Non-Invasive Prenatal Testing

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Introduction

graph Gestational age distribution at time of non-invasive prenatal testing
Gestational age distribution at time of non-invasive prenatal testing (2014)[1]
Trisomy 21 karyotype cartoon

Non-Invasive Prenatal Testing (NIPT) include new techniques that analyzes cell-free fetal DNA circulating in maternal blood or from fetal cells in the cervical canal.

Testing of circulating cell-free fetal DNA (ccffDNA) can be carried out after 10 weeks (between 10-22 weeks) analysis can take a week or more. It has been most useful for replacing amniocentesis in testing for the trisomies; Trisomy 21, Trisomy 18, and Trisomy 13.

There are other pages that refer to postnatal diagnostic testing. (More? Neonatal Diagnosis)


This Embryology site is a developmental educational resource, it does not provide specific clinical details, you should always refer to a health professional.


Diagnosis Links: Prenatal Diagnosis | Pregnancy Test | Amniocentesis | Chorionic villus sampling | Ultrasound | Alpha-Fetoprotein | Pregnancy-associated plasma protein-A | Fetal Blood Sampling | Magnetic Resonance Imaging | Computed Tomography | Non-Invasive Prenatal Testing | Fetal Cells in Maternal Blood | Preimplantation Genetic Screening | Comparative Genomic Hybridization | Genome Sequencing | Neonatal Diagnosis | Category:Prenatal Diagnosis | Fetal Surgery | Classification of Diseases | Category:Neonatal Diagnosis
| Assisted Reproductive Technology | In Vitro Fertilization | Journal - Prenatal diagnosis

Some Recent Findings

  • Fetal genome profiling at 5 weeks of gestation after noninvasive isolation of trophoblast cells from the endocervical canal [2] "We have isolated intact trophoblast cells from Papanicolaou smears collected noninvasively at 5 to 19 weeks of gestation for next-generation sequencing of fetal DNA. ...The data revealed fetal DNA fractions of 85 to 99.9%, with 100% correct fetal haplotyping. This noninvasive platform has the potential to provide comprehensive fetal genomic profiling as early as 5 weeks of gestation."
  • Uptake, outcomes, and costs of implementing non-invasive prenatal testing for Down's syndrome into UK NHS maternity care[3] "Eight maternity units across the United Kingdom between 1 November 2013 and 28 February 2015. All pregnant women with a current Down's syndrome risk on screening of at least 1/1000. 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. ...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." Trisomy 21 | United Kingdom Statistics
  • Fetal aneuploidy screening with cell-free DNA in late gestation[4]"The aim of this study was to evaluate clinical use of NIPT at gestational ages of 23 weeks and above. A cohort of 5579 clinical patients with singleton gestations of 23 weeks or greater submitting a blood sample for NIPT in an 18-month period were selected for this study. ...Of 5372 reported late-gestation samples, 151 (2.8%) were reported as aneuploidy detected or suspected. In late-gestation samples, the overall observed positive predictive value (PPV) for NIPT was 64.7%, with an observed PPV of 100% in the subset of cases with multiple clinical indications including abnormal ultrasound findings. NIPT is a highly accurate prenatal screening option for women after 23 weeks of gestation. Women who presented for NIPT in the latter stages of pregnancy more frequently specified clinical indications of abnormal ultrasound findings than women who entered screening earlier in pregnancy."
  • Open source non-invasive prenatal testing platform and its performance in a public health laboratory[5] "o 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. 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. 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."
  • An Economic Analysis of Cell-Free DNA Non-Invasive Prenatal Testing in the US General Pregnancy Population[6] "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. ...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."
  • Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: population based cohort study[7] "To assess the accuracy of fetal RHD genotyping using cell-free fetal DNA in maternal plasma at different gestational ages. ...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." (fetal erythroblastosis) Blood Development
  • Noninvasive Prenatal Testing: The Future Is Now[8] "Prenatal detection of chromosome abnormalities has been offered for more than 40 years, first by amniocentesis in the early 1970s and additionally by chorionic villus sampling (CVS) in the early 1980s. ...The ability to isolate fetal cells and fetal DNA from maternal blood during pregnancy has opened up exciting opportunities for improved noninvasive prenatal testing (NIPT). Direct analysis of fetal cells from maternal circulation has been challenging given the scarcity of fetal cells in maternal blood (1:10,000-1:1,000,000) and the focus has shifted to the analysis of cell-free fetal DNA, which is found at a concentration almost 25 times higher than that available from nucleated blood cells extracted from a similar volume of whole maternal blood. There have now been numerous reports on the use of cell-free DNA (cfDNA) for NIPT for chromosomal aneuploidies-especially trisomy (an extra copy of a chromosome) or monosomy (a missing chromosome)-and a number of commercial products are already being marketed for this indication. This article reviews the various techniques being used to analyze cell-free DNA in the maternal circulation for the prenatal detection of chromosome abnormalities and the evidence in support of each."
  • Noninvasive whole-genome sequencing of a human fetus[9] "Analysis of cell-free fetal DNA in maternal plasma holds promise for the development of noninvasive prenatal genetic diagnostics. Previous studies have been restricted to detection of fetal trisomies, to specific paternally inherited mutations, or to genotyping common polymorphisms using material obtained invasively, for example, through chorionic villus sampling. Here, we combine genome sequencing of two parents, genome-wide maternal haplotyping, and deep sequencing of maternal plasma DNA to noninvasively determine the genome sequence of a human fetus at 18.5 weeks of gestation. "
  • A noninvasive test to determine paternity in pregnancy[10] "Our approach shows that noninvasive prenatal paternity testing can be performed within the first trimester with the use of a maternal blood sample."
More recent papers  
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Non-Invasive Prenatal Testing

Andrea Dall'Asta, Silvia Schievano, Jan L Bruse, Gowrishankar Paramasivam, Christine Tita Kaihura, David Dunaway, Christoph C Lees Quantitative analysis of fetal facial morphology using 3D ultrasound and statistical shape modelling: a feasibility study. Am. J. Obstet. Gynecol.: 2017; PubMed 28209493

M Bunnell, C Zhang, C Lee, D W Bianchi, L Wilkins-Haug Confined Placental Mosaicism for 22q11.2 Deletion as the Etiology for Discordant Positive NIPT Results. Prenat. Diagn.: 2017; PubMed 28198030

B L Gammon, S A Kraft, M Michie, M Allyse "I think we've got too many tests!": Prenatal providers' reflections on ethical and clinical challenges in the practice integration of cell-free DNA screening. Ethics Med Public Health: 2017, 2(3);334-342 PubMed 28180146

Maria C Neofytou, Kyriakos Tsangaras, Elena Kypri, Charalambos Loizides, Marios Ioannides, Achilleas Achilleos, Petros Mina, Anna Keravnou, Carolina Sismani, George Koumbaris, Philippos C Patsalis Targeted capture enrichment assay for non-invasive prenatal testing of large and small size sub-chromosomal deletions and duplications. PLoS ONE: 2017, 12(2);e0171319 PubMed 28158220

Idit Maya, Shiri Yacobson, Sarit Kahana, Josepha Yeshaya, Tamar Tenne, Ifaat Agmon-Fishman, Lital Cohen-Vig, Mordechai Shohat, Lina Basel-Vanagaite, Reuven Sharony The cut-off value for normal nuchal translucency evaluated by chromosomal microarray analysis. Ultrasound Obstet Gynecol: 2017; PubMed 28133835

Costs

A recent 2014 Canadian study[11] identified the cost of NIPT ranges from US$800 to US$2000 in the USA and from US$500 to US$1500 elsewhere.


Inheritance Genetics

Pedigree chart


Links: Genetic risk maternal age | Trisomy 21

Australia

A recent publication from NHMRC Medical Genetic Testing: information for health professionals (2010). This paper covers background information on all types of genetic tests, not just those associated with prenatal diagnosis.

Types of genetic tests

  • Somatic cell genetic testing involves testing tissue (usually cancer) for non-heritable mutations. This may be for diagnostic purposes, or to assist in selecting treatment for a known cancer.
  • Diagnostic testing for heritable mutations involves testing an affected person to identify the underlying mutation(s) responsible for the disease. This typically involves testing one or more genes for a heritable mutation.
  • Predictive testing for heritable mutations involves testing an unaffected person for a germline mutation identified in genetic relatives. The risk of disease will vary according to the gene, the mutation and the family history.
  • Carrier testing for heritable mutations involves testing for the presence of a mutation that does not place the person at increased risk of developing the disease, but does increase the risk of having an affected child developing the disease.
  • Pharmacogenetic testing for a genetic variant that alters the way a drug is metabolised. These variants can involve somatic cells or germline changes. Even if these variants are heritable (that is germline changes), the tests are usually of relevance to genetic relatives only if they are being treated with the same type of medication.


Links: NHMRC - Medical Genetic Testing: information for health professionals

USA

A new site developed by NIH "GeneTests" provides medical genetics information resources available at no cost to all interested persons. It contains educational information, a directory of genetic testing laboratories and links to other databases such as OMIM.


Links: GeneTests | Medline Plus - Genetic Testing


Ethics of Testing

Major developmental abnormalities detected early enough can be resolved far more easily than those discovered late in a pregnancy.

What are the ethical questions that are raised by prenatal testing? Future individual rights or parents rights? But what about diseases, like Huntington's, where a diagnostic test can be made but there are no current treatments for the postnatal (95% of cases adult onset) disease?

Huntington's disease

Guidelines for the molecular genetics predictive test

Recommendation 2.1 "the test is available only to individuals who have reached the age of majority."
Recommendation 7.2 "the couple requesting antenatal testing must be clearly informed that if they intend to complete the pregnancy if the fetus is a carrier of the gene defect, there is no valid reason for performing the test."

(excerpt from: IHA and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease.)

Movies

Panorama Test

Links: YouTube

References

  1. Ron M McCullough, Eyad A Almasri, Xiaojun Guan, Jennifer A Geis, Susan C Hicks, Amin R Mazloom, Cosmin Deciu, Paul Oeth, Allan T Bombard, Bill Paxton, Nilesh Dharajiya, Juan-Sebastian Saldivar Non-invasive prenatal chromosomal aneuploidy testing - clinical experience: 100,000 clinical samples. PLoS ONE: 2014, 9(10);e109173 PubMed 25289665
  2. Chandni V Jain, Leena Kadam, Marie van Dijk, Hamid-Reza Kohan-Ghadr, Brian A Kilburn, Craig Hartman, Vicki Mazzorana, Allerdien Visser, Michael Hertz, Alan D Bolnick, Rani Fritz, D Randall Armant, Sascha Drewlo Fetal genome profiling at 5 weeks of gestation after noninvasive isolation of trophoblast cells from the endocervical canal. Sci Transl Med: 2016, 8(363);363re4 PubMed 27807286
  3. Lyn S Chitty, David Wright, Melissa Hill, Talitha I Verhoef, Rebecca Daley, Celine Lewis, Sarah Mason, Fiona McKay, Lucy Jenkins, Abigail Howarth, Louise Cameron, Alec McEwan, Jane Fisher, Mark Kroese, Stephen Morris 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, 354;i3426 PubMed 27378786
  4. Patricia A Taneja, Tracy L Prosen, Eileen de Feo, Kristina M Kruglyak, Meredith Halks-Miller, Kirsten J Curnow, Sucheta Bhatt Fetal aneuploidy screening with cell-free DNA in late gestation. J. Matern. Fetal. Neonatal. Med.: 2016;1-5 PubMed 27124739
  5. Peter Johansen, Stine R Richter, Marie Balslev-Harder, Caroline B Miltoft, Ann Tabor, Morten Duno, Susanne Kjaergaard Open source non-invasive prenatal testing platform and its performance in a public health laboratory. Prenat. Diagn.: 2016; PubMed 27027563
  6. Peter Benn, Kirsten J Curnow, Steven Chapman, Steven N Michalopoulos, John Hornberger, Matthew Rabinowitz An Economic Analysis of Cell-Free DNA Non-Invasive Prenatal Testing in the US General Pregnancy Population. PLoS ONE: 2015, 10(7);e0132313 PubMed 26158465 | PLoS One.
  7. Lyn S Chitty, Kirstin Finning, Angela Wade, Peter Soothill, Bill Martin, Kerry Oxenford, Geoff Daniels, Edwin Massey Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: population based cohort study. BMJ: 2014, 349;g5243 PubMed 25190055 | BMJ.
  8. Errol R Norwitz, Brynn Levy Noninvasive prenatal testing: the future is now. Rev Obstet Gynecol: 2013, 6(2);48-62 PubMed 24466384
  9. Jacob O Kitzman, Matthew W Snyder, Mario Ventura, Alexandra P Lewis, Ruolan Qiu, Lavone E Simmons, Hilary S Gammill, Craig E Rubens, Donna A Santillan, Jeffrey C Murray, Holly K Tabor, Michael J Bamshad, Evan E Eichler, Jay Shendure Noninvasive whole-genome sequencing of a human fetus. Sci Transl Med: 2012, 4(137);137ra76 PubMed 22674554
  10. Xin Guo, Philip Bayliss, Marian Damewood, John Varney, Emily Ma, Brett Vallecillo, Ravinder Dhallan A noninvasive test to determine paternity in pregnancy. N. Engl. J. Med.: 2012, 366(18);1743-5 PubMed 22551147


Reviews

Jean Gekas, Sylvie Langlois, Vardit Ravitsky, François Audibert, David Gradus van den Berg, Hazar Haidar, François Rousseau Non-invasive prenatal testing for fetal chromosome abnormalities: review of clinical and ethical issues. Appl Clin Genet: 2016, 9;15-26 PubMed 26893576

Heather Skirton, Lesley Goldsmith, Leigh Jackson, Celine Lewis, Lyn S Chitty Non-invasive prenatal testing for aneuploidy: a systematic review of Internet advertising to potential users by commercial companies and private health providers. Prenat. Diagn.: 2015; PubMed 26266986

Megan Allyse, Mollie A Minear, Elisa Berson, Shilpa Sridhar, Margaret Rote, Anthony Hung, Subhashini Chandrasekharan Non-invasive prenatal testing: a review of international implementation and challenges. Int J Womens Health: 2015, 7;113-26 PubMed 25653560

Peter Benn Non-Invasive Prenatal Testing Using Cell Free DNA in Maternal Plasma: Recent Developments and Future Prospects. J Clin Med: 2014, 3(2);537-65 PubMed 26237390


Articles

Diane Van Opstal, Malgorzata I Srebniak Cytogenetic confirmation of a positive NIPT result: evidence-based choice between chorionic villus sampling and amniocentesis depending on chromosome aberration. Expert Rev. Mol. Diagn.: 2016; PubMed 26864482

Genevieve Fairbrother, John Burigo, Thomas Sharon, Ken Song Prenatal screening for fetal aneuploidies with cell-free DNA in the general pregnancy population: a cost-effectiveness analysis. J. Matern. Fetal. Neonatal. Med.: 2015;1-5 PubMed 26000626

Roy Straver, Cees B M Oudejans, Erik A Sistermans, Marcel J T Reinders Calculating the fetal fraction for Non Invasive Prenatal Testing based on Genome-wide nucleosome profiles. Prenat. Diagn.: 2016; PubMed 26996738

T Ohnhaeuser, D Schmitz Non-invasive Prenatal Testing (NIPT): Better Meet an Expert!: The Case of a Late Detected Trisomy 13 Reveals Structural Problems in NIPT Counselling and Highlights Substantial Risks for the Reproductive Autonomy. Geburtshilfe Frauenheilkd: 2016, 76(3);277-279 PubMed 27064737

Lucie Orhant, Olivia Anselem, Mélanie Fradin, Pierre Hadrien Becker, Caroline Beugnet, Nathalie Deburgrave, Gilles Tafuri, Franck Letourneur, François Goffinet, Laïla Allach El Khattabi, France Leturcq, Thierry Bienvenu, Vassilis Tsatsaris, Juliette Nectoux Droplet Digital PCR combined with minisequencing, a new approach to analyze fetal DNA from maternal blood: application to the non-invasive prenatal diagnosis of achondroplasia. Prenat. Diagn.: 2016; PubMed 26850935

Emily C Higuchi, Jane P Sheldon, Brian J Zikmund-Fisher, Beverly M Yashar Non-invasive prenatal screening for trisomy 21: Consumers' perspectives. Am. J. Med. Genet. A: 2015; PubMed 26553705


Books

PubMed Health

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Prenatal Diagnosis Terms

  • ART - Assisted Reproductive Technology a general term to describe all the clinical techniques used to aid fertility.
  • blastomere biopsy - An ART preimplantation genetic diagnosis technique carried out at cleavage stage (day 3), excluding poor quality embryos, detects chromosomal abnormalities of both maternal and paternal origin. May not detect cellular mosaicism in the embryo.
  • blastocyst biopsy - An ART preimplantation genetic diagnosis technique carried out at blastocyst stage (day 4-5), removes several trophoblast (trophoderm) cells, detects chromosomal abnormalities of both maternal and paternal origin and may detect cellular mosaicism.
  • cell-free fetal deoxyribonucleic acid - (cffDNA) refers to fetal DNA circulating and isolated from the plasma portion of maternal blood.
  • false negative rate - The proportion of pregnancies that will test negative given that the congenital anomaly is present.
  • false positive rate - The proportion of pregnancies that will test positive given that the congenital anomaly is absent.
  • negative predictive value - The probability that a congenital anomaly is absent given that the prenatal screening test is negative.
  • Non-Invasive Prenatal Testing - (NIPT) could refer to ultrasound or other imaging techniques, but more frequently used to describe analysis of cell-free fetal DNA circulating in maternal blood.
  • polar body biopsy - (PB biopsy) An ART preimplantation genetic diagnosis technique that removes either the first or second polar body from the zygote. As these are generated by oocyte meiosis they detects chromosomal abnormalities only on the female genetics.
  • positive predictive value - The probability that a congenital anomaly is present given that the prenatal screening test is positive.
  • pre-implantation genetic diagnosis - (PGD, pre-implantation genetic screening) a diagnostic procedure for embryos produced through Assisted Reproductive Technology (ART, in vitro fertilisation, IVF) for genetic diseases that would generate developmental abnormalities or serious postnatal diseases.
  • prenatal screening sensitivity - (detection rate) The probability of testing positive on a prenatal screening test if the congenital anomaly is present.
  • prenatal screening specificity - The probability of testing negative on a prenatal screening test if the congenital anomaly is absent.
  • single nucleotide polymorphisms - (SNPs) the variation in a single DNA nucleotide that occurs at a specific position in the genome.
Other Terms Lists  
Terms Lists: ART | Birth | Bone | Cardiovascular | Gastrointestinal | Genetic | Hearing | Heart | Immune | Integumentary | Neural | Oocyte | Palate | Placenta | Renal | Spermatozoa | Ultrasound | Vision | Historic | Glossary


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Cite this page: Hill, M.A. 2017 Embryology Non-Invasive Prenatal Testing. Retrieved February 27, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Non-Invasive_Prenatal_Testing

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