Andreas Sauerbrei, Peter Wutzler
Institute of Virology and Antiviral Therapy, Friedrich-Schiller University, Jena, Germany
Frequency and Consequences ofVaricella-Zoster
In most industrial countries, chickenpox is a rare disease during pregnancy as more than 90% of women of child-bearing age possess virus-specific IgG class antibodies. Only 3-4% of women in Germany were found to be susceptible to primary varicella-zoster virus (VZV) infection . In early reports, the average incidence of varicella in pregnant women was calculated as 0.7 per 1,000 pregnancies [2, 3], but the current rates appear to be 2-3 per 1,000 pregnancies .
Varicella during pregnancy may occasionally lead to serious maternal and fetal diseases (table 1). Pregnant women who contract varicella are at risk of severe pneumonia associated with life-threatening ventilatory compromise and death. The disease seems to occur more often in the third trimester  and must be regarded as a medical emergency. In the general population, varicella pneumonia has a mortality of 10-20% but in pregnancy it may be as high as 45%. More recent studies, however, suggest that the mortality has decreased to 10-11% for both non-pregnant and pregnant patients most likely due to the effects of antiviral therapy and better respiratory management .
At any stage during pregnancy, chickenpox may cause intrauterine infection. Maternal varicella resulting in viremia may transmit the virus to the fetus by either transplacental spread, or by ascending infection from lesions in the birth canal. Furthermore, direct contact or respiratory droplet can lead to infection after birth. The consequences for the infant depend on the time of maternal disease. They range from asymptomatic infection to fetal loss especially in case of severe maternal disease. Primary VZV infection during first two trimesters
Table 1. Varicella-zoster virus infections and their potential consequences during pregnancy
Maternal varicella/zoster timing
Consequences for mother/ fetus/term neonate
5th-20th (24th) weeks Varicella at any stage, especially in third trimester Varicella near term: >5 days before delivery Varicella near term: <4-5 days before to 2 days after delivery
Intrauterine death, neonatal or infantile zoster Congenital varicella syndrome
(risk: 2%, mortality: 30%) Maternal pneumonia (risk:
10-20%, mortality: 10-45%) Neonatal varicella at ages 10 (-12) days
(risk: 20-50%, mortality: 0%) Neonatal varicella 0-4 days after birth (risk: 20-50%, mortality: 0-3%) Neonatal varicella 5-10 (-12) days after birth (risk: 20-50%, mortality: 20-25%) No risk for severe maternal, fetal or neonatal infections
Normal zoster at any stage of pregnancy may result in intrauterine infection in up to 25% of the cases [7-10]. The rate of abortion following acute varicella does not exceed the rate of abortion in pregnant women without chickenpox [7-11]. A congenital varicella syndrome (CVS) can be expected in about 12% of infected fetuses . On the basis of prospective studies in Europe and North America, the incidence of embryopathy and fetopathy after maternal varicella infection in the first 20 weeks of pregnancy is estimated to be about 1-2% [9, 11]. Maternal infection near-term is associated with a substantial risk of neonatal varicella. Serious disseminated infections with visceral involvement may occur in the infant .
Nearly 20% of infants with intrauterine acquired VZV primary infection develop neonatal or infantile zoster, usually with uncomplicated course . The disease is thought to represent reactivation of the virus after primary infection in utero. The relatively short viral latency period may be explained by the immature cell-mediated immune response in young children.
On the basis of current knowledge, zoster during pregnancy is not associated with birth defects [9, 14]. Although there are some reports of infants with congenital malformations being born to mothers with a history of zoster during early pregnancy, no case showed laboratory evidence of intrauterine infection with VZV In addition, maternal zoster during the perinatal period does not cause problems for newborn infants  as the infants possess specific maternal IgG class antibodies and there is usually no longer viremic spread of VZV unless the woman is immunocompromised.
Congenital Varicella Syndrome
Since the first report by Laforet and Lynch , nearly 130 infants born with signs of CVS have been described in the English and German literature, most of them during the last 10-15 years . In principal, CVS has to be expected after maternal chickenpox between the 5th and 24th gestational weeks. Nearly 80% of all cases have been observed between the 9th and 20th weeks of gestation. Before the 5th and after the 24th gestational weeks, the probability of CVS is extremely low.
The characteristic clinical findings consist of skin lesions in dermatomal distribution (fig. 1), neurological defects, eye diseases, and limb hypoplasia (table 2). Less frequent abnormalities include muscle hypoplasia, affections of the internal organs as well as gastrointestinal, genitourinary, and cardiovascular manifestations . There were only small differences regarding to the dependence of symptoms on the onset of maternal chickenpox. In early infection, neurological defects and limb hypoplasia were more numerous than skin lesions and eye diseases which were dominant when maternal disease occurred later. No relationship has been reported in the literature between number of clinical features, gestational age of maternal varicella and immune response in the infant . Nearly 30% of infants born with signs of CVS died during the first months of life. A follow-up report in the literature demonstrates that in spite of initially poor prognosis a good long-term outcome can occur in patients with CVS .
The route of fetal infection is considered to be transplacental. Ascending infection from the epithelium of the cervix uteri is also conceivable . On the basis of the segmental distribution of some of the signs, it was postulated that the CVS is not the immediate consequence of intrauterine varicella, but caused by intrauterine zoster-like VZV reactivations with accompanying encephalitis . In a recently published case report, a widespread non-productive VZV infection has been described in non-neural fetal tissues within 2 weeks following the onset of chickenpox in the mother . Immunologic studies suggest that the fetus is not able to mount a VZV-specific cell-mediated immune response .
Most cases of CVS have been reported on the basis of the described main clinical symptoms without laboratory evidence of intrauterine infection. However, the causal relationship between maternal varicella infection and congenital abnormalities would be most convincingly verified by detection of the virus, viral antigens or viral DNA in the infant. With the use of polymerase chain reaction (PCR) and nucleic acid hybridization assays, VZV DNA can be detected in fetal or infantile tissue samples, cerebrospinal fluid and/or amniotic
Table 2. Main symptoms of infants with congenital varicella syndrome cited in the literature
Skin lesions (cicatricial scars, skin loss) Neurological defects or diseases (cortical atrophy, spinal cord atrophy, limb paresis, seizures, microcephaly, Horner's syndrome, encephalitis, dysphagia) Eye diseases (microphthalmia, enophthalmia, chorioretinitis, cataract, nystagmus, anisocoria, optic atrophy) Limb hypoplasia and other skeletal anomalies Intrauterine retardation Gastrointestinal abnormalities Muscle hypoplasia Genitourinary abnormalities Affections of internal organs Developmental delay Defects of the cardiovascular system Defects of other organs
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