What would be missed in the first trimester if nuchal translucency measurement is replaced by cell free DNA foetal aneuploidy screening?

Abstract The aim of this study was to evaluate which chromosomal abnormalities in our cohort of foetuses with increased nuchal translucency (NT) in the first trimester of pregnancy could be detected by cell free (cf)DNA screening as well. There were 775 singleton pregnancies referred for cytogenetic testing due to an increased NT (≥3.0 mm). Chromosome aberrations were investigated using karyotyping or chromosomal microarray analysis (CMA). Karyotyping had been chosen for foetal cytogenetic testing by 446 patients, and CMA by 329 patients. Common aneuploidies (trisomies 21, 18, 13 and sex aneuploidies) were detected in 2.2% (99/446) and 1.8% (59/329) cases, respectively. In 329 with CMA testing, clinically significant copy number variations (CNVs) other than common aneuploidies were detected in 2.7% cases; among these, five had a pathogenic microscopic CNV, which could have been detected by karyotyping. There were four cases (1.2%) having a pathogenic submicroscopic CNV, which could have been missed by karyotyping. The total CMA detection rate (23.4%) was not statistically different from that (24.2%) by karyotyping (p > .05). The percentage of chromosomal aberrations, which cfDNA screening would miss in patients with increased NT in the first trimester, might be the same as in those with normal NT. Impact statement What is already known about this topic? First trimester NT is a powerful marker for screening for common aneuploidies. cfDNA screening is more accurate than any standard screening with NT. The need of NT in the era of prenatal screening using cfDNA is debated. What does this study add? An increased NT did not identify any additional aneuploidies that were detected by cfDNA screening. What are the implications of these findings for clinical practice and/or further research? The percentage of chromosomal aberrations which cfDNA screening would miss in patients with increased NT might be the same as in those with normal NT.

[1]  M. Plana,et al.  Analysis of cell‐free DNA in maternal blood in screening for aneuploidies: updated meta‐analysis , 2017, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[2]  W. V. van IJcken,et al.  The influence of SNP‐based chromosomal microarray and NIPT on the diagnostic yield in 10,000 fetuses with and without fetal ultrasound anomalies , 2017, Human mutation.

[3]  F. S. Jørgensen,et al.  Discordant non‐invasive prenatal testing (NIPT) – a systematic review , 2017, Prenatal diagnosis.

[4]  S. Blackwell,et al.  The role of ultrasound in women who undergo cell‐free DNA screening , 2017, American journal of obstetrics and gynecology.

[5]  C. Liao,et al.  Submicroscopic chromosomal abnormalities in fetuses with increased nuchal translucency and normal karyotype , 2017, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[6]  E. Bernabé,et al.  Analysis of cell‐free fetal DNA in maternal blood for detection of trisomy 21, 18 and 13 in a general pregnant population and in a high risk population – a systematic review and meta‐analysis , 2017, Acta obstetricia et gynecologica Scandinavica.

[7]  L. Platt,et al.  The value of the first trimester ultrasound in the era of cell free DNA screening , 2016, Prenatal diagnosis.

[8]  M. Knapen,et al.  Enlarged NT (≥3.5 mm) in the first trimester – not all chromosome aberrations can be detected by NIPT , 2016, Molecular Cytogenetics.

[9]  R. Berkowitz,et al.  Noninvasive prenatal screening or advanced diagnostic testing: caveat emptor. , 2016, American journal of obstetrics and gynecology.

[10]  L. Wilkins-Haug,et al.  What is the role of the 11‐ to 14‐week ultrasound in women with negative cell‐free DNA screening for aneuploidy? , 2016, Prenatal diagnosis.

[11]  M. Knapen,et al.  False Negative NIPT Results: Risk Figures for Chromosomes 13, 18 and 21 Based on Chorionic Villi Results in 5967 Cases and Literature Review , 2016, PloS one.

[12]  F. D. de Vries,et al.  Is prenatal cytogenetic diagnosis with genomic array indicated in pregnancies at risk for a molecular or metabolic disorder? , 2015, Genetics in Medicine.

[13]  Y. Blumenfeld,et al.  Genomic microarray in fetuses with increased nuchal translucency and normal karyotype: a systematic review and meta‐analysis , 2015, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[14]  A. Papageorghiou,et al.  Estimation of Detection Rates of Aneuploidy in High-Risk Pregnancy Using an Approach Based on Nuchal Translucency and Non-Invasive Prenatal Testing: A Cohort Study , 2015, Fetal Diagnosis and Therapy.

[15]  G. Hannum,et al.  Detection of fetal subchromosomal abnormalities by sequencing circulating cell-free DNA from maternal plasma. , 2015, Clinical chemistry.

[16]  R. Galjaard,et al.  Benefits and Burdens of Using a SNP Array in Pregnancies at Increased Risk for the Common Aneuploidies , 2015, Human mutation.

[17]  H. Peeters,et al.  Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management , 2015, European Journal of Human Genetics.

[18]  K. Nicolaides,et al.  Is high fetal nuchal translucency associated with submicroscopic chromosomal abnormalities on array CGH? , 2014, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[19]  J. Sonek,et al.  First Trimester Ultrasound Assessment for Fetal Aneuploidy , 2014, Clinical obstetrics and gynecology.

[20]  K. Nicolaides,et al.  Replacing the Combined Test by Cell-Free DNA Testing in Screening for Trisomies 21, 18 and 13: Impact on the Diagnosis of Other Chromosomal Abnormalities , 2014, Fetal Diagnosis and Therapy.

[21]  Yanyan Zhang,et al.  Non-invasive fetal sex determination by maternal plasma sequencing and application in X-linked disorder counseling , 2014, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[22]  M. Reinders,et al.  WISECONDOR: detection of fetal aberrations from shallow sequencing maternal plasma based on a within-sample comparison scheme , 2013, Nucleic acids research.

[23]  D. Ledbetter,et al.  Chromosomal microarray versus karyotyping for prenatal diagnosis. , 2012, The New England journal of medicine.

[24]  G. Rizzo,et al.  Introducing array comparative genomic hybridization into routine prenatal diagnosis practice: a prospective study on over 1000 consecutive clinical cases , 2011, Prenatal diagnosis.

[25]  Yama W. L. Zheng,et al.  Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study , 2011, BMJ : British Medical Journal.

[26]  Kypros H Nicolaides,et al.  Screening for fetal aneuploidies at 11 to 13 weeks , 2011, Prenatal diagnosis.