Clinical Utility and Outcomes of Non-Invasive Prenatal Testing for Rare Chromosomal Abnormalities: Analysis of 94,125 Pregnancies

Background: Non-invasive prenatal testing (NIPT) has demonstrated robust performance in detecting common trisomies and copy number variations (CNVs). However, its clinical utility for rare chromosomal abnormalities (RCAs) remains controversial due to low positive predictive value (PPV).
Methods: This study retrospectively analyzed the data of 94,125 cases that underwent NIPT at Ganzhou Maternal and Child Health Hospital in China. This dataset was used to evaluate NIPT performance in RCAs detection and track pregnancy outcomes of positive cases.
Results: In the cohort of 94,125 pregnancies undergoing NIPT, 336 cases (0.36%) were found to carry RCAs. Among these, 101 cases underwent validation through karyotyping and/or chromosome microarray analysis (CMA). Of the 101 validated cases, 7 were true positives (PPV=6.93%). Additionally, 3 cases showed uniparental disomy (UPD) matching NIPT-reported chromosomal anomalies. 66 of the 266 singleton neonates were classified as small-for-gestational-age (SGA), with an SGA rate of 24.81%.
Conclusions: This study found that most NIPT-detected RCAs were associated with maternal age, while T7 occurred independently of maternal age. Concurrent use of karyotyping and CMA, rather than karyotyping alone, reduces culture bias and improves PPV. Both biological and methodological factors contribute to the low PPV of NIPT for RCAs. Despite suboptimal PPV, RCAs-positive cases exhibit significantly elevated risks of fetal loss, SGA, and UPD, though not preterm birth. Thus, NIPT-detected RATs retain clinical significance for risk stratification and pregnancy management.