Beyond the Tip of the Iceberg: The Clinical Impact of Maternal Nonprimary Cytomegalovirus Infection

Background: Nonprimary maternal cytomegalovirus (CMV) infections, resulting from reactivation or reinfection in seropositive women, are increasingly recognized as contributors to congenital CMV (cCMV) disease. However, their clinical impact compared with primary infections remains insufficiently characterized. Methods: We conducted a retrospective cohort study of symptomatic cCMV identified from a single-center series (2005–2022) and a multicenter registry (2023–2025). Infants were included if they had a positive urine CMV polymerase chain reaction within the first 3 weeks of life and met criteria for symptomatic infection based on central nervous system involvement. Maternal infection type (primary vs. nonprimary) was determined by serologic testing. Clinical characteristics, neuroimaging findings and auditory outcomes were compared between groups. Results: We identified 360 symptomatic infants; maternal infection type was unknown in 55, leaving 305 for analysis [243 (79.7%) primary; 62 (20.3%) nonprimary]. The proportion of nonprimary infections among symptomatic cases increased from 11.4% in 2005–2009 to 37.3% in 2020–2025 (odds ratio: 4.77; 95% confidence interval: 1.63–13.92; P = 0.004). Absolute counts mirrored these trends: nonprimary 5 of 44 in 2005–2009 to 22 of 59 in 2020–2025. Clinical manifestations, including neuroimaging and hearing outcomes, were broadly similar between groups. Conclusions: In the era of maternal screening and interventions focused on primary CMV infection, nonprimary infections represent a rising share of symptomatic cCMV and a relevant clinical burden. These findings highlight the importance of recognizing nonprimary infections in clinical care and public health planning and support the need to reassess current strategies for maternal counseling and neonatal care.