Congenital Varicella Syndrome

Etiology

The varicella-zoster virus (VZV) is a human alphaherpesvirus with worldwide distribution and is highly contagious.[4] This virus is responsible for chickenpox (primary VZV infection) and herpes zoster (or shingles) infection (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, leading to viremia and widespread dissemination. As the viremia increases, new cutaneous vesicular lesions erupt, with individuals typically having 250 to 500 lesions in varying evolution stages. 

The incubation period for varicella is typically between 10 to 21 days. Individuals with primary infection may also experience a prodrome of fever, malaise, abdominal pain, and headaches. Patients with chickenpox are considered contagious from 1 to 2 days before developing the rash until all skin lesions have crusted over. Varicella infection in pregnant women can spread via the placenta and infect the fetus.[5][6]

After chickenpox, the virus becomes latent in the dorsal root ganglia.  It can later reactivate as herpes zoster (or shingles). The clinical manifestation of herpes zoster includes a painful vesicular rash in a dermatomal distribution, followed by postherpetic neuralgia.  Direct contact with the vesicles may be contagious, especially in non-immune or immunocompromised hosts. Herpes zoster does not pose a risk to a developing fetus due to circulating protective maternal antibodies transmitted through placental transfer.[7][6]

Epidemiology

Varicella infection during pregnancy is uncommon due to widespread immunity in women of childbearing age after having chickenpox or varicella immunization which was introduced in 1995. Varicella infection in a seronegative pregnant female occurs if she acquires person-to-person transmission from direct contact with varicella-zoster lesions or respiratory droplets spread from an infected person with chickenpox. Clinical presentation and the severity of the neonate will depend on when the mother contracted the virus during the pregnancy. 

Congenital varicella syndrome (CVS) results when a mother is infected with the VZV during the first half of pregnancy. The highest risk (2%) occurs in the second trimester between 13 and 20 weeks of gestation.[8] CVS has been reported in rare cases as late as 28 weeks of gestation.[9] Since the first described cases in 1947, the overall number of neonates that have been reported to have congenital varicella syndrome is approximately 41 cases per year in the US, 4 cases per year in Canada, and 7 cases per year in the United Kingdom.[9][10] 

When a pregnant woman develops a varicella infection around delivery, neonatal varicella infection may occur. Mother to child transmission can occur in three ways: transplacental viremia, direct contact with skin lesions or blood during delivery, and post-natal contact by respiratory droplets or skin contact with infected vesicles.  Infants are at the highest risk for severe varicella infection when maternal infection develops 5 days before and 2 days after delivery. In that time period, the baby will be exposed to high viremia but will not have adequate time to acquire maternal protective antibodies.[7]

History and Physical

Congenital Varicella Syndrome defects involve the skin, the limbs, eyes, and the central and autonomic nervous systems. Characteristic scarring skin lesions known as cicatrix occur in a dermatomal distribution throughout the body. Limb abnormalities include hypoplasia, atrophy, or malformed digits. Typical ocular defects include chorioretinitis, cataracts, and nystagmus. Central nervous system abnormalities include microcephaly, cortical atrophy, seizures, and mental retardation. Autonomic nervous system dysfunction can also occur, leading to neurogenic bladder, hydronephrosis, esophageal dilation, and gastrointestinal reflux.[6][11][5]

Infants born to mothers with varicella within the high-risk period for neonatal varicella infection are initially well appearing.  If they become symptomatic, they will usually present with classical vesicular skin lesions. Disseminated disease with pneumonia, hepatitis, meningoencephalitis, and severe coagulopathy resulting from liver failure and thrombocytopenia can also occur.[6]

Evaluation

For congenital varicella syndrome, sampling of fetal blood or amniotic fluid does not reliably identify cases.[6] Prenatal ultrasounds may be used to identify 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.[12]

For neonatal varicella infection, confirmation of the virus in the mother is prudent. The diagnosis of varicella in pregnant women can often be made from the classic clinical presentation of a diffuse vesicular rash in various stages of evolution. If the diagnosis is in question, the base of a vesicular skin lesion can be scraped for direct fluorescent antibody testing or PCR. Viral cultures can also be obtained but often take up to 1 week to yield results.[5] These diagnostic studies should also be performed on suspicious lesions presenting on the infant's body.

Treatment / Management

Since the cardiovascular manifestations result from intrauterine damage to the developing fetus, antiviral therapy in the newborn period would not be expected to have much impact on the sequelae. However, if the infant develops clinical signs of active infection, acyclovir should be administered intravenously. The therapy duration is determined based on control of active VZV replication with either cessation of new skin lesion formation or with negative VZV PCR testing. 

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 after the maternal symptoms appear in the two days after delivery.  Intravenous immune globulin (IVIG) is an alternative if VZIG is unavailable. Infants should be treated even if the mother was also administered VZIG. These infants should be monitored carefully, and early treatment with intravenous acyclovir should be administered for breakthrough varicella infection.[6][10]

Differential Diagnosis

Other TORCH infections, including cytomegalovirus (CMV), herpes simplex virus (HSV), rubella, and toxoplasmosis, need to be considered.[13] Neonates with congenital CMV may present with microcephaly, periventricular calcifications, ventriculomegaly, chorioretinitis, sensorineural hearing loss, and petechiae.  Congenital HSV can be distinguished with a vesicular rash or disseminate infection, including hepatitis and coagulopathy in a baby born to a mother with active genital HSV lesions at the time of delivery.  Congenital rubella syndrome presents 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 side effects of VZIG and acyclovir use in the perinatal period have not been well established at this time. However,  the benefits of mitigating severe and possibly life-threatening infections outweigh the theoretical risk.[5]

Prognosis

The overall prognosis of infants born with congenital varicella syndrome is poor, often fatal in roughly 30% of infected babies within the first month of life. Death in infancy often results from intractable gastrointestinal reflux, severe recurrent aspiration pneumonia, and respiratory failure.[6][7]

For infants with neonatal varicella infection, if untreated, the mortality rate is as high as 31%. Death typically occurs from varicella pneumonia. The mortality rate decreases to 7% when VZIG is administered.[5][14]

Complications

Both congenital varicella syndrome and neonatal varicella infection have a high mortality rate. Those who survive can develop infant herpes zoster (shingles) within the first or second year of life without having primary chickenpox infection.[15]