Neonatal cytomegalovirus (CMV) infection is caused by Cytomegalovirus (CMV), the most common congenital viral infection. CMV belongs to the herpesvirus family and is a double-stranded DNA virus, named for the characteristic cytomegalic inclusions seen in infected cells during replication. CMV has various strains differentiated by antigenic properties, but the DNA sequence homology among strains is at least 80%–90%. CMV is widespread in nature and, once it infects the human body, can remain in a latent state for life, particularly in individuals with normal immune function. The occurrence of infection is influenced by environmental factors, socioeconomic status, gender, and age. Statistics indicate that congenital CMV infection affects 0.5%–2% of live births in developed countries and is the most common infectious cause of congenital hearing loss and neurodevelopmental disabilities.
Primary infection during pregnancy or reactivation of latent CMV due to maternal immunosuppression, as well as reinfection with a different CMV strain (superinfection), can lead to transplacental infection of the fetus, which is referred to as congenital infection. Intrapartum infection occurs when CMV-contaminated maternal secretions are inhaled during delivery. Postnatal infection can result from early exposure to CMV-containing saliva or urine from the mother, consumption of virus-containing breast milk, or blood transfusion. Since 58%–69% of breast milk may contain CMV, breast milk serves as an important route of postnatal infection.
Clinical Manifestations
Congenital Infection (Intrauterine Infection)
When the mother has a primary CMV infection, 30%–50% of fetuses may become infected, potentially leading to miscarriage, stillbirth, neonatal death, preterm birth, or intrauterine growth restriction (IUGR). Among affected neonates, 10%–15% exhibit multi-organ and multi-system involvement at birth. Mortality occurs in 20%–30% during the neonatal period, mainly due to disseminated intravascular coagulation (DIC), liver failure, or severe secondary bacterial infections. More than 10% die within the first year of life. For survivors, 60%–90% develop sequelae, with neurological sequelae occurring in 50%–90% of cases. Among the 85%–90% of infants with subclinical infection at birth, 10%–15% later develop long-term complications.
In cases of maternal reinfection, only 0.5%–3% of fetuses are affected. Among infected neonates, 85%–90% are asymptomatic at birth, but 10%–15% of those with subclinical infection develop sequelae, most often limited to hearing loss. Early intervention for hearing impairment prevents delays in language development.
Common clinical symptoms include jaundice, hepatosplenomegaly, liver dysfunction, respiratory distress, interstitial pneumonia, myocarditis, petechiae, thrombocytopenia, anemia, meningoencephalitis, microcephaly, periventricular calcifications, and ventriculomegaly.
Common sequelae include sensorineural hearing loss, intellectual or motor developmental delays, cerebral palsy, epilepsy, vision impairment, incomplete enamel calcification, and bronchopulmonary dysplasia. Sensorineural hearing loss is the most frequent complication, occurring in 10%–15% of asymptomatic cases and as much as 60% of symptomatic cases. Hearing loss often emerges around one year of age, is typically bilateral, and tends to progress over time. Virological testing during the first 2–3 weeks of life confirms the diagnosis in these cases.
Intrapartum or Postnatal Infection:
The incubation period ranges from 4–12 weeks, with most cases presenting as subclinical infections. In the neonatal period, clinical manifestations primarily include hepatitis and interstitial pneumonia. Full-term neonates generally experience a self-limiting course with a favorable prognosis. Preterm infants, however, may present with additional complications such as mononucleosis, hematologic abnormalities, and myocarditis, with a mortality rate as high as 20%. Blood transfusion-related transmission can lead to fatal outcomes.
Laboratory Testing
Viral Isolation
Viral isolation is the most specific diagnostic method. CMV in high concentrations is frequently detected in urine, where shedding may persist for months to years. However, viral shedding is intermittent, so repeated urine samples are required to improve detection. Other samples, such as cerebrospinal fluid (CSF) or saliva, may also be tested for viral isolation.
Detection of CMV Markers
CMV markers, such as characteristic cytoplasmic inclusions, viral antigens, particles, or genetic material, can be identified in various tissues or exfoliated cells. The most specific and sensitive techniques include DNA hybridization tests to detect CMV in patient samples and PCR-based amplification of specific CMV gene fragments to detect minimal amounts of the virus. Fresh morning urine or CSF pellet smears may be examined under a microscope for typical inclusion bodies. While this method is highly specific, it has a low sensitivity, often requiring multiple samples to yield a positive result.
Serological Detection of CMV IgG, IgM, and IgA Antibodies
Since IgM and IgA antibodies do not cross the placenta, the detection of these antibodies in cord blood or neonatal serum within the first two weeks of life indicates congenital infection. However, their low concentrations reduce detection rates. Maternal IgG antibodies cross the placenta and decline postnatally, reaching their lowest levels by 6–8 weeks. A persistent increase in serum IgG titers for over six months suggests intrauterine infection.
Treatment
Ganciclovir
Ganciclovir is the first-line treatment for symptomatic congenital CMV infection. The recommended dosage is 12 mg/kg per day, divided into two doses, administered intravenously for 6 weeks to 6 months. However, due to the widespread prevalence of CMV infection, the complex pathogenesis of the virus, and the fact that ganciclovir only inhibits viral replication without eradicating the virus, prolonged use may result in drug resistance and long-term adverse effects. These include neutropenia, thrombocytopenia, liver and kidney dysfunction, gastrointestinal and neurological complications. The indications for ganciclovir use should therefore be strictly controlled:
- Congenital CMV infection with central nervous system involvement.
- CMV infection with significant active symptoms such as pneumonia, hepatitis, or encephalitis.
Asymptomatic or mild cases, particularly postnatally acquired infections, generally do not warrant ganciclovir treatment.
Management of Complications
Early intervention is essential for cases of hearing impairment, and cochlear implants may be necessary in some instances.