Chapter 54: Congenital and Perinatal Human Cytomegalovirus Infections

EPIDEMIOLOGY OF CONGENITAL HUMAN CYTOMEGALOVIRUS INFECTIONS

Introduction

The natural history of congenital human cytomegalovirus (HCMV) infection has been studied exhaustively for nearly 4 decades, yet critical features of this intrauterine infection continue to be redefined as contemporary methodologies are employed to further investigate the biology of the virus and the disease. Perhaps this is most strikingly illustrated by the surprising findings that have been obtained from the application of next-generation nucleic acid sequence technologies to studies of the genetic diversity of viruses isolated from infants with congenital infections.¹ These studies have confirmed earlier studies that utilized comparatively crude methodologies to define genetic variation among viruses isolated from infants with congenital HCMV infections as well from viruses isolated from different sites in a single infant.^{2, 3, 4, 5, and 6}

Together, these studies have documented that individuals, including fetuses infected in utero, are not infected with a single strain of virus but a collection of genetically distinct viruses that in some cases approaches the genetic sequence diversity that closely resembles that found in RNA viruses.¹ These findings coupled with a more complete understanding of the limited protection afforded by preexisting maternal immunity prior to conception in the prevention of superinfection/reinfection during pregnancy have challenged many long-held concepts of the natural history of congenital HCMV infections and argued that the natural history of this congenital infection must in some populations be redefined.

Case Definition and Incidence

The case definition of congenital HCMV infection that has been used in most large natural history studies of this infection has remained unchanged for decades and requires the isolation of replicating HCMV from the urine of an infant within the first 2 weeks of life.⁷ Since the early 2000s, the widespread use of polymerase chain reaction (PCR) in diagnostic laboratories has resulted in the increasing utilization of this technology in the diagnosis of congenital HCMV infections. Although PCR detection of HCMV is viewed by most investigators as equivalent to isolation of replicating virus, the possibility of false positives must be considered when samples such as saliva from breast-feeding infants are assayed. Positive PCR reactions in such cases can be confirmed by tissue culture isolation of virus from the urine of the infant or, alternatively, PCR analysis of urine from the infant.⁷ Using either tissue culture isolation of HCMV or PCR detection, investigators have reported that HCMV is the most common virus infection in the newborn infant that is acquired in utero, with reported rates between 0.5% and 2.0% in different populations throughout the world⁸ (Table 54-1). A large screening study of approximately 100,000 newborn infants in the United States that is nearing completion has reported that congenital HCMV infection occurs in about 0.5% of live births⁷ (Table 54-1).