Hepatitis B cell-free DNA in non-invasive prenatal testing as an early biomarker of viral infectivity

Non-invasive prenatal testing (NIPT) was initially developed to detect chromosomal abnormalities in fetuses through the analysis of cell-free fetal DNA in maternal blood. Recent advancements have expanded NIPTs applications to include the detection of viral infections during pregnancy. However, interpreting pathogen-derived cell-free DNA (cf-DNA) remains clinically complex. This study explores the clinical relevance of hepatitis B virus (HBV) cf-DNA using a dataset of approximately 500,000 NIPT visits and an independent validation cohort of 582 pregnant women (40 HBV-infected), aligned with HBV epidemiology from both population and individual perspectives. Our analysis reveals that HBV cf-DNA is a strong biomarker of high viral infectivity rather than a general marker of infection, suggesting its potential to identify pregnant women at heightened risk of vertical transmission by the end of the first trimester. Additionally, HBV-positive women showed a small but consistent reduction in fetal fraction relative to HBV-negative women across gestational weeks 9-17, an association compatible with an early effect of HBV on the placental contribution to cell-free DNA, although the observational design and unmeasured maternal covariates preclude causal inference.