Chromosome microarray analysis(CMA) can identify clinically significant microdeletions and microduplications, providing valuable insights into the genetic basis of various disorders. Our study was to evaluate clinical management and prognosis of fetuses with prenatal variants of unknown significance (VOUS) and determine diagnostic approaches for subsequent pregnancies. This study included 2,953 fetuses undergoing chromosome microarray analysis (CMA) at the Prenatal Diagnostic Center of Changzhou Maternal and Child Health Care Hospital from January 2018 to December 2022, identifying 162 cases with VOUS. Parent-of-origin testing determined the origin of copy number variations (CNVs). Prenatal genetic counseling was provided, and outcomes were followed for 3-36 months post-birth. All 162 VOUS cases received prenatal genetic counseling. Among these, 123 continued the pregnancy; 22 chose termination, and 17 were lost to follow-up. Of the continuations, 116 delivered at term, and 7 preterm. Post-birth follow-up showed 5/123 live-born fetuses developed relevant clinical phenotypes. Parent-of-origin testing in 21 cases identified 18 hereditary and 3 de novo variants. Additionally, five subsequent pregnancies were monitored, with two undergoing amniocentesis and three receiving low-risk non-invasive prenatal testing (NIPT), all with positive outcomes. VOUS, occurring in approximately 5% of cases, require comprehensive prenatal genetic counseling and show generally favorable outcomes. Despite low association with adverse clinical phenotypes, the importance of postnatal follow-up and regular report updates is emphasized to detect potential clinical associations early.