Congenital Cytomegalovirus Infection: Improved Understanding of Maternal Immune Responses That Reduce the Risk of Transplacental Transmission.

Congenital human cytomegalovirus (CMV) infection is a common cause of severe and permanent neurological injury in newborns. A meta-analysis concluded that congenital CMV infection occurs in approximately 0.65% of newborns in the United States [1]. The prevalence was similar when data from a prospective multicenter study was analyzed. This study of over 100,000 newborns identified congenital CMV infection in approximately 0.5% of all deliveries [2]. Of the 20 000– 30 000 infants born in the United States each year with congenital CMV, at least 10% will exhibit long-term neurodevelopmental sequelae, including mental retardation, seizure disorders, cerebral palsy, microcephaly, and sensorineural hearing loss [3]. The burden on society elicited by congenital CMV is substantial, and strategies to prevent infections in women of childbearing age are urgently needed. CMV can infect the fetus either in the context of primary maternal infection during pregnancy, or following viral reactivation or reinfection in women already known to be CMV-seropositive prior to pregnancy. Transmission of virus to the developing fetus—even in the face of preconception immunity—can result in neurological sequelae. The likelihood of congenital CMV is directly proportional to the seroprevalence rates among women of childbearing age in the population being examined [4, 5]. Overall, as many as three-quarters of congenital CMV infections occur in women with preconception immunity [6], an observation that greatly complicates both the optimal anticipatory laboratory monitoring and clinical management strategies that should be employed during pregnancies at risk for vertical viral transmission. Irrespective of whether congenital transmission occurs in the context of primary or nonprimary maternal infection, the key (and unanswered) questions are: How do we predict which women are going to transmit CMV infection to the developing fetus; and how do we know which infants will have sequelae if transmission occurs? Unfortunately, the answers are unknown, largely because knowledge of the nature of the maternal immune response(s) required for protection against congenital CMV transmission remains incomplete. Protection clearly requires more than just immunoglobulin G (IgG) antibodies against CMV. Immunologic parameters postulated to confer protection of the placenta and fetus include both innate (natural killer cell) and adaptive (CD4+ and CD8 T cell, virus-neutralizing, and high-avidity antibody) responses [7–9]. Virus-neutralizing antibody may not only need to target the immunodominant CMV glycoprotein B (gB), but also CMV proteins involved in epithelial and endothelial cell entry (the “pentameric complex” of glycoproteins gH/gL/UL128/130/131). Neutralizing antibodies may also need to confer cross-protection against reinfection with genetically divergent CMV strains. Some of the proposed immune responses implicated in prevention of transmission of CMV from mother to fetus are summarized in Table 1. An improved knowledge of what is required to protect the fetus against CMV infection is vital for development of an effective (but as-yet hypothetical) preconception vaccine [10]. Against this backdrop, 2 articles in the current issue of Clinical Infectious Diseases provide us with new insights into the maternal immune correlates of protection against transmission of CMV during pregnancy. In the study reported by Fornara and colleagues from Pavia, Italy, the evolution of CMV-specific T-cell immunity was examined in a group of 44 pregnant women with evidence of primary infection during pregnancy, and results were E D I T O R I A L C O M M E N T A R Y