The Role of Congenital Cytomegalovirus Infection in Adverse Birth Outcomes: A Review of the Potential Mechanisms

Abstract

Human cytomegalovirus (CMV) is a major cause of nonhereditary adverse birth outcomes, including hearing and visual loss, neurologic deficits, and intrauterine growth retardation (IUGR), and may contribute to outcomes such as stillbirth and preterm delivery. However, the mechanisms by which CMV could cause adverse birth outcomes are not fully understood. This study reviewed proposed mechanisms underlying the role of CMV in stillbirth, preterm birth, and IUGR. Targeted literature searches were performed in PubMed and Embase to identify relevant articles. Several potential mechanisms were identified from in vitro studies in which laboratory-adapted and low-passage strains of CMV and various human placental models were used. Potential mechanisms identified included impairment of trophoblast progenitor stem cell differentiation and function, impairment of extravillous trophoblast invasiveness, dysregulation of Wnt signaling pathways in cytotrophoblasts, tumor necrosis factor-α mediated apoptosis of trophoblasts, CMV-induced cytokine changes in the placenta, inhibition of indoleamine 2,3-dioxygenase activity, and downregulation of trophoblast class I major histocompatibility complex molecules. Inherent challenges for the field remain in the identification of suitable in vivo animal models. Nonetheless, we believe that our review provides useful insights into the mechanisms by which CMV impairs placental development and function and how these changes could result in adverse birth outcomes.

Neurotrophic factor levels in the serum and cerebrospinal fluid of neonates infected with human cytomegalovirus

“…It often manifests as a dominant infection in fetuses and infants whose immune system is not yet fully developed, which can lead to damage to multiple organ systems. HCMV infection can lead to placental dysfunction, fetal growth restriction in utero , preeclampsia‐like symptoms, premature delivery, and stillbirth 14 . In the present study, analysis of clinical information revealed that the white blood cell count and protein content in the CSF of neonates in the HCMV‐infected group were significantly higher than those in the control group ( P < 0.05).…”

Infections at the maternal–fetal interface: an overview of pathogenesis and defence

“…Given that other recent reviews have provided thorough overviews of the mechanisms by which CMV might be vertically transmitted 115 – 117 , here we provide a more focused overview. CMV has been shown to infect trophoblasts, but with substantial gestational age-related differences in infectivity 28 .…”

Single Nucleotide Polymorphisms of Interleukins and Toll-like Receptors and Neuroimaging Results in Newborns with Congenital HCMV Infection

“…It has been documented that maternal serological status before pregnancy and the timing of maternal HCMV infection during pregnancy (the earlier the infection, the greater the damage of fetal brain) have an impact [ 47 ]. Additionally, HCMV may cause placental damage and dysfunction, including impaired villous growth and differentiation, as well as placental cells apoptosis directly through the viral cytopathic effect or via excessive immune defense [ 48 ]. The placental insufficiency has a negative impact on fetal growth and may be a cause of prematurity during maternal HCMV infection [ 48 ].…”

“…Additionally, HCMV may cause placental damage and dysfunction, including impaired villous growth and differentiation, as well as placental cells apoptosis directly through the viral cytopathic effect or via excessive immune defense [ 48 ]. The placental insufficiency has a negative impact on fetal growth and may be a cause of prematurity during maternal HCMV infection [ 48 ].…”