The clinical utility of non-invasive prenatal testing in pregnancies with ultrasound anomalies

Abstract

OBJECTIVE: This study aims to evaluate the application of non-invasive prenatal testing (NIPT) as an alternative to invasive diagnostic prenatal testing for pregnancies with abnormal ultrasound findings. METHOD: A retrospective analysis was performed of 251 single and multiple pregnancies at high risk for fetal chromosomal abnormalities based on ultrasonographic examination, where NIPT was performed as first-tier genetic test. NIPT was performed by massively parallel sequencing of cell-free DNA in maternal plasma, allowing genome-wide detection of whole-chromosome as well as partial autosomal aneuploidies, as currently in the Dutch laboratories, sex chromosomes are not analysed. RESULTS: NIPT was performed at a median gestational age of 20 weeks, indicated by the presence of multiple congenital anomalies (n=13), isolated structural anomalies (n=57), increased nuchal translucency ≥ 3.5 mm (n=58), softmarkers (n=73), growth restriction (n=40), and other anomalies (n=10). NIPT results were normal in 224 (89.2%), inconclusive in one (0.4%) and abnormal in 26 pregnancies (10.4%). Most genetic aberrations detected were common whole-chromosome aneuploidies: trisomy 21 (n=13), trisomy 18 (n=6), and trisomy 13 (n=3). There were four other abnormal NIPT results, of which one was highly suspect for confined placental mosaicism and one was of maternal origin. If NIPT results were normal, ultrasonographic follow-up or newborn examinations indicated diagnostic genetic testing in 33 pregnancies (14.7% of 224). Clinically relevant genetic aberrations were revealed in seven cases (3.1% of 224), of which two were whole-chromosome aneuploidies: trisomy 13, and monosomy X. As sex chromosomal aberrations are not included in the analysis, the last cannot be considered a false negative result. Other discordant findings were subchromosomal (<20 Mb, n=2) and monogenic aberrations (n=3). CONCLUSION: NIPT should not be recommended for the genetic evaluation of the aetiology of ultrasound anomalies, as both resolution and sensitivity, or negative predictive value, are inferior to those of conventional karyotyping and microarray analysis. Nonetheless, some pregnant women consider NIPT to be an acceptable alternative to invasive diagnostic testing