[en] OBJECTIVE: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies. METHODS: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic-diamniotic twin cohort. RESULTS: Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic-monoamniotic and 25 triplet cases. Two monochorionic-diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic-diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12-100%) and a specificity of 100% (95% CI 99.86-100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06-95.44%) sensitivity and 100% (95% CI 99.86-100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65-100%) sensitivity and 99.96% (95% CI 99.79-99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies. CONCLUSION: Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic-diamniotic twin gestations.
Disciplines :
Genetics & genetic processes
Author, co-author :
van Riel, Margot
Brison, Nathalie
Baetens, Machteld
Blaumeiser, Bettina
BOEMER, François ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Laboratoire Biochimie Génétique
Bourlard, Laura
BULK, Saskia ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Clinique de génétique
De Leener, Anne
Désir, Julie
Devriendt, Koenraad
Dheedene, Annelies
Duquenne, Armelle
Fieremans, Nathalie
Fieuw, Annelies
GATOT, Jean-Stéphane ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Laboratoire Cytogénétique
GRISART, Bernard ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Secteur commun biologie moléculaire
Janssens, Sandra
Khudashvili, Naïri
Lannoo, Lore
Marichal, Axel
Meunier, Colombine
PALMEIRA, Léonor ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Service de génétique
Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 2017;50:302-14. doi: 10.1002/uog.17484
Chen M, Jiang F, Guo Y, Yan H, Wang J, Zhang L, et al. Validation of fetal DNA fraction estimation and its application in noninvasive prenatal testing for aneuploidy detection in multiple pregnancies. Prenat Diagn 2019;39:1273-82. doi: 10.1002/pd.5597
Leung TY, Qu JZZ, Liao GJW, Jiang P, Cheng YKY, Chan KCA, et al. Noninvasive twin zygosity assessment and aneuploidy detection by maternal plasma DNA sequencing. Prenat Diagn 2013;33:675-81. doi: 10.1002/pd.4132
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;35(suppl):S64-8. doi: 10.1016/j.placenta.2013.11.014
Bender W, Dugoff L. Screening for aneuploidy in multiple gestations: the challenges and options. Obstet Gynecol Clin North Am 2018;45:41-53. doi: 10.1016/j.ogc.2017.10.004
Benn P, Borrell A, Chiu RWK, Cuckle H, Dugoff L, Faas B, et al. Position statement from the chromosome abnormality screening committee on behalf of the board of the international society for prenatal diagnosis. Prenat Diagn 2015;35:725-34. doi: 10.1002/pd.4608
Screening for fetal chromosomal abnormalities. ACOG Practice Bulletin No. 226. American College of Obstetricians and Gynecologists. Obstet Gynecol 2020;136:e48-69. doi: 10.1097/AOG.0000000000004084
Audibert F, De Bie I, Johnson JA, Okun N, Wilson RD, Armour C, et al. No. 348-Joint SOGC-CCMG guideline: update on prenatal screening for fetal aneuploidy, fetal anomalies, and adverse pregnancy outcomes [published erratum appears in J Obstet Gynaecol Can 2018;40:1109]. J Obstet Gynaecol Can 2017;39:805-17. doi: 10.1016/j.jogc.2017.01.032
Palomaki GE, Chiu RWK, Pertile MD, Sistermans EA, Yaron Y, Vermeesch JR, et al. International Society for Prenatal Diagnosis Position Statement: cell free (cf)DNA screening for Down syndrome in multiple pregnancies. Prenat Diagn 2020 Oct 5 [Epub ahead of print]. doi: 10.1002/pd.5832
Prats P, Rodríguez I, Comas C, Puerto B. Systematic review of screening for trisomy 21 in twin pregnancies in first trimester combining nuchal translucency and biochemical markers: a meta-analysis. Prenat Diagn 2014;34:1077-83. doi: 10.1002/pd.4431
Raman L, Dheedene A, De Smet M, Van Dorpe J, Menten B. WisecondorX: improved copy number detection for routine shallow whole-genome sequencing. Nucleic Acids Res 2019; 47:1605-14. doi: 10.1093/nar/gky1263
Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med 1998;17:873-90. doi: 10.1002/(SICI)1097-0258(19980430)17
Belgian Society for Human Genetics Prenatal Committee. Belgian guidelines for managing incidental findings detected by NIPT. Accessed August 26, 2020. http://www.beshg.be/download/guidelines/BELGIAN_GUIDELINES_FOR_MANAGING_INCIDENTAL_FINDINGS_DETECTED_BY_NIPT_20190905.pdf
del Gaudio D, Shinawi M, Astbury C, Tayeh MK, Deak KL, Raca G. Diagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG). Genet Med 2020;22:1133-41. doi: 10.1038/s41436-020-0782-9
Grömminger S, Yagmur E, Erkan S, Nagy S, Schöck U, Bonnet J, et al. Fetal aneuploidy detection by cell-free DNA sequencing for multiple pregnancies and quality issues with vanishing twins. J Clin Med 2014;3:679-92. doi: 10.3390/jcm3030679
Takeda E, Suzumori N, Kumagai K, Inuzuka S, Oseto K, Ohigashi Y, et al. Performance and outcomes of noninvasive prenatal testing for twin pregnancies in Japan. J Obstet Gynaecol Res 2018;44:1909-14. doi: 10.1111/jog.13744
Le Conte G, Letourneau A, Jani J, Kleinfinger P, Lohmann L, Costa JM, et al. Cell-free fetal DNA analysis in maternal plasma as screening test for trisomies 21, 18 and 13 in twin pregnancy. Ultrasound Obstet Gynecol 2018;52:318-24. doi: 10.1002/uog.18838
Yang J, Qi Y, Hou Y, Guo F, Peng H, Wang D, et al. Performance of non-invasive prenatal testing for trisomies 21 and 18 in twin pregnancies. Mol Cytogenet 2018;11:47. doi: 10.1186/s13039-018-0392-2
Galeva S, Gil MM, Konstantinidou L, Akolekar R, Nicolaides KH. First-trimester screening for trisomies by cfDNA testing of maternal blood in singleton and twin pregnancies: factors affecting test failure. Ultrasound Obstet Gynecol 2019;53:804-9. doi: 10.1002/uog.20290
Gil MM, Galeva S, Jani J, Konstantinidou L, Akolekar R, Plana MN, et al. Screening for trisomies by cfDNA testing of maternal blood in twin pregnancy: update of the Fetal Medicine Foundation results and meta-analysis. Ultrasound Obstet Gynecol 2019;53:734-42. doi: 10.1002/uog.20284
Dyr B, Boomer T, Almasri EA, Wardrop JL, Rafalko J, Chibuk J, et al. A new era in aneuploidy screening: cfDNA testing in .30,000 multifetal gestations: experience at one clinical laboratory. PLoS One 2019;14:e0220979. doi: 10.1371/journal.pone.0220979
Motevasselian M, Saleh Gargari S, Younesi S, Pooransari P, Saadati P, Mirzamoradi M, et al. Non-invasive prenatal test to screen common trisomies in twin pregnancies. Mol Cytogenet 2020;13:5. doi: 10.1186/s13039-020-0475-8
Chibuk J, Rafalko J, Boomer T, McCullough R, McLennan G, Wyatt P, et al. Cell-free DNA screening in twin pregnancies: a more accurate and reliable screening tool. Prenat Diagn 2020; 40:1-9. doi: 10.1002/pd.5797
Grati FR, Malvestiti F, Ferreira JCPB, Bajaj K, Gaetani E, Agrati C, et al. Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results. Genet Med 2014;16:620-4. doi: 10.1038/gim.2014.3
Malvestiti F, Agrati C, Grimi B, Pompilii E, Izzi C, Martinoni L, et al. Interpreting mosaicism in chorionic villi: results of a monocentric series of 1001 mosaics in chorionic villi with follow-up amniocentesis. Prenat Diagn 2015;35:1117-27. doi: 10.1002/pd.4656
Brison N, Neofytou M, Dehaspe L, Bayindir B, Van Den Bogaert K, Dardour L, et al. Predicting fetoplacental chromosomal mosaicism during non-invasive prenatal testing. Prenat Diagn 2018;38:258-66. doi: 10.1002/pd.5223
van der Meij KRM, Sistermans EA, Macville MVE, Stevens SJC, Bax CJ, Bekker MN, et al. TRIDENT-2: national implementation of genome-wide non-invasive prenatal testing as a first-tier screening test in The Netherlands. Am J Hum Genet 2019;105:1091-101. doi: 10.1016/j.ajhg.2019.10.005
Van Den Bogaert K, Lannoo L, Brison N, Gatinois V, Baetens M, Blaumeiser B, et al. Outcome of publicly-funded nationwide first-tier non-invasive prenatal screening. Genet Med 2021 Feb 9 [Epub ahead of print]. doi: 10.1038/s41436-021-01101-4
Audibert F, Gagnon A, No. 262-Prenatal screening for and diagnosis of aneuploidy in twin pregnancies. J Obstet Gynaecol Can 2017;39:e347-61. doi: 10.1016/j.jogc.2017.06.015
Boyle B, Morris JK, McConkey R, Garne E, Loane M, Addor MC, et al. Prevalence and risk of Down syndrome in monozygotic and dizygotic multiple pregnancies in Europe: implications for prenatal screening. BJOG Int J Obstet Gynaecol 2014; 121:809-20. doi: 10.1111/1471-0528.12574
Balaguer N, Mateu-Brull E, Serra V, Simón C, Milán M. Should vanishing twin pregnancies be systematically excluded from cell-free fetal DNA testing? Prenat Diagn 2020 Aug 24 [Epub ahead of print]. doi: 10.1002/pd.5817
Zou Y, Cui L, Xue M, Yan J, Huang M, Gao M, et al. Applications of noninvasive prenatal testing in vanishing twin syndrome pregnancies after treatment of assisted reproductive technology in a single center. Prenat Diagn 2020;41:226-33. doi: 10.1002/pd.5836
Pylyp LY, Spynenko LO, Verhoglyad NV, Mishenko AO, Mykytenko DO, Zukin VD. Chromosomal abnormalities in products of conception of first-trimester miscarriages detected by conventional cytogenetic analysis: a review of 1000 cases. J Assist Reprod Genet 2018;35:265-71. doi: 10.1007/s10815-017-1069-1
Grati FR, Ferreira J, Benn P, Izzi C, Verdi F, Vercellotti E, et al. Outcomes in pregnancies with a confined placental mosaicism and implications for prenatal screening using cell-free DNA. Genet Med 2020;22:309-16. doi: 10.1038/s41436-019-0630-y
Bevilacqua E, Gil MM, Nicolaides KH, Ordoñez E, Cirigliano V, Dierickx H, et al. Performance of screening for aneuploidies by cell-free DNA analysis of maternal blood in twin pregnancies. Ultrasound Obstet Gynecol 2015;45:61-6. doi: 10.1002/uog.14690
Gil MM, Quezada MS, Revello R, Akolekar R, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 2015;45:249-66. doi: 10.1002/uog.14791
Sarno L, Revello R, Hanson E, Akolekar R, Nicolaides KH. Prospective first-trimester screening for trisomies by cell-free DNA testing of maternal blood in twin pregnancy. Ultrasound Obstet Gynecol 2016;47:705-11. doi: 10.1002/uog.15913