Discordant findings in genome-wide noninvasive prenatal testing for rare chromosomal abnormalities, adverse pregnancy outcomes, and maternal malignancies: a systematic review and meta-analysis.

Abstract

Genome-wide noninvasive prenatal testing has introduced new challenges in clinical interpretation, for example, due to discrepancies between noninvasive prenatal testing and confirmatory invasive results caused by confined placental mosaicism. These discordant cases often involve rare autosomal trisomies, frequently attributed to placental mosaicism. Complex, multichromosomal false-positive genome-wide noninvasive prenatal testing results are usually not due to placental mosaicism but rather to maternal malignancy, for example. This study aimed to assess chromosome-specific associations with pregnancy complications and uniparental disomy in false-positive rare autosomal trisomies and the prevalence of maternal malignancies in complex, multichromosomal genome-wide noninvasive prenatal testing results. A systematic search of 5 databases-MEDLINE (via PubMed), Embase, Cochrane, Scopus, and Web of Science-was conducted on August 28, 2025. Cohort studies using massively parallel sequencing were included. The study population was pregnant women who had undergone genome-wide noninvasive prenatal testing and had a known pregnancy outcome. Data extraction followed a standardized protocol, risk of bias was assessed using the Quality in Prognostic Studies tool, and statistical analyses were performed in R (v4.1.2) using a random-effects model. Sixteen eligible studies encompassing 681,633 pregnancies were included. Rare autosomal trisomy-positive results occurred in only 0.2% of cases and 80% were false positives. Notably, ∼35% of these were associated with adverse pregnancy outcomes, predominantly involving chromosomes 2, 4, 11, 16, and 22. Uniparental disomy was most commonly associated with trisomies 15 and 16. In cases with complex genome-wide noninvasive prenatal testing findings, 40% were ultimately diagnosed with maternal malignancy, primarily breast cancer and lymphoma. Discordant genome-wide noninvasive prenatal testing results are associated with an increased risk of placenta-mediated complications. Among rare autosomal trisomies, trisomy 16 and, to a lesser extent, trisomy 4 consistently showed the highest risks. These results imply that chromosome-specific risk stratification could inform prenatal counseling and follow-up. Additionally, complex, multichromosomal genome-wide noninvasive prenatal testing results were occasionally associated with maternal malignancies. This emphasizes the importance of considering both maternal and fetal contributions when interpreting such results.