Background: Prenatal diagnosis is offered after fetal anomalies detected by ultrasonography, biochemical screening, non-invasive prenatal testing (NIPT), or other tests to establish etiology and guide decisions. Chromosomal microarray analysis (CMA) is the first-tier test. Whole-exome sequencing (WES) is increasingly used after negative CMA in fetuses with structural anomalies, but evidence for trio-WES as a first-tier test across broader indications is limited. Despite widespread WES-based CNV calling, prenatal comparisons of trio-WES versus CMA for detecting aneuploidy and copy-number variants (CNVs) are lacking. Methods: We conducted a prospective multicenter cohort of 1,382 singleton pregnancies from seven prenatal centers in China. Based on indications for invasive testing, cases were stratified into low-risk indications (LRI; traditionally CMA alone) and high-risk indications (HRI; sequential or concurrent testing of CMA and WES). Two hundred pregnancies undergoing termination prior to genetic testing formed a separate TOP cohort; the remaining 1,182 cases comprised the prospective cohort and underwent independent trio-WES and CMA in parallel. A custom enhanced exome captures interrogated aneuploidy, CNVs, single-nucleotide variants (SNVs), indels, and uniparental disomy (UPD). Clinically relevant findings were validated and reported. The primary outcome was pregnancy outcome with at least 3 months postpartum follow-up. Findings: Trio-WES yielded an overall diagnostic rate of 17.22% (238/1,382), including an incremental 7.38% (102/1,382) from SNVs/indels beyond CMA. In LRI group, yield was 4.02% (9/224), driven by SNVs/indels. The TOP cohort had a 37.5% (75/200) yield versus 13.79% (163/1,182) in the prospective cohort (p