Positive and negative predictive values of noninvasive prenatal tests in group of women with high and low risk of the fetal aneuploidies

The article describes the results of application of the two most common commercial non-invasive prenatal tests (NIPTs), Harmony and Panorama. The pregnant women were divided into the high and low risk groups due to prenatal screening of the first trimester results. A total number of cases: 5,076 (1710 Harmony and 3366 Panorama), of which 592 twins. High-risk group: 2921 patients: 1926 (Panorama) and 995 (Harmony); low risk group: 2155: 1440 (Panorama) and 715 (Harmony). The high risk of chromosome pathology of the fetus according to the results of NIPT was determined in 144 observations, including 89 for trisomy 21, 14 for trisomy 18, 10 for trisomy 13 and 26 - for the pathology of sex chromosomes. Prenatal karyotyping was performed for 134 patients: for 110 cases chromosomal abnormalities were detected, in one case the patient refused to perform invasive prenatal test (newborn was diagnosed with trisomy 21). For 4,930 patients with low risk of chromosomal pathology of the fetus in according to the, childbirth was completed with a child with normal phenotype. cffDNA for two false-negative cases was less 4.6%. The calculated values of the sensitivity, specificity, and the positive (PPV) and negative (NPV) predictive values in the complete group of tested without stratification for the risk of chromosome pathology of the fetus, calculated from the prenatal screening of the first trimester, were 95.2%, 99.3%, 64.5% and 99.9%, respectively, for Harmony and 98.9%, 99.4%, 83.6%, 99.9% for Panorama, which corresponds to the manufacturer’s specifications. In the group of patients with high risk for prenatal screening of the first trimester, the values of the PPV and NPV were 85.6% and 99.9% for Panorama, respectively, while 73.9% and 99.9% for Harmony. For the group of low-risk patients: for the Panorama a PPV was 78.9%, while NPV was 100%; for the Harmony NPV was 100%, while the PPV - 37.5%. For low-risk women group in both NIPTs low NPV is mainly owing to the presence of false positive results for X monosomy. The obtained results indicate that it is not rationally to perform NIPT to detect aneuploidy on sex chromosomes, especially in the low-risk group for chromosomal pathology the fetus.

неинвазивный пренатальный тест, внеклеточная ДНК (внДНК), доля фетальной ДНК, беременные, пренатальный скрининг хромосомных анеуплоидий, частые трисомии, прогностическая ценность положительного результата (ПЦПР), прогностическая ценность отрицательного результата (ПЦОР), noninvasive prenatal test, extracellular DNA (cfDNA), fetal DNA, pregnant, prenatal screening of chromosomal aneuploidy, trisomy, positive predictive value (PPV), negative predictive value (NPV)

1. Jenderny J. Chromosome aberrations in a large series of spontaneous miscarriages in the German population and review of the literature. Mol Cytogenet. 2014;7:38.

2. Lo YM, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997;350(9076):485-7.

3. Tjoa ML, Cindrova-Davies T, Spasic-Boskovic O, et al. Trophoblastic oxidative stress and the release of cell-free feto-placental DNA. Am J Pathol. 2006;169:400-4.

4. McLaren J, Taylor DJ, Bell SC. Increased incidence of apoptosis in non-labour-affected сytotrophoblast cells in term fetal membranes overlying the cervix. Hum Reprod. 1999;14:2895-900.

5. Guibert J, Benachi A, Grebille AG, et al. Kinetics of SRY gene appearance in maternal serum: detection by real time PCR in early pregnancy after assisted reproductive technique. Hum Reprod. 2003;18(8):1733.

6. Taglauer ES, Wilkins-Haug L & Bianchi DW. Review: cell-free fetal DNA in the maternal circulation as an indication of placental health and disease. Placenta. 2014;28:S6-S68.

7. Wang E, Batey A, Struble C, et al. Gestational age and maternal weight effects on fetal cell-free DNA in maternal plasma. Prenat. Diagn. 2013;33(7):662-6.

8. Krishna I, Badell M, Loucks TL, et al. Adverse perinatal outcomes are more frequent in pregnancies with a low fetal fraction result on noninvasive prenatal testing. Prenat Diagn. 2016;36(3):210-5.

9. Hudecova I, Sahota D, Heung MM, et al. Maternal Plasma Fetal DNA Fractions in Pregnancies with Low and High Risks for Fetal Chromosomal Aneuploidies. PLoS One. 2014;9(2):e88484.

10. Fan HC, Blumenfeld YJ, Chitkara U, et al. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl AcadSci USA. 2008;105(42):16266-71.

11. Sparks AB, Wang ET, Struble CA, et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat Diagn. 2012;32(1):3-9.

12. Sparks AB, Struble CA, Wang ET et al. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;206(4):319.e1-9.

13. Stokowski R, Wang E, White K, et al. Clinical performance of non?invasive prenatal testing (NIPT) using targeted cell?free DNA analysis in maternal plasma with microarrays or next generation sequencing (NGS) is consistent across multiple controlled clinical studies. Prenat Diagn. 2015;35(12):1243-6.

14. Nicolaides KH, Syngelaki A, del Mar Gil M, et al. Prenatal detection of fetal triploidy from cell-free DNA testing in maternal blood. Fetal Diagn Ther 2014;35:212-7.

15. Sarno L, Revello R, Hanson E, et al. Prospective first-trimester screening for trisomies by cell-free DNA testing of maternal blood in twin pregnancy. Ultrasound Obstet Gynecol. 2016;47(6):705-11.

16. Zimmermann B, Hill M, Gemelos G, et al. Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. Prenat Diagn. 2012;32(13):1233-41.

17. Ashoor G, Poon L, Syngelaki A, et al. Fetal Fraction in Maternal Plasma Cell-Free DNA at 11-13 Weeks’ Gestation: Effect of Maternal and Fetal Factors. Fetal Diagn Ther 2012;31:237-43.

18. Gregg AR, Skotko BG, Benkendorf JL, et al. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genet Med. 2016;18(10):1056-65.

19. Баранова ЕЕ, Беленикин МС, Жученко ЛА, Ижевская ВЛ. Неинвазивные пренатальные тесты: рекомендации 2016 и перспективы. Медицинская Генетика. 2017. №8:3-10.

20. Rava RP, Srinivasan A, Sehnert AJ, Bianchi DW. Circulating fetal cell-free DNA fractions differ in autosomal aneuploidies and monosomy X. Clin Chem. 2014;60(1):243-50.

21. Grati FR. Chromosomal Mosaicism in Human Feto-Placental Development: Implications for Prenatal Diagnosis. J Clin Med. 2014;3(3):809-37.