Genomics‐based non‐invasive prenatal testing for detection of fetal chromosomal aneuploidy in pregnant women

Mylène Badeau; Carmen Lindsay; Jonatan Blais; Leon Nshimyumukiza; Yemisi Takwoingi; Sylvie Langlois; France Légaré; Yves Giguère; Alexis F Turgeon; William Witteman; François Rousseau

doi:10.1002/14651858.CD011767.pub2

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Figure 1

Difference between massively parallel shotgun sequencing (MPSS) and targeted massively parallel sequencing (TMPS). Genomics‐based non‐invasive prenatal testing (gNIPT) aims to count the number of copies of DNA fragments from the chromosomes of interest (chromosome 21 (Chrom. 21) in this example) present in circulating cell‐free DNA (ccfDNA) from a pregnant woman, relative to a reference set of chromosomes (Ref. Chrom.). DNA fragments circulating in maternal blood in the case of a euploid (left) and aneuploid (right) pregnancy are illustrated (top). MPSS produces a large number of sequence reads from all chromosomes while TMPS generates a larger proportion of reads from the chromosomes of interest (bottom). In both methods, sequence reads can be used to detect a slight excess of fetal genomic material coming from the chromosome of interest. Figure was created by FR.

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Figure 2

Current clinical pathway and three proposed uses of genomics‐based non‐invasive prenatal testing (gNIPT). Currently (on the left), pregnant women can have a prenatal screening test consisting of biomarkers or ultrasound, or both. For high‐risk pregnant women, an invasive diagnostic test (karyotyping) is offered. In the present review, we propose 3 different clinical pathways. First, gNIPT could be used as a triage test, to decide which pregnant women should receive further testing. Second, gNIPT could be used to replace current prenatal screening tests. Finally, gNIPT could be used to replace current invasive diagnostic tests (if diagnostic performance permits). At any point in a clinical pathway, a pregnant woman may decide not to proceed with other tests (not shown in the figure). Figure was designed by CL, JB, MB and YT.

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Figure 3

PRISMA flow diagram for selection of studies from January 2007 to October 2016.

#: number, DTA: diagnostic test accuracy, NTIS: The National Technical Information Service and WHO ICTRP: World Health Organization International Clinical Trials Registry Platform.

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Figure 4

Risk of bias and applicability concerns summary: review authors' judgements about each domain for each of the studies included for massively parallel shotgun sequencing (MPSS).

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Figure 5

Risk of bias and applicability concerns summary: review authors' judgements about each domain for each study included for targeted massively parallel sequencing (TMPS).

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Figure 6

Risk of bias and applicability concerns (all tests included): review authors' judgements about each domains presented as percentages across included studies. MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing.

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Figure 7

Forest plot of MPSS and TMPS for T21 in unselected pregnant women undergoing aneuploidy screening. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 8

Forest plot of MPSS and TMPS for T21 in pregnant women selected at high risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 9

Forest plot of MPSS and TMPS for T18 in pregnant women selected at high risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 10

Forest plot of MPSS and TMPS for T13 in pregnant women selected at high risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 11

Forest plot of MPSS and TMPS for 45,X in pregnant women selected at high risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 12

Forest plot of MPSS and TMPS for 47,XXX, 47,XXY and 47,XYY in pregnant women selected at high risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 13

Forest plot of MPSS and TMPS for autosomes (T21, T18 and T13 combined) in unselected pregnant women undergoing aneuploidy screening. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 14

Forest plot of MPSS and TMPS for autosomes (T21, T18 and T13) in pregnant women selected at high risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 15

Forest plot of MPSS and TMPS for SCA (45,X, 47,XXX, 47,XXY and 47,XYY combined) in pregnant women selected at high risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 16

Forest plot of traditional screening tests for T21, T18 and T13 in unselected pregnant women undergoing aneuploidy screening. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 17

Forest plot of traditional screening tests for autosomes (T21, T18 and T13 combined) in unselected pregnant women undergoing aneuploidy screening. FN: false negative, FP: false positive, TN: true negative and TP: true positive.

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Figure 18

Forest plot of comparative studies of TMPS and traditional screening tests for autosomes (T21, T18 and T13 combined) in unselected pregnant women undergoing aneuploidy screening. FN: false negative, FP: false positive, TN: true negative and TP: true positive.

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Figure 19

Forest plot of traditional screening tests for autosomes (T21, T18 and T13 combined) in pregnant women with mixed prior risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 20

Forest plot of MPSS and TMPS for autosomes (T21, T18 and T13 combined) in pregnant women with mixed prior risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 21

Forest plot of MPSS and TMPS for T21, T18 or T13 in pregnant women with mixed prior risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 22

Forest plot of MPSS and TMPS for SCA (45,X, 47,XXX, 47,XXY and 47,XYY combined) in pregnant women with mixed prior risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Figure 23

Forest plot of MPSS and TMPS for 45,X, 47,XXY or 47,XYY in pregnant women with mixed prior risk of fetal aneuploidy. FN: false negative, FP: false positive, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, TN: true negative and TP: true positive.

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Test 1

MPSS T21.

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Test 2

MPSS T18.

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Test 3

MPSS T13.

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Test 4

MPSS 45,X.

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Test 5

MPSS 47, XXX.

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Test 6

MPSS 47,XXY.

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Test 7

MPSS 47,XYY.

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Test 8

MPSS all 7 aneuploidies.

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Test 9

MPSS, autosomes.

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Test 10

MPSS, SCA.

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Test 11

TMPS T21.

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Test 12

TMPS T18.

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Test 13

TMPS T13.

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Test 14

TMPS 45,X.

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Test 15

TMPS 47,XXX.

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Test 16

TMPS 47,XXY.

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Test 17

TMPS 47,XYY.

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Test 18

TMPS all 7 aneuploidies.

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Test 19

TMPS, autosomes.

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Test 20

TMPS, SCA.

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Test 21

Traditional screening tests, autosomes.

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Test 22

Traditional screening tests T21.

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Test 23

Traditional screening tests T18.

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Test 24

Traditional screening tests T13.

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Summary of findings 1. Summary characteristics of included studies

Summary characteristics of included studies
Review question	What is the diagnostic accuracy of massively parallel shotgun sequencing (MPSS) and targeted massively parallel sequencing (TMPS) using circulating cell‐free DNA (ccfDNA) in maternal blood for the detection of common fetal aneuploidies (T21, T18, T13, 45,X, 47,XXY, 47,XXX and 47,XYY) in pregnant women according to their prior risk of fetal aneuploidy?
Importance (rationale)	These new genomics‐based non‐invasive prenatal testing (gNIPT) approach report higher sensitivity and lower false positive rate than traditional screening tests. gNIPT is already advertised and marketed. How gNIPT should be used in clinical practice should be assessed in order to provide a framework for its use.
Study design	There were 40 prospective cohort studies, 8 retrospective cohort studies, 16 case‐control studies and 1 prospective and retrospective cohort study.
Population	Pregnant women of any age, ethnicity and gestational age, with singleton or multifetal pregnancy who had a screening test for fetal aneuploidy using gNIPT and received a reference standard. 42 studies enrolled pregnant women selected at high risk of fetal aneuploidy, 5 enrolled unselected pregnant women undergoing aneuploidy screening and 18 enrolled pregnant women from a mixed‐risk population of fetal aneuploidy. 48 studies included only women with singleton pregnancy, 5 included only multifetal pregnancies, 4 included either type of pregnancy and 8 did not report type of pregnancy. 10 studies included only women in the first trimester (15 weeks or less), 21 studies included women in the first 2 trimesters (29 weeks or less), 24 studies included women in the 3 trimesters (42 weeks or less) and 10 studies (15%) did not report gestational age.
Index tests	gNIPT by MPSS (44 studies) or TMPS (21 studies), including 5 studies that compared a gNIPT with a traditional screening test. 37 studies were industry‐funded or were written by 1 or more authors affiliated with a company who sells gNIPT. 22 studies were not reported to be funded by industry but samples were sequenced and analysed by a commercial laboratory. 3 studies had no links with industry.
Target conditions	36 studies reported results for only autosomes (T21, T18, T13), 4 for only SCA (45,X, 47,XXY, 47,XXX and 47,XYY), and 25 for both autosomes and SCA.
Reference standard	Fetal karyotyping performed on cells obtained from chorionic villi sampling, amniotic fluid, placental tissue, a fetus lost by miscarriage or other equivalent and recognised methods on the same materials for autosomes and SCA. If fetal karyotyping was not performed, we used neonatal clinical examination or medical records from birth (for autosomes only). Only 1 reference standard was used for all pregnant women included in 36 studies while multiple reference standards were used in 29 studies.
Risk of bias	The QUality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool was used to assess the methodological quality of included studies. No study was assessed as being at low risk of bias across all domains. For the patient selection domain, no study was assessed as being at low risk of bias. For the index test, reference standard and flow and timing domains, the risk of bias was low for 94%, 77% and 23% of studies, respectively.
Applicability concerns	Applicability was of low concern for all studies in the index test and reference standard domains because the studies matched the review question. In the patient selection domain, 47 (71%) studies were judged to be of low applicability concern because they included pregnant women matching the review question.
45,X: Turner syndrome, 47,XXX: triple X syndrome, 47,XXY: Klinefelter syndrome, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing, T21: trisomy 21, T18: trisomy 18, T13: trisomy 13.

Summary of findings 1. Summary characteristics of included studies

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Summary of findings 2. Performance of gNIPT for detection of T21

Performance of gNIPT for detection of T21
Test strategy	Number of studies	Number of affected pregnancies (Number of unaffected pregnancies)^a	Sensitivity % (95% CI)	Specificity % (95% CI)	Median prevalence^b % (range)	Missed cases (FN)^c	False positives (FP)^d
Unselected pregnant women
MPSS	1	8 (1733)	100 (67.6 to 100)	100 (99.8 to 100)	0.46 (0.24 to 5.21)	0	0
TMPS	4	88 (20,679)	99.2 (78.2 to 100)	100 (> 99.9 to 100)		4	0
Traditional screening test^e	1	38 (15,803)	78.9 (63.7 to 88.9)	94.6 (94.2 to 94.9)		97	5375
Implications	460 of 100,000 pregnancies expected to be affected by T21; MPSS will detect all cases and no pregnant woman will undergo an unnecessary invasive test; with TMPS, 4 cases will be missed and no pregnant woman will undergo unnecessary invasive test; and with traditional screening tests, 363 cases will be detected and 5375 unaffected pregnant women will undergo unnecessary invasive test.
Selected high‐risk pregnant women
MPSS	30	1048 (15,937)	99.7 (98.0 to 100)	99.9 (99.8 to 100)	4.95 (0.44 to 27.66)	15	95
TMPS	6	246 (4380)	99.2 (96.8 to 99.8)	100 (99.8 to 100)	4.95 (0.44 to 27.66)	40	0
Difference between MPSS and TMPS			0.53 (‐0.73 to 1.78)	‐0.03 (‐0.11 to 0.04)	NA
Implications	4950 of 100,000 pregnancies expected to be affected by T21; 4936 and 4911 cases will be detected while 15 and 40 cases will be missed by MPSS and TMPS, respectively; and of 95,050 expected pregnancies unaffected by T21, 95 and 0 pregnant women will undergo unnecessary invasive tests with MPSS and TMPS, respectively.
MPSS: massively parallel shotgun sequencing, NA; not applicable, TMPS: targeted massively parallel sequencing, T21: trisomy 21. ^aUnaffected pregnancies: we included patients with any other aneuploidy than the one under analysis with all euploid cases as "unaffected" pregnancies. ^bThe median prevalence and range were calculated by using all prospective or retrospective studies for each category considered. ^cMissed cases per 100,000 tested. FN: false negatives. ^dFalse positives per 100,000 tested. A false positive result may lead to unnecessary invasive tests depending on choices by the pregnant woman. ^eTraditional screening tests are first‐trimester combined test, second‐trimester quadruple test, second‐trimester fully integrated test, second‐trimester sequential test or second‐trimester triple test.

Summary of findings 2. Performance of gNIPT for detection of T21

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Summary of findings 3. Performance of gNIPT for detection of T18

Performance of gNIPT for detection of T18
Test strategy	Number of studies	Number of affected pregnancies (Number of unaffected pregnancies)^a	Sensitivity % (95% CI)	Specificity % (95% CI)	Median prevalence^b % (range)	Missed cases (FN)^c	False positives (FP)^d
Unselected pregnant women
MPSS	1	2 (1739)	100 (34.3 to 100)	99.9 (99.7 to 100)	0.11 (0.06 to 0.36)	0	100
TMPS	3	22 (20,553)	90.9 (70.0 to 97.7)	100 (99.9 to 100)		10	0
Traditional screening test^e	1	10 (15,831)	80.0 (49.0 to 94.3)	99.7 (99.6 to 99.8)		22	300
Implications	109 of 100,000 pregnancies expected to be affected by T18; MPSS will detect all cases and 100 unaffected pregnant women will undergo an unnecessary invasive test; with TMPS, 10 cases will be missed and no unaffected pregnant woman will undergo unnecessary invasive test; and with traditional screening tests, 87 cases will be detected, 22 will be missed and 300 unaffected pregnant women will undergo unnecessary invasive test.
Selected high‐risk pregnant women
MPSS	28	332 (16,180)	97.8 (92.5 to 99.4)	99.9 (99.8 to 100)	1.46 (0.22 to 17.02)	32	99
TMPS	5	112 (4010)	98.2 (93.1 to 99.6)	100 (99.8 to 100)	1.46 (0.22 to 17.02)	26	0
Difference between MPSS and TMPS			‐0.41 (‐4.11 to 3.28)	‐0.06 (‐0.14 to 0.03)	NA
Implications	1463 of 100,000 pregnancies expected to be affected by T18; 1431 and 1437 cases will be detected while 32 and 26 cases will be missed by MPSS and TMPS, respectively; and of 98,537 expected unaffected by T18, 99 and 0 pregnant women will undergo unnecessary invasive test with MPSS and TMPS, respectively.
MPSS: massively parallel shotgun sequencing, NA: not applicable, TMPS: targeted massively parallel sequencing, T18: trisomy 18. ^aUnaffected pregnancies: we included patients with any other aneuploidy than the one under analysis with all euploid cases as "unaffected" pregnancies. ^bThe median prevalence and range were calculated by using all prospective or retrospective studies for each category considered. ^cMissed cases per 100,000 tested. FN: false negatives. ^dFalse positives per 100,000 tested. A false positive result may lead to unnecessary invasive tests depending on choices by the pregnant woman. ^eTraditional screening tests are first‐trimester combined test, second‐trimester quadruple test, second‐trimester fully integrated test, second‐trimester sequential test or second‐trimester triple test.

Summary of findings 3. Performance of gNIPT for detection of T18

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Summary of findings 4. Performance of gNIPT for detection of T13

Performance of gNIPT for detection of T13
Test strategy	Number of studies	Number of affected pregnancies (Number of unaffected pregnancies)^a	Sensitivity % (95% CI)	Specificity % (95% CI)	Median prevalence^b % (range)	Missed cases (FN)^c	False positives (FP)^d
Unselected pregnant women
MPSS	1	1 (1740)	100 (20.7 to 100)	100 (99.8 to 100)	0. 12 (0.01 to 0.52)	0	0
TMPS	3	8 (14,154)	65.1 (9.16 to 97.2)	100 (99.9 to 100)		41	0
Traditional screening test^e	1	2 (11,183)	50.0 (9.45 to 90.5)	99.7 (99.6 to 99.8)		59	300
Implications	118 of 100,000 pregnancies expected to be affected by T13; MPSS will detect all cases and no unaffected pregnant woman will undergo an unnecessary invasive test; with TMPS, 41 cases will be missed and no unaffected pregnant woman will undergo unnecessary invasive test; and with traditional screening tests, 59 cases will be missed and 300 unaffected pregnant women will undergo unnecessary invasive test.
Selected high‐risk pregnant women
MPSS	20	128 (13,810)	95.8 (86.1 to 98.9)	99.8 (99.8 to 99.9)	1.09 (0.04 to 3.54)	46	198
TMPS	2	20 (293)	100 (83.9 to 100)^f	100 (98.7 to 100)^f	1.09 (0.04 to 3.54)	0	0
Implications	1087 of 100,000 pregnancies expected to be affected by T13; 1041 and 1087 cases will be detected while 46 and 0 cases will be missed by MPSS and TMPS, respectively; and of 98,913 expected unaffected by T13, 198 and 0 pregnant women will undergo unnecessary invasive test with MPSS and TMPS, respectively.
MPSS: massively parallel shotgun sequencing, NA: not applicable, TMPS: targeted massively parallel sequencing, T13: trisomy 13. ^aUnaffected pregnancies: we included patients with any other aneuploidy than the one under analysis with all euploid cases as "unaffected" pregnancies. ^bThe median prevalence and range were calculated by using all prospective or retrospective studies for each category considered. ^cMissed cases per 100,000 tested. FN: false negatives. ^dFalse positives per 100,000 tested. A false positive result may lead to unnecessary invasive tests depending on choices by the pregnant woman. ^eTraditional screening tests are first‐trimester combined test, second‐trimester quadruple test, second‐trimester fully integrated test, second‐trimester sequential test or second‐trimester triple test. ^fSimple pooling used to obtain summary estimates of sensitivity, specificity or both.

Summary of findings 4. Performance of gNIPT for detection of T13

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Summary of findings 5. Performance of gNIPT for detection of 45,X

Performance of gNIPT for detection of 45,X
Test strategy	Number of studies	Number of affected pregnancies (Number of unaffected pregnancies)^a	Sensitivity % (95% CI)	Specificity % (95% CI)	Median prevalence^b % (range)	Missed cases (FN)^c	False positives (FP)^d
Selected high‐risk pregnant women
MPSS	12	119 (7440)	91.7 (78.3 to 97.1)	99.6 (98.9 to 99.8)	1.04 (0.27 to 18.58)	86	396
TMPS	4	79 (985)	92.4 (84.1 to 96.5)	99.8 (98.3 to 100)	1.04 (0.27 to 18.58)	79	198
Difference between MPSS and TMPS			‐0.74 (‐11.1 to 9.60)	‐0.23 (‐0.82 to 0.36)	NA
Implications	1039 of 100,000 pregnancies expected to be affected by 45X; 953 and 960 cases will be detected while 86 and 79 cases will be missed by MPSS and TMPS, respectively; and of 98,961 expected unaffected by 45X, 396 and 198 pregnant women will undergo unnecessary invasive test with MPSS and TMPS, respectively.
45,X: Turner syndrome, MPSS: massively parallel shotgun sequencing, NA: not applicable, TMPS: targeted massively parallel sequencing. ^aUnaffected pregnancies: we included patients with any other aneuploidy than the one under analysis with all euploid cases as "unaffected" pregnancies. ^bThe median prevalence and range were calculated by using all prospective or retrospective studies for each category considered. ^cMissed cases per 100,000 tested. FN: false negatives. ^dFalse positives per 100,000 tested. A false positive result may lead to unnecessary invasive tests depending on choices by the pregnant woman.

Summary of findings 5. Performance of gNIPT for detection of 45,X

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Summary of findings 6. Performance of gNIPT for detection of autosomes aneuploidies (T21, T18 and T13 combined)

Performance of gNIPT for detection of autosomes aneuploidies (T21, T18 and T13 combined)
Test strategy	Number of studies	Number of affected pregnancies (Number of unaffected pregnancies)^a	Sensitivity % (95% CI)	Specificity % (95% CI)	Median prevalence^b % (range)	Missed cases (FN)^c	False positives (FP)^d
Unselected pregnant women
MPSS	1	11 (1730)	100 (74.1 to 100)	99.9 (99.7 to 100)	0,63 (0.32 to 5.73)	0	99
TMPS	4	118 (20,649)	94.9 (89.1 to 97.7)	99.9 (99.8 to 99.9)		32	99
Traditional screening test^e	4	120 (22,247)	ND^f			ND
Implications	632 of 100,000 pregnancies expected to be affected by T21, T18 or T13; 632 and 600 cases will be detected whereas 0 and 32 cases will be missed by MPSS and TMPS, respectively; and of 99,368 unaffected, 99 pregnant women will undergo unnecessary invasive test with MPSS or TMPS.
Selected high‐risk pregnant women
MPSS	32	1508 (15,797)	98.8 (97.2 to 99.5)	99.9 (99.7 to 100)	5.85 (0.67 to 46.81)	70	94
TMPS	7	378 (4282)	98.9 (97.2 to 99.6)	99.9 (99.8 to 100)	5.85 (0.67 to 46.81)	64	94
Difference between MPSS and TMPS			‐0.11 (‐1.58 to 1.35)	‐0.08 (‐0.22 to 0.07)	NA
Implications	5851 of 100,000 pregnancies expected to be affected by T21, T18 or T3; 5781 and 5787 cases will be detected, whereas 70 and 64 cases will be missed by MPSS and TMPS, respectively; and of 94,149 unaffected, 94 pregnant women will undergo unnecessary invasive test with MPSS or TMPS.
MPSS: massively parallel shotgun sequencing, NA: not applicable, ND: no data available, TMPS: targeted massively parallel sequencing, T13: trisomy 13, T18: trisomy 18, T21: trisomy 21. ^aUnaffected pregnancies: we included patients with any other aneuploidy than the one under analysis with all euploid cases as "unaffected" pregnancies. ^bThe median prevalence and range were calculated by using all prospective or retrospective studies for each category considered. ^cMissed cases per 100,000 tested. FN: false negatives. ^dFalse positives per 100,000 tested. A false positive result may lead to unnecessary invasive tests depending on choices by the pregnant woman. ^eTraditional screening tests are first‐trimester combined test, second‐trimester quadruple test, second‐trimester fully integrated test, second‐trimester sequential test or second‐trimester triple test. ^fSummary sensitivity and specificity were not obtained for traditional screening tests because the four studies used different cut‐offs to determine test positivity. Three of the four studies compared TMPS and traditional screening tests in the same population (direct comparison).

Summary of findings 6. Performance of gNIPT for detection of autosomes aneuploidies (T21, T18 and T13 combined)

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Summary of findings 7. Performance of gNIPT for detection of sex chromosome aneuploidies (45,X, 47,XXX, 47,XXY and 47,XYY combined)a

Performance of gNIPT for detection of sex chromosome aneuploidies (45,X, 47,XXX, 47,XXY and 47,XYY combined)
Test strategy	Number of studies	Number of affected pregnancies (Number of unaffected pregnancies)^b	Sensitivity % (95% CI)	Specificity % (95% CI)	Median prevalence^c % (range)	Missed cases (FN)^d	False positives (FP)^e
Selected high‐risk pregnant women
MPSS	12	151 (7452)	91.9 (73.8 to 97.9)	99.5 (98.8 to 99.8)	1.53 (0.45 to 18.58)	124	492
TMPS	4	96 (968)	93.8 (86.8 to 97.2)	99.6 (98.1 to 99.9)	1.53 (0.45 to 18.58)	95	394
Difference between MPSS and TMPS			‐1.85 (‐13.3 to 9.60)	‐0.06 (‐0.82 to 0.71)	NA
Implications	1535 of 100,000 pregnancies expected to be affected by SCA; 1411 and 1440 cases will be detected while 124 and 95 cases will be missed by MPSS and TMPS, respectively; of 98,465 unaffected by SCA, 492 and 394 pregnant women will undergo unnecessary invasive test with MPSS and TMPS, respectively.
45,X: Turner syndrome, 47,XXX: triple X syndrome, 47,XXY: Klinefelter syndrome, MPSS: massively parallel shotgun sequencing, NA: not applicable, ND: no data available, TMPS: targeted massively parallel sequencing ^aWe did not assess the accuracy of gNIPT individually for 47,XXX, 47,XXY and 47,XYY due to paucity data. ^bUnaffected pregnancies: we included patients with any other aneuploidy than the one under analysis with all euploid cases as "unaffected" pregnancies. ^cThe median prevalence and range were calculated by using all prospective or retrospective studies for each category considered. ^dMissed cases per 100,000 tested. FN: false negatives. ^eFalse positives per 100,000 tested. A false positive result may lead to unnecessary invasive tests depending on choices by the pregnant woman.

Summary of findings 7. Performance of gNIPT for detection of sex chromosome aneuploidies (45,X, 47,XXX, 47,XXY and 47,XYY combined)a

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Table 1. Characteristics of target conditions

Target condition	Affected births^a /100,000	Clinical features	Prognosis
T21	140 to 230^b,c	Intellectual disability (mild to moderate), neurodevelopmental problems, characteristic dysmorphic features, congenital defects (cardiac (44% to 58%) and gastrointestinal system (4% to 10%)), vision or hearing impairment (38% to 80%) and obstructive sleep apnoea syndrome (57%)^d,e	Mean and median life expectancies are estimated to be 51 and 58 years old^f
T18	59^c	Severe intellectual disability and a wide range of significant malformations (cardiac defects, gastrointestinal system defects, renal anomalies, central nervous system defects (apnoea and seizures))^d,g	Most affected fetuses die in utero. Median survival has been estimated at 14 days (95% confidence interval (CI) 10 to 20) and 8% (95% CI 4 to 14) reach 1 year of age^h
T13	23^c	Severe intellectual disability, seizures and several dysmorphic features, malformations of the extremities, cardiac defects, renal anomalies, and abdominal wall defects^d,i	Most affected fetuses die in utero. Median survival time has been estimated at 10 days (95% CI 7 to 19) and 8% (95% CI 4 to 14) reach 1 year of age^h
45,X	30 to 50^c,j	Learning disabilities (70%), short stature, congenital heart diseases (30%) and gonadal dysgenesis (90% with amenorrhoea and infertility due to early ovarian failure)^k,l	Mortality in 45,X women is 3‐fold higher than in the general population with an average life span of 69 years^m
47,XXY	12^c	Learning disabilities (> 75%), small testes (> 95%), azoospermia (> 95%), male infertility (91% to 99%), decreased testosterone level (63% to 85%) and gynaecomastia (38% to 75%)^l,n	Life expectancy is slightly shorter (approximately 2 years) than euploid menⁿ
47,XXX	6^c	Developmental delays (motor and speech), learning or intellectual disability, attention deficits (25% to 35%), mood disorders (anxiety and depression), tall stature (80% to 89%), clinodactyly (42% to 65%), hypotonia in infancy (55% to 71%), genitourinary malformations and congenital heart defects^o	Mortality significantly increased with a median survival age of 70.9 years compare to 81.7 years for euploid females^p
47,XYY	3^c	Developmental delays (speech, language and motor), attention deficit disorder (52%), tall stature (78%), central adiposity, macrocephaly (33%), hypotonia (63%), clinodactyly (52%), hypertelorism (59%) and testicular enlargement for age (50%) but no increase in genital anomalies^q	Mortality increased with a reduction of life span of 10.3 years compared to euploid men^r
45,X: Turner syndrome, 47,XXX: triple X syndrome, 47,XXY: Klinefelter syndrome, T21: trisomy 21, T18: trisomy 18, T13: trisomy 13. ^aIncluding live births, fetal deaths and terminations of pregnancy. ^b(Christianson 2006; Parker 2010) ^c(Wellesley 2012) ^d(Driscoll 2009) ^e(Irving 2012; Weijerman 2010) ^f(Wu 2013b) ^g(Cereda 2012) ^h(Wu 2013a) ⁱ(Chen 2009) ^j(Stochholm 2006) ^k(Karnis 2012; Mazzanti 1998; Sybert 2004) ^l(Tyler 2004) ^m(Saenger 1996; Schoemaker 2008) ⁿ(Groth 2013) ^o(Tartaglia 2010) ^p(Stochholm 2010b) ^q(Bardsley 2013; Leggett 2010) ^r(Stochholm 2010a).

Table 1. Characteristics of target conditions

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Table 2. Reported accuracy of commercially available genomics‐based non‐invasive prenatal testsa

Test name (Company, country)	Method	Aneuploidy	Reported sensitivity % (95% CI)	Reported specificity % (95% CI)	Reported false positive rate %
Bambni™ Test (Berry Genomics Co. Ltd, China)	MPSS	T21	100.0 (ND)	> 99.9 (ND)	< 0.1
		T18	100.0 (ND)	> 99.9 (ND)	< 0.1
		T13	100.0 (ND)	> 99.9 (ND)	< 0.1
		45,X	100.0 (ND)	99.8 (ND)	0.0
		47,XXX	100.0 (ND)	100.0 (ND)	0.1
		47,XXY	100.0 (ND)	100.0 (ND)	0.0
		47,XYY	100.0 (ND)	100.0 (ND)	0.0
GENOMOM (Genome Care, Korea)	MPSS	T21, T18 and T13	99.0 (ND)	ND	ND
GENOMOM (Genome Care, Korea)	MPSS	SCA	95.0 (ND)	ND	ND
Harmony™ prenatal test (Ariosa Diagnostics, Inc., USA)	Oligo TMPS	T21	> 99.0 (ND)	> 99.9 (ND)	< 0.1
		T18	97.4 (ND)	> 99.9 (ND)	< 0.1
		T13	93.8 (ND)	> 99.9 (ND)	< 0.1
		45,X^b	96.3 (81.7 to 99.8)	99.5 (98.1 to 99.9)	0.5
		47,XXX^b	100.0 (ND)	99.5 (98.1 to 99.9)	0.5
		47,XXY^b	100.0 (61.0 to 100.0)	100.0 (99.0 to 100.0)	0.0
IONA^® test (Premaitha Health plc, UK)	MPSS	T21	> 99.0 (ND)	> 99.0 (ND)	< 1.0
		T18	> 99.0 (ND)	> 99.0 (ND)	< 1.0
		T13	> 99.0 (ND)	> 99.0 (ND)	< 1.0
(Laboratoire CERBA, France)	MPSS	T21, T18 and T13	> 99.8 (ND)	> 99.8 (ND)	< 0.2
MaterniT21™ Plus test (Sequenom Inc., USA)	MPSS	T21	99.1 (96.6 to 99.9)	99.9 (99.7 to 99.9)	0.1
		T18	> 99.9 (93.9 to 100.0)	99.6 (99.3 to 99.7)	0.4
		T13	91.7 (61.0 to 99.0)	99.7 (98.5 to 99.5)	0.3
		combined sex aneuploidies	96.2 (ND)	99.7 (ND)	0.3
MomGuard™ (LabGenomics, Korea)	MPSS	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	> 99.0 (ND)	ND	ND
NIFTY™ test (Bejing Genomics Institute (BGI), China)	MPSS	T21	99.2 (ND)	100 (ND)	0
		T18	98.2 (ND)	100 (ND)	0
		T13	100 (ND)	100 (ND)	0
		45,X	> 99.9 (ND)	> 99.9 (ND)	< 0.1
Panorama™ prenatal test^c (Natera, Inc., USA)	SNP TMPS	T21	> 99.9 (ND)	100 (ND)	0
		T18	> 96.4 (ND)	> 99.9 (ND)	< 0.1
		T13	> 99.9 (ND)	100 (ND)	0
		45,X	> 92.9 (ND)	> 99.9 (ND)	< 0.1
PrenaTest^® (LifeCodexx AG, Germany)	MPSS	T21	98.7 (ND)	99.9 (ND)	0.1
		T18	100 (ND)
		T13	100 (ND)
		45,X	90.9 (ND)	98.8 (ND)	1.2
		47,XYY	100 (ND)	98.8 (ND)	1.2
Prendia (Genesupport, Switzerland)	MPSS	T21	100.0 (88.8 to 100.0)	100.0 (98.0 to 100.0)	0.0
		T18	95.8 (76.8 to 99.7)	100.0 (97.0 to 100.0)	0.0
		T13	100.0 (74.6 to 100.0)	100.0 (98.1 to 100.0)	0.0
		45,X	100.0 (74.6 to 100.0)	100.0 (98.1 to 100.0)	0.0
		47,XXX	100.0 (46.2 to 100.0)	100.0 (98.2 to 100.0)	0.0
Tranquility (Genoma, Switzerland)	MPSS	T21	99.9 (ND)	99.8 (ND)	0.2
		T18	99.9 (ND)	99.9 (ND)	0.1
		T13	99.9 (ND)	99.7 (ND)	0.3
verifi^® prenatal test (Illumina, Inc., USA)	MPSS	T21	99.5 (98.7 to 99.5)	99.8 (98.9 to 99.9)	0.2
		T18	97.3 (94.2 to 98.2)	99.7 (99.5 to 99.9)	0.3
		T13	98.0 (95.6 to 98.9)	99.8 (99.8 to 99.9)	0.2
		45,X	95.0 (75.1 to 99.9)	99.0 (97.6 to 99.7)	1.0
VisibiliT™ (Sequenom Inc., USA)	MPSS	T21	> 99.0 (80.8 to 100)	> 99.9 (99.5 to 100)	< 0.1
VisibiliT™ (Sequenom Inc., USA)	MPSS	T18	> 99.0 (65.5 to 100)	> 99.9 (99.5 to 100)	< 0.1
45,X: Turner syndrome, 47,XXX: triple X syndrome, 47,XXY: Klinefelter syndrome, T21: trisomy 21, T18: trisomy 18, T13: trisomy 13 CI: confidence interval, MPSS: massively parallel shotgun sequencing, ND: no data available, TMPS: targeted massively parallel sequencing and SNP: single nucleotide polymorphism. ^a(Ariosa Diagnostics 2016; BGI 2014; BGI 2016; Berry Genomics 2016; Genoma 2016; Genome Care 2016; Illumina 2014; Illumina 2016; LabGenomics 2016; LifeCodexx 2016; Natera 2016; Genesupport 2016; Premaitha Health plc 2016; Sequenom 2016). ^b(Hooks 2014). ^cDNA of maternal and paternal origin are needed.

Table 2. Reported accuracy of commercially available genomics‐based non‐invasive prenatal testsa

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Table 3. Traditional screening tests (mostly for T21)a

Screening tests

First trimester

(before 14 weeks’ gestation)

Second trimester

(14 to 20 weeks’ gestation)

Ultrasonography

NT measurement

Various morphologic measurements that modify the prior risk established

Combined test

hCG (free β or total)

PAPP‐A

NT measurement

Triple test

hCG (free β or total)

Quadruple test

hCG (free β or total)

inhibin A

Sequential test^b

free β hCG

PAPP‐A

NT measurement

Invasive test is offered if 1^st trimester result is positive

Quadruple test is offered if 1^st trimester result is negative

Contingent test^b

free β hCG

PAPP‐A

NT measurement

Invasive test is offered if 1^st trimester result is positive

Quadruple test is offered after an intermediate 1^st trimester result

No test is offered after a low‐risk result

Serum integrated test^c

PAPP‐A

Triple or Quadruple test

Integrated test^c

PAPP‐A

NT measurement

Quadruple test

Maternal age is often included in the algorithm for prenatal screening tests. AFP: alpha‐fetoprotein, hCG: human chorionic gonadotropin, NA: not applicable, NT: nuchal translucency, PAPP‐A: pregnancy associated plasma protein A and uE3: unconjugated estriol.

^a(Gekas 2009; Okun 2008; Wald 2005).
^bA test result was available after first‐trimester screening test.
^cSingle test result available after second‐trimester screening test.

Table 3. Traditional screening tests (mostly for T21)a

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Table 4. Characteristics of included studies by type of gNIPT

Study ID	Target condition(s)	Study design and participants	Prior risk	Index test details	Cutpoint	Reference standard	Comparator
MPSS
Alberti 2015	T21	Case‐control study (1:2) from a prospective cohort 976 singleton pregnancies enrolled, 183 were analysed	High risk	Illumina HiSeq 2000 sequencer without multiplexing In‐house test FF measured	Z score of 3	Fetal karyotype^a
Benachi 2015	T21, T18, T13	Blinded retrospective study 900 singleton or twin pregnancies enrolled, 886 were analysed	High risk	Illumina v3 flow‐cell on a HiSeq 1500 sequencer in 12‐plex Commercial ‐ Laboratoire CERBA FF measured	Z score of 3 for T21; 3.95 for T18 and T13	Fetal karyotype or neonatal clinical examination
Bianchi 2012	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	Nested case‐control study (1:4) from a prospective cohort (MELISSA) 2882 singleton pregnancies enrolled, 503 for T21, 502 for T18, 501 for T13 and 489 for 45,X were analysed	High risk	Illumina HiSeq 2000 sequencer in 6‐plex Commercial test ‐ Verinata FF measured	Different cutpoints used for autosomes and SCA^b	Fetal karyotype
Bianchi 2013	T21, T18, T13, 45,X	Retrospective study from stored plasma 2882 singleton pregnancies enrolled, 113 were analysed	High risk	Illumina TrueSeq 3.0 sequencing chemistry Commercial test ‐ Verinata	Different cutpoints used for autosomes and SCA^b	Fetal karyotype
Bianchi 2014a	T21, T18, T13	Blinded prospective cohort study 2052 singleton pregnancies enrolled, 1952 for T21 and T18, and 1914 for T13 were analysed	High, low and without prior risk	Illumina HiSeq 2000 in 8‐plex Commercial ‐ verifi^® prenatal test FF measured	NCV of 4; resequenced if NCV is between 3 and 4	Fetal or postnatal karyotype, neonatal clinical examination or medical record from birth	Standard screening (T21 only with mixed cutpoints) which include first‐trimester combined test or a second‐trimester result (quadruple, serum integrated, fully integrated, or sequential).
Bijok 2014	T21, T18, T13	Prospective cohort study 10 singleton pregnancies enrolled, 9 were analysed	High risk	IIIumina Genome Analyzer IIx or HiSeq 2000 sequencer in multiplex Commercial ‐ NIFTY™ test, BGI‐Shenzhen FF measured	NR	Fetal karyotype
Canick 2012	T21, T18, T13	Case‐control study 4664 pregnant women enrolled, 27 multifetal pregnancies were analysed	High risk	Illumina HiSeq 2000 sequencer in 4‐plex Commercial test ‐ Sequenom, Inc. FF measured	Z score of 3	Fetal karyotype
Chen 2011	T18, T13	Nested case‐control study from prospective and retrospective cohorts 392 singleton pregnancies enrolled, 289 were analysed	High risk	Illumina Genome Analyzer IIx in 2‐plex Commercial test ‐ Sequenom, Inc.	Z score of 3	Fetal karyotype
Chiu 2011	T21	Blinded case‐control study (1:5) from prospective and retrospective cohorts 824 singleton pregnancies enrolled, 753 were analysed by 8‐plex method and 314 by 2‐plex method	Mostly high (> 1/300) and some intermediate risk (between 1/300 and 1/1000)	Illumina Genome Analyzer II in 8‐plex and 2‐plex Commercial test ‐ Sequenom, Inc. FF measured	Z score of 3	Fetal karyotype
Ehrich 2011	T21	Blinded case‐control study (1:11) from prospective cohort 480 pregnant women enrolled, 449 were analysed	High risk	Illumina Genome Analyzer IIx sequencer in 4‐plex Commercial test ‐ Sequenom, Inc. FF measured	Z score of 2.5	Fetal karyotype
Fiorentino 2016	T21, T18, T13	Blinded prospective cohort study 7103 singleton pregnancies enrolled, 7082 were analysed	Mostly high risk and without prior risk	Illumina HiSeq 2500 sequencer in 15‐plex, SAFeR™ algorithm. Commercial ‐ Genoma's prenatal test FF measured	NCV of 4; aneuploidy suspected if NCV is between 3 and 4	Fetal karyotype or neonatal clinical examination
Hou 2012	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	Prospective cohort study 308 singleton pregnancies enrolled, 205 were analysed	High risk	IIIumina HiSeq 2000 sequencer Commercial test ‐ BGI‐Shenzhen	NR	Fetal karyotype
Huang 2014	T21, T18	Blinded prospective cohort study 189 twin pregnancies enrolled, 189 were analysed	High risk	IIIumina Genome Analyzer IIx or HiSeq 2000 sequencer Commercial test ‐ BGI‐Shenzhen	L score of 1 and t score of 2.5 including warning zone	Fetal karyotype
Jeon 2014	T21, T18	Prospective cohort study 155 singleton pregnancies enrolled, 155 were analysed	High risk	Ion Torrent PGM or HiSeq 2000 sequencers, 10 samples per Chip Commercial test ‐ Genome Care	Z score of 2.566 for T21; 2.459 for T18.	Fetal karyotype
Jiang 2012	T21, T18, T13, 45,X, 47,XXY, 47, XYY	Prospective cohort study 903 pregnant women enrolled, 903 were analysed	High risk	IIIumina Genome Analyzer IIx or HiSeq 2000 sequencer in multiplex Commercial ‐ NIFTY™ test, BGI‐Shenzhen FF measured	Different cutpoints used for autosomes and SCA^b	Fetal karyotype
Johansen 2016	T21, T18, T13	Prospective cohort study 375 singleton pregnancies enrolled, 173 were analysed	High risk	Ion Proton™ sequencer in 5‐plex In‐house test FF measured	Z score of 4 (unclassified if Z score is between 3 and 4) and WISECONDOR of 1%	Fetal karyotype
Ke 2015	T21, T18, T13	Prospective cohort study 2340 singleton pregnancies enrolled, 2340 were analysed	High risk	High throughput sequencing platform Commercial test ‐ BGI‐Shenzhen	T score of 3	Fetal karyotype or newborn outcome
Kim 2016	T21	Blinded prospective cohort study 101 pregnant women enrolled, 101 were analysed	High risk	Ion Proton™ sequencer in multiplex Commercial test ‐ Genome Care	Z score of 2.10 for Ion Proton™	Fetal karyotype
Lau 2012	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	Blinded prospective cohort study 108 singleton pregnancies enrolled, 108 were analysed	Mostly high risk	IIIumina HiSeq 2000 sequencers in 12‐plex Commercial ‐ NIFTY™ test, BGI‐Shenzhen	Different cutpoints used for autosomes and SCA^b	Fetal karyotype
Lee 2015	T21, T18, T13 and SCA (no case found)	Blinded prospective cohort study 93 singleton and multifetal pregnancies enrolled, 92 were analysed	High risk	Illumina MiSeq sequencer in 12‐plex or NextSeq sequencer in 96‐plex Commercial test ‐ MomGuard™, LabGenomics FF measured	Z score of 4 (intermediate risk if Z score is between 2.5 and 4) for T21 and T18; 2.8 for T13 (intermediate risk if Z score is between 1.9 and 2.8)	Fetal or neonatal karyotype
Lefkowitz 2016	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	Retrospective cohort, blinded case‐control study 5321 pregnant women enrolled but 1222 were selected and 1166 were analysed	High risk	IIIumina HiSeq 2000 sequencer in 6‐plex or uniplex Commercial test ‐ Sequenom, Inc. FF measured	Different cutpoints used for autosomes and SCA^b	Fetal karyotype
Liang 2013	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	Blinded prospective cohort study 435 singleton and twin pregnancies enrolled, 412 were analysed	High risk	Illumina HiSeq 2000 sequencer in 8‐plex or 12‐plex Commercial test ‐ Berry Genomics Co. Ltd. FF measured	Different cutpoints used for autosomes and SCA^b	Fetal karyotype
Liu 2012	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	Prospective cohort study 153 pregnant women enrolled, 153 were analysed	High risk	Illumina HiSeq sequencer in multiplex.	Z score of 3	Fetal karyotype
Ma 2016	T21, T18, T13	Blinded retrospective (archived samples) and prospective cohorts study 10,598 singleton pregnancies enrolled, 10,579 were analysed	High and low risk	Sequencing on BGISEQ‐1000 in 16 or 24‐plex Commercial test ‐ BGI‐Shenzhen	Z score of 3	Fetal karyotype or postnatal follow‐up
Mazloom 2013	45,X, 47,XXX, 47,XXY, 47,XYY	Blinded prospective cohort study 1975 singleton pregnancies enrolled, 411 samples from the validation set were analysed	High risk	Illumina v3 flow‐cell on a HiSeq 2000 sequencer in 12‐plex Laboratory test development by Sequenom, Inc. FF measured	Different cutpoints used for the four SCA^b	Fetal karyotype
Palomaki 2012	T21, T18, T13	Nested case‐control study (1:3) 4664 pregnant women enrolled but 1988 singleton pregnancies were selected and 1971 were analysed	High risk	Illumina HiSeq 2000 sequencer in 4‐plex Commercial test ‐ Sequenom, Inc. FF measured	Z score of 3 for T21; 3.88 for T18; 7.17 for T13	Fetal karyotype
Papageorghiou 2016a	T21, T18, T13	Retrospective cohort, case‐control study (1:9) 442 singleton and twin pregnancies enrolled, 426 singleton pregnancies were analysed	High risk	Ion Proton™ sequencer in 8‐plex Commercial ‐ IONA^® test, Premaitha Health (public limited company in UK) FF measured	Likelihood ratio of 1 and maternal age‐adjusted probability risk score	Fetal karyotype or medical record from birth
Papageorghiou 2016b	T21, T18, T13	Retrospective cohort, case‐control study (1:9) 442 singleton and twin pregnancies enrolled, 11 twin pregnancies were analysed	High risk	Ion Proton™ sequencer in 8‐plex Commercial ‐ IONA^® test, Premaitha Health (public limited company in UK) FF measured	Likelihood ratio of 1 and maternal age‐adjusted probability risk score	Fetal karyotype or medical record from birth
Poon 2016	T21, T18, T13	Retrospective cohort, blinded nested case‐control study 242 singleton pregnancies enrolled, 241 were analysed	High risk	Ion Proton™ sequencer, IONA^® software algorithm Commercial ‐ IONA^® test, Premaitha Health (public limited company in UK) FF measured	NR (authors used the same gNIPT than Papageorghiou 2016a)	Fetal karyotype
Porreco 2014	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	Blinded prospective cohort study 4170 singleton pregnancies enrolled, 3322 for autosomes, 3278 for 45,X and 47,XXX and 3201 for 47,XXY and 47,XYY were analysed	High risk	Illumina HiSeq 2000 sequencer in 12‐plex Commercial test ‐ Sequenom, Inc. FF measured	Different cutpoints used for autosomes and SCA^b	Fetal karyotype or medical record from birth
Sehnert 2011	T21, T18, T13, 45,X	Retrospective (archived samples) cohort study 1014 singleton and multifetal pregnancies enrolled but only 47 singleton pregnancies in the test set were analysed in this review.	High risk	IIIumina Genome Analyzer IIx sequencer in uniplex Commercial test ‐ Verinata	Different cutpoints used for autosomes and SCA^b	Fetal karyotype
Shaw 2014	T21, T18, T13, 45,X, 47, XXX, 47,XXY, 47,XYY	Prospective cohort study 201 singleton and multifetal pregnancies enrolled, 200 were analysed	High and low risk	Illumina v2 HiSeq 2000 sequencer in 12‐plex Commercial test ‐ Berry Genomics Co. Ltd.	Different cutpoints used for autosomes and SCA^b	Fetal karyotype or medical record from birth
Song 2013	T21, T18, T13, 45,X, 47,XXX, 47, XXY, 47,XYY (SCA data not shown in this review)	Blinded prospective cohort study 1916 singleton pregnancies enrolled, 1741 were analysed	Without prior risk	Illumina v2 HiSeq2000 in 12‐plex Commercial test‐ Berry Genomics Co. Ltd.	Z score of 3	Fetal or postnatal karyotype or medical record from birth	Triple test for T21 and T18 (cutpoint of 1 in 270).
Song 2015	T21, T18, T13, 45,X, 47,XXX, 47,XYY	Blinded prospective cohort study 213 singleton pregnancies enrolled, 204 were analysed	High risk	Illumina v2 HiSeq 2000 sequencer in 12‐plex Commercial test ‐ Berry Genomics Co. Ltd. FF measured	Z score of 3	Fetal karyotype or neonatal clinical examination or both
Stumm 2014	T21, T18, T13	Prospective cohort, blinded study for T21 and unblinded for T18 and T13 522 singleton pregnancies enrolled, 472 were analysed	High risk	Illumina HiSeq 2000 sequencer in 12‐plex (DAP.21 algorithm without CG correction) Commercial test ‐ LifeCodexx AG FF measured	MAD‐based Z score of 3 for T21; 3.2 for T18; 3.9 for T13	Fetal karyotype
Sukhikh 2015	T21, T18, T13, 45,X	Prospective cohort study 200 pregnant women enrolled, 200 were analysed	High risk	Ion Proton™ sequencer In‐house test	T score of 5 for T21 and T18; 4 for T13; 0.04 Chrom. X and 0.04 Chrom. Y for 45,X	Fetal karyotype
Sung‐Hee 2015	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	Retrospective study 918 singleton pregnancies enrolled, 901 were analysed	High risk	IIIumina Genome Analyzer IIx or HiSeq 2000 sequencer in 12‐plex Commercial ‐ NIFTY™ test, BGI‐Shenzhen FF measured	L score of 1 and t score of 2.5	Fetal karyotype or medical record from birth
Tynan 2016	T21, T18, T13	Blinded retrospective cohort study 1100 singleton pregnancies enrolled, 1048 were analysed	High and without prior risk	Illumina HiSeq 2000 or HiSeq 2500 sequencers in multiplex Commercial ‐ VisibiliT™ test, Sequenom, Inc. FF measured	risk score of 1%	Fetal karyotype or medical record from birth
Wang 2014	T21, T18, T13, 45,X	Prospective cohort study 136 singleton pregnancies enrolled, 136 were analysed	High risk	Illumina HiSeq 2000 sequencer Commercial ‐ NIFTY™ test, BGI‐Shenzhen	NR	Fetal or neonatal karyotype or clinical examination at 42 days after birth or both
Wang 2015a	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	Prospective cohort study 917 pregnant women enrolled, 917 were analysed	High risk	Illumina v2 HiSeq 2000 flow cell on a HiSeq sequencer Commercial test ‐ Berry Genomics Co. Ltd	Z score of 3 for T21, T18 and T13; ‐3 for Chrom. X and 3 for Chrom. Y for sex Chrom. classification.	Fetal karyotype or clinical follow‐up to 6 months from birth
Yao 2014	T21, T18, T13 and SCA (SCA data not shown in this review)	Retrospective study 5950 singleton pregnancies enrolled, 5530 were analysed	High, low and without prior risk	IIIumina Genome Analyzer IIx or HiSeq 2000 sequencer in 12‐plex Commercial ‐ NIFTY™ test, BGI‐Shenzhen FF measured	Different cutpoints used for autosomes and SCA^b	Fetal karyotype or clinical follow‐up
Zhang 2016	T21, T18, 45,X, 47,XXX (SCA data not shown in this review)	Blinded prospective cohort study 87 singleton pregnancies enrolled, 87 were analysed	High risk	Illumina HiSeq 2000 sequencer in 12‐plex Commercial test ‐ Berry Genomics Co. Ltd.	Z score of 3 for T21 (no other cutpoint reported)	Fetal or neonatal karyotype or neonatal clinical examination
Zhou 2014a	T21, T18, T13	Blinded prospective cohort study 306 singleton pregnancies enrolled, 301 were analysed	High, low and without prior risk	IIIumina Genome Analyzer IIx or HiSeq 2000 sequencer in 12‐plex Commercial ‐ NIFTY™ test, BGI‐Shenzhen FF measured	L score of 1 and t score of 2.5	Fetal or neonatal karyotype or birth outcome
Zhou 2014b	T21, T18, T13	Blinded prospective cohort study 7705 singleton pregnancies enrolled, 3950 were analysed	High, low and without prior risk	IIIumina Genome Analyzer IIx or HiSeq 2000 sequencer in 12‐plex Commercial ‐ NIFTY™ test, BGI‐Shenzhen FF measured	L score of 1 and t score of 2.5	Fetal or neonatal karyotype or birth outcome
TMPS
Ashoor 2012	T21, T18	Nested case‐control study (1:3) from a prospective cohort 400 singleton pregnancies enrolled, 397 were analysed	High risk	DANSR assay (FORTE algorithm), Illumina HiSeq 2000 in 96‐plex Commercial ‐ Harmony™ prenatal test, Ariosa Diagnostics, Inc.	NR (usually Harmony™ prenatal test uses FORTE risk score of 1%)	Fetal karyotype
Ashoor 2013	T13	Blinded prospective cohort study 2167 singleton pregnancies enrolled, 1949 were analysed	High and low risk	DANSR assay (FORTE algorithm), Illumina HiSeq 2000 in 96‐plex Commercial ‐ Harmony™ prenatal test, Ariosa Diagnostics, Inc. FF measured	FORTE risk score of 1%	Fetal karyotype or neonatal clinical examination
Bevilacqua 2015	T21, T18, T13	Prospective cohort study 515 multifetal pregnancies enrolled, 340 were analysed Women with singleton pregnancies were excluded (incomplete 2 x 2 table).	High and without prior risk	DANSR assay (FORTE algorithm), Illumina HiSeq 2000 in 96‐plex Commercial ‐ Harmony™ prenatal test, Ariosa Diagnostics, Inc. FF measured	NR (usually Harmony™ prenatal test uses FORTE risk score of 1%)	Fetal or neonatal karyotype
Comas 2015	T21, T18, T13, 45,X, 47,XXX, 47, XXY, 47,XYY (SCA data not shown in this review)	Blinded prospective cohort study 333 singleton pregnancies enrolled, 312 were analysed	High and without prior risk	DANSR assay (FORTE algorithm) or SNP‐based method Commercial ‐ Panorama™ test, Natera, Inc. or Harmony™ prenatal test, Ariosa Diagnostics, Inc. FF measured	Harmony™ prenatal test: NR (usually Harmony™ prenatal test uses FORTE risk score of 1%) Panorama™ test: NR	Fetal karyotype or neonatal clinical examination
del Mar Gil 2014	T21, T18, T13	Retrospective cohort study 207 multifetal pregnancies enrolled, 192 twin pregnancies were analysed	Without prior risk	DANSR assay (FORTE algorithm), Illumina HiSeq 2000 in 96‐plex Commercial ‐ Harmony™ prenatal test, Ariosa Diagnostics, Inc. FF measured	NR (usually Harmony™ prenatal test uses FORTE risk score of 1%)	Fetal karyotype
Gil 2016	T21, T18, T13	Prospective cohort study 11,692 singleton pregnancies enrolled, 3633 were analysed	High and intermediate risk^c	DANSR assay (usually with FORTE algorithm) Commercial ‐ Harmony™ prenatal test, Ariosa Diagnostics, Inc.	NR (usually Harmony™ prenatal test uses FORTE risk score of 1%)	Fetal or postnatal karyotype or neonatal clinical examination
Hall 2014	T13	Case‐control study (1:3)/1000 singleton pregnancies enrolled, 64 were analysed.	High risk	SNP‐based method (NATUS algorithm), IIIumina Genome Analyzer IIx or HiSeq sequencer, 11,000 or 19,488‐plex targeted PCR Commercial ‐ Natera's prenatal test FF measured	NR	Fetal karyotype or genetic testing of cord blood, buccal, saliva or products of conception
Hooks 2014	45,X, 47,XXX, 47, XXY, 47,XYY	Case‐control study from archived samples 432 singleton pregnancies enrolled, 414 were analysed	High risk	DANSR assay (FORTE algorithm), Illumina HiSeq 2000 in 96‐plex Commercial ‐ Harmony™ prenatal test, Ariosa Diagnostics, Inc. FF measured	NR (usually Harmony™ prenatal test uses FORTE risk score of 1%)	Fetal karyotype
Jackson 2014	T21, T18, T13	Prospective cohort study 1228 pregnant women enrolled, 1161 were analysed	High and low risk	DANSR assay (FORTE algorithm) Commercial ‐ Harmony™ prenatal test, Ariosa Diagnostics, Inc.	NR (usually Harmony™ prenatal test uses FORTE risk score of 1%)	Fetal karyotype or medical record from birth
Korostelev 2014	T21, T18, T13, 45,X, 47,XXX, 47, XXY, 47,XYY	Prospective cohort study 1968 singleton pregnancies enrolled, 685 were analysed	High and without prior risk	SNP‐based method (NATUS algorithm), IIIumina Genome Analyzer IIx or HiSeq sequencer, > 19,000‐plex targeted PCR Commercial ‐ Natera's prenatal test FF measured	NR	Fetal karyotype or medical record from birth
Nicolaides 2012	T21, T18	Retrospective study from archived plasma 2230 singleton pregnancies enrolled, 1949 were analysed	Without prior risk	DANSR assay (usually with FORTE algorithm) Commercial ‐ Harmony™ prenatal test, Ariosa Diagnostics, Inc. FF measured	Risk score of 1%	Fetal karyotype or neonatal clinical examination	First‐trimester combined test (cutpoint of 1 in 150).
Nicolaides 2013	T21, T18, T13, 45,X, 47,XXX, 47,XXY, 47,XYY	Blinded prospective cohort study 242 singleton pregnancies enrolled, 229 were analysed	High risk	SNP‐based method (NATUS algorithm), IIIumina Genome Analyzer IIx or HiSeq sequencer, 19,488‐plex targeted PCR Commercial ‐ Natera's prenatal test FF measured	NR	Fetal karyotype
Nicolaides 2014a	45,X, 47,XXX, 47,XXY, 47,XYY	Case‐control study (archived samples) 177 singleton pregnancies enrolled, 172 were analysed	High risk	DANSR assay (FORTE algorithm), Illumina HiSeq 2000 in 96‐plex Commercial ‐ Harmony™ prenatal test FF measured	FORTE risk score of 1%	Fetal karyotype
Norton 2012	T21, T18	Blinded prospective cohort study 4002 singleton pregnancies enrolled, 3080 were analysed	High risk	DANSR assay (FORTE algorithm), Illumina HiSeq 2000 in 96‐plex Commercial test‐ Ariosa Diagnostics, Inc. FF measured	FORTE risk score of 1%	Fetal karyotype
Norton 2015	T21, T18, T13	Blinded prospective cohort study 18,955 singleton pregnancies enrolled, 15,841 were analysed	Without prior risk	DANSR assay (FORTE algorithm) Commercial ‐ Harmony™ prenatal test, Ariosa Diagnostics, Inc. FF measured	NR (usually Harmony™ prenatal test uses FORTE risk score of 1%)	Fetal or postnatal karyotype, neonatal clinical examination or medical record from birth	First‐trimester combined test (cutpoint of 1 in 270 for T21 and 1 in 150 for T18 and T13).
Pergament 2014	T21, T18, T13, 45,X	Blinded prospective cohort study 1064 singleton pregnancies enrolled, 963 were analysed	High and low risk	SNP‐based method (NATUS algorithm), IIIumina Genome Analyzer IIx or HiSeq sequencer, 19,488‐plex targeted PCR Commercial ‐ Natera's prenatal test FF measured	NR	Fetal karyotype or genetic testing of cord blood, buccal, saliva or products of conception or birth outcome
Persico 2016	T21, T18, 45,X, 47,XXX, 47,XXY, 47,XYY	Blinded prospective cohort study 259 singleton pregnancies enrolled, 249 were analysed	High risk	SNP‐based method (NATUS algorithm), IIIumina Genome Analyzer IIx or HiSeq sequencer, 19,488‐plex targeted PCR Commercial ‐ Natera's prenatal test FF measured	Risk score of 1%	Fetal karyotype
Quezada 2015	T21, T18, T13	Prospective cohort study 2905 singleton pregnancies enrolled, 2785 were analysed	Without prior risk	DANSR assay (FORTE algorithm) Commercial ‐ Harmony™ prenatal test FF measured	NR (usually Harmony™ prenatal test uses FORTE risk score of 1%)	Fetal or postnatal karyotype, neonatal clinical examination or medical record from birth	First‐trimester combined test (cutpoint of 1 in 100 for T21).
Samango‐Sprouse 2013	45,X, 47,XXX, 47,XXY, 47,XYY	Blinded prospective cohort study 201 singleton pregnancies (with known SCA and euploid pregnancies) enrolled, 186 were analysed	High and low risk	SNP‐based method (NATUS algorithm), IIIumina HiSeq sequencer, 19,488‐plex targeted PCR Commercial ‐ Natera's prenatal test FF measured	NR	Fetal karyotype or genetic testing of cord blood, buccal, saliva or products of conception
Sparks 2012a	T21, T18	Case‐control study from a prospective cohort 338 singleton pregnancies enrolled, 167 were analysed	High risk	DANSR assay (FORTE algorithm), Illumina HiSeq 2000 in 96‐plex Commercial test‐ Ariosa Diagnostics, Inc. FF measured	NR	Fetal karyotype
Verweij 2013	T21	Blinded prospective cohort study 595 singleton pregnancies enrolled, 504 were analysed	High risk	DANSR assay (FORTE algorithm), Illumina HiSeq 2000 in 96‐plex Commercial test‐ Ariosa Diagnostics, Inc. FF measured	FORTE risk score of 1%	Fetal karyotype
45,X: Turner syndrome, 47,XXX: triple X syndrome, 47,XXY: Klinefelter syndrome, DANSR: digital analysis of selected regions, FF: fetal fraction DNA, FORTE: fetal‐fraction optimised risk of trisomy evaluation, MAD: Median absolute deviation, MPSS: massively parallel shotgun sequencing, NATUS: Next‐generation Aneuploidy Test Using SNPs, NCV: normalised chromosome value, SCA: sex chromosome aneuploidy, SNP: single‐nucleotide polymorphism,TMPS: targeted massively parallel sequencing, T21: trisomy 21, T18: trisomy 18 and T13: trisomy 13. ^aFetal karyotype include traditional banding techniques, spectral karyotype, fluorescence in situ hybridisation, array comparative genomic hybridisation or quantitative fluorescence polymerase chain reaction. ^bDifferent cutpoints used for autosomes or SCA as follows: Bianchi 2012: NCV of 4 (aneuploidy suspected if NCV is between 2.5 and 4) for T21, T18, and T13; NCV for Chrom. X of ‐4 and NCV for Chrom. Y of 2.5 for 45,X; NCV for Chrom. X of 4 and NCV for Chrom. Y of 2.5 for 47,XXX; NCV for Chrom. X between ‐2.5 and 2.5 and NCV for Chrom. Y > 33 for 47,XXY; NCV for Chrom. X of ‐4 and NCV for Chrom. Y of 4 for 47,XYY with NCV for Chrom. Y is two times greater than expected NCV Chrom. X. Bianchi 2013: NCV of 4 (aneuploidy suspected if NCV is between 3 and 4) for T21, T18, and T13; NCV for Chrom. X of ‐3 and NCV for Chrom. Y of 3 for 45,X. Jiang 2012: t score of 3 and logarithmic LR of 1 for T21, T18 and T13; if female fetus, t score of ‐2.5 for 45,X and 47,XXX; t score of 2.5 combined with estimation of fetal ccfDNA concentration by Chrom. X and Y independently for 47,XXY and 47,XYY. Lau 2012: Z score of 3 for T21, T18 and T13; if female fetus, Z score for Chrom. X of ‐3 for 45,X; if female fetus, Z score for Chrom. X of 3 for 47,XXX; if male fetus, Z score for Chrom. Y of 3 for 47,XXY. Lefkowitz 2016: Z score of 3 for T21; Z score of 3.95 for T18 and T13; Z scores for SCA see Mazloom 2013. Liang 2013: Z score of 3 for T21; 5.91 for T18; 5.72 for T13; ± 2.91 for Chrom. X and ± 3 for Chrom. Y for sex chromosome classification. Mazloom 2013: Z score of 3.5 for 47,XXX (non‐reportable regions between 2.5 and 3.5); Z score of ‐3.5 for 45,X (non‐reportable regions between ‐2.5 and ‐3.5); Z score of ‐3.5 for 47,XYY with Chrom. Y representation; between ‐3.5 and 3.5 for 47,XXY with Chrom. Y representation. Porreco 2014: Z score of 3 for T21; Z score of 3,95 for T18 and T13; Z score of 3.5 for 47,XXX (non‐reportable regions between 2.5 and 3.5); Z score of ‐3.5 for 45,X (non‐reportable regions between ‐2.5 and ‐3.5); Z score of ‐3.5 for 47,XYY with Chrom. Y representation; Z score between ‐3.5 and 3.5 for 47,XXY with Chrom. Y representation. Sehnert 2011: NCV of 4 (unclassified if NCV is between 2.5 and 4) for T21, T18, and T13; NCV for Chrom. Y of ‐2.0 SDs from the mean of male samples and NCV for Chrom. X of ‐3.0 SDs from the mean of female samples for sex chromosome classification. Shaw 2014: Z score of 3 for T21, T18, and T13; Z score of ‐3 for Chrom. X and 3 for Chrom. Y for sex chromosome classification. Yao 2014: T score of 2.5 for T21, T18 and T13; if female fetus, T score for Chrom. X of ‐2.5 for 45,X and 2.5 for 47,XXX; if male fetus, T score for Chrom. X of 2.5 combined with estimation of fetal ccfDNA concentration by Chrom. X (expected value of zero) for 47,XXY; if male fetus, T score for Chrom. X of 2.5 and R‐value (the ratio of the fetal DNA fraction estimated by chromosome Y to that estimated by chromosome X) between 1.8 and 2.2 for 47,XYY. ^cPregnant women with a first‐trimester combined test selected for their risk of fetal aneuploidy (cutpoint of 1 in 100 for high risk and 1 in 101 to 1 in 2500 for intermediate risk).

Table 4. Characteristics of included studies by type of gNIPT

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Table 5. Manufacturers of gNIPT used in the included studies by prior risk of fetal aneuploidy

Company	Number of studies	Number of affected/unaffected pregnancies^a	Number of studies with pregnant women without prior risk of fetal aneuploidy	Number of studies with high‐risk pregnant women	Number of studies with mixed risk^b cohort
Ariosa Diagnostics, Inc.	15	594/32,302	4	6	5
Bejing Genomics Institute (BGI)	12	427/24,724	0	7	5
Sequenom, Inc.	9	904/8486	0	7	2
Berry Genomics Co. Ltd	6	147/3414	1	4	1
Natera, Inc.	6	276/2103	0	3	3
Illumina, Inc.	4	273/2342	0	3	1
In‐house	3	114/442	0	3	0
Premaitha Health plc	3	99/579	0	3	0
Genome Care	2	21/235	0	2	0
CERBA	1	113/745	0	1	0
Genoma	1	105/6977	0	0	1
LabGenomics	1	8/84	0	1	0
LifeCodexx AG	1	55/417	0	1	0
Not reported	1	5/148	0	1	0
Total	65	3141/82,998	5	42	18
^aWe included pregnancies with any other aneuploidy than the one under analysis with all euploid cases as "unaffected" pregnancies. ^bMixed‐risk cohort included a mix of pregnant women without prior risk, low risk or high risk of fetal aneuploidy.

Table 5. Manufacturers of gNIPT used in the included studies by prior risk of fetal aneuploidy

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Table 6. Reasons for patient exclusion

Study ID	Number of pregnant women enrolled	Reasons for exclusion	Number of women with results for 2 x 2 table analysis
Alberti 2015	976	701 not selected for the case‐control study 23 selected for reference set 8 selected for pretesting phase 47 low amount of DNA 11 low fetal fraction DNA or assay failure 3 haemolysed samples Total: 793	183
Ashoor 2012	400	3 samples failed amplification and sequencing	397
Ashoor 2013	2167	165 selected for first phase (case‐control study not included in this review) 53 failed amplification or sequencing Total: 218	1949
Benachi 2015	900	8 without reference standard result 6 low fetal fraction DNA or result appeared atypical Total: 14	886
Bevilacqua 2015	2362	1847 not selected 159 without follow‐up 11 failed samples 5 failed samples and were without follow‐up Total: 2022	340
Bianchi 2012	2882	127 ineligible 45 without karyotype 85 multifetal pregnancies 2091 not selected for this case‐control study 2 for tracking issue 16 without fetal DNA detected Total: 2366 In addition, other samples excluded from 2 x 2 tables for censored complex karyotype: 13 for T21 14 for T18 15 for T13 27 for 45,X	503 (T21) 502 (T18) 501 (T13) 489 (45,X)
Bianchi 2013	2882	2769 not selected for the study	113
Bianchi 2014a	2052	10 failed blood quality control 72 without clinical outcome 17 without gNIPT result 28 without standard screening result 1 without gNIPT result and without standard screening result Total for T21 and T18: 100 Total for T13: 128	1952 (T21 and T18) 1914 (T13)
Bijok 2014	10	1 low fetal fraction DNA	9
Canick 2012	4664	4637 not selected for the case‐control study	27
Chen 2011	392	103 selected for reference control	289
Chiu 2011	824	46 failed quality control for blood sampling 12 without karyotype 2 twin pregnancies 11 failed quality control for sequencing Total: 71 (8‐plex)	753 (8‐plex)
Comas 2015	333	17 without follow‐up 3 unrepeated tests 1 failed test second time^a and without follow‐up Total: 21	312
del Mar Gil 2014	207	11 low fetal fraction DNA 4 laboratory processing failures Total: 15	192
Ehrich 2011	480	13 preanalytic failure (including 9 for low plasma volume and 4 processing errors) 18 failed quality control at second time (including 7 for low fetal fraction DNA) Total: 31	449
Fiorentino 2016	7103	21 failed quality control (unrepeated tests)	7082
Gil 2016	11,692	7994 patients did not undergo a gNIPT 45 failed tests first time^b 20 failed tests second time Total: 8059	3633
Hall 2014	> 1000	About 932 samples not selected for the case‐control study 4 failed quality control Total: 936	64
Hooks 2014	432	18 low fetal fraction DNA, unusually high variation in ccfDNA counts or failed QC	414
Hou 2012	308	103 patients did not undergo a gNIPT	205
Huang 2014	189	NR	189
Jackson 2014	1228	7 with other abnormal ultrasound 14 opted for CVS without gNIPT 32 declined all testing 14 failed tests twice Total: 67	1161
Jeon 2014	155	NR	155
Jiang 2012	903	NR	903
Johansen 2016	375	191 not selected for validation set 11 low fetal fraction DNA Total: 202	173
Ke 2015	2340	NR	2340
Kim 2016	101	NR	101
Korostelev 2014	1968	1043 without follow‐up 240 samples did not undergo a gNIPT Total: 1283	685
Lau 2012	108	NR	108
Lee 2015	93	1 low fetal fraction DNA	92
Lefkowitz 2016	5321	4099 not selected for the study 11 for incomplete follow‐up 3 with confirmed mosaicism 11 low fetal fraction DNA 29 for technical reasons 2 for maternal event Total: 4155 (autosomes) In addition: 22 sequencing failures for SCA Total: 4177 (SCA)	1166 (autosomes) 1144 (SCA)
Liang 2013	435	11 without karyotype 12 failed quality control Total: 23	412
Liu 2012	153	NR	153
Ma 2016	10,598	14 with incomplete follow‐up 5 failed quality control Total: 19	10,579
Mazloom 2013	1975	1564 selected for the training set	411
Nicolaides 2012	2230	181 ineligible 46 low fetal fraction DNA 54 assay failures Total: 281	1949
Nicolaides 2013	242	13 failed quality control	229
Nicolaides 2014a	177	1 failed quality control 4 low fetal fraction DNA Total: 5	172
Norton 2012	4002	774 ineligible 57 low fetal fraction DNA 91 assay failures Total: 922	3080
Norton 2015	18,955	381 ineligible 64 withdrawn 384 handling errors 308 without standard screening test result 1489 without follow‐up 192 low fetal fraction DNA 83 no fetal fraction DNA 213 high assay variance or assay failures Total: 3114	15,841
Palomaki 2012	4876	2888 not selected for this study 17 failed tests second time (mostly for low fetal fraction DNA) Total: 2905	1971
Papageorghiou 2016a	442	11 twin not selected 3 low fetal fraction DNA 2 failed quality control Total: 16	426
Papageorghiou 2016b	442	426 singleton not selected 3 low fetal fraction 2 failed quality control Total: 431	11
Pergament 2014	1064	13 not selected (other aneuploidies) 85 samples failed quality control for all five chromosomes (including 65 for low fetal fraction DNA) Total: 98 In addition, 3 samples failed only for T21 (total for T21: 101) 2 samples failed only for T18 and 45,X (total for T18 and 45,X: 100) 1 sample failed only for T13 (total for T13: 99)	963 (T21) 964 (T18 and 45,X) 965 (T13)
Persico 2016	259	8 low fetal fraction DNA 2 failed internal quality control Total: 10	249
Poon 2016	242	1 low fetal fraction DNA	241
Porreco 2014	4170	320 for insufficient sample volume 390 failed quality control 24 with incomplete follow‐up 6 without invasive procedure In addition, 54 failed quality control and 54 for complex autosome karyotypes^c (total: 108 for autosomes) 102 failed quality control or other^d and 50 for complex SCA karyotype (total: 152 for 45,X and 47,XXX) 182 low fetal fraction DNA or other^d and 47 for complex SCA karyotype (total: 229 for 47,XXY and 47,XYY)	3322 (T21, T18, T13) 3278 (45,X, 47,XXX) 3201 (47,XXY, 47,XYY)
Quezada 2015	2905	66 without follow‐up 1 lost in mail 38 low fetal fraction DNA 15 assay failures Total: 120	2785
Samango‐Sprouse 2013	201	12 low fetal fraction DNA or poor DNA quality 2 without gNIPT result 1 with conflicting algorithm metrics Total: 15	186
Sehnert 2011	1014	895 not selected for sequencing 71 selected for training set 1 twin pregnancy Total: 967	47
Shaw 2014	201	1 for early GA	200
Song 2013	1916	102 without follow‐up 64 failed quality control 9 failed quality control and without follow‐up Total: 175	1741
Song 2015	213	8 without follow‐up 1 failed quality control Total: 9	204
Sparks 2012a	338	171 selected for training set	167
Stumm 2014	522	8 without reference standard 9 without consent 1 previously analysed 14 failed sequencing quality control 18 failed libraries Total: 50	472
Sukhikh 2015	200	NR	200
Sung‐Hee 2015	918	8 ineligible 9 without follow‐up Total: 17	901
Tynan 2016	1100	28 library preparation failures or failed quality control 24 for discretionary non reporting Total: 52	1048
Verweij 2013	595	75 ineligible 7 low fetal fraction DNA 9 laboratory processing failures or specimen issues Total: 91	504
Wang 2014	136	NR	136
Wang 2015a	917	NR	917
Yao 2014	5950	420 without follow‐up	5530
Zhang 2016	87	NR	87
Zhou 2014a	306	5 without follow‐up	301
Zhou 2014b	7705	4 low fetal fraction DNA 3751 without follow‐up Total: 3755	3950
ccfDNA: circulating cell‐free DNA, CVS: chorionic villi sampling, GA: gestational age, gNIPT: genomics‐based non‐invasive prenatal testing, NR: not reported by authors. ^aSecond time: sample failed the second gNIPT assay. ^bFirst time: sample failed the initial gNIPT assay. ^cComplex autosome karyotypes are mosaic, triploidies, unbalanced rearrangements with missing or duplicated genetic material. ^dOther are copy number variation of the X chromosome is confounded by maternal component and cannot be determined.

Table 6. Reasons for patient exclusion

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Table 7. Proportion of pregnant women with a reference standard and assay failure during gNIPT process

Study ID	Failure rate at first attempt (%)	Repeated tests^a (%)	Failure rate of repeated tests (%)	Final failure rate total (%)	Aneuploid^b samples (%)	Euploid^b samples (%)
MPSS
Alberti 2015	61/244 (25%)	0	NA	61/244 (25%)	NR	NR
Benachi 2015	42/892 (4.7%)	42 (100%) with second aliquot	6/42 (14.3%)	6/892 (0.7%)	2.7%	0.4%
Bianchi 2012	16/519 (3.1%)	0	NA	16/356 (3.1%)	NR	NR
Bianchi 2014a	18/1970 (0.9%)	0^c	NA	T21 and T18: 18/1970 (0.9%) T13: 18/1932 (0.9%)	NR	NR
Bijok 2014	1/10 (10.0%)	0	NA	1/10 (10.0%)	50%	0%
Chiu 2011	11/764 (1.4%)	0	NA	11/764 (1.4%)	NR	NR
Ehrich 2011	20/467 (4.3%)	20 (100%) resequenced	18/20 (90%)	18/467 (3.9%)	NR	NR
Fiorentino 2016	100/7103 (1.4%)	79 (79%) with new sampling	0 (0%)	21/7103 (0.3%)	0%	0.3%
Johansen 2016	NR	2 with second aliquot or resequenced were in the grey zone (between affected and unaffected)	NR	11/184 (6%)^d	5.8%	6.1%
Lee 2015	1/93 (1.1%)	0	NA	1/93 (1.1%)	NR	NR
Lefkowitz 2016	Autosomes: 42/1208 (3.5%) SCA: 64/1208 (5.3%)	0	NA	Autosomes: 42/1208 (3.5%) SCA: 64/1208 (5.3%)	Autosomes: 3.8% SCA: 29.7%	Autosomes: 3.4% SCA: 4.5%
Liang 2013	12/424 (2.8%)	0	NA	12/424 (2.8%)	NR	NR
Ma 2016	5/10,584 (0.05%)	0	NA	5/10,584 (0.05%)	NR	NR
Mazloom 2013	21/432 (4.9%)	0	NA	21/432 (4.9%)	11.8%	4.3%
Palomaki 2012	110/1988 (5.5%)	105 (95.5%) with second aliquot and 5 (4.5%) resequenced	17/110 (15.5%)	17/1988 (0.9%)	1.0%	0.8%
Papageorghiou 2016a Papageorghiou 2016b	5/431 (1.2%)	0	NA	5/431 (1.2%)	NR	NR
Poon 2016	1/242 (0.4%)	0	NA	1/242 (0.4%)	0%	0.5%
Porreco 2014	Autosomes: 108/3430 (3.1%) 45,X and 47,XXX: 152/3430 (4.4%) 47,XXY and 47,XYY: 229/3430 (6.7%)	0	NA	Autosomes: 108/3430 (3.1%) 45,X and 47,XXX: 152/3430 (4.4%) 47,XXY and 47,XYY: 229/3430 (6.7%)	NR	NR
Song 2013	73/1814 (4.0%)	0	NA	73/1814 (4.0%)	0%	4.0%
Song 2015	1/205 (0.5%)	0	NA	1/205 (0.5%)	NR	NR
Stumm 2014	32/504 (6.3%)	0	NA	32/504 (6.3%)	3.5%	6.7%
Sung‐Hee 2015	21/908 (2.3%)	16 (76.2%) with new sampling	2/16 (12.5%)	7/908 (0.8%)	NR	NR
Tynan 2016	52/1100 (4.7%)	0	NA	52/1100 (4.7%)	0%	4.9%
Yao 2014	0	0	NA	0	NA	NA
Zhou 2014a	0	0	NA	0	NA	NA
Zhou 2014b	141/3954 (3.6%)	141 (100%) with new sampling	4/141 (2.8%)	4/3954 (0.1%)	NR	NR
Overall range of final assay failure for MPSS				0% to 25%	0% to 50%	0% to 6.7%
TMPS
Ashoor 2012	3/400 (0.8%)	0	NA	3/400 (0.8%)	0%	1%
Ashoor 2013	53/2002 (2.6%)	0	NA	53/2002 (2.6%)	0%	2.7%
Bevilacqua 2015	29/356 (8.1%)	26 (90%) with 2^nd aliquot	13/26 (50%)	16/356 (4.5%)	NR	NR
Comas 2015	9/316 (2.8%)	6 (67%) with new sampling	1/6 (16.7%)	4/316 (1.3%)	NR	NR
del Mar Gil 2014	15/207 (7.2%)	0	NA	15/207 (7.2%)	23%	6%
Gil 2016	99/3698 (2.8%)	54 (54,5%) with new sampling	20/54 (37%)	65/3698 (1.8%)	NR	NR
Hall 2014	4/68 (5.9%)	0	NA	4/68 (5.9%)	11.8%	3.9%
Hooks 2014	18/432 (4.2%)	0	NA	18/432 (4.2%)	NR	NR
Jackson 2014	NR	NR	14 (NR)	14/1175 (1.2%)	NR	NR
Nicolaides 2012	100/2049 (4.9%)	0	NA	100/2049 (4.9%)	9.1%	4.9%
Nicolaides 2013	13/242 (5.4%)	0	NA	13/242 (5.4%)	6.3%	5.2%
Nicolaides 2014a	5/177 (2.8%)	0	NA	5/177 (2.8%)	5.1%	1.7%
Norton 2012	148/3228 (4.6%)	0	NA	148/3228 (4.6%)	NR	NR
Norton 2015	488/16,329 (3.0%)	0	NA	488/16,329 (3.0%)	20.6%	2.9%
Pergament 2014	T21: 88/1051 (8.4%) T18, 45,X: 87/1052 (8.3%) T13: 86/1053 (8.2%)	0	NA	T21: 88/1051 (8.4%) T18, 45,X: 87/1052 (8.3%) T13: 86/1053 (8.2%)	All five chromosomes (n = 85): 15.2%	All five chromosomes (n = 85): 7.1%
Persico 2016	10/259 (3.9%)	0	NA	10/259 (3.9%)	8.4%	2.1%
Quezada 2015	122^e/2838 (4.2%)	110 (90.1%) with new sampling	41/110 (37.3%)	53/2838 (1.9%)	4.1%	1.8%
Samango‐Sprouse 2013	15/201 (7.5%)	0	NA	15/201 (7.5%)	6.3%	7.6%
Verweij 2013	51/520 (9.8%)	51 (100%) with 2^nd aliquot	16/51 (31.4%)	16/520 (3.1%) NR	NR	NR
Overall range of final assay failure for TMPS				0.8% to 7.5%	0% to 23%	1% to 7.63%
CVS: chorionic villi sampling, FF: fetal fraction DNA, GA: gestational age, NA: not applicable, NR: not reported by authors, QC: quality control. ^aRepeated tests included second aliquot (aliquot from first sampling), resequenced (same library) or new sampling. ^baneuploid: proportion of failed samples of aneuploid cases out of all aneuploid tested with reference standard and gNIPT result. euploid: proportion of failed samples of euploid cases out of all euploid tested with reference standard and gNIPT result. ^cAuthors decided to resequence 12 samples with gNIPT results. They were in the grey zone (between affected and unaffected) and were resequenced in uniplex. All repeated tests were in affected or unaffected zone. ^dOnly the final failure rate was reported.The failure rate at first attempt was not reported nor the failure rate of repeated tests. ^eAuthor reported 123 failed tests but this number included one sample lost in the mail and so did not undergo the sequencing process.

Table 7. Proportion of pregnant women with a reference standard and assay failure during gNIPT process

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Table 8. Data for 47,XXX, 47,XXY and 47,XYY according to the prior risk of fetal aneuploidy and gNIPT approach

Test		Number of studies	Number of affected pregnancies	Number of unaffected pregnancies^a
47,XXX
Selected high risk pregnant women	MPSS	5	8	5441
Selected high risk pregnant women	TMPS	2	6	580
47,XXY
Selected high risk pregnant women	MPSS	7	14	6466
Selected high risk pregnant women	TMPS	3	8	827
47,XYY
Selected high risk pregnant women	MPSS	7	11	6418
Selected high risk pregnant women	TMPS	1	3	169
^aUnaffected pregnancies: we included pregnancies with any other aneuploidy than the one under analysis with all euploid cases as "unnon affected".

Table 8. Data for 47,XXX, 47,XXY and 47,XYY according to the prior risk of fetal aneuploidy and gNIPT approach

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Table 9. Subgroup analyses of MPSS and TMPS (type of pregnancy and gestational age)

Test subgroups		Number of studies	Number of affected pregnancies	Number of unaffected pregnancies^a	Sensitivity^b % (95% CI)	Specificity^b % (95% CI)
Pregnancy type
Autosomes (T21, T18 and T13 combined), unselected population
MPSS	singleton	1	11	1730	100 (74.1 to 100)	99.9 (99.7 to 100)
TMPS	singleton	3	107	20,468	95.5 (87.4 to 98.4)	99.9 (99.8 to 100)
TMPS	multifetal	1	11	181	90.9 (62.3 to 98.4)	100 (97.9 to 100)
Autosomes (T21, T18 and T13 combined), selected high‐risk population
MPSS	singleton	19	1087	11,180	98.3 (97.3 to 98.9)	99.6 (99.5 to 99.7)
MPSS	multifetal	3	21	206	95.2 (72.9 to 99.3)	100 (98.2 to 100)^c
TMPS	singleton	7	378	4282	98.9 (97.2 to 99.6)	99.9 (99.8 to 100)
SCA (45,X, 47,XXX, 47,XXY and 47,XYY combined), selected high‐risk population
MPSS	singleton	7	101	4690	88.3 (52.9 to 98.1)	99.3 (97.5 to 99.8)
TMPS	singleton	4	96	968	93.8 (86.8 to 97.2)	99.6 (98.1 to 99.9)
Gestational age
Autosomes (T21, T18 and T13 combined), unselected population
MPSS	≤29 weeks	1	11	1730	100 (74.1 to 100)	99.9 (99.7 to 100)
TMPS	≤15 weeks	4	118	20,649	94.9 (89.1 to 97.7)	99.9 (99.8 to 99.9)
Autosomes (T21, T18 and T13 combined), selected high‐risk population
MPSS	≤15 weeks	3	49	532	100 (92.7 to 100)^c	100 (99.3 to 100)^c
	≤29 weeks	12	594	4605	98.3 (96.9 to 99.1)	99.3 (99.0 to 99.5)
	≤42 weeks	13	729	7831	98.9 (95.0 to 99.8)	99.9 (99.8 to 99.9)
TMPS	≤15 weeks	2	128	498	99.2 (95.7 to 99.9)^c	100 (99.2 to 100)^c
	≤29 weeks	2	33	535	97.0 (84.7 to 99.5)^c	100 (99.3 to 100)^c
	≤42 weeks	2	163	3084	99.4 (95.8 to 99.9)	99.9 (99.7 to 100)
SCA (45,X, 47,XXX, 47,XXY and 47,XYY combined), selected high‐risk population
MPSS	≤15 weeks	1	2	202	0.00 (0.00 to 65.8)	99.5 (97.2 to 99.9)
	≤29 weeks	5	58	996	86.5 (63.1 to 96.0)	95.1 (93.5 to 96.3)
	≤42 weeks	5	89	6103	95.8 (80.3 to 99.2)	99.6 (99.4 to 99.7)
TMPS	≤15 weeks	2	58	343	93.1 (83.0 to 97.4)	99.7 (98.0 to 100)
TMPS	≤42 weeks	1	34	380	97.1 (85.1 to 99.5)	98.9 (97.3 to 99.6)
45,X: Turner syndrome, 47,XXX: triple X syndrome, 47,XXY: Klinefelter syndrome, T21: trisomy 21, T18: trisomy 18, T13: trisomy 13 CI: confidence interval, MPSS: massively parallel shotgun sequencing, SCA: sex chromosome aneuploidies, TMPS: targeted massively parallel sequencing. ^aWe included pregnancies with any other aneuploidy than the one under analysis with all euploid cases as "unaffected" pregnancies. ^bFor two or more studies, the sensitivities and specificities are the summary estimates obtained from meta‐analysis. ^cSimple pooling used to obtain summary estimates of sensitivity, specificity or both.

Table 9. Subgroup analyses of MPSS and TMPS (type of pregnancy and gestational age)

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Table 10. Direct comparisons of gNIPT and traditional screening tests for autosomes (T21, T18 and T13 combined) in unselected population of pregnant women undergoing aneuploidy screening

Study	Sensitivity (true positives/cases) %		Difference % (95% CI)	Specificity (true negatives/unaffected^a) %		Difference % (95% CI)
	MPSS	Traditional screening tests		MPSS	Traditional screening tests
Song 2013	100 (11/11)	54.6 (6/11)	45.5 (10.0 to 72.0)	99.9 (1729/1730)	86.0 (1487/1730)	14.0 (12.4 to 15.7)
	TMPS	Traditional screening tests		TMPS	Traditional screening tests
Nicolaides 2012	100 (10/10)	100 (10/10)	0.00 (‐27.8 to 27.8)	99.9 (1937/1939)	95.5 (1852/1939)	4.38 (3.51 to 5.40)
Norton 2015	98.0 (49/50)	78.0 (39/50)	20.0 (7.44 to 33.3)	99.9 (15,779/15,791)	94.1 (14,860/15,791)	5.82 (5.46 to 6.20)
Quezada 2015	91.5 (43/47)	100 (49/49)	‐8.51 (‐19.9 to 0.40)	99.7 (2730/2738)	95.6 (2663/2787)	4.16 (3.40 to 5.00)
CI: confidence interval, MPSS: massively parallel shotgun sequencing, TMPS: targeted massively parallel sequencing. ^aWe included pregnancies with any other aneuploidy than the one under analysis with all euploid cases as "unaffected" pregnancies.

Table 10. Direct comparisons of gNIPT and traditional screening tests for autosomes (T21, T18 and T13 combined) in unselected population of pregnant women undergoing aneuploidy screening

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Table 11. Sensitivity analyses

Test	Number of studies	Number of affected pregnancies	Number of unaffected pregnancies^a	Summary sensitivity % (95% CI)	Summary specificity % (95% CI)	P value^b
Case‐control studies excluded
Autosomes (T21, T18 and T13 combined), selected high‐risk population
MPSS	22	696	11,293	98.3 (95.1 to 99.4)	99.9 (99.8 to 100)	0.72
TMPS	4	219	3,813	98.6 (95.8 to 99.6)	99.9 (99.8 to 100)	0.72
SCA (45,X, 47,XXX, 47,XXY and 47,XYY combined), selected high‐risk population
MPSS	10	98	5,872	91.9 (73.8 to 97.9)	99.5 (98.8 to 99.8)	0.41
TMPS	2	6	472	93.8 (86.8 to 97.2)	99.6 (98.1 to 99.9)	0.41
Exclusion of studies with less than 10 pregnancies with aneuploidy
Autosomes (T21, T18 and T13 combined), selected high‐risk population
MPSS	21	1458	13,921	98.7 (96.8 to 99.4)	99.8 (99.5 to 100)	0.07
TMPS	7	378	4,282	98.9 (97.2 to 99.6)	99.9 (99.8 to 100)	0.07
SCA (45,X, 47,XXX, 47,XXY and 47,XYY combined), selected high‐risk population
MPSS	6	130	5,761	94.5 (80.6 to 98.6)	99.4 (97.6 to 99.8)	0.28
TMPS	2	90	496	94.4 (87.3 to 97.7)	99.0 (97.6 to 99.6)	0.28
45,X: Turner syndrome, 47,XXX: triple X syndrome, 47,XXY: Klinefelter syndrome, T21: trisomy 21, T18: trisomy 18, T13: trisomy 13 CI: confidence interval, MPSS: massively parallel shotgun sequencing, SCA: sex chromosome aneuploidies, TMPS: targeted massively parallel sequencing. ^aWe included pregnancies with any other aneuploidy than the one under analysis with all euploid cases as "unaffected" pregnancies. ^bThe P value indicates the statistical significance of the difference in model fit and was obtained from likelihood ratio tests comparing models with and without a covariate for test type.

Table 11. Sensitivity analyses

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Table Tests. Data tables by test

Test	No. of studies	No. of participants
1 MPSS T21 Show forest plot	41	50133

2 MPSS T18 Show forest plot	38	49003

3 MPSS T13 Show forest plot	29	46090

4 MPSS 45,X Show forest plot	14	7867

5 MPSS 47, XXX Show forest plot	5	5449

6 MPSS 47,XXY Show forest plot	8	6588

7 MPSS 47,XYY Show forest plot	8	6629

8 MPSS all 7 aneuploidies Show forest plot	44	50864

9 MPSS, autosomes Show forest plot	43	50453

10 MPSS, SCA Show forest plot	14	7911

11 TMPS T21 Show forest plot	16	32487

12 TMPS T18 Show forest plot	12	30319

13 TMPS T13 Show forest plot	10	22868

14 TMPS 45,X Show forest plot	6	2214

15 TMPS 47,XXX Show forest plot	2	586

16 TMPS 47,XXY Show forest plot	4	1021

17 TMPS 47,XYY Show forest plot	2	358

18 TMPS all 7 aneuploidies Show forest plot	21	35275

19 TMPS, autosomes Show forest plot	18	34473

20 TMPS, SCA Show forest plot	6	2214

21 Traditional screening tests, autosomes Show forest plot	5	24279

22 Traditional screening tests T21 Show forest plot	2	17753

23 Traditional screening tests T18 Show forest plot	2	17747

24 Traditional screening tests T13 Show forest plot	1	11185

Table Tests. Data tables by test

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