INTRODUCTION: This study aimed to evaluate the occurrence of clinically relevant (sub)microscopic chromosomal aberrations in fetuses with the nuchal translucency (NT) range from 3.0 to 3.4 mm, which would be potentially missed by cfDNA testing. METHODS: A retrospective data analysis of 271 fetuses with NT between 3.0 and 3.4 mm and increased first trimester combined test (CT) risk in five cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed. RESULTS: A chromosomal aberration was identified in 18.8% fetuses (1:5; 51/271). In 15% (41/271) of cases, trisomy 21, 18, or 13 were found. In 0.7% (2/271) of cases, sex chromosome aneuploidy was found. In 1.1% (3/271) of cases, CNV >10 Mb was detected, which would potentially also be detected by genome-wide cfDNA testing. The residual risk for missing a submicroscopic chromosome aberration in the presented cohorts is 1.8% (1:54; 5/271). CONCLUSION: Our results indicate that a significant number of fetuses with increased CT risk and presenting NT of 3.0-3.4 mm carry a clinically relevant chromosomal abnormality other than common trisomy. Invasive testing should be offered, and counseling on NIPT should include the test limitations that may result in NIPT false-negative results in a substantial percentage of fetuses.

Centre of Medical Genetics and Reproductive Medicine GENNET Prague Czechia

Department of Clinical Genetics Erasmus MC Rotterdam The Netherlands

Department of Genetics Polish Mother's Memorial Hospital Research Institute Lodz Poland

Department of Medical Biotechnology Medical University of Lodz Lodz Poland

Department of Medical Genetics Institute of Paediatrics Faculty of Medicine Jagiellonian University Medical College Krakow Poland

Department of Obstetrics and Perinatology University Hospital Krakow Poland

Hi Gen Centrum Medyczne Krakow Poland

Instituto de Genética Médica y Molecular Madrid Spain

ITHACA International Research Network in Rare Diseases Hospital Universitario La Paz Madrid Spain

Unidade de Citogenética Departamento de Genética Humana Instituto Nacional de Saúde Doutor Ricardo Jorge Lisbon Portugal

See more in PubMed

Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. . Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175–84. PubMed PMC

Levy B, Burnside RD. Are all chromosome microarrays the same? What clinicians need to know. Prenat Diagn. 2019;39(3):157–64. PubMed

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. J Obstet Gynaecol Can. 2017;39(9):805–17. PubMed

RANZCOG . Prenatal screening and diagnostic testing for fetal chromosomal and genetic conditions; 2018; p. 1–35.

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–ObstetricsCommittee on GeneticsSociety for Maternal-Fetal Medicine . Screening for fetal chromosomal abnormalities: ACOG practice bulletin, number 226. Obstet Gynecol. 2020;136(4):e48–69. PubMed

Sieroszewski P, Haus O, Zimmer M, Wielgos M, Latos-Bielenska A, Borowiec M, et al. . Recommendations for prenatal diagnostics of the polish society of gynaecologists and obstetricians and the polish society of human genetics. Ginekol Pol. 2022;93(5):427–37. PubMed

Armour CM, Dougan SD, Brock J-A, Chari R, Chodirker BN, DeBie I, et al. . Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada. J Med Genet. 2018;55(4):215–21. PubMed PMC

Gardiner C, Wellesley D, Kilby M, Kerr B. Recommendations for the use of chromosome microarray in pregnancy; 2015.

Society for Maternal-Fetal Medicine SMFM Electronic address pubs@smfmorg; Norton ME, Biggio JR, Kuller JA, Blackwell SC. The role of ultrasound in women who undergo cell-free DNA screening. Am J Obstet Gynecol. 2017;216(3):B2–7. PubMed

Grande M, Jansen FAR, Blumenfeld YJ, Fisher A, Odibo AO, Haak MC, et al. . Genomic microarray in fetuses with increased nuchal translucency and normal karyotype: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2015;46(6):650–8. PubMed

Klapwijk JE, Srebniak MI, Go A, Govaerts LCP, Lewis C, Hammond J, et al. . How to deal with uncertainty in prenatal genomics: a systematic review of guidelines and policies. Clin Genet. 2021;100(6):647–58. PubMed PMC

Maya I, Yacobson S, Kahana S, Yeshaya J, Tenne T, Agmon-Fishman I, et al. . Cut-off value of nuchal translucency as indication for chromosomal microarray analysis. Ultrasound Obstet Gynecol. 2017;50(3):332–5. PubMed

Grossman TB, Bodenlos KL, Chasen ST. Abnormal nuchal translucency: residual risk with normal cell-free DNA screening. J Matern Fetal Neonatal Med. 2020;33(18):3062–7. PubMed

Petersen OB, Smith E, Van Opstal D, Polak M, Knapen MF, Diderich KE, et al. . Nuchal translucency of 3.0‐3.4 mm an indication for NIPT or microarray? Cohort analysis and literature review. Acta Obstet Gynecol Scand. 2020;99(6):765–74. PubMed PMC

Zhao XR, Gao L, Wu Y, Wang YL. Application of chromosomal microarray in fetuses with increased nuchal translucency. J Matern Fetal Neonatal Med. 2020;33(10):1749–54. PubMed

Hui L, Pynaker C, Bonacquisto L, Lindquist A, Poulton A, Kluckow E, et al. . Reexamining the optimal nuchal translucency cutoff for diagnostic testing in the cell-free DNA and microarray era: results from the Victorian Perinatal Record Linkage study. Am J Obstet Gynecol. 2021;225(5):527.e1–e12. PubMed

Sagi-Dain L, Singer A, Ben Shachar S, Josefsberg Ben Yehoshua S, Feingold-Zadok M, Greenbaum L, et al. . Risk of clinically significant chromosomal microarray analysis findings in fetuses with nuchal translucency from 3.0 mm through 3.4 mm. Obstet Gynecol. 2021;137(1):126–31. PubMed

Wang C, Tang J, Tong K, Huang D, Tu H, Zhu J. Chromosomal microarray analysis versus noninvasive prenatal testing in fetuses with increased nuchal translucency. J Hum Genet. 2022;67(9):533–9. PubMed PMC

Coello-Cahuao E, Sánchez-Durán MÁ, Calero I, Higueras MT, García MA, Rodó C, et al. . Array study in fetuses with nuchal translucency above the 95th percentile: a 4-year observational single-centre study. Arch Gynecol Obstet. 2023;307(1):285–92. PubMed

de Ginecología SE, de Diagnóstico Prenatal AE. Cribado y diagnóstico precoz de anomalías genéticas. In: Prog obstet ginecol; 2018. p. 605–29.

Hui L, Ellis K, Mayen D, Pertile MD, Reimers R, Sun L, et al. . Position statement from the International Society for Prenatal Diagnosis on the use of non-invasive prenatal testing for the detection of fetal chromosomal conditions in singleton pregnancies. Prenat Diagn. 2023;43(7):814–28. PubMed

Pasquini L, Ponziani I, Spataro E, Masini G, Biancareddu E, Cordisco A, et al. . Elevated nuchal translucency, is it time to discuss the cut off? Int J Gynaecol Obstet. 2023;163:540–6. PubMed

Srebniak MI, Joosten M, Knapen M, Arends LR, Polak M, van Veen S, et al. . Frequency of submicroscopic chromosomal aberrations in pregnancies without increased risk for structural chromosomal aberrations: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2018;51(4):445–52. PubMed

Maya I, Salzer Sheelo L, Brabbing-Goldstein D, Matar R, Kahana S, Agmon-Fishman I, et al. . Residual risk for clinically significant copy number variants in low-risk pregnancies, following exclusion of noninvasive prenatal screening-detectable findings. Am J Obstet Gynecol. 2022;226(4):562.e1–e8. PubMed

Torres F, Barbosa M, Maciel P. Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications. J Med Genet. 2016;53(2):73–90. PubMed

Brabbing-Goldstein D, Reches A, Svirsky R, Bar-Shira A, Yaron Y. Dilemmas in genetic counseling for low-penetrance neuro-susceptibility loci detected on prenatal chromosomal microarray analysis. Am J Obstet Gynecol. 2018;218(2):247.e1–e12. PubMed

Äyräs O, Eronen M, Tikkanen M, Rahkola-Soisalo P, Paavonen J, Stefanovic V. Long-term neurodevelopmental outcome of children from euploid pregnancies with increased nuchal translucency in the first trimester screening. Prenat Diagn. 2015;35(4):362–9. PubMed

Hellmuth SG, Pedersen LH, Miltoft CB, Petersen OB, Kjaergaard S, Ekelund C, et al. . Increased nuchal translucency thickness and risk of neurodevelopmental disorders. Ultrasound Obstet Gynecol. 2017;49(5):592–8. PubMed

van der Steen SL, Diderich KE, Riedijk SR, Verhagen-Visser J, Govaerts LC, Joosten M, et al. . Pregnant couples at increased risk for common aneuploidies choose maximal information from invasive genetic testing. Clin Genet. 2015;88(1):25–31. PubMed

van der Steen SL, Riedijk SR, Verhagen-Visser J, Govaerts LC, Srebniak MI, Van Opstal D, et al. . The psychological impact of prenatal diagnosis and disclosure of susceptibility loci: first impressions of parents’ experiences. J Genet Couns. 2016;25(6):1227–34. PubMed PMC

Govaerts L, Srebniak M, Diderich K, Joosten M, Riedijk S, Knapen M, et al. . Prenatal diagnosis of susceptibility loci for neurodevelopmental disorders - genetic counseling and pregnancy outcome in 57 cases. Prenat Diagn. 2017;37(1):73–80. PubMed

Salomon LJ, Alfirevic Z, Audibert F, Kagan KO, Paladini D, Yeo G, et al. . ISUOG updated consensus statement on the impact of cfDNA aneuploidy testing on screening policies and prenatal ultrasound practice. Ultrasound Obstet Gynecol. 2017;49(6):815–6. PubMed

Bardi F, Kagan KO, Bilardo CM. First-trimester screening strategies: a balance between costs, efficiency and diagnostic yield. Prenat Diagn. 2023;43(7):865–72. PubMed

Kelley J, McGillivray G, Meagher S, Hui L. Increased nuchal translucency after low-risk noninvasive prenatal testing: what should we tell prospective parents? Prenat Diagn. 2021;41(10):1305–15. PubMed