Talk:Non-Invasive Prenatal Testing

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Cite this page: Hill, M.A. (2019, December 13) Embryology Non-Invasive Prenatal Testing. Retrieved from

circulating cell-free fetal DNA


Non-invasive prenatal testing to detect chromosome aneuploidies in 57,204 pregnancies

Mol Cytogenet. 2019 Jun 20;12:29. doi: 10.1186/s13039-019-0441-5. eCollection 2019.

Xue Y#1,2, Zhao G#3, Li H1,2, Zhang Q1,2, Lu J1,2, Yu B4, Wang T1,2.

BACKGROUND: Non-invasive prenatal testing (NIPT) has been widely used to detect common fetal chromosome aneuploidies, such as trisomy 13, 18, and 21 (T13, T18, and T21), and has expanded to sex chromosome aneuploidies (SCAs) during recent years, but few studies have reported NIPT detection of rare fetal chromosome aneuploidies (RCAs). In this study, we evaluated the clinical practical performance of NIPT to analyze all 24 chromosome aneuploidies among 57,204 pregnancies in the Suzhou area of China. METHODS: This was a retrospective analysis of prospectively collected NIPT data from two next-generation sequencing (NGS) platforms (Illumina and Proton) obtained from The Affiliated Suzhou Hospital of Nanjing Medical University. NIPT results were validated by karyotyping or clinical follow-up. RESULTS: NIPT using the Illumina platform identified 586 positive cases; fetal karyotyping and follow-up results validated 178 T21 cases, 49 T18 cases, 4 T13 cases, and 52 SCAs. On the Proton platform, 270 cases were positive during NIPT. Follow-up confirmed 85 T21 cases, 17 T18 cases, 4 T13 cases, 28 SCAs, and 1 fetal chromosome 22 aneuploidy case as true positives. There were 5 false-negative results, including 4 T21 and 1 T18 cases. The NGS platforms showed similar sensitivities and positive predictive values (PPVs) in detecting T21, T18, T13 and SCAs (p > 0.01). However, the Proton platform showed better specificity in detecting 45, X and the Illumina platform had better specificity in detecting T13 (p < 0.01). The major factor contributing to NIPT false-positives on the Illumina platform was false SCAs cases (65.11%). Maternal chromosome aneuploidies, maternal cancers, and confined placental mosaicism caused discordant results between fetal karyotyping and NIPT. CONCLUSION: NIPT with NGS showed good performance for detecting T13, T18, and T21. The Proton platform had better performance for detecting SCAs, but the NIPT accuracy rate for detecting RCAs was insufficient. KEYWORDS: Chromosome aneuploidies; NIPT; Next generation sequencing; Performance PMID: 31249627 PMCID: PMC6584990 DOI: 10.1186/s13039-019-0441-5


Uptake, outcomes, and costs of implementing non-invasive prenatal testing for Down's syndrome into NHS maternity care: prospective cohort study in eight diverse maternity units

BMJ. 2016 Jul 4;354:i3426. doi: 10.1136/bmj.i3426.

Chitty LS1, Wright D2, Hill M3, Verhoef TI4, Daley R5, Lewis C1, Mason S6, McKay F6, Jenkins L6, Howarth A5, Cameron L7, McEwan A8, Fisher J9, Kroese M7, Morris S4.


OBJECTIVE: To investigate the benefits and costs of implementing non-invasive prenatal testing (NIPT) for Down's syndrome into the NHS maternity care pathway. DESIGN: Prospective cohort study. SETTING: Eight maternity units across the United Kingdom between 1 November 2013 and 28 February 2015. PARTICIPANTS: All pregnant women with a current Down's syndrome risk on screening of at least 1/1000. MAIN OUTCOME MEASURES: Outcomes were uptake of NIPT, number of cases of Down's syndrome detected, invasive tests performed, and miscarriages avoided. Pregnancy outcomes and costs associated with implementation of NIPT, compared with current screening, were determined using study data on NIPT uptake and invasive testing in combination with national datasets. RESULTS: NIPT was prospectively offered to 3175 pregnant women. In 934 women with a Down's syndrome risk greater than 1/150, 695 (74.4%) chose NIPT, 166 (17.8%) chose invasive testing, and 73 (7.8%) declined further testing. Of 2241 women with risks between 1/151 and 1/1000, 1799 (80.3%) chose NIPT. Of 71 pregnancies with a confirmed diagnosis of Down's syndrome, 13/42 (31%) with the diagnosis after NIPT and 2/29 (7%) after direct invasive testing continued, resulting in 12 live births. In an annual screening population of 698 500, offering NIPT as a contingent test to women with a Down's syndrome screening risk of at least 1/150 would increase detection by 195 (95% uncertainty interval -34 to 480) cases with 3368 (2279 to 4027) fewer invasive tests and 17 (7 to 30) fewer procedure related miscarriages, for a non-significant difference in total costs (£-46 000, £-1 802 000 to £2 661 000). The marginal cost of NIPT testing strategies versus current screening is very sensitive to NIPT costs; at a screening threshold of 1/150, NIPT would be cheaper than current screening if it cost less than £256. Lowering the risk threshold increases the number of Down's syndrome cases detected and overall costs, while maintaining the reduction in invasive tests and procedure related miscarriages. CONCLUSIONS: Implementation of NIPT as a contingent test within a public sector Down's syndrome screening programme can improve quality of care, choices for women, and overall performance within the current budget. As some women use NIPT for information only, the Down's syndrome live birth rate may not change significantly. Future research should consider NIPT uptake and informed decision making outside of a research setting. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

PMID 27378786

Open source non-invasive prenatal testing platform and its performance in a public health laboratory

Prenat Diagn. 2016 Mar 30. doi: 10.1002/pd.4819. [Epub ahead of print]

Johansen P1, Richter SR1, Balslev-Harder M1, Miltoft CB2, Tabor A2, Duno M3, Kjaergaard S1.


OBJECTIVE: To introduce NIPT for fetal autosomal trisomies and gender in a Danish public health setting, using semi-conductor sequencing and published open source scripts for analysis. METHODS: Plasma derived DNA from a total of 375 pregnant women (divided into 3 datasets) was whole-genome sequenced on the Ion Proton™ platform and analyzed using a pipeline based on WISECONDOR for fetal autosomal aneuploidy detection and SeqFF for fetal DNA fraction estimation. We furthermore validated a fetal sex determination analysis. RESULTS: The pipeline correctly detected 27/27 trisomy 21, 4/4 trisomy 18 and 3/3 trisomy 13 fetuses. Neither false negatives nor false positives (chromosomes 13, 18 and 21) were observed in our validation dataset. Fetal sex was identified correctly in all but one triploid fetus (172/173). SeqFF showed a strong correlation (R2  = 0.72) to Y-chromosomal content of the male fetus samples. DISCUSSION: We have implemented NIPT into Danish health care using published open source scripts for autosomal aneuploidy detection and fetal DNA fraction estimation showing excellent false negative and false positive rates. SeqFF provides a good estimation of fetal DNA fraction. This coupled with an analysis of fetal sex provides a complete NIPT workflow, which may easily be adapted for implementation in other public health laboratories. This article is protected by copyright. All rights reserved.

PMID 27027563


An Economic Analysis of Cell-Free DNA Non-Invasive Prenatal Testing in the US General Pregnancy Population

PLoS One. 2015 Jul 9;10(7):e0132313. doi: 10.1371/journal.pone.0132313. eCollection 2015. Benn P1, Curnow KJ2, Chapman S3, Michalopoulos SN4, Hornberger J5, Rabinowitz M3.


OBJECTIVE: Analyze the economic value of replacing conventional fetal aneuploidy screening approaches with non-invasive prenatal testing (NIPT) in the general pregnancy population. METHODS: Using decision-analysis modeling, we compared conventional screening to NIPT with cell-free DNA (cfDNA) analysis in the annual US pregnancy population. Sensitivity and specificity for fetal aneuploidies, trisomy 21, trisomy 18, trisomy 13, and monosomy X, were estimated using published data and modeling of both first- and second trimester screening. Costs were assigned for each prenatal test component and for an affected birth. The overall cost to the healthcare system considered screening costs, the number of aneuploid cases detected, invasive procedures performed, procedure-related euploid losses, and affected pregnancies averted. Sensitivity analyses evaluated the effect of variation in parameters. Costs were reported in 2014 US Dollars. RESULTS: Replacing conventional screening with NIPT would reduce healthcare costs if it can be provided for $744 or less in the general pregnancy population. The most influential variables were timing of screening entry, screening costs, and pregnancy termination rates. Of the 13,176 affected pregnancies undergoing screening, NIPT detected 96.5% (12,717/13,176) of cases, compared with 85.9% (11,314/13,176) by conventional approaches. NIPT reduced invasive procedures by 60.0%, with NIPT and conventional methods resulting in 24,596 and 61,430 invasive procedures, respectively. The number of procedure-related euploid fetal losses was reduced by 73.5% (194/264) in the general screening population. CONCLUSION: Based on our analysis, universal application of NIPT would increase fetal aneuploidy detection rates and can be economically justified. Offering this testing to all pregnant women is associated with substantial prenatal healthcare benefits.

PMID 26158465


Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: population based cohort study

BMJ. 2014 Sep 4;349:g5243. doi: 10.1136/bmj.g5243.

Chitty LS1, Finning K2, Wade A3, Soothill P4, Martin B5, Oxenford K6, Daniels G2, Massey E2.


OBJECTIVES: To assess the accuracy of fetal RHD genotyping using cell-free fetal DNA in maternal plasma at different gestational ages. DESIGN: A prospective multicentre cohort study. SETTING: Seven maternity units in England. PARTICIPANTS: RhD negative pregnant women who booked for antenatal care before 24 weeks' gestation. INTERVENTIONS: Women who gave consent for fetal RHD genotyping had blood taken at the time of booking for antenatal care and, when possible, at other routine visits such as for Down's syndrome screening between 11 and 21 weeks' gestation, at the anomaly scan at 18-21 weeks, and in the third trimester when blood was taken for the routine antibody check. The results of cord blood analysis, done routinely in RhD negative pregnancies, were also obtained to confirm the fetal RHD genotyping. MAIN OUTCOME MEASURES: The accuracy of fetal RHD genotyping compared with RhD status predicted by cord blood serology. RESULTS: Up to four analyses per woman were performed in 2288 women, generating 4913 assessable fetal results. Sensitivity for detection of fetal RHD positivity was 96.85% (94.95% to 98.05%), 99.83% (99.06% to 99.97%), 99.67% (98.17% to 99.94%), 99.82% (98.96% to 99.97%), and 100% (99.59% to 100%) at <11, 11-13, 14-17, 18-23, and >23 completed weeks' gestation, respectively. Before 11 weeks' gestation 16/865 (1.85%) babies tested were falsely predicted as RHD negative. CONCLUSIONS: Mass throughput fetal RHD genotyping is sufficiently accurate for the prediction of RhD type if it is performed from 11 weeks' gestation. Testing before this time could result in a small but significant number of babies being incorrectly classified as RHD negative. These mothers would not receive anti-RhD immunoglobulin, and there would be a risk of haemolytic disease of the newborn in subsequent pregnancies. © Chitty et al 2014.

PMID 25190055