Non-invasive Prenatal Testing Using Cell-free Fetal DNA (cffDNA)
Circulating cell-free fetal DNA (ccfDNA) crosses the placenta and can be isolated in maternal plasma. As early as 8-10 weeks of gestation these fetal DNA fragments can comprise 6-10% of the total cell free DNA in maternal plasma. Laboratories have developed tests that analyze cffDNA as a non-invasive screening tool for detecting fetal chromosomal abnormalities such as trisomy 21 (Down Syndrome), trisomy 18 (Edward Syndrome), and trisomy 13 (Patau Syndrome). Examples of these CLIA regulated tests include MaterniT21 PLUS® (T13, 16, 18, 21, 22 and sex-linked), Verifi® Prenatal Test (T13, 18, and 21), Harmony™ Prenatal Test (T13, 18, and 21), Panorama™ Prenatal Test (T13, 18, 21 and sex-linked), InformaSerq™ (T13, 18, 21 and sex-linked) and QNatal™ (T13, 18, and 21). Some of these tests have also been investigated for the use in detecting sex-linked abnormalities such as Turner Syndrome (XO in females) and Klinefelter Syndrome (XXX or XXY in males).
The American College of Obstetricians and Gynecologists (ACOG) guidelines recommend that all women be offered screening for fetal aneuploidy (abnormal number of chromosomes). This screening has traditionally involved a thorough prenatal and family history, and a combination of maternal serum markers, and fetal ultrasounds (i.e., nuchal translucency, pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, and alpha-fetoprotein). If the first-trimester screening results indicates an elevated risk of aneuploidy the ACOG recommendation is to offer the individual a cell-free fetal DNA screening or other diagnostic test.
Laboratories have also explored the potential for identifying fetal Rh status using the cell-free fetal DNA technology. Examples of these tests are SensiGene® and SEQureDX®.
Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) to detect fetal aneuploidy is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) for the determination of fetal sex is considered not medically necessary.
Non-invasive prenatal testing of maternal plasma in twin/multiple gestations using cell-free fetal DNA (cffDNA) is considered investigational.
Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) for the detection of other fetal aneuploidy or chromosomal abnormalities including but not limited to the following is considered investigational:
Fetal sex chromosome aneuploidies
Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) to determine fetal RHD genotyping is considered investigational.
See also: First-Trimester Detection of Down’s Syndrome Using Fetal Ultrasound Markers Combined with Maternal Serum Assessment
Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) is considered medically appropriate if ALL of the following criteria are met:
Conventional screening shows ANY ONE of the following:
Maternal age 35 or older by estimated date of confinement (EDC)
Fetal ultrasonographic findings indicate an increased risk of aneuploidy
History of a prior pregnancy with a trisomy
Standard screening tests are positive for aneuploidy [e.g. pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP), free beta-human chorionic gonadotropin (hCG), unconjugated estriol (UE3), dimeric inhibin-A (DIA)]
Parents are known to have a balanced Robertsonian translocation (a rare form of chromosomal rearrangement in the 13, 14, 15, 21, or 22 pairs)
Testing is indicated to determine presence of ANY ONE of the following chromosomal abnormalities:
Trisomy 21 - Down Syndrome
Trisomy 18 - Edward Syndrome
Trisomy 13 - Patau Syndrome
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Before testing, women should receive counseling regarding the potential for false positive results. Studies to date do report rare false positives and no biological or processing explanations for these false positives have been discerned. In the absence of substantial data to characterize a false positive the professional organizations advise karyotyping tests (i.e. amniocentesis or chorionic villa sampling) to confirm a positive result.
There is insufficient evidence that noninvasive prenatal testing using cell-free fetal DNA is accurate for detecting fetal aneuploidy in twin and multiple pregnancies. The clinical utility of early sex chromosome aneuploidy detection is also unclear.
110th Congress: S. 1810: (2008, January). Amendment to the Public Health Service Act of 2008: support services to patients receiving a positive test diagnosis for Down syndrome or other prenatally and postnatally diagnosed conditions Retrieved March 10,2017 from http://thomas.loc.gov.
American College of Obstetricians and Gynecologists / Society for Maternal-Fetal Medicine (2016, May) Practice bulletin #162: prenatal diagnostic testing for genetic disorders. Retrieved March 10, 2017 from: http://www.acog.org.
American College of Obstetricians and Gynecologists, Committee on Genetics; Society of Maternal-Fetal Medicine. (2015, September). Cell-free DNA Screening for fetal aneuploidy. committee opinion number 640. Retrieved August 7, 2015 from: http://www.acog.org.
American College of Obstetricians and Gynecologists, Committee on Genetics; Society of Maternal-Fetal Medicine. (2016, May). Practice Bulletin Number 163: Screening for Fetal Aneuploidy. Retrieved May 13, 2016 from: http://www.acog.org.
Bianchi, D., Parker, L., Wentworth, J., Madankumar, R., Saffer, C., Das, A., et. al. (February 2014) DNA sequencing versus standard prenatal aneuploidy screening. The New England Journal of Medicine. Vol. 370, No. 9, 800-808. (Level 2 evidence)
BlueCross BlueShield Association. Medical Policy Reference Manual. (10:2016). Noninvasive prenatal screening for fetal aneuploidies using cell-free fetal DNA. (4.01.21). Retrieved March 10, 2017 from BlueWeb. (40 articles and/or guidelines reviewed)
BlueCross BlueShield Association. Medical Policy Reference Manual. (11:2015). Noninvasive fetal RhD genotyping using cell-free fetal DNA. (2.04.108). Retrieved March 10, 2017 from BlueWeb. (9 articles and/or guidelines reviewed)
Dondorp, W., de Wert, G., Bombard, Y., Bianchi, D., Bergmann, C., Borry, P., et. al., (2015) Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. European Journal of Human Genetics (2015) 23, 1438–1450. (Level 5 evidence)
ECRI Institute. Emerging Technology Reports - Evidence Analysis. (2014, April). Cell-free fetal DNA tests for prenatal screening of fetal aneuploidies. Retrieved January 16, 2015 from ECRI Institute. (62 articles and/or guidelines reviewed)
Li, W., Wang, P., Chuang, C., Chang, Y., Yang, M., Chen, C. et. al. (2015, February) Noninvasive prenatal testing for fetal trisomy in a mixed risk factors pregnancy population. Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 122-5. (Level 4 evidence)
Norton, M., Jocobsson, B., Swamy, G., Laurent, L., Ranzini, A., Brar, H., et. al. (April 2015) Cell-free DNA analysis for noninvasive examination of trisomy. The New England Journal of Medicine. Vol. 372, No. 17, 1589-1597. (Level 2 evidence)
Palomaki, G., Deciu, C., Kloza, E., Lambert-Messerlian, G., Haddow, J., Neveux, L., et al. (2012). DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genetics in Medicine, 14 (3), 296- 305. (Level 3 evidence - Industry supported)
Sparks, A., Struble, C., Wang, E., Song, K., & Oliphant, A. (2012). Noninvasive prenatal detection and selective analysis of cell free DNA obtained from maternal blood: evaluation of trisomy 21 and trisomy 18. American Journal of Obstetrics and Gynecology, 206 (319) e1-9. (Level 3 evidence - Industry supported)
Taylor-Phillips, S., Freeman, K., Geppert, J., Agbebiyi, A., Uthman, O., Madan, J., et. al. (2015, November) Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. British Medical Journal (BMJ) 2016;6:e010002. (Level 1 evidence)
Technology Evaluation Center. (2013, April). Sequencing-based tests to determine fetal down syndrome (Trisomy 21) from maternal plasma DNA. (Vol. 27, No. 10). Chicago: BlueCross BlueShield Association. (57 articles and/or guidelines reviewed)
Technology Evaluation Center. (2014, December). Noninvasive prenatal cell-free fetal DNA-based screening for aneuploidies other than trisomy 21. (Vol. 29, No. 7). Chicago: BlueCross BlueShield Association. (55 articles and/or guidelines reviewed)
Tiblad, E., Wilkman, A., Ajne, G., Blanck, A., Jansson, Y., Karlssom, A., et al. (2013). Targeted routine antenatal anti-D prophylaxis in the prevention of RhD immunization – Outcome of a new antenatal screening and prevention program. Public Library of Science, 8 (8), e70984. (Level 4 evidence)
Winifred S. Hayes, Inc. GTE Report. (2013, August, latest update search March 2015). Noninvasive prenatal testing. Retrieved March 10, 2017 from www.hayesinc.com. (93 articles and/or guidelines reviewed)
ORIGINAL EFFECTIVE DATE: 6/8/2013
MOST RECENT REVIEW DATE: 4/13/2017
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