IUGR and congenital cytomegalovirus infection.

Intrauterine growth restriction (IUGR), a condition in which the fetus is pathologically growth restricted in utero, remains a serious problem. Although the term is often used interchangeably with small for gestational age (SGA), it is important for studies to differentiate these conditions. The latter term refers to all infants in whom the birth weight is below the 10th percentile for the gestational age, which for a full-term infant corresponds to a weight <2500 g. Infants may be constitutionally SGA simply because of their heredity. Pathological IUGR also is not a single entity and has multiple causes, including poor maternal nutrition, chronic hypertension, diabetes, genetic abnormalities, smoking, substance abuse, preeclampsia, and intrauterine infections such as cytomegalovirus, rubella, syphilis, or toxoplasmosis. The etiology of IUGR can be extrinsic to the fetus, as when uteroplacental insufficiency causes diminished transport of nutrients and oxygen, or intrinsic to the fetus, as when growth restriction results from chromosomal abnormalities or fetal infection. The origin of the IUGR can also be both intrinsic and extrinsic to the fetus, as when maternal infection results in both placental insufficiency and fetal infection. In approximately half of IUGR cases, however, there may be no identifiable cause, and such cases are classified as idiopathic. It has been known for >50 years that intrauterine infection with human cytomegalovirus (CMV), a member of the herpesvirus group, could damage the central nervous system of the fetus [1, 2]. In fact, CMV is the major viral cause of birth defects. Between 0.5% and 2.5% of all newborns are infected with CMV, and of the 5%–10% who are symptomatic at birth, sequelae develop in most; these include microcephaly, sensorineural hearing loss, optic atrophy, and chorioretinitis, and motor disabilities. Even in the asymptomatic group, approximately 15% will later show progressive hearing loss, visual impairment, or cognitive disabilities. Infection of the fetus can occur in CMV-seronegative women because of primary infection, or in women with preexisting immunity because of reactivation of endogenous virus from a prior infection or reinfection with a new virus. However, the risk of transmission to the fetus is higher during primary infection (approximately 40%) than in CMV-seropositive women (1%). Although it was previously believed that only congenitally infected children born to women who had a primary infection had sequelae leading to permanent disability, it is now appreciated that hearing loss and other neurological disabilities occur in 10%–20% of congenitally infected children born to women with preexisting immunity [3–6]. In both situations, sensorineural hearing loss is the most common outcome. In the past when more sensitive assays were not available, IUGR was one indicator of congenital CMV disease. Although it has been established that congenital CMV infection resulting from primary infection of the mother has severe outcomes, including placental damage and IUGR, it has been difficult to show a definitive association of IUGR with congenital CMV infection in infants who had no other clinical manifestations. One of the earliest studies suggesting a link was by Starr and Gold [7], who in 1969 reported that 93% of >1000 infants born at the Cleveland Metropolitan General Hospital were tested for CMV infection. This was before polymerase chain reaction and DNA-based diagnostic assays, and identification of congenital CMV infection required inoculation of urine samples from 1–2-day-old infants into tissue culture and observation for evidence of CMV cytopathic effect. CMV infection was confirmed in 1.5% of the infants, and none had clinical manifestations of cytomegalic inclusion disease. The only abnormal finding was that the birth weights of the infected infants were significantly lower than those of the uninfected infants, and this difference was not due to premature delivery. Received and accepted 4 February 2014; electronically published 12 February 2014. Correspondence: Deborah H. Spector, PhD, Department of Cellular and Molecular Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0712 ([email protected]). The Journal of Infectious Diseases 2014;209:1497–9 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiu092