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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 and the clinical manifestations are dependent on the gestational age of the fetus.
• An estimated of 25% fetuses are infected with varicella when the mother has a primary 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-relate to the period of gestation when the innervation of the eyes and limbs occur.
• The risk of developing congenital varicella is (lower) 0.55% between weeks 0 and 12 and is higher (1.4%) between weeks 13 and 20.
• 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.

Causes

Congenital Varicella Syndrome is caused by Varicella zoster virus (VZV), a human alpha herpes virus.

Differentiating Congenital Varicella Syndrome From Other Diseases

The most important congenital infections, which can be transmitted vertically from mother to fetus are the TORCH infections. These infections have overlapping features and hence, must be differentiated from Congenital Varicella Syndrome:

Congenital Infection	Cardiac Findings	Skin Findings	Ocular Findings	Hepatosplenomegaly	Hydrocephalus	Microcephaly	Intracranial Calcifications	Hearing deficits
Congenital Varicella Syndrome		- Cicatrical Skin Lesions Skin Edema	Micropthalmus Cataracts	✔		✔	✔
Toxoplasmosis		Petechiae Purpura Maculopapular rash	Chorioretinitis	✔	✔	✔	Diffuse intracranial calcifications
Congenital Syphils		Petechiae Purpura Maculopapular rash	Chorioretinitis Glaucoma	✔
Rubella	Patent ductus arteriosus (PDA) Pulmonary artery stenosis Coarctation of the aorta Myocarditis	Petechiae Purpura	Chorioretinitis Cataracts Glaucoma Microphthalmia	✔	✔	✔		✔
Cytomegalovirus (CMV)	✔	Petechiae Purpura	Chorioretinitis	✔		✔	Periventricular calcifications	✔
Herpes simplex virus (HSV)	Myocarditis	Petechiae Purpura Vesicles	Chorioretinitis	✔	✔	✔		✔
Parvovirus B19	Myocarditis	Petechiae Subcutaneous edema	Chorioretinitis Cataracts	✔

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.

Prognosis

In fetuses with severe infection termination of the pregnancy is recommended and infants born with congenital varicella syndrome the prognosis is poor. Infants die at a early age due to recurrent aspiration pneumonia and respiratory failure.

Complications

• Fetal demise
• Intrauterine growth restriction
• Premature delivery
• Developmental Delay

Diagnosis

History and Symptoms

Symptoms of primary infection in Mother :

• Primary infection in the mother presents with fever, malaise and a maculopapular skin rash in the beginnning which becomes vesicular and crust over with healing. The disease is infectious 48 hours before the appearance of rash until the vesicles crust over.

Symptoms in the Neonate

• Skin Rash
• Shortened hands and legs with malformed fingers
• Cloudiness of the cornea
• Small head size
• Seizures
• Yellowish discolouration of the eyes and skin

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	Cortical atrophy/porencephaly Developmental Delay Autonomic instability
Musculoskeletal system	Limb hypoplasia Muscle hypoplasia
Systemic Manifestations	Intrauterine growth retardation
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.

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. Ultrasound is usally done 4 weeks after the primary infection as earlier ultrasound might fail to detect anomalies. 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

Treatment

Medical Therapy

• Varicella infection doesnot progress postnatally, so treatment with acyclovir is not indicated.

Surgical Therapy

There are no surgical therapies for treatment of congenital varicella syndrome.

Prevention

Primary Prevention

• Documentation of previous varicella infection and vaccination status in all pregnant women at the first antenatal visit.
• 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.
• In pregnant women with positive IgG, pregnant women are reassured that the IgG antibodies would protect the baby.
• In pregnant women with negative IgG, counseling regarding the risks of varicella infection and education regarding the measures to avoid contact with varicella are recommended 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 72-96 hours of exposure as postexposure prophylaxis. Passive immunization is not proven to reduce viremia therefore its role in preventing congenital varicella syndrome is not well established. It is only recommended to prevent maternal complications of varicella in pregnancy.