BACKGROUND: Introduction of cell-free fetal DNA (cff-DNA) testing in maternal blood opened possibilities to improve the performance of combined first-trimester screening (cFTS) in terms of better detection of trisomies and lowering invasive testing rate. The use of new molecular methods, such as chromosomal microarray analysis (CMA) and next-generation sequencing (NGS), has shown benefits in prenatal diagnosis of chromosomal and genetic diseases, which are not detectable with cff-DNA screening, but require an invasive procedure.
METHODS: The objective of this study was to evaluate prospectively during two years performance of CMA and NGS in high-risk pregnancies. Initially, we investigated 14,566 singleton pregnancies with cFTS. A total of 334 high-risk pregnancies were selected for CMA diagnostic performance evaluation and 28 cases of highly dysmorphic fetuses for NGS analysis. CMA study group was divided into two groups based on the indications for testing; group A patients with high-risk for trisomies after cFTS, but normal ultrasound and group B patients who met criteria for CMA as a first-tier diagnostic test.
RESULTS: The diagnostic yield of CMA was overall 3.6% (1.6% in Group A and 6.0% in Group B). In NGS analysis group, we report diagnostic yield of 17.9%.
CONCLUSIONS: The use of CMA in high-risk pregnancies is justified and provides relevant clinical information in 3.6% of the cases. NGS analysis in fetuses with multiple anomalies shows promising results, but more investigations are needed for a better understanding of practical applications of this molecular diagnosis method in prenatal settings.

OBJECTIVE: The present study aimed to determine the diagnostic value of prenatal chromosomal microarray analysis (CMA) for fetuses with several indications of being at high risk for various conditions.
METHODS: This retrospective analysis included 1256 pregnancies that were prenatally evaluated due to high-risk indications using invasive CMA. The indications for invasive prenatal diagnosis mainly included ultrasound anomalies, high-risk for maternal serum screening (MSS), high-risk for non-invasive prenatal tests (NIPT), family history of genetic disorders or birth defects, and advanced maternal age (AMA). The rate of clinically significant genomic imbalances between the different groups was compared.
RESULTS: The overall prenatal diagnostic yield was 98 (7.8%) of 1256 pregnancies. Clinically significant genomic aberrations were identified in 2 (1.5%) of 132 patients with non-structural ultrasound anomalies, 36 (12.7%) of 283 with structural ultrasound anomalies, 2 (4.5%) of 44 at high-risk for MSS, 38 (26.6%) of 143 at high-risk for NIPT, 11 (3.8%) of 288 with a family history, and 7 (2.1%) of 328 with AMA. Submicroscopic findings were identified in 29 fetuses, 19 of whom showed structural ultrasound anomalies.
CONCLUSIONS: The diagnostic yields of CMA for pregnancies with different indications greatly varied. CMA could serve as a first-tier test for structural anomalies, especially multiple anomalies, craniofacial dysplasia, urinary defects, and cardiac dysplasia. Our results have important implications for genetic counseling.