The role of the placenta in the pathogenesis of congenital cytomegalovirus infection: is the benefit of cytomegalovirus immune globulin for the newborn mediated through improved placental health and function?

Received 25 June 2006; accepted 26 June 2006; electronically published 6 September 2006. Reprints or correspondence: Dr. Mark R. Schleiss, University of Minnesota Medical School, Center for Infectious Diseases and Microbiology Translational Research, 2001 6th Ave. SE, Minneapolis, Minnesota, 55455 (schleiss@umn.edu). Clinical Infectious Diseases 2006; 43:1001–3 2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4308-0008$15.00 Congenital infection with human cytomegalovirus (CMV) is common and underrecognized. In the United States and Europe, estimates regarding the frequency of congenital CMV infection range from 0.5% to 1% of all newborns [1]. Although the majority of infants with congenital CMV infection appear healthy at birth, many go on to experience serious neurodevelopmental sequelae. These sequelae include cerebral palsy, seizures, microcephaly, mental retardation, developmental delay, and sensorineural hearing loss, which may occur, to varying degree, in up to 15% of all infected infants [2–6]. The magnitude of the disability caused by congenital CMV infection is immense, and the attendant financial costs are high. It is estimated that ∼40,000 infants per year have congenital CMV infection in the United States and that 8000 of these infants will require complex medical and surgical care as a result of the consequences of this infection. In the 1990s, the estimated costs associated with congenital CMV infection were estimated to be ∼$1.9 billion annually [7]. Children with congenital CMV-induced sequelae have a wide range of special needs, and they often require extensive interventions from health care providers, such as cochlear implantation, speech therapy, neurodevelopmental assessments, and, in severe cases, lifelong custodial care. Thus, the benefit of any successful intervention that could target prevention of in utero transmission of CMV would be substantial. The optimal strategy for prevention of congenital CMV infection has not yet been defined. Much attention has been focused on the potential for CMV vaccines to prevent transmission of CMV to the fetus. The potential utility of this strategy is supported by epidemiological observations indicating that preconceptual immunity to CMV provides protection against both infection and disease in the newborn [8]. Further evidence of the protective effect of preconceptual CMV immunity was noted in a study that demonstrated that prior immunity protected young women of childbearing age against reinfection following intense exposure to the virus in the secretions of young children attending group day care [9]. In another study, preconceptual immunity was estimated to have an efficacy of ∼70% in preventing congenital CMV infection in subsequent pregnancies [10]. The Institute of Medicine, in its 1999 assessment of the costeffectiveness of potential new vaccine priorities for the new millennium, identified a hypothetical CMV vaccine (modeled on the assumption that it would be given to adolescents) as the highest-level priority for any new vaccine for the 21st century [11]. A report from the National Vaccine Advisory Committee reinforced the Institute of Medicine recommendations, further emphasizing the significant toll that CMV infections exert on newborns [7]. In spite of the theoretical value of a CMV vaccine, there are no vaccines currently licensed for clinical use [12]. The barriers to implementation of vaccination against CMV include uncertainty regarding the optimal vaccine strategy (should it be a live-attenuated vaccine or a protein subunit vaccine? If a subunit vaccine, which viral proteins should be employed? What is the optimal expression strategy? ), uncertainty about the optimal population to be vaccinated (should the target population be young women of childbearing age or adolescents? Should universal vaccination of infants be considered? ), and unanswered regulatory questions (what are the barriers to moving vaccine candidates