester ß‐core fragment and oestriol, 5% FPR	Second trimester ITA, 5% FPR	Second trimester ß‐core fragment to oestriol ratio, 5% FPR
Second trimester ß‐core fragment and oestriol, 5% FPR	–
Second trimester ITA, 5% FPR	–	–
Second trimester ß‐core fragment to oestriol ratio, 5% FPR	–	1.5 (0.7 to 3.0); P = 0.27 (K = 2)
Second trimester ß‐core fragment, 5% FPR	–	2.2 (1.1 to 4.5); P = 0.02 (K = 2)	–	1.5 (0.8 to 2.8); P = 0.21 (K = 3)
Direct comparisons were made using only data from studies that compared each pair of tests in the same population. Ratio of diagnostic odds ratios (DOR)s were computed by division of the DOR for the test in the column by the DOR for the test in the row. If the ratio of DORs is greater than one, then the diagnostic accuracy of the test in the column is higher than that of the test in the row; if the ratio is less than one, the diagnostic accuracy of the test in the row is higher than that of the test in the column. AFP: alpha‐fetoprotein; CI: confidence interval; DORs: diagnostic odds ratio; FPR: false positive rate; ITA: invasive trophoblast antigen

Table 1. Direct comparisons of the diagnostic accuracy of five urine tests in combination with maternal age

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Table 2. Indirect comparisons of the diagnostic accuracy of five urine tests in combination with maternal age

Ratio of DOR (95% CI); P value			Second trimester AFP and ß‐core fragment to oestriol ratio, risk 1:58	Second trimester ß‐core fragment and oestriol, 5% FPR	Second trimester ITA, 5% FPR	Second trimester ß‐core fragment to oestriol ratio, 5% FPR
		Studies	1	2	1	3
	Studies	DOR (95% CI)	186 (22, 1560)	50 (30 to 84)	43 (17 to 110)	38 (24 to 59)
Second trimester ß‐core fragment and oestriol, 5% FPR	2	50 (30 to 84)	3.7 (0.4 to 33.0); P = 0.24
Second trimester ITA, 5% FPR	1	43 (17 to 110)	4.3 (0.4 to 44.0); P = 0.22	1.2 (0.4 to 3.4); P = 0.78
Second trimester ß‐core fragment to oestriol ratio, 5% FPR	3	38 (24 to 59)	4.9 (0.6 to 43.4); P = 0.15	1.3 (0.7 to 2.6); P = 0.41	1.1 (0.4 to 3.2); P = 0.80
Second trimester ß‐core fragment, 5% FPR	5	25 (18 to 36)	7.3 (0.8 to 63.1); P = 0.07	2.0 (1.1 to 3.7); P = 0.03	1.7 (0.6 to 4.6); P = 0.30	1.5 (0.8 to 2.6); P = 0.18
Indirect comparisons were made using all available data. Ratio of diagnostic odds ratios (DOR)s were computed by division of the DOR for the test in the column by the DOR for the test in the row. If the ratio of DORs is greater than one, then the diagnostic accuracy of the test in the column is higher than that of the test in the row; if the ratio is less than one, the diagnostic accuracy of the test in the row is higher than that of the test in the column. AFP: alpha‐fetoprotein; CI: confidence interval; DORs: diagnostic odds ratio; FPR: false positive rate; ITA: invasive trophoblast antigen

Table 2. Indirect comparisons of the diagnostic accuracy of five urine tests in combination with maternal age

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Table Tests. Data tables by test

Test	No. of studies	No. of participants
1 Betacore, 1st trimester urine test, 5% FPR Show forest plot	1	516

2 Betacore, 2nd trimester urine test, 5% FPR Show forest plot	6	9613

3 Betacore, 2nd trimester urine test, cutpoint mixed Show forest plot	7	10124

4 Gonadotropin, 2nd trimester urine test, risk 1:100 Show forest plot	1	105

5 Gonadotropin, 2nd trimester urine test, risk 1:384 Show forest plot	1	105

6 Gonadotropin, 2nd trimester urine test, 95% percentile Show forest plot	1	105

7 ITA, 1st trimester urine test, 5% FPR Show forest plot	2	579

8 ITA, 2nd trimester urine test, 3.74MoM Show forest plot	1	2051

9 ITA, 2nd trimester urine test, 5% FPR Show forest plot	3	2748

10 Total hCG, 1st trimester urine test, 5% FPR Show forest plot	1	516

11 Total hCG, 2nd trimester urine test, 5% FPR Show forest plot	1	390

12 Free ßhCG, 1st trimester urine test, 5% FPR Show forest plot	1	516

13 Free ßhCG, 2nd trimester urine test, 5% FPR Show forest plot	3	1517

14 Oestriol, 2nd trimester urine test, 5% FPR Show forest plot	2	1472

15 Betacore to oestriol ratio, 2nd trimester urine test, 5% FPR Show forest plot	2	1649

16 Betacore and oestriol, 2nd trimester 5% FPR Show forest plot	1	315

17 AFP and ITA, 2nd trimester urine test, 3% FPR Show forest plot	1	524

18 AFP and ITA, 2nd trimester urine test, 5% FPR Show forest plot	1	524

19 AFP and ITA, 2nd trimester urine test,10% FPR Show forest plot	1	524

20 AFP and ITA, 2nd trimester urine test, 15% FPR Show forest plot	1	524

21 AFP, uE3 and ITA, 2nd trimester urine test, 3% FPR Show forest plot	1	524

22 AFP, uE3 and ITA, 2nd trimester urine test, 5% FPR Show forest plot	1	524

23 AFP, uE3 and ITA, 2nd trimester urine test, 10% FPR Show forest plot	1	524

24 AFP, uE3 and ITA, 2nd trimester urine test, 15% FPR Show forest plot	1	524

25 Age, betacore, 2nd trimester urine test, 1% FPR Show forest plot	2	2083

26 Age, betacore, 2nd trimester urine test, 3% FPR Show forest plot	2	2083

27 Age, betacore, 2nd trimester urine test, 5% FPR Show forest plot	5	3419

28 Age, betacore, 2nd trimester urine test, 10% FPR Show forest plot	1	926

29 Age, betacore, 2nd trimester urine test, 15% FPR Show forest plot	1	953

30 Age, betacore, 2nd trimester urine test, 20% FPR Show forest plot	1	926

31 Age, ITA, 2nd trimester urine test, 5% FPR Show forest plot	1	1016

32 Age, oestriol, 2nd trimester urine test, 5% FPR Show forest plot	1	474

33 Age, free ßhCG, 2nd trimester urine test, 5% FPR Show forest plot	2	879

34 Age, betacore to oestriol ratio, 2nd trimester urine test, 1% FPR Show forest plot	1	1157

35 Age, betacore to oestriol ratio, 2nd trimester urine test, 3% FPR Show forest plot	1	1157

36 Age, betacore to oestriol ratio, 2nd trimester urine test, 5% FPR Show forest plot	3	2088

37 Age, free ßhCG to oestriol ratio, 2nd trimester urine test, 5% FPR Show forest plot	1	474

38 Age, oestriol and free ßhCG, 2nd trimester, 5% FPR Show forest plot	1	474

39 Age, betacore to free ßhCG ratio, 2nd trimester, 5% FPR Show forest plot	1	474

40 Age, betacore and oestriol, 2nd trimester 1% FPR Show forest plot	1	1157

41 Age, betacore and oestriol, 2nd trimester, 3% FPR Show forest plot	1	1157

42 Age, betacore and oestriol, 2nd trimester, 5% FPR Show forest plot	2	1631

43 Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:10 Show forest plot	1	356

44 Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:20 Show forest plot	1	356

45 Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:30 Show forest plot	1	356

46 Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:58 Show forest plot	1	356

47 Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:270 Show forest plot	1	356

48 Age, AFP and betacore to oestriol ratio, 2nd trimester, risk 1:526 Show forest plot	1	356

Table Tests. Data tables by test

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