Cytomegalovirus (CMV) infections acquired by very-low-birthweight (VLBW) infants are incompletely characterized. To examine CMV transmission in VLBW infants, we evaluated maternal DNAlactia, infant ...DNAemia, and presence of clinical disease in a blinded study in VLBW infants in our newborn intensive care unit (NICU). To examine these issues, 200 VLBW infants were enrolled in a surveillance study, with weekly breast milk and infant whole blood samples collected, as available. Virologic (breast milk and infant whole blood real time PCR) and immunologic (IgG, IgM, and IgG avidity) correlates were evaluated. A chart review examined whether infants had symptoms compatible with CMV disease. DNAlactia was identified in 65/150 (43%) of lactating mothers. Nine CMV infections were identified in 9/75 CMV-exposed infants (12% of exposed infants). A higher median breast milk viral load (DNAlactia) correlated with an increased likelihood of DNAemia (
= 0.05). Despite potential symptoms compatible with CMV infection, clinicians had not considered the diagnosis of CMV in 6/9 cases (66%). All of these infants had chronic lung disease at discharge. There was no correlation between IgG antibody titer or IgG avidity index and the likelihood of transmission or CMV disease. In conclusion, in VLBW infants receiving milk from seropositive mothers, CMV infections are commonly acquired, and are frequently unrecognized. Future studies are needed to determine whether routine surveillance for CMV of either breast milk or infant plasma is beneficial in preventing or recognizing infection.
Abstract
Background
CMV can be transmitted to babies after birth through breast milk and such infections may lead to a “sepsis-like syndrome” with neutropenia, hepatitis, and viremia. CMV infections ...can be epidemiologically characterized by envelope glycoprotein (gB) genotypes - gB1, gB2, gB3 and gB4. The role of specific genotypes in pathogenesis and immune control of infection is incompletely characterized. These studies aimed to characterize viral and host correlates of breast-milk transmission of CMV in a neonatal intensive care unit (NICU) setting.
Methods
200 infants were enrolled in a prospective study of infants <1500 grams at birth in the NICU at the University of MN Masonic Children’s Hospital. Breast milk samples were available from 164 mothers, representing 184 infants (including twin pairs). We compared CMV IgM titer (Gold Standard Diagnostics Corp, CA) and CMV IgG titer (Diamedix, FL) in non-viremic infants of seropositive mothers for whom we had available serum (n=48 infants), and in eight infants with DNAemia. Positive CMV Breast milk samples from 65 mothers were further characterized by a multiplex real-time PCR assay, to characterize and compare gB genotypes.
Results
The prevalence of DNAlactia in the breast milk was 65/150 (43%). There were 49 mothers for whom CMV was present in breast milk, for which we also had infant whole blood samples (58 infants; 40 singletons and 9 twin pairs). Eight infants, exposed to CMV in the breast milk, developed CMV viremia (8/58=13%). Clinicians had not tested for CMV in 5/8 cases. Anti-CMV IgM antibodies were detected in 6/8 (75%) viremic infants. One non-viremic infant with CMV infection was identified solely by the IgM assay. There was no difference in ELISA IgG titers between infants with CMV viremia, and nonviremic infants. The subset of 65 CMV positive breast milk samples, 25 were positive for gB1 (39%), 13 were positive for gB2 (20%), 23 were positive for gB3 (35%) and 11 were positive for gB4 (17%); 11 samples were positive for multiple gB genotypes. For six samples, the gB genotype was unable to be determined. The gB genotype was determined for 5 of eight breast milk samples from mothers of the viremic babies with gB1 being the most common. In 3 of the 8 viremic samples, genotype was unable to be determined.
Conclusion
Breast milk from CMV-seropositive lactating mothers in a NICU setting can lead to transmission of infection and development of symptomatic CMV disease, which may not be recognized by clinicians. The distribution of gB genotypes in breast milk is similar to that observed in other CMV epidemiological analyses, and multiple genotypes may be identified in lactating seropositive women. Since gB is a critical target in CMV vaccine design, understanding strain-specific transmission may have implications for understanding the impact of pre-pregnancy vaccination on breast milk transmission. Purified recombinant gB vaccines studied in clinical trials are based on based on the Towne strain of CMV, gB1 genotype (DOI: 10.1128/JVI.01695-18). Future studies should examine the impact of strain-specificity of vaccination on circulation of CMV strains in infants with CMV disease.
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