Sandbox: Reddy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Historical Perspective

• In 1947, the first case of congenital varicella syndrome was reported.
• In 1987, Alkalay coined the term fetal varicella syndrome.

Pathophysiology

Pathogenesis

Primary infection during the period of gestation:

• Once a pregnant women has a primary varicella infection, transplacental transmission of the virus can take place affecting the fetus in utero. The clinical manifestations of the infection in the fetus are dependent on the gestational age of the fetus.
• An estimated 25% of fetuses are infected if the mother has a varicella infection during the period of gestation, but only less than 2% of fetus develop congenital varicella syndrome.
• The risk of developing severe manifestations is high when the infection occurs before 20 weeks of gestation, which co-relates to the period of gestation when the innervation of the eyes and limbs occur. The overall risk of developing congenital varicella syndrome is around 2% when the mother has infection before 20 weeks of gestation.
• VZV is a neurotrophic virus and the pathogenesis of the wide variety of manifestations in the fetus is unclear, but it is proposed to be related to reactivation of the virus in the fetus and not related to the maternal VZV virus.
• VZV virus is present in the sensory ganglia of the posterior roots of the spinal cord during the latent phase, reactivation of the virus in results in the destruction of the nervous tissue resulting in the characteristic cicatrical skin lesions, limb hypoplasia, bladder denervation, and bulbar palsy.
• The presence of diffuse calcifications in the liver, spleen, myocardium and brain support a mechanism of hematogenous spread.
• VZV has a very short incubation period, between 8 to 14 days and the timing for identification of infection in the fetus is important.

Natural History, Prognosis and Complications

Natural History

Varicella infection during pregnancy can result in congenital varicella syndrome, neonatal varicella and clinical zoster during infancy, the outcomes are dependent on the gestational age of fetus. Early gestational period infection via the transplacental route results in congenital varicella syndrome which presents with features such as low birthweight, cutaneous scarring, limb hypoplasia, microcephaly, cortical atrophy, chorioretinitis, cataracts. In cases with the onset of varicella infection in the pregnant mother within 5 days before delivery or 2 days after delivery can result in neonatal varicella with skin lesions and severe manifestation such as encephalitis and pneumonia.

Prognosis

Prognosis of infants with congenital varicella syndrome is poor. Infants die at a early age due to recurrent aspiration pneumonia and respiratory failure.

Complications

• Fetal demise
• Intrauterine growth restriction
• Hydrops
• Limb deformities
• Microcephaly

Diagnosis

Physical Examination

Clinical manifestations suggestive of Congenital varicella syndrome include:

	Clinical Manifestations in congenital varicella syndrome
Skin	Cicatricial lesions( Zig-Zag scarring in dermatomal distribution) Hypopigmentation
Eye	Chorioretinitis Cataracts Micropthalmia Anisocoria
Central Nervous System	Intrauterine encephalitis Cortical atrophy/porencephaly Seizures Mental retardation Autonomic instability
Musculoskeletal system	Limb hypoplasia Muscle hypoplasia
Gastrointestinal	Gastrointestinal reflux
Systemic Manifestations	Intrauterine growth retardation Developmental delay
Urinary Tract	Hydroureter Hydronephrosis

Laboratory Findings

The diagnosis of congenital varicella syndrome is based on a documented history of varicella infection during the pregnancy and the presence of fetal manifestations on ultrasound.
Diagnosis of primary infection in the mother : In pregnant women diagnosis of a primary infection requires a combination of clinical manifestations and series of diagnostic tests. The tests are performed on the samples from the vesicular skin lesions and include the following:

• Culture for VZV, but takes 10 to 12 days to obtain the results.
• Direct fluroscent antigen staining with monoclonal antibodies detects the VZV glycoproteins in the cells.
• PCR for the VZV
• Serological tests are not useful for the dectection of primary infection in the mother as it takes time for the IgG antibodies to be produced aganist VZV and majority of the women have a positive IgG as a result of vaccination or previous infection of varicella.

Prenatal Diagnosis

• Sequential ultrasound of the fetus is helpful to establish the presence of varicella infection and assess the severity of intrauterine infection.
• Amniocentesis should be performed 4 weeks after the primary infection in the mother, positive amniotic PCR for VZV can establish the presence of infection but does not provide evidence regarding the presence of infection or the severity of infection in the fetus. There is no established evidence to recommend amniocentesis for the diagnosis and is not performed on regular basis.

Imaging Studies

Ultrasound

• Sequential ultrasound in women with varicella infection during the period of gestation is the preffered diagnostic investigation to identify anomalies in the fetus. The findings suggestive of congenital varicella syndrome include limb deformities, microcephaly and hydrops.
• The following is a list of features that can be present in the fetus with varicella fetopathy:
  • Cutaneous scars
  • Musculoskeletal deformities such as limb hypoplasia and contractures
  • Intrauterine growth restriction
  • Ventriculomegaly, microcephaly with polymicrogyria, and porencephaly
  • Micropthalmia and congenital cataracts
  • Calcification in the brain, spleen and liver
  • Features of Hydrops fetalis such as skin edema, hepatosplenomegaly
  • Polyhydramnios

Prevention

Primary Prevention

• In all pregnant women documentation of varicella infection in the past and the pre-conceptional vaccination should be be documented.
• If the pregnant women has no previous infection or is not vaccinated, VZV IgG antibody testing must be done to determine the maternal immune status. These patients must be counseled regarding the risks of varicella infection as vaccination aganist VZV is contraindicated during the pregnancy.
• Women who are seronegative should recieve two doses of the vaccine during the postpartum period 4 to 8 weeks apart with no effect on breast feeding.
• Women can be vaccinated during the preconception period, but are adviced to avoid conceiving for a month after the last dose of the vaccine.

Secondary Prevention

• In pregnant women with exposure to varicella, passive immunization with varicella zoster virus antibodies (VZV IgG) should be administered after 72-96hours of exposure. Passive immnuniaztion with immmunoglobulins decreases the risk of severe disease in the mother, but its efficacy in preventing the disease to the fetus is not established.