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Cytomegalovirus (CMV) is the most common congenital viral infection in the developed world, with an overall birth 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 high risk for demonstration of subsequent neurologic sequelae, including sensorineural hearing loss (SNHL), mental retardation, microcephaly, development delay, seizure disorders, and cerebral palsy. Antiviral therapy of children with symptomatic central nervous system (CNS) congenital CMV infection is effective at reducing the risk of long-term disabilities and should be offered to families with affected newborns. An effective pre-conceptual vaccine against CMV could, by preventing congenital infection, protect against long-term neurological 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 child-bearing age.
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 8th decade of life and establishes lifelong latency in monocytes and granulocytes.1-3 Maternal transmission to the fetus of a new or reactivated latent infection may occur at any gestation, leading to congenital CMV. About 20,000-40,000 infants per year in the United States are born with congenital CMV infection, with a corresponding incidence of 0.6 - 0.7% of all deliveries of the developed world, making CMV the most common congenital viral infection.4-7 CMV is mostly asymptomatic or mildly symptomatic in infants, children, and adults, however can be devastating to immunocompromised hosts including infected newborns, and results in the greatest long-term neurodevelopment morbidity of all the perinatally acquired viral infections. The most frequent sequel is sensorineural hearing loss (SNHL), of which CMV is the leading nonhereditary cause overall.8, 9
Despite its frequency and substantial consequences, congenital CMV is less known to the general population compared to other conditions with lesser prevalence such as Down Syndrome, fetal alcohol syndrome, and spina bifida. This lack of awareness is problematic given that the only way currently to prevent fetal infection is by prevention, with good hygeine practices with 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.
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._ENREF_1010-16 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.17 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 United States. Seroprevalence is higher among non-whites and among individuals of lower socioeconomic status.18, 19 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 ten times more likely to seroconvert than women in other comparison groups.12, 20, 21 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.20 A lack of public awareness of CMV is a major barrier to disease control. A recent study, using a national mail survey designed to be similar to the US population, showed that awareness of CMV was very low.20 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.22
CMV infection may be acquired in the newborn via congenital, intrapartum and antenatal routes of infection. 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.23 Post-natal acquisition of CMV has little significance, is not associated with long-term disability, and rarely causes clinical signs of any illness in term infants. The exception is low-birth weight premature infants. Premature babies appear to be at particularly high risk for CMV-associated disease. These infants may additionally have symptoms of 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.24, 25 For premature infants acquiring infection postnatally, CMV’s ability to cause long-term sequelae independent from prematurity remains unclear, though minor effects on motor development have been suggested.25-27 A recent study suggested that postnatal CMV infection of preterm infants did not result in an increased risk of SNHL.28
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 a primary maternal CMV infection. It is estimated that 1-4% of CMV seronegative mothers will become infected during pregnancy, and 30-40% of these infected women will transmit virus to the fetus. Non-primary 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 10-30% of women with preconception immunity become re-infected, and 1-3% will transmit to the fetus.5, 6, 19, 29, 30 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% - 12.7% of all neonates with congenital CMV according to 2 recent meta-analyses.4, 5 Clinical findings include IUGR, 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.31
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.32 Neonatal enteroviral infections, particularly infections with the recently described parechoviruses, can be associated with fetal brain injury and long-term sequalae.33 Neonatal HSV infection may present with seizures, parvovirus B19 with hepatomegaly and anemia, and lymphocytic choriomeningitis virus with microcephaly, chorioretinitis and intracranial calcifications.34
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 40-58% of infants who are symptomatic at birth go on to develop sequelae4, and these may include sensorineural hearing loss, vision loss, mental retardation, seizure disorder, cerebral palsy, visual deficits, or developmental delay.31, 35, 36 Approximately 13.5% of the asymptomatic neonates may still go on to develop neurodevelopment injury, which is most commonly manifest as hearing loss.4 Hearing loss is most common when CMV infection occurs in the first or second trimester.37, 38 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.39-43 About 21% of all hearing loss at birth and 25% of hearing loss at 4 years of age is attributable to congenial CMV infection; therefore, these children require regular hearing evaluations and early intervention.44
There is no universal screening for CMV in mothers or newborns. Pregnant mothers can be diagnosed by seroconversion from IgG -negative to IgG-positive status, or by positive IgM if confirmed with low-avidity IgG (IgM may remain positive for 6-9 months after the end of acute phase infection).30 Fetal infection is diagnosed by positive viral culture or 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.45 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. 46-48
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 be considered in infants with more subtle potential manifestations of illness, such as subtle growth retardation, or a failed newborn hearing screen. Once the diagnosis is confirmed, further laboratory tests, imaging, and eye and hearing assessments are indicated. CBC and LFTs may reveal pancytopenia and hepatitis, and coagulation studies bay be abnormal in the setting of hepatitis. Renal function is checked as a baseline prior to beginning treatment with ganciclovir (see below). Neuroimaging assessment: available techniques include cerebral ultrasound, CT, and MRI for suspected or proven congenital infection. Lesions that occur before 19 weeks post menstrual age include lissencephaly with a thin cortex, cerebellar hypoplasia, ventriculomegaly, periventricular calcification and delayed myelination. At 18-24 weeks, migrational abnormalities may occur such as polymicrogyria, occasionally schizencephaly, periventricular cysts and cerebellar hypoplasia. CNS lesions may include delayed myelination, dysmyelination and white matter disease. In all cases, calcification is a common finding. A range of seizure disorders, including infantile spasm, have been described, and ongoing consultation with a pediatric neurologist may be necessary.49 Cranial ultrasound is a good screening tool, with subsequent MRI being recommended for definitive evaluation (Figure 1).50, 51 Ophthalmologic assessment should be performed on all infants with congenital CMV infection. Ophthalmological signs are seen in a large percentage of symptomatic infants and include chorioretinitis, optic atrophy, and cortical visual impairment.52 Strabmismus is also a common long-term ophthalmologic complication.53 Audiological 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.39 At a minimum, audiological assessment should be performed every 6 months for the first three years of life, and annually thereafter. For children with severe-to-profound hearing loss caused by congenital CMV, cochlear implantation is a successful intervention.54, 55 Hypoplasia and hypocalcification of tooth enamel is common in children with congenital CMV infection56, 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. A number of suggested diagnostic studies and potential specialty referrals are noted in Table 2; 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.
Treatment of congenital CMV infection with antivirals should be instituted in infants with evidence of central nervous system (CNS) involvement, including SNHL, and should be considered in infants with serious end-organ disease (hepatitis, pneumonia, thrombocytopenia). The cornerstone of antiviral therapy is ganciclovir, which was the first compound licensed specifically for treatment of CMV infections. Ganciclovir is a synthetic acyclic nucleoside analog, structurally similar to guanine. Its structure is similar to that of acyclovir, and, like acyclovir, it requires phosphorylation for antiviral activity. Following phosphorylation by a viral protein known as UL97, cellular enzymes phosphorylate the monophosphate form to di- and tri-phosphate metabolites; the ganciclovir triphosphate metabolite then exerts its antiviral effect in the CMV-infected cell. The first reports of the use of ganciclovir therapy for congenital CMV infection date to the late 1980s57. In subsequent reports,58, 59 ganciclovir has been shown to be generally safe and well-tolerated when used in newborns, and has appeared to be useful in the management of severe, focal, end-organ disease in infants. It is important to note that no sustained effect on CMV shedding at mucosal sites can be expected: once therapy is completed, infants resume excreting of CMV in urine and saliva.
It has become increasingly clear that ganciclovir also provides long-term neurodevelopmental benefit for some infants with congenital CMV infection, as demonstrated in a phase III randomized double-blind study of parenteral ganciclovir in neonates with symptomatic congenital CMV infection.60 This study indicated that 84% of 25 ganciclovir recipients either had improved hearing, or maintained normal hearing between baseline and 6 months. In contrast, only 59% of 17 control patients had improved or stable hearing (p=.06). Results were even more encouraging when the study and control groups were compared for subsequent maintenance of normal hearing. None (0%) of 25 ganciclovir recipients had worsening in hearing between baseline and 6 month follow-up, compared to 7 (41%) of 17 control patients (p<.01). The study further examined whether a therapeutic benefit was noted after 12 months of follow-up. Among 43 patients who had a BSER at both baseline and at 1 year or beyond, five (21%) of 24 ganciclovir recipients had worsening of hearing, versus 13 (68%) of 19 control patients (p<.01). A subsequent report compared long-term neurodevelopmental outcomes in infants treated with GCV and untreated infants, using the Denver Developmental Screening Test.61 This study indicated that receiving intravenous ganciclovir therapy had fewer developmental delays at 6 and 12 months compared with untreated infants.
Based on these data as well as the data regarding ganciclovir treatment and hearing outcomes, 6 weeks of intravenous ganciclovir therapy is recommended in the management of babies with symptomatic congenital CMV disease involving the CNS (Figure 2). Treatment should be initiated within the first month of life. Infants need to be monitored closely for toxicity, especially neutropenia, which may be observed in up to 60% of infants on long-term therapy.62 Care must be taken, and dosage adjustments made, when treating infants with impaired renal function.63 Treatment of infants with ganciclovir should be approached with realistic expectations, and should be undertaken with the assistance of an expert familiar with the use of this medication in infants. The risk of toxicity needs to be explained to parents, and it must be stressed that ganciclovir will not reverse established CNS injury. If neutropenia occurs on therapy, human granulocyte colony-stimulating factor therapy can be administered, and is usually effective in restoring an adequate neutrophil count, such that therapy may be continued. Ganciclovir or valganciclovir (if able to take enteral medication, see below) may also be considered in neonates with symptomatic end-organ disease other than CNS disease (hepatitis, pneumonia, thrombocytopenia), but the efficacy of treatment for non-CNS symptomatic congenital CMV infection has not been assessed large multi-center studies (Figure 2).
An alternative to intravenous ganciclovir for neonates who can take enteral medication is the use of its oral prodrug, valganciclovir. This approach is attractive insofar as it obviates the need for placement of a central venous catheter for six weeks of intravenous therapy. Valganciclovir is very well absorbed following oral administration. It is rapidly metabolized following oral dosing into ganciclovir. A suspension formulation is licensed and available, and although not licensed for the treatment of congenital CMV, its use can be considered as an alternative to intravenous therapy. Studies in neonates have demonstrated stable drug levels following oral dosing.63, 64 Currently, data from a clinical trial of 6 weeks versus 6 months of valganciclovir performed by the Collaborative Antiviral Study Group is being analyzed, toward the goal of determining whether long-term therapy confers additional neurodevelopmental benefits to infants.62 Although anecdotal reports from uncontrolled studies suggest that long-term oral therapy is well tolerated and possibly effective65, 66, there is insufficient evidence at this point to recommend a long-term (6 months) course of therapy of infants with congenital CMV infection. Similarly, it remains unclear if treatment initiated beyond the neonatal period provides any benefit with respect to neurodevelopmental outcomes, although additional studies of this question are warranted.
Consensus guidelines for antiviral management of congenital CMV have not been formulated in the US, though some recommended guidelines from Europe have been published with proposed treatment algorithms (Figure 2).48, 67 Other antiviral agents are available for CMV infection, including drugs such as foscarnet and cidofovir68, but there is very little experience with the use of these agents in infants, and at the current time their usefulness is limited to exceptional circumstances, such as the emergence of antiviral resistance to ganciclovir and/or in the treatment of immunocompromised infants with serious CMV end-organ disease.69
Development of a CMV vaccine is the most promising strategy for addressing the problem of congenital CMV. An effective vaccine could, by preventing neurological sequelae and other disabilities, provide a newborn with a lifetime of benefit. A report from the Institute of Medicine of the National Academy of Sciences placed CMV in its highest priority category for vaccine development, concluding that a vaccine would be strongly cost saving.70 Several CMV vaccines are currently being evaluated in a number of clinical trials. A live, attenuated strain of CMV, the Towne strain, has been evaluated as a potential vaccine in a number of studies, including several studies in immunocompromised solid organ transplant patients at risk for CMV disease.71-73 Although Towne vaccine has elicited humoral and cellular immune responses in these studies and demonstrated an effect on CMV disease, its potential as a vaccine against congenital CMV infection was called into question in a study of young women with children attending group day care. In this study, Towne vaccine showed no reduction in the infection rate of Towne-vaccinated mothers compared with placebo-inoculated mothers.74 An approach to improve the immunogenicity of a live virus CMV vaccine has recently been undertaken by engineering recombinant ‘chimeras’ of the attenuated Towne strain and the less attenuated, low-passage Toledo strain, and these vaccines are also in clinical trials.75 In addition to live virus vaccines, purified protein and DNA subunit vaccines are also in clinical trials.76 These vaccines focus on the virally-encoded proteins that are the key targets of both the humoral and cellular immune response to CMV. A vaccine based on the immunodominant CMV envelope glycoprotein, gB, was recently studied in adolescent and young adult women, with the primary end-point reported in this study being time to primary CMV infection. Primary CMV infection was confirmed in 8% in the vaccine group, compared to 14% in the placebo group, an overall efficacy of 50%.77 Additional evidence of the efficacy of the gB subunit vaccine was demonstrated in a placebo-controlled phase II study in solid organ transplant recipients.78 Ongoing and future clinical trials will hopefully lead to the licensure of a CMV vaccine in the not-to-distant future.
In addition to active immunization strategies, passive immunization, based on administration of anti-CMV immune globulin to women at risk of transmitting CMV to the fetus, is currently an intensely active area of clinical research. In a study of pregnant women with a primary CMV infection, whose amniotic fluid contained either CMV or CMV DNA, subjects were offered intravenous CMV hyperimmune globulin (HIG), in two different dose regimens, a “therapy” regimen or a “prevention” regimen.79 In the therapy group, only 1/31 women gave birth to an infant with CMV disease (defined as an infant who was symptomatic at birth and handicapped at two or more years of age), compared with 7 of 14 women in an untreated control group. Similar benefits were noted in the prevention group. The administration of HIG to women in the primary infection group was associated with significant reductions in placental pathology, and with regression of cerebral structural abnormalities in some infants.80, 81 Another retrospective, observational study of HIG reported a trend toward reduced intrauterine transmission of CMV.82 The use of HIG during pregnancy has also been reported to be associated with improved neurodevelopmental outcomes in infants in the first year of life.83 Randomized controlled trials of HIG are warranted in high-risk pregnancies, to validate the protective effect of passive immunization.
Congenital CMV infection is common and under-recognized. Pediatricians and primary care physicians should be familiar with maternal risk factors and clinical clues in newborns that might suggest the diagnosis of congenital infection. Increased public awareness is needed, particularly among women of child-bearing age. Therapeutic options are available, both for women who have transmitted CMV to the developing fetus, as well as for symptomatic newborns. Children with congenital CMV infection are at risk for adverse neurodevelopmental outcomes, particularly SNHL. The pediatrician plays an essential role in the long-term anticipatory management of children with congenital CMV infection. Progress toward development of a CMV vaccine has accelerated. Eventual licensure of a vaccine coupled with increased recognition of the importance of this common and disabling disease will make inroads into reducing the impact of this virus on the health and well-being of children. Parents of children with congenital CMV have formed support groups and created web sites for fostering knowledge and awareness (e.g., www.buckbuck.org; www.congenitalcmvfoundation.org; www.averysjourney.com; www.stopcmv.org) and these organizations can be a useful source of information for parents and clinicians alike who are seeking answers regarding this major public health problem.
SUPPORT Support from NIH HD044864, HD038416 is acknowledged.
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