Borderline Z-scores in Non-Invasive Prenatal Screening: Does Its Presence Hold Clinical Significance?

Abstract Background This study aimed to investigate the utility of repeated testing for the detection of fetal cell-free DNA (cfDNA) from maternal peripheral blood in cases with borderline Z-scores, and to analyze the associated pregnancy outcomes. Methods A retrospective analysis was conducted on 83,443 pregnant women who voluntarily underwent non-invasive prenatal testing (NIPT) at the Affiliated Women and Children's Hospital of Ningbo University between January 2020 and January 2024. Pregnant women whose initial NIPT results indicated borderline Z-scores were subsequently followed up. Results Among 83,443 pregnant women undergoing NIPT, 700 cases (0.84%) initially showed borderline Z-scores. After retesting, this number decreased to 211 cases (0.25%), and further decreased to 26 cases (0.03%) after re-sampling. Among the initial 700 cases, 34 exhibited abnormal NIPT results, corresponding to a positive rate of 5.29%. Subsequent prenatal diagnosis confirmed a total of 6 fetal abnormalities, including one case of trisomy 13 mosaicism, one case of trisomy 21 mosaicism, one case of 47,XXY, two cases of copy number variations (CNVs), and one case with B-ultrasound findings indicating an abnormality (nuchal translucency [NT] of 3.5 mm and omphalocele). The overall rate of fetal abnormalities was 0.9%. Conclusion Initial NIPT outcomes suggested elevated screening positive rates and a higher incidence of fetal abnormalities among cases with borderline Z-scores compared to the general population. Establishing a defined borderline Z-score threshold in NIPT protocols is crucial to mitigate the risk of missed screenings. Implementing reconstruction and/or re-sampling procedures significantly reduces the failure rate attributed to borderline Z-scores, facilitating the accurate identification of most of pregnancies with normal fetal development and decreasing the need for unnecessary invasive prenatal diagnostic interventions. Pregnant women with detection failures due to borderline Z-scores should be actively counseled and encouraged to pursue prenatal diagnosis.