KEY POINTS

• 1.
  

  Cytomegalovirus (CMV) infection is acquired in the postnatal period primarily from mother’s milk feeding.

  
  
• 2.
  

  Postnatal CMV (pCMV) infection is usually asymptomatic in healthy term infants. Among very low birth weight (VLBW, birth weight <1500 g) infants, infection occurs in ∼6.5% and is associated with a sepsis-like syndrome in ∼1% but is rarely fatal.

  
  
• 3.
  

  Symptomatic pCMV infection is associated with lower gestation, younger age at acquisition, and an increased number of preexisting comorbid conditions.

  
  
• 4.
  

  VLBW pCMV infection has been variably associated with increased risk of chronic lung disease, retinopathy of prematurity, hearing loss, and neurodevelopmental impairment.

  
  
• 5.
  

  There are no standard recommendations for use of antiviral therapies for pCMV infection.

  
  
• 6.
  

  Prevention of pCMV transmission from mother to preterm infant is an area of ongoing research that has focused on methods to inactivate the virus in milk. The risks and benefits of such approaches remain unclear.

Introduction

Human cytomegalovirus (CMV) is a double-stranded DNA virus of the beta-herpes family. Primary infection with CMV commonly occurs via mucosa, but transmission can also occur after a transfusion or transplant or in utero. Like other herpes viruses, CMV persists after primary infection, predominantly by residing in myeloid cells where the virus does not replicate and avoids elimination by the host immune system. During times of altered immune function, such as immunosuppression for transplant therapy, the virus can reactivate, proliferate with multiorgan involvement, and cause substantial morbidity and mortality. In neonates, both congenital CMV infection (cCMV) and postnatally acquired CMV infection (pCMV) occur almost exclusively among infants born to CMV-infected mothers. cCMV may occur in the newborn due to primary maternal infection during pregnancy or with reactivation of a latent maternal infection, with resulting transplacental or intrapartum transmission. In contrast, pCMV is primarily acquired via breast milk feeding. A majority of lactating women with latent CMV infection (positive for CMV-specific immunoglobulin G [IgG] serum antibodies) experience viral reactivation with secretion of CMV in breast milk. This reactivation is localized in mammary tissue without consistent maternal viremia. Although vertical CMV transmission during pregnancy can be devastating for the immune-naïve fetus, primary infection from breast milk in the postnatal period is largely asymptomatic among both term and preterm infants. Preterm and very-low birth weight (VLBW, birth weight <1500 g) infants, however, may manifest acute illness after pCMV, with symptoms ranging from isolated laboratory abnormalities to acute clinical decompensation. ^, In the following, we will address neonatal CMV infection, with an emphasis on pCMV among preterm, VLBW infants.

Viral Pathogenesis

CMV entry into host cells is driven by interactions between glycoprotein complexes present on the outermost lipid envelope of the virus and host receptors ( Fig. 33.1 ). ^, Once intracellular, a tightly regulated sequence of immediate early, early, and late gene expression occurs. Viral effects on the host cell can include a variety of outcomes including lysis, immune evasion, immune activation, and an altered cellular environment, depending on the type of cell, stage of development (especially important in fetal infection), and the immune state of the host. Mechanisms of CMV persistence and immune evasion involve a multipronged approach by viral gene products against each arm of human immune defense. The virus produces cytokines that mimic host interleukin 10 and suppress inflammation; interferes with immune action requiring major histocompatibility complex I and II presentation; slows cell apoptosis; encodes microRNAs that alter cell cycle regulation; and produces a chemokine that is thought to allow dissemination of the virus in the body. ^, CMV establishes latency in specific hematopoietic cell lines, establishing life-long persistence.

Illustration of Cytomegalovirus (CMV) Structure.

(Figure made in collaboration with Biorender.com.)

Disease Pathogenesis

Despite a robust host immune response and tropism for a variety of organ systems, CMV infection is clinically asymptomatic in most immunocompetent hosts. Symptomatic clinical illness among transplant recipients and cCMV infants is associated with high viral load. Although viral load may have a predictive role in cCMV sequelae and is used for decision-making in transplant settings, ^, the relationship between viral load and pCMV clinical disease among preterm infants remains unclear. ^, CMV viral replication causes cell lysis and immune-mediated injury that together create a clinical picture similar to bacterial sepsis with multiorgan involvement. Among solid-organ transplant recipients, CMV reactivation/infection appears to cause an additional “indirect effect,” resulting in increased secondary infection, decreased graft survival, and increased mortality that are reduced by CMV prophylaxis. Latent infection among immunocompetent hosts may also alter the baseline immune state by active engagement of mechanisms required to maintain latency. In a study of 210 twins, discordant CMV carriage in monozygotic twins altered 50% of immune markers. Latent CMV infection has been associated with altered cardiovascular health outcomes, attributed to this altered immune state.

Perinatal Epidemiology

A multicenter study of 34,989 primarily term-born infants in 7 US hospitals (2008–09) reported a 0.5% incidence of cCMV infection. A single-center study conducted from 1993 to 2008 among 4594 VLBW infants found cCMV in a similar proportion (0.39%). The incidence of pCMV among preterm infants has varied in different reports. Using blood or urine CMV polymerase chain reaction (PCR) screening of VLBW infants at regular intervals from birth to 90 days, a study set in the United States found that pCMV occurred in 33/381 (8.7%) among those fed breast milk from CMV-positive mothers; no pCMV occurred among infants who were not fed mother’s milk. In a study conducted in Germany, VLBW infants were tested biweekly with urine CMV PCR testing until hospital discharge and then again at 3 to 6 months of age. Of the 78 CMV-positive mothers and their 92 infants, CMV acquisition was reported in 21/92 infants (23%) while in the hospital and an additional 12/92 (13%) after discharge, for a total of 36% with pCMV. Differences in duration of follow-up, amount of breast milk ingested, and use of fresh or frozen milk may all account for the difference in transmission rates observed in these studies. Estimated seroprevalence for CMV in United States among women 20 to 49 years of age is 61.3% (95% confidence interval [CI], 58.9%–63.6%). In a meta-analysis of 17 pCMV studies, annual pCMV incidence was estimated to be 2800 VLBW infants (6.5%; 95% CI, 3.7%–10.9%), with 1500 symptomatic cases (3.4%; 95% CI, 1.7%–5.8%) and 600 manifesting sepsis-like syndrome (1.4%; 95% CI, 0.7%–2.4%). Estimations using frozen-thawed breast milk showed lower transmission rates but similar rates of symptomatic disease and sepsis-like presentation.

Preterm pCMV

With the use of leuko-reduced and irradiated blood products, CMV transmission via mother’s milk is the primary cause of pCMV. High rates of viral DNA detection in breast milk have been reported across diverse racial/ethnic cohorts in multiple studies: 70% (Italy), 76% (United States), >80% (Sweden), 87% (Japan), 94% (Taiwan), and 95% (Netherlands). ^{, ,} CMV is detected in breast milk as early at 3 days to as late as 1 month postpartum. Viral transmission is low when breast milk contains viral DNA alone (<10%) but approaches 50% when infectious virus is also present. In all prospective studies, rates of infection are many-fold higher than rates of symptomatic disease. ^{, , ,} Table 33.1 lists risk factors for transmission and symptomatic presentation.

Clinical Features of CMV Infection

Symptomatic congenital infection has a wide spectrum of presentation, from isolated hearing deficit to multisystem organ involvement and severe neurologic deficits, with severity of injury related to fetal age at acquisition. A detailed discussion of the prevention, diagnosis and treatment of cCMV can be found in the review by Rawlinson et al. Term and preterm infants commonly acquire pCMV from breast milk feeding without signs of infection. In preterm infants the immature immune system, combined with a lack of maternally derived CMV antibody, contribute to the risk for symptomatic disease. Both direct viral damage and immune dysregulation may result in end organ injury. ^, Although there is an accepted causal link for manifestations such as bone marrow suppression (with evidence for direct tissue invasion, prevention with prophylaxis, and reversal with treatment), ^, causation is more difficult to establish with preterm outcomes that have a multifactorial pathogenesis, such as chronic lung disease, necrotizing enterocolitis (NEC), or childhood neurologic sequelae. ^{, ,} Attribution of clinical symptoms to pCMV is limited by the small number of cases in prospective studies ( Table 33.2 ). ^{, , , , ,} and variation in case definition and ascertainment bias for symptomatic infants. ^{, , ,} Severe sepsis-like illness can occur, particularly among extremely low birth weight infants. Isolated thrombocytopenia, respiratory decompensation, and colitis are commonly reported signs in symptomatic pCMV cases among VLBW infants. ^, CMV-associated enteritis can present as atypical NEC, and CMV-specific antigens and DNA have been identified in resected intestinal specimens in NEC cases ^, ; however, latent CMV can be enriched at sites of inflammation, complicating attribution. In a post hoc analysis of a prospective screening study, NEC (≥stage II) was significantly related to pCMV (adjusted hazard ratio, 8.45; 95% CI, 1.83–38.9). In contrast, a study addressing the impact of pasteurizing mother’s milk found decreased pCMV transmission after pasteurization but a trend toward higher incidence of NEC. Longer-term outcomes associated with pCMV infection in preterm infants are summarized in Tables 33.3 and 33.4 .

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