CONTRIBUTIONWhat are the novel findings of this work? With the introduction of fetal cell-free DNA (cfDNA) as a screening test for fetal aneuploidy, the utility of the components of first-trimester combined screening, such as nuchal translucency (NT) measurement, has been challenged. We found that conventional cfDNA testing would miss 12-19% of genetic anomalies in fetuses with NT > 99 th centile, thus questioning its suitability as a screening test in patients with increased NT.
What are the clinical implications of this work?All pregnant women should be offered an 11-13-week ultrasound scan for NT and early anatomy assessment, irrespective of the applied aneuploidy screening method. If the 11-13-week scan is performed with no prior cfDNA testing, then the finding of an increased NT > 99 th centile should discourage the use of cfDNA testing.
ABSTRACTObjective To assess the frequency of atypical chromosomal and submicroscopic anomalies, as well as fetal structural abnormalities, observed on first-trimester ultrasound scan in fetuses with nuchal translucency (NT) thickness > 99 th centile, in order to evaluate the suitability of using standard cell-free DNA (cfDNA) testing as the sole screening test in these pregnancies.
MethodsThis was a retrospective cohort study of 226 fetuses with NT > 99 th centile at 11-14 weeks' gestation, setting in which greater than 95% of pregnant women receive first-trimester combined screening. All patients underwent genetic testing by means of quantitative fluorescence polymerase chain reaction and chromosomal microarray analysis, mainly in chorionic villus samples. We assessed the theoretical yield of two cfDNA testing models, targeted cfDNA (chromosomes 21, 18 and 13) and extended cfDNA (chromosomes 21, 18, 13 and sex chromosomes), and compared it with that of cytogenetic testing and ultrasound assessment in the first and second or third trimesters.
ResultsIn the 226 fetuses analyzed, cytogenetic testing revealed 84 (37%) anomalies, including 68 typical aneuploidies (involving chromosomes 13, 18 or 21), six sex chromosome aneuploidies (four cases of monosomy X and two of trisomy X), three clinically relevant atypical chromosomal anomalies (one trisomy 22, one trisomy 21 mosaicism and one unbalanced translocation), five submicroscopic pathogenic variants and two cases with Noonan syndrome. Targeted and extended cfDNA testing would miss at least 12% (10/84) and 19% (16/84), respectively, of genetic anomalies, accounting for 4.4% and 7.1% of the fetuses with an increased NT, respectively. Finally, of the 142 fetuses with no identified genetic anomaly, a major fetal malformation was observed in 15 (10.6%) fetuses at the early anomaly scan, and in 19 (13.4%) in the second or third trimester.Conclusions cfDNA does not appear to be the appropriate genetic test in fetuses with NT > 99 th centile, given that it would miss 12-19% of genetic anomalies in this group. Additionally, first-trimester ultrasound