Risk Of Fetalneonatal Infection

In addition to postnatal spread by the airborne route, varicella may spread by the transplacental route from mother to infant. The transmission rate by this route is thought to be 25-50%; this is lower than the rate of transmission following household exposure, which is closer to 90% (7). Women with active varicella at term are at risk of infecting their infants by the transplacental route as well as from exposure to external lesions following the baby's birth. It appears, however, that infants infected transpla-centally are most at risk to develop severe varicella (see below). Fortunately, the immune response of the mother can have an impact in mitigating the course of varicella in the infant. Administration of varicella-zoster immune globulin (VZIG) can also compensate for this response in the infant.

The risk of infection of the offspring if the mother has gestational zoster appears to be minimal. This probably reflects the fact that individuals with zoster usually have high titers of antibodies to VZV. These high levels of antibodies are transferred from the mother to the fetus or infant and serve to protect against or modify the infection with VZV. In contrast, women who develop varicella have no detectable VZV antibodies during the period when they are viremic. Thus, transfer of the virus to the fetus at a high multiplicity of infection is likely to occur in varicella (see Fig. 1).

Fetal risks associated with maternal varicella include development of the congenital varicella syndrome, severe varicella in the infant, and the occurrence of zoster in infancy or early childhood (7). The chances of developing these complications are related to the timing of maternal varicella regarding gestation.

Table 1

Manifestations of the Congenital Varicella Syndrome in Infants With Developmental Defects Born to Women With VZV Infections in Pregnancy (1947-1998) (N = 77)

Table 1

Manifestations of the Congenital Varicella Syndrome in Infants With Developmental Defects Born to Women With VZV Infections in Pregnancy (1947-1998) (N = 77)

Defect

%

Skin scars"

61

Eye abnormalities

56

Chorioretinitis

27

Horner's/anisocoria

16

Microphthalmia

19

Cataract

19

Nystagmus

13

Abnormal limb6

47

Hypoplasia

36

Equinovarus

14

Abnormal/absent digits

10

Cortical atrophy/mental retardation

40

Prematurity/low birth weight

36

Early death

26

Dysphagia/aspiration

19

Gastrointestinal tract abnormalities

12

Urinary tract abnormalities

10

"Cicatricial in 79%.

611/28 (39%) with hypoplastic limb had mental retardation or early death. (Modified from ref. 14, p. 698.)

"Cicatricial in 79%.

611/28 (39%) with hypoplastic limb had mental retardation or early death. (Modified from ref. 14, p. 698.)

Congenital Varicella Syndrome

Congenital varicella syndrome was first described in 1947 but seems to have been forgotten until 1974, when a newly recognized case was described in Canada (9). Following this case report and review of the literature, many other reports of infants with a similar constellation of birth and developmental defects after maternal varicella followed (7,10). Eventually, it became possible to specifically implicate VZV causally in these "classic" birth defects by the use of polymerase chain reaction (PCR). Unlike infants with the congenital rubella syndrome, babies with the congenital varicella syndrome do not asymptomatically shed virus at birth or afterward. If they develop zoster, and about 18% will do so, then it is possible to demonstrate VZV by culture or other specific means. Using PCR, moreover, it has been possible to demonstrate VZV DNA in affected tissues, such as the skin scars typical of the syndrome. Approximately 75 affected infants have now been reported (7). Only a few classic cases have been viro-logically proven, leading to the definition of the syndrome. Most of the cases were diagnosed on clinical grounds only, but the signs and symptoms are so similar that there is little question about the existence of this syndrome.

The most frequently observed abnormalities are listed in Table 1. Cicatricial skin scars are the most common abnormality, observed in more than 50% of reported affected infants (7). Eye damage of various types and limb abnormalities are extremely

Fig. 2. This infant, whose mother had varicella during the 13th to 15th weeks of pregnancy, had bilateral microphthalmia with cataracts and an atrophic left leg. The infant died of broncho-pneumonia at age 6.5 months. (From ref. 9 with permission.)

striking. The eyes may be hypoplastic, and there may be chorioretinitis, cataract, Horner's syndrome, and nystagmus. The typical limb deformity is hypoplasia, which is thought to be related to failure of the normal development of the nervous system of the extremity, which prohibits normal growth. In terms of pathogenesis of the syndrome, it has been proposed that these infants not only experience varicella in utero, but also experience zoster, which leads to the neurological damage. The skin scarring is frequently observed in a dermatomal distribution. Various degrees of involvement of the central nervous system have been described, with resultant motor and mental retardation. Many infants with severe forms of this syndrome have died in infancy or early childhood (Fig. 2).

Zoster during the first year of postnatal life, which is normally exceedingly rare, is extremely common in children with the congenital varicella syndrome; 18% of reported cases have manifested zoster (7). This occurrence probably also relates to an increased incidence of latent infection when varicella develops in fetal life. By analogy, in animal models of latent infection with herpes simplex virus, the incidence of viral reactivation is directly related to the extent of latent infection in ganglia (11).

Although it was once thought that the fetal risk from the congenital varicella syndrome was confined to maternal varicella in the first trimester, it is clear from the many published cases that the risk extends into the second trimester (Table 2). About half the reported cases have occurred after maternal varicella in the second trimester (7).

It appears that maternal varicella does not increase the incidence of spontaneous abortion (7). It is hoped that one effect of widespread use of varicella vaccine will be

Table 2

Risks to Pregnant Women and Their Offspring From VZV

Varicella

Maternal Bacterial superinfection (skin, soft tissue)

Disseminated varicella with primary viral pneumonia Death

Fetus/neonate Congenital varicella syndrome (2% after maternal varicella in first or second trimester) Disseminated varicella (born 4 days before or 2 days after maternal onset of rash) Development of zoster in early childhood

Zoster

Maternal Rash with pain

Fetus/neonate Little or no risk the virtual elimination of the congenital varicella syndrome, analogous to that which has occurred with congenital rubella. There is no evidence that the varicella vaccine virus causes the congenital syndrome, but vaccination is contraindicated during pregnancy. As it did for the rubella vaccine, the CDC has established a registry for outcomes of women inadvertently vaccinated during pregnancy (12). To date, only about 50 such women have been followed to term. Before firm conclusions can be made, observation and follow-up of several hundred vaccinated susceptible women will be necessary. At present, there is no evidence of teratogenicity of the vaccine virus.

Severe Varicella in the Newborn Infant

Despite the potential severity and striking appearance of babies with the congenital syndrome, its occurrence is rare, developing in only an estimated 2% of offspring of women with varicella in the first or second trimester. Thus, the usual outcome of the fetus from maternal varicella is that the baby is well at birth and subsequently. However, if the mother has the onset of her varicella just prior to delivery, the outcome can be severe disseminated varicella in the baby. In this case, the pathogenesis is thought to relate to the immunosuppression of the mother, the immaturity of cell-mediated immunity in the young infant, and the absence of maternal antibodies in the fetus when the mother's onset of rash is between 4 days before and 2 days after delivery (7) (Fig. 1).

Since the institution, about 30 years ago, of the recommendation for passive immunization of exposed newborns with VZIG as soon as possible after birth, it is rare for a newborn infant to die of disseminated varicella. Before VZIG became available, one study suggested a 20% fatality rate when the mother had onset of rash less than 4 days and up to 2 days after onset of rash at delivery (13). Infants in whom varicella is fatal often have a disseminated infection with pneumonia, extensive hemorrhagic skin vesicles, hepatitis, and thrombocytopenia. Mothers whose onset of rash is more than 48 hours after delivery may transmit varicella to their babies, but the disease is usually not severe because they transfer antibodies as well (7).

Nursery outbreaks of varicella are rare, although exposure of infants in the nursery is not uncommon. It is hypothesized that most newborns are somewhat protected from varicella because of the presence of maternally derived antibodies to VZV. It is known that the presence of maternal antibodies may not fully protect very young infants from clinical varicella, but they usually develop a mild, modified form of chickenpox if they become ill (7).

Zoster

Another outcome of maternal varicella is zoster in the young infant with no history of varicella in postnatal life. In general, zoster in young children is extremely rare. Zoster is increased in frequency, however, in infants whose mothers had gestational varicella, but it does not appear to be as frequent as zoster in babies with the congenital varicella syndrome. Zoster in these infants is often mild and not particularly painful. The rate of zoster in these babies is probably on the order of 3%, which is significantly higher than would normally be seen but obviously is not a serious health threat.

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