The guidelines/consensus articles considered for the description and technical characteristics of technology and the health problem and current use of the technology domains were elaborated by different medical colleges or societies from the UK, USA, Australia, etc. (see Appendix 1, Table A1).
Only one was evidence based [38].
The clinical effectiveness and safety were assessed for five screening pathways:
1. NIPT as a primary screening test as a replacement for FCT 2. Prenatal screening based on NIPT as part of FCT
3. NIPT as an add-on to FCT for the high-risk population
4. NIPT as an add-on to FCT for the high- and intermediate-risk population 5. NIPT as a replacement for invasive testing
Direct evidence for the clinical effectiveness and safety domains was found only for the first pathway (total replacement of FCT). This evidence derives from five paired comparative studies and four noncomparative studies performed in singleton pregnancies. Moreover, two studies on twin preg-nancies offered NIPT as a primary screening strategy to some of the women included, alt hough results were reported jointly with those of women offered NIPT as a second-tier test (high-risk preg-nancies). The question regarding NIPT as an add-on to FCT in women with high risk of aneu-ploidies was answered indirectly from pooled data derived from 26 retrieved studies on singleton pregnancies which assessed NIPT as a second-tier test in these populations. The add-on strategy for intermediate-risk patients was addressed in only one study. Six studies provided data on the accuracy of NIPT for twin populations. No evidence was found regarding the performance of these tests in combination with FCT and/or NT assessment. The scenario of NIPT as a diag nostic test will not be considered as none of the tests are currently indicated for this purpose. No data exist regarding patient-relevant outcomes (Table 2). Detailed information about studies included in the assessment can be found in Appendix 1 (Tables A2–A5).
The evidence included in the ethical analysis, organisational aspects, patients and social aspects, and legal aspects domains comes from 14 quantitative surveys, questionnaires or interviews and two systematic reviews. One of the systematic reviews, which focused on factors affecting the clinical use of noninvasive testing, used a mixed method approach to identify key features of the studies included. The other used thematic analysis to explore Internet advertising of NIPT.
Ongoing clinical trials and research projects identified can be found in Appendix 1 (Table A6).
The search identified five systematics reviews and/or meta-analyses and five health technology assessment reports which were not included because they did not comply with the PICO question.
Detailed information about these documents can be found in Appendix 1 (Table A7).
Table 2: Main characteristics of studies included for the clinical effectiveness and safety domains Authors and year
or study name
Study type and target condition Number of women enrolled
Intervention(s) Main endpoints
Sarno et al. [39], 2016
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
10,698 Index test trademark: Harmony® prenatal test Comparator: no intervention
Reference standard: fetal karyotype (method used not specified)
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Comas et al. [40], 2015
Prospective DTA trial (cross-sectional design) Trisomy 21
333 Index test trademark: Harmony® prenatal test or Panorama™ test
Comparator: no intervention
Reference standard: CVS or amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Norton et al. [31], 2015
Prospective, multicentre comparative DTA trial (cross-sectional design) NIPT analysis blinded to clinical information
Trisomies 21, 18 and 13 and other an-euploidies (45,X maker
chromosomes, unbalanced translocations, unbalanced translocations, 7p deletion, 5p deletion/duplication, 1q41 deletion and isochromosome Yp)
18,955 Index test trademark: Harmony® prenatal test Comparator: standard screening (NT and biochemical analytes, i.e., PAPP-A and total hCG or β-hCG
Reference standard: CVS, products of conception or neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV.
Effectiveness of prenatal screening with NIPT vs. screening without NIPT Reduction in children born with undiagnosed trisomies 13, 18 and 21 Reduction in uptake of invasive testing
Pérez-Pedregosa et al. [41], 2015
Prospective comparative DTA trial (cross-sectional design)
Trisomies 21 and 18
582 Index test trademark: Harmony® prenatal test Comparator: standard screening, i.e., NT with serum biochemical assays (PAPP-A and total hcG or β-hCG) Reference standard: CVS or amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV Effectiveness of prenatal screening with NIPT vs. screening without NIPT Reduction in uptake of invasive testing Quezada et al.
[42], 2015
Prospective, comparative DTA trial (cross-sectional design)
Trisomies 21, 18 and 13
2905 Index test trademark: Harmony® prenatal test Comparator: standard screening, i.e., NT and fetal CRL with serum biochemical assays (PAPP-A and total hCG or β-hCG)
Reference standard: CVS or amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV Effectiveness of prenatal screening with NIPT vs. screening without NIPT Reduction in children born with undiagnosed trisomies 13, 18 and 21
Authors and year or study name
Study type and target condition Number of women enrolled
Intervention(s) Main endpoints
Reduction in uptake of invasive testing Zhang et al. [43],
2015
Prospective, multicentre DTA trial (cross-sectional design)
Trisomies 21, 18 and 13
147,314 Index test trademark: NA (Illumina HiSeq200 platform) Comparator: no intervention
Reference standard: CVS or amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Bianchi et al.
[30], 2014 CARE study
Prospective, blinded, multicentre DTA trial (cross-sectional design) NIPT analysis blinded to clinical data and outcomes
Trisomies 21, 18 and 13
2042 Index test trademark: Verifi™ prenatal test Comparator: standard screening, i.e., serum biochemical assays in the first trimester (PAPP-A and total hCG or β-hCG) or second trimester (maternal serum α-fetoprotein, hCG, unconjugated oestriol and inhibin A) with or without NT
Reference standard: CVS or amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV Effectiveness of prenatal screening with NIPT vs. screening without NIPT Reduction in children born with undiagnosed trisomies 13, 18 and 21 Reduction in uptake of invasive testing Pergament et al.
[44], 2014
Prospective DTA trial (cross-sectional design)
Trisomies 21, 18 and 13 and monosomy X
1064 Index test trademark: NA (SNPs) Comparator: no intervention
Reference standard: amniocentesis, CVS, products of conception or genetic testing of umbilical cord blood, buccal sample or saliva
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Song et al. [45], 2013
Prospective, comparative DTA trial Trisomies 21, 18 and 13 and SCA (45,X and 47,XXy syndrome)
1916 Index test trademark: NA (Illumina HiSeq2000 platform)
Comparator: triple serum screening in the second trimester (α-fetoprotein, free β-hCG and
unconjugated oestriol)
Reference standard: amniocentesis, CVS, cordocentesis or neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV Effectiveness of prenatal screening with NIPT vs. screening without NIPT Increase in the number of children born with other unconfirmed chromosomal anomalies
Reduction in children born with undiagnosed trisomies 13, 18 and 21 Reduction in the number of
miscarriages or stillbirths of individuals affected by trisomies 13, 18 and 21 Reduction in uptake of invasive testing
Authors and year or study name
Study type and target condition Number of women enrolled
Intervention(s) Main endpoints
Kim et al. [46], 2016
Prospective DTA trial (cross-sectional design) Trisomy 21
101 Index test trademark: NA (Ion semiconductor-based sequencing)
Comparator: no intervention Reference standard: amniocentesis
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Ma et al. [47], 2016
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
2439 Index test trademark: NA (BGISEQ-1000/
combinatorial probe-anchor ligation sequencing-cPAL platform)
Comparator: no intervention
Reference standard: CVS or amniocentesis or cordocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Oepkes et al.
[48], 2016 TRIDENT study
Prospective multicentre DTA trial (cross-sectional design)
Trisomies 21, 18 and 13
1390 Index test trademark: NA (Illumina HiSeq2500 platform or Life Technologies 5500 W SOLID) Comparator: no intervention
Reference standard: CVS or amniocentesis, ultrasound data, genetic testing in products of conception and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Persico et al.
[49], 2016
Prospective, multicentre DTA trial (cross-sectional design)
Trisomies 21, 18 and 13
259 Index test trademark: NA (SNPs) Comparator: no intervention
Reference standard: CVS or amniocentesis and/or aCGH
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Zhang et al. [50], 2016
Prospective DTA trial (cross-sectional design)
Trisomies 21, 18 and 13 and Turner syndrome
87 Index test trademark: Verifi™ Prenatal Test Comparator: no intervention
Reference standard: amniocentesis, neonatal blood karyotyping and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Benachi et al.
[51], 2015
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
900 Index test trademark: NA (Illumina HiSeq1500 platform)
Comparator: no intervention
Reference standard: CVS or amniocentesis
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Authors and year or study name
Study type and target condition Number of women enrolled
Intervention(s) Main endpoints
Hernández-Gómez et al. [52], 2015
Prospective DTA trial (cross-sectional design) Trisomy 18 and monosomy X
42 Index test trademark: Harmony® prenatal test Comparator: no intervention
Reference standard: amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Ke et al. [53], 2015
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
2340 Index test trademark: NA (Illumina HiSeq2000 platform)
Comparator: no intervention
Reference standard: amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Lee et al. [54], 2015
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
93 Index test trademark: NA (MiSeq and NextSeq (Illumina))
Comparator: no intervention
Reference standard: amniocentesis, CVS cordocentesis, neonatal peripheral blood or products of conception
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Sago et al. [55], 2015
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
7740 Index test trademark: MaterniT PLUS Comparator: no intervention
Reference standard: amniocentesis or CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Sánchez-Usabiaga et al.
[56], 2015
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
270 Index test trademark: NA (SNPs) Comparator: no intervention
Reference standard: CVS or amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Song et al. [57], 2015
Prospective DTA trial (cross-sectional design)
Trisomies 21, 18 and 13 and SCA
213 Index test trademark: NA (Illumina HiSeq 2000 platform)
Comparator: no intervention
Reference standard: amniocentesis or CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Authors and year or study name
Study type and target condition Number of women enrolled
Intervention(s) Main endpoints
Wang et al. [58], 2015
Prospective DTA trial (cross-sectional design) Trisomies 21 and 18
917 Index test trademark: NA (Illumina HiSeq2000 platform)
Comparator: no intervention
Reference standard: standard karyotyping, FISH and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Jeon et al. [59], 2014
Prospective DTA trial (cross-sectional design) Trisomies 21 and 18
155 Index test trademark: NA (Ion Proton™ system) Comparator: no intervention
Reference standard: amniocentesis
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Korostelev et al.
[60], 2014
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
1968 Index test trademark: NA (SNPs) Comparator: no intervention
Reference standard: amniocentesis, chromosomal microarray analysis or neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Porreco et al.
[61], 2014
Prospective DTA trial (cross-sectional design)
Trisomies 21, 18 and 13 and SCA (Turner syndrome, trisomy X, Klinefelter syndrome and 47,XYY syndrome)
4170 Index test trademark: NA (Illumina HiSeq2000 platform)
Comparator: no intervention
Reference standard: amniocentesis or CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Stumm et al.
[62], 2014
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
522 Index test trademark: NA (Illumina HiSeq2000 platform)
Comparator: no intervention
Reference standard: amniocentesis, CVS or cordocentesis
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Willems et al.
[63], 2014
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
3000 Index test trademark: Harmony® prenatal test Comparator: no intervention
Reference standard: amniocentesis or CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Zhou et al. [64], 2014
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
7705 Index test trademark: NA Comparator: no intervention
Reference standard: amniocentesis or neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Authors and year or study name
Study type and target condition Number of women enrolled
Intervention(s) Main endpoints
Liang et al. [65], 2013
Prospective DTA trial (cross-sectional design)
Trisomies 21, 18, 13 and 9 and SCA (Turner syndrome, XXX, XXY or XYY)
435 Index test trademark: NA (Illumina HiSeq2000 platform)
Comparator: no intervention Reference standard: amniocentesis
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Nicolaides et al.
[66], 2013
Prospective DTA trial (cross-sectional design)
Trisomies 21, 18 and 13 and Turner syndrome
242 Index test trademark: NA (SNPs) Comparator: no intervention Reference standard: CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Verweij et al.
[67], 2013
Prospective DTA trial (cross-sectional design) Trisomy 21
595 Index test trademark: NA Comparator: no intervention
Reference standard: amniocentesis or CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Lau et al. [68], 2012
Prospective DTA trial (cross-sectional design)
Trisomies 21, 18 and 13 and SCA (Turner syndrome and Klinefelter syndrome)
108 Index test trademark: Verifi™ prenatal test Comparator: no intervention
Reference standard: amniocentesis or CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Norton et al. [69], 2012
Prospective DTA trial (cross-sectional design) Trisomies 21 and 18
4002 Index test trademark: Harmony® prenatal test Comparator: no intervention
Reference standard: amniocentesis or CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Ehrich et al. [70], 2011
Prospective DTA trial (cross-sectional design) Trisomy 21
480 Index test trademark: NA (GAIIx sequencer; Illumina) Comparator: no intervention
Reference standard: amniocentesis or CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Gil et al. [71], 2016
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
4012
(460 classified as high risk and 3552 classified as intermediate risk)
Index test trademark: Harmony® prenatal test Comparator: no intervention
Reference standard: CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Authors and year or study name
Study type and target condition Number of women enrolled
Intervention(s) Main endpoints
Fosler et al. [72], 2017
Prospective DTA trial (cross-sectional design) Trisomy 21
487 Index test trademark: Verifi™ prenatal test Comparator: no intervention
Reference standard: amniocentesis, CVS or ultrasound findings
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
467 Index test trademark: Harmony™ prenatal test Comparator: no intervention
Reference standard: fetal karyotype (not specified method used)
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Tan et al. [73], 2016
Prospective DTA trial (cross-sectional design) Trisomy 21
565 Index test trademark: NA (MPS) Comparator: no intervention
Reference standard: amniocentesis or CVS
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Bevilacqua et al.
[74], 2015
Prospective DTA trial (cross-sectional design) Trisomy 21
515 Index test trademark: Harmony™ prenatal test Comparator: no intervention
Reference standard: amniocentesis, CVS or neonatal blood examination
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Huang et al. [75], 2014
Prospective DTA trial (cross-sectional design) Trisomies 21 and 18
189 Index test trademark: NA Comparator: no intervention
Reference standard: amniocentesis, CVS or cordocentesis
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Lau et al. [76], 2013
Prospective DTA trial (cross-sectional design) Trisomy 21
12 Index test trademark: NA
Comparator: first- or second-trimester screening and/or first-trimester ultrasound marker screening (NT, fetal nasal bone and Doppler assessment of the tricuspid valve and ductus venosus)
Reference standard: amniocentesis, CVS or cordocentesis
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Abbreviations: aCGH=microarray-based comparative genomic hybridisation; CARE=Comparison of Aneuploidy Risk Evaluations; CRL=crown–rump length; CVS=chorionic villus sampling;
DTA=diagnostic test accuracy; FISH=fluorescence in situ hybridisation; FN=false negative; FP=false positive; hCG=human chorionic gonadotropin; β-hCG=β subunit of human chorionic gonadotropin;
MPS=massive parallel sequencing; NA=not available; NIPT=noninvasive prenatal test; NPV=negative predictive value; NT=nuchal translucency; PAPP-A=pregnancy-associated plasma protein A;
PPV=positive predictive value; S=sensitivity; SNP=single nucleotide polymorphism; Sp=specificity; TN=true negative; TP=true positive; SCA=sex chromosome aneuploidy.