Abstract: Objective To discuss the guiding significance of noninvasive genetic testing combined with single ultrasound soft index abnormality in fetal chromosome screening and its influence on perinatal outcome. Methods A total of 410 pregnant women with abnormal soft index of ultrasound were selected from January 2018 to December 2018 in our hospital. As the subjects of this study, 410 pregnant women with positive soft index of ultrasound were tested for non-invasive genes, and pregnant women with high risk of non-invasive gene detection were tested for invasiveness, and chromosome karyotype analysis of villus tissue and amniotic fluid was carried out. The accuracy of diagnosis, chromosome abnormalities and positive distribution of indicators, and perinatal outcomes of high-risk pregnant women in non-invasive gene test results were observed. Results A total of 11 non-invasive high-risk fetuses were detected in 410 pregnant women with positive single ultrasound soft index, and 8 of 11 non-invasive high-risk fetuses showed abnormal trisomy 21. Compared with other abnormal karyotypes, the incidence of abnormal karyotypes in non-invasive high-risk pregnant women was higher. Karyotype abnormalities in non-invasive high-risk pregnant women included trisomy 13, trisomy 18, trisomy 21 and trisomy 21. Abnormal pregnant women choose full-term delivery. Conclusion On the basis of three-dimensional ultrasound, prenatal screening for pregnant women with abnormal ultrasound soft indicators can be detected by non-invasive gene method, which can effectively improve the accuracy of screening, and the use of non-invasive gene detection also has a relatively high quality screening effect. It can effectively reduce the probability of clinical use of invasive screening, and significantly reduce the risk of abortion of pregnant women. It is worth popularizing and applying in clinic.