Congenital Varicella Syndrome

Etiology

The varicella-zoster virus (VZV) is a highly contagious human α-herpesvirus with a worldwide distribution. VZV is responsible for chickenpox (primary VZV infection) and herpes zoster infection (shingles, reactivation of latent infection). Chickenpox is acquired through contact with respiratory droplets or fluid from shingles lesions. Initially, viral replication occurs in the respiratory tract. The virus then invades local lymph nodes, resulting in viremia and widespread dissemination. As viremia increases, new cutaneous vesicular lesions erupt, with individuals typically having 250 to 500 lesions at varying stages of evolution.[5][6]

The incubation period for varicella is typically 10 to 21 days. Individuals with primary infection may also experience a prodrome of fever, malaise, abdominal pain, and headache. Chickenpox, or acute varicella zoster infection, is considered contagious from 1 to 2 days before rash onset until all skin lesions have crusted. In pregnant women, varicella infection can spread via the placenta and infect the fetus.[7][8] 

After the initial chickenpox infection, the virus becomes latent in the dorsal root ganglia, where it can later reactivate as herpes zoster (or shingles). Herpes zoster clinical manifestations include a painful vesicular rash in a dermatomal distribution, followed by postherpetic neuralgia.[6] Direct contact with the vesicles may be contagious, especially in nonimmune or immunocompromised individuals. Maternal herpes zoster does not pose a risk to a developing fetus because protective maternal antibodies are transferred through the placenta.[8][9]

Epidemiology

Varicella infection during pregnancy is uncommon because of widespread immunity among women of childbearing age who have previously had chickenpox or received the varicella immunization, introduced in 1995. Varicella infection in a seronegative pregnant woman occurs when she comes into direct contact with varicella-zoster lesions or inhales respiratory droplets from a person with chickenpox. The clinical presentation and severity of the disease in the neonate depend on the timing of maternal infection during gestation.[3]

Congenital varicella syndrome (CVS) results when maternal VZV infection occurs during the first half of pregnancy. The highest risk (2%) occurs in the second trimester between 13 and 20 weeks of gestation.[4] CVS has been reported in rare cases as late as 28 weeks of gestation. Since the first reported cases in 1947, approximately 41 cases per year have been reported in the US, 4 in Canada, and 7 in the United Kingdom.[7][10]

Neonatal varicella infection may occur when a pregnant woman develops varicella infection near delivery. Mother-to-child transmission occurs in 3 ways: transplacental viremia, direct contact with skin lesions or blood during delivery, and postnatal contact by respiratory droplets or skin contact with infected vesicles. Infants are at the highest risk of developing severe varicella infection when maternal infection develops 5 days before and 2 days after delivery. In that time period, the neonate will be exposed to high viremia without sufficient time to acquire protective maternal antibodies.[11]

History and Physical

Manifestations of congenital varicella syndrome involve the skin, extremities, eyes, and central and autonomic nervous systems. Characteristic scarring skin lesions known as cicatrices occur in a dermatomal distribution throughout the body. Extremity abnormalities include hypoplasia, atrophy, and malformed digits. Typical ocular defects include chorioretinitis, cataracts, and nystagmus. Central nervous system abnormalities include microcephaly, cortical atrophy, seizures, and intellectual disability.

Autonomic nervous system dysfunction can also occur, leading to neurogenic bladder, hydronephrosis, esophageal dilation, and gastrointestinal reflux.[4][11] Infants born to mothers with varicella during the high-risk period for neonatal varicella infection initially appear well. If they become symptomatic, they will usually present with vesicular skin lesions. Disseminated disease with pneumonia, hepatitis, meningoencephalitis, and severe coagulopathy resulting from liver failure and thrombocytopenia.[4][11]

Evaluation

Fetal blood or amniotic fluid sampling does not reliably identify congenital varicella syndrome. Prenatal ultrasonography may be used to identify the severe manifestations of intrauterine VZV infection. These findings include asymmetric limb shortening or malformations, intestinal and hepatic echogenic foci, intrauterine growth restriction, cerebral anomalies, including hydrocephalus and microcephaly, and fetal hydrops or fetal demise.[3][11]

Confirmation of maternal viral infection is important when neonatal varicella infection is suspected. The diagnosis of varicella in pregnant women is often based on a diffuse vesicular rash at various stages of evolution.[3] If the diagnosis is in question, the base of a vesicular skin lesion can be scraped for direct fluorescent antibody testing or polymerase chain reaction testing. Viral cultures can also be obtained; however, the results often take up to 1 week. These diagnostic studies should also be performed on infants with suspicious lesions.[3]

Treatment / Management

Because the cardiovascular manifestations result from intrauterine damage to the developing fetus, antiviral therapy in the newborn period is unlikely to alter long-term sequelae. However, if the infant develops clinical signs of active infection, acyclovir should be administered intravenously. Treatment duration is determined by the control of active VZV replication, as evidenced by either the cessation of new skin lesion formation or negative VZV polymerase chain reaction testing.[12](B2)

If a mother develops chickenpox infection during the high-risk time period for neonatal varicella infection (5 days before through 2 days after delivery), infants should receive varicella-zoster immune globulin (VZIG) immediately after birth or as soon as the maternal symptoms appear in the 2 days after delivery. Intravenous immune globulin (IVIG) is an alternative if VZIG is unavailable. Infants should be treated even if the mother was administered VZIG. These infants should be monitored carefully, and early treatment with intravenous acyclovir should be administered for breakthrough varicella infection.[4][7]

Differential Diagnosis

Other congenital infections, including cytomegalovirus (CMV), herpes simplex virus (HSV), rubella, and toxoplasmosis, should be considered in the differential diagnosis.[13] Neonates with congenital CMV may present with microcephaly, periventricular calcifications, ventriculomegaly, chorioretinitis, sensorineural hearing loss, and petechiae.[14] A vesicular rash or disseminated infection, including hepatitis and coagulopathy, can distinguish congenital HSV in a neonate born to a mother with active genital HSV lesions at delivery. Congenital rubella syndrome can present with cataracts and congenital heart disease. Congenital toxoplasmosis can present with chorioretinitis, hydrocephalus, intracranial calcifications, and a maculopapular rash.

Toxicity and Adverse Effect Management

The long-term adverse effects of VZIG and acyclovir during the perinatal period have not been well established. However, the benefits of mitigating severe, potentially life-threatening infection outweigh the theoretical risk.[7]

Prognosis

The overall prognosis of infants with CVS is poor, and approximately 30% of infected neonates do not survive the first month of life. Death in infancy often results from intractable gastrointestinal reflux, severe recurrent aspiration pneumonia, and respiratory failure.[4][11] The mortality rate of untreated neonatal varicella infection is as high as 31%. Death typically occurs from varicella pneumonia. The mortality rate decreases to 7% when VZIG is administered.[12]

Complications

Both congenital varicella syndrome and neonatal varicella have high associated mortality. Survivors may develop infant herpes zoster (shingles) during the first or second year of life, even without clinically apparent primary varicella infection.