Intrauterine growth restriction caused by underlying congenital cytomegalovirus infection

(See the editorial commentary by Spector on pages 1497–9.) Human cytomegalovirus (HCMV) is the most common cause of congenital viral infection and permanent birth defects in the United States and occurs more frequently than other well-known disabilities, including Down syndrome, fetal alcohol syndrome, and neural tube defects [1]. Primary maternal infection in the first trimester of pregnancy poses a 30%–40% risk of virus transmission with birth defects that include mental retardation, neuromotor disabilities, intrauterine growth restriction (IUGR), and hearing loss [2–4]. Poor outcome is associated with viral replication, inflammation, edema, and fibrinoid development in the placenta [5, 6]. In contrast, immune women have a low risk (0.2%–2.0%) of virus transmission, and infected babies are largely asymptomatic [2, 7]. Maternal neutralizing immunoglobulin G (IgG) suppresses HCMV replication in the placenta, and viral antigens are sequestered in syncytiotrophoblasts without infection of underlying cytotrophoblasts [8–12]. Recent studies revealed that the placental-fetal unit in congenital infection is hypoxic and that levels of a secreted form of the vascular endothelial growth factor (VEGF) receptor, fms-like tyrosine kinase 1 (sFlt1), are elevated in amniotic fluid [13]. In contrast, treatment of primary maternal infection after seroconversion with hyperimmune globulin enriched for HCMV IgG reduces transmission and improves outcome [14]. Analysis of these placentas revealed infection was suppressed and development of the syncytiotrophoblast surface and numbers of blood vessels in chorionic villi increased [13]. Infants with IUGR, birth weights less than 10th percentile, have a perinatal morbidity and mortality 5–30 times that of infants with higher weights [15]. In the present study, we focused on idiopathic IUGR, a manifestation of maternal and fetal disorders, to determine whether underlying congenital HCMV infection was involved. We found serological evidence of primary and recurrent maternal infection, viral replication in blood vessels of floating villi and the chorion, and viral proteins in the amniotic epithelium. Development of large fibrinoids with avascular villi, edema, and impaired cytotrophoblast differentiation reduced placental functions, resulting in hypoxia and IUGR.