Positive predictive value estimates for noninvasive prenatal testing from data of a prenatal diagnosis laboratory and literature review

Abstract

Objective: Since 2011, noninvasive prenatal testing (NIPT) has undergone rapid expansion with both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this testing tool, have lagged behind. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations to inform pre- and posttest counseling, pre/perinatal decision making, and medical risk assessment/management.Methods: A retrospective study among women referred for invasive prenatal diagnosis to confirm positive NIPT results between January 2017 and December 2020. Prenatal diagnosis testing were taken including karyotype, chromosomal microarray analysis (CMA) or CNV-seq. Positive predictive values (PPV) were calculated.Results: A total of 468 women were recruited. The PPVs for trisomy 21, 18, 13 were 86.1%, 57.8%, 25.0%, respectively. The PPV for RCAs and CNVs were 17.0%, 40.4% respectively. Detection of SCAs had PPV of 20% for monosomy X, 23.5% for 47,XXX, 68.8% for 47,XXY and 62.5% for 47,XYY. High-risk groups had a significant increase in the number of true positive cases compared to the low and moderate risk groups.Conclusion: T13, Monosomy X, RCA are associated with lower PPVs. Improvement of the cell-free fetal DNA screening technology and continued monitoring of its performance is important.

Multicenter clinical experience with non‐invasive cell‐free DNA screening for monosomy X and related X‐chromosome variants

“…All TP had a mosaic 45,X or another X chromosome variant, and none had a 45,X karyotype (Table 1). For one case (Table 1, case 55) without fetal anomalies and a low-risk DNA screening result (1/33; 3%), an incidental diagnosis of a mosaic 45,X (mos 45,X [11]/46,XX [20]) was made after birth during a genetic work-up for thrombocytopenia of unknown origin. Thus, the cfDNA screening result for this pregnancy was an FN (Figure 2).…”

“…Karyotype analysis on the product of conception was 45,X (case 5). For the three other cases (20,23,44), prenatal ultrasound did not show fetal anomalies and parents decided for postnatal genetic diagnostic testing. For cases 20 and 23, the postnatal karyotype showed a mosaic 45,X, while case 44 was an FP and the newborn had a 46,XX karyotype.…”

“…However, the positive predictive value (PPV) for detection of 45,X by cfDNA screening is much lower than for trisomy 21, ranging from 9% to 40%, and various factors limit its performance. [20][21][22][23][24][25][26] Confined placental mosaicism (CPM) and true fetal mosaicism are more common for monosomy X than for other chromosomal abnormalities. 27 The performance of cfDNA testing for SCA can also be affected by undiagnosed maternal sex chromosome abnormalities, such as X-chromosome deletions or mosaic Xchromosome aneuploidy, including the well-described somatic maternal loss of the second X chromosome with increasing maternal age.…”

“…Cell‐free DNA (cfDNA)‐based non‐invasive prenatal screening for common aneuploidies and additional sex chromosome aneuploidies (SCA), including monosomy X, is now offered by commercial laboratories and has resulted in a larger number of pregnancies identified to be at an increased risk for fetal Turner syndrome. However, the positive predictive value (PPV) for detection of 45,X by cfDNA screening is much lower than for trisomy 21, ranging from 9% to 40%, and various factors limit its performance 20–26 . Confined placental mosaicism (CPM) and true fetal mosaicism are more common for monosomy X than for other chromosomal abnormalities 27 .…”

Invasive Prenatal Diagnostic Testing for Aneuploidies in Singleton Pregnancies: A Comparative Review of Major Guidelines

“…cfDNA is based on the analysis of circulating fractions of fetal DNA in maternal serum to achieve prenatal screening for aneuploidies [ 37 , 38 ]. cfDNA is a screening and not diagnostic test and therefore should not substitute IPDT (NSGC).…”