Cytomegalovirus is the commonest congenital viral infection in the developed world, with an overall prevalence of approximately 0.6%. Approximately 10% of congenitally infected infants have signs and symptoms of disease at birth, and these symptomatic infants have a substantial risk of subsequent neurologic sequelae. These include sensorineural hearing loss, mental retardation, microcephaly, development delay, seizure disorders, and cerebral palsy. Antiviral therapy for children with symptomatic congenital cytomegalovirus infection is effective at reducing the risk of long-term disabilities and should be offered to families with affected newborns. An effective preconceptual vaccine against CMV could protect against long-term neurologic sequelae and other disabilities.
Key points
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In the developed world, cytomegalovirus (CMV) is the most common congenital viral infection, with an overall birth prevalence of approximately 0.6%.
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Approximately 10% of congenitally infected infants have signs and symptoms of disease at birth, and these symptomatic infants have a substantial risk of subsequent neurologic sequelae. These include sensorineural hearing loss, mental retardation, microcephaly, development delay, seizure disorders, and cerebral palsy.
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The public health impact of congenital CMV infection is underestimated and underrecognized by both the lay public and health care providers.
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Antiviral therapy for children with symptomatic central nervous system congenital CMV infection is effective at reducing the risk of long-term disabilities and should be offered to families with affected newborns.
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An effective preconceptual vaccine against CMV could, by preventing congenital infection, protect against long-term neurologic sequelae and other disabilities. A variety of active and passive immunization strategies are in clinical trials and are likely to be licensed in the next few years. Until a vaccine is licensed, preventive strategies aimed at reducing transmission should be emphasized and public awareness increased, particularly among women of childbearing age.
Introduction
Cytomegalovirus (CMV) is a ubiquitous herpesvirus spread by close interpersonal contact through saliva, blood, genital secretions, urine, or breast milk that infects up to 90% of the US population by the eighth decade of life and establishes lifelong latency in monocytes and granulocytes. Maternal transmission to the fetus of a new or reactivated latent infection may occur at any gestation, leading to congenital CMV. About 20,000 to 40,000 infants per year in the United States are born with congenital CMV infection, with a corresponding incidence of 0.6% to 0.7% of all deliveries of the developed world, making CMV the most common of the congenital viral infections. CMV is mostly asymptomatic or mildly symptomatic when acquired as a primary infection in infants, children, and adults; however, it can be devastating to immunocompromised hosts, including infected newborns, and results in more long-term neurodevelopmental morbidity than any other perinatally acquired infection. The most frequently observed neurodevelopmental sequela is sensorineural hearing loss (SNHL): indeed, congenital CMV infection is estimated to be the leading nonhereditary cause of SNHL.
Despite its frequency and disabling consequences, congenital CMV is less known to the general population than other conditions with lower prevalence, such as Down syndrome, fetal alcohol syndrome, and spina bifida. This lack of awareness is problematic given that currently the only way to prevent fetal infection is through careful hygienic practices, such as hand washing and avoidance of potential sources of CMV. This review summarizes the current state of knowledge regarding the epidemiology, pathogenesis, diagnosis, treatment, and prognosis of congenital CMV infection. New and emerging strategies for prevention and therapy are emphasized, including vaccines currently in clinical trials. Key principles of management, including appropriate use of consultants, are summarized. Finally, potential resources for parents raising a child with symptomatic congenital CMV infection are provided.
Epidemiology
Cytomegalovirus is a ubiquitous infection and most individuals are eventually exposed to this agent. There is no seasonality to infection. Patient populations with an increased incidence of primary infection include breastfeeding infants, toddlers and care providers in group daycare, and sexually active adolescents. CMV infections are generally asymptomatic in immunocompetent individuals, but may produce a heterophile-negative mononucleosis syndrome in approximately 10% of primary infections in older children and adults. CMV seroprevalence demonstrates striking geographic and racial variation and tends to be highest in South America, Africa, and Asia and lowest in Western Europe and the United States. Seroprevalence is higher among nonwhites and among individuals of lower socioeconomic status. The factors responsible for geographic and racial variation in seroprevalence remain incompletely understood.
The biggest risk factor for CMV transmission in women of reproductive age is exposure to urine and saliva of young children, and mothers of children who are shedding CMV are 10 times more likely to seroconvert than women in other comparison groups. Children in group daycare represent a particularly important reservoir of CMV. It is postulated that maternal CMV infection could be prevented during pregnancy through education and behavioral changes. However, many women have not heard of CMV; obstetricians may not discuss CMV prevention with their patients, and these opportunities are missed. A lack of public knowledge of CMV is a major barrier to disease control. A recent study using a national mail survey showed that awareness of CMV was very low. Only 7% of men and 13% of women had heard of congenital CMV. Awareness of other congenital infections, such as rubella and toxoplasmosis, was slightly greater despite their lesser prevalence. This lack of awareness is particularly troubling given that CMV is fairly easy to inactivate through simple hand-washing interventions.
Congenital and perinatal CMV infections: clinical presentation
CMV infection may be acquired in an infant via congenital, intrapartum, or postnatal routes. Infection of the newborn may occur secondary to exposure to CMV-infected cervical secretions during vaginal delivery or via ingestion of CMV-infected breast milk, but these types of infections rarely result in significant symptoms or sequelae in term babies. Postnatal acquisition of CMV by breast-feeding has little significance, is not associated with long-term disability, and rarely causes clinical signs of illness in term infants. In contrast, low-birth-weight premature infants are at significant risk for CMV disease following acquisition of infection via breast milk. CMV also can cause disease in a premature infant when acquired by transfusion. Premature infants may demonstrate worsening respiratory status, neutropenia, or septic appearance (with apnea, bradycardia, pallor, and bowel distention) at the onset of infection, regardless of whether the virus was acquired postnatally from human milk or transfusions. For premature infants acquiring infection postnatally, CMV’s ability to cause long-term sequelae independent from prematurity remains unclear, although minor effects on motor development have been suggested. A recent study suggested that postnatal CMV infection of preterm infants did not result in an increased risk of SNHL.
Congenital CMV occurs transplacentally and may result in symptomatic or asymptomatic infection in the neonate. The likelihood of fetal transmission and symptomatic disease is much greater during primary versus nonprimary maternal CMV infection. It is estimated that 1% to 4% of CMV-seronegative mothers will become infected during pregnancy, and 30% to 40% of these infected women will transmit the virus to the fetus. Nonprimary maternal CMV infections can also result in fetal transmission. These infections may represent reactivated latent infection or reinfection with a new strain in seropositive women. Currently it is estimated that 10% to 30% of women with preconception immunity become reinfected, and 1% to 3% will transmit to the fetus. Symptoms of disease in the newborn and long-term neurodevelopmental sequelae can occur after transmission in the setting of primary or recurrent infection. Symptoms occur in 11% to –12.7% of all neonates with congenital CMV according to 2 recent meta-analyses. Clinical findings include intrauterine growth restriction, hydrops, generalized petechiae, purpura, thrombocytopenia, jaundice, hepatosplenomegaly, pneumonitis, microcephaly, periventricular calcifications, seizures, chorioretinitis, sensorineural hearing loss, bone abnormalities, abnormal dentition, and hypocalcified enamel. Table 1 summarizes the frequencies of these findings as noted in a review of 106 infants with symptomatic congenital CMV infection, as well as the most common associated laboratory abnormalities.
| Finding | Frequency (%) |
|---|---|
| Petechiae | 76 |
| Neurologic, one or more of the following: | 68 |
| Microcephaly | 53 |
| Lethargy/hopotonia | 27 |
| Poor suck | 19 |
| Seizures | 7 |
| Jaundice | 67 |
| Hepatosplenomegaly | 60 |
| Small for gestational age (weight <10 percentile) | 50 |
| Prematurity (<38 wk gestation) | 34 |
| Elevated ALT (>80 units/L) | 83 |
| Thrombocytopenia: | |
| <100 × 10 3 /mm 3 | 77 |
| <50 × 10 3 /mm 3 | 53 |
| Conjugated hyperbilirubinemia: | |
| Direct bilirubin >2 mg/dL | 81 |
| Direct bilirubin >4 mg/dL | 69 |
| Hemolysis | 51 |
| Increased CSF protein (>120 mg/dL) | 46 |
The differential diagnosis of congenital CMV includes other congenital viral infections, toxoplasmosis, and syphilis, given that many of the presenting symptoms are nonspecific. For example, rubella may also present with petechiae, bony defects, and sensorineural hearing loss. Neonatal enteroviral infections, particularly infections with the recently described parechoviruses, can be associated with fetal brain injury and long-term sequalae. Neonatal HSV infection may present with seizures; parvovirus B19 may present with hepatomegaly and anemia; and lymphocytic choriomeningitis virus may present with microcephaly, chorioretinitis, and intracranial calcifications.
Long-term sequelae occur following both symptomatic and asymptomatic congenital infections, with the more frequent and severe sequelae occurring in symptomatic infants. It has been estimated that 40% to 58% of infants who are symptomatic at birth go on to develop sequelae, and these may include sensorineural hearing loss, vision loss, mental retardation, seizure disorder, cerebral palsy, visual deficits, or developmental delay. Approximately 13.5% of the asymptomatic neonates may still go on to develop neurodevelopment injury, which most commonly manifests as hearing loss. Hearing loss is most common when CMV infection occurs in the first or second trimester. Sensorineural hearing loss following symptomatic or asymptomatic congenital infection is often progressive, can be unilateral or bilateral, and may be absent at birth, only to become clinically manifest later in childhood. About 21% of all hearing loss at birth and 25% of hearing loss at 4 years of age is attributable to congenital CMV infection; therefore, these children require regular hearing evaluations and early intervention.
Diagnostic evaluation
There is no universal screening for CMV in mothers or newborns. Pregnant mothers can be diagnosed by seroconversion from immunoglobin G (IgG) -negative to IgG-positive status, or by positive immunoglobin M (IgM) if confirmed with low-avidity IgG (IgM may remain positive for 6–9 months after the end of acute phase infection). Fetal infection is diagnosed by positive viral culture or polymerase chain reaction (PCR) from amniotic fluid. Diagnosis in the neonate is made by viral detection in body fluids via PCR, culture, or antigen testing (pp65 antigen) within the first 3 weeks of life. The finding of CMV antibodies or viral DNA after this point makes congenital versus postnatally acquired infection difficult to distinguish. Antibody titers cannot reliably make the diagnosis as maternal CMV IgG crosses the placenta, and neonates mount weak IgM responses. The preferred specimens are saliva and urine as newborns shed high levels of the virus from these fluids. Saliva samples may be more easily obtained and have been shown to be as reliable as urine samples in diagnosing CMV, so some propose that saliva PCR should be considered the investigation of choice.
For the primary care clinician, having an appropriate index of suspicion is key. In addition to the signs, symptoms, and laboratory abnormalities noted in Table 1 , CMV diagnostic studies should also be considered in infants with more subtle potential manifestations of illness, such as mild growth retardation, or a failed newborn hearing screen. Once the diagnosis is confirmed, further laboratory tests, imaging, and eye and hearing assessments are indicated. Complete blood count and liver function tests may reveal pancytopenia and hepatitis, and coagulation studies may be abnormal in the setting of hepatitis. Renal function is checked as a baseline before beginning treatment with ganciclovir (see later discussion). A range of seizure disorders, including infantile spasm, have been described, and ongoing consultation with a pediatric neurologist may be necessary. Neuroimaging is an important component of management. Available techniques for neuroimaging assessment include cerebral ultrasound, computed tomography, and magnetic resonance imaging (MRI) for suspected or proven congenital infection. Cranial ultrasound is a good screening tool, with subsequent MRI being recommended for definitive evaluation, particularly for infants with abnormal ultrasound examination, microcephaly, or neurological findings ( Fig. 1 ). A recent review elegantly summarized the pattern of neurodevelopmental injury as a function of timing of acquisition of brain infection in utero. This review noted that lesions occurring prior to 18 weeks gestational age commonly include lissencephaly with thin cerebral cortex, cerebellar hypoplasia, ventriculomegaly, periventricular calcification, and delay in myelination. At 18 to 24 weeks, migrational abnormalities may occur, including polymicrogyria, schizencephaly, and periventricular cysts. Third trimester infections may be associated with central nervous system (CNS) lesions that may include delayed myelination, dysmyelination, calcification, and white matter disease. Ophthalmologic assessment should be performed on all infants with congenital CMV infection. Ophthalmologic signs are seen in a large percentage of symptomatic infants and include chorioretinitis, optic atrophy, and cortical visual impairment. Strabismus is also a common long-term ophthalmologic complication. Audiologic assessment should be performed on all infants with congenital CMV infection; as noted, SNHL may be absent at birth, and progressive in nature, and frequent evaluations are required throughout childhood to evaluate for the possibility of hearing deterioration. At a minimum, audiologic assessment should be performed every 6 months for the first 3 years of life and annually thereafter. For children with severe-to-profound hearing loss caused by congenital CMV, cochlear implantation is a successful intervention. Hypoplasia and hypocalcification of tooth enamel are common in children with congenital CMV infection, and regular dental visits are an important component of the long-term care of these infants. Children with evidence of cerebral palsy may require consultative care from a clinician expert in the management of this disorder. Several suggested diagnostic studies and potential specialty referrals are noted in Box 1 ; however, it should be noted that the range of management issues for any given child may be quite variable, and not all children with congenital CMV will require all of these services.
Potential diagnostic studies
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Diagnostic virology
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PCR and/or culture of infant urine, blood, and saliva
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Specimens must be obtained before day 21 of life to confirm congenital infection (vs postnatal acquisition)
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Neurodiagnostic imaging
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Head ultrasound, good screening examination in neonatal period
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MRI of brain more definitive for symptomatic/affected infants
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Ophthalmologic evaluation
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Audiologic evaluation
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Newborn hearing screening in nursery
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Definitive auditory-evoked response on follow-up evaluation
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Complete blood count, platelet counts, transaminases, bilirubin for symptomatic infants
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Electroencephalography if seizures clinically evident or suspected
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Potential consultants
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Audiology
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Otolaryngology
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Pediatric infectious disease
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Neurology
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Physical medicine/rehabilitation
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Orthopedics
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Developmental pediatrics
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Pediatric ophthalmology
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Pediatric dentistry
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Not all children with congenital CMV will require all of these studies. The need for specific studies will be guided by the clinical picture in the individual child.
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