Borderline Z-scores in non-invasive prenatal screening: does its presence hold clinical significance?

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 six 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 re-construction 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.