Fetal varicella syndrome

An excellent review of fetal varicella syndrome (FVS) has been recently published (16). The syndrome is a consequence of transplacental transfer of maternal varicella infection occurring during the first 20 weeks of pregnancy, although a recent report (17) has cited the occurrence of the syndrome after maternal varicella at 25 weeks of gestation. The anomalies associated with intrauterine infection with varicella were first described in 1947 (18) and the existence of a fetal varicella syndrome was initially postulated in 1974 (19). Low birth weight is an almost constant feature of the FVS. The other features can be grouped as dermatological, neurological, ophthalmological, skeletal, gastrointestinal and genito-urinary abnormalities

Cicatrical skin lesions with underlying hypoplasia of tissues are well-recognized manifestations of the syndrome. At birth these areas may look like area of skin loss that became cicatricial after several weeks. Characteristically, the skin scars are depressed, pigmented and often have a zigzag configuration. The neurological abnormalities include mental retardation, seizures and cortical atrophy. Spinal cord atrophy, limb paresis and cerebellar aplasia have also been reported. Other neurological manifestations include hypotonia, hyper-reflexia, intermittent myoclonic seizures, dorsal radiculitis, Horner's syndrome, deafness, developmental delay and learning disabilities. Ophthalmological abnormalities associated with the syndrome include chorioretinitis, nystagmus, anisocoria, microphthalmia, cataract, corneal opacities, squint, hypoplasia of the optic disc and optic atrophy. The skeletal anomalies include limb hypoplasia, equinovarus, calcaneovalgus and hypoplasia of mandible, clavicle, scapula, ribs, fingers and toes. These anomalies arise either directly due to cicatricial lesions causing reduction abnormalities, or could occur secondary to denervation of limbs, which leads to diminished muscle mass and poor growth. Gastrointestinal abnormalities associated with the syndrome include gastroesophageal reflux, duodenal stenosis, jejunal dilatation, microcolon and anal sphincter malfunction. These anomalies probably result due to the damage to the autonomic nervous system and the spinal cord. Neurogenic bladder has been described with FVS.

FVS occurs primarily when mother suffers from chickenpox during the first half of pregnancy. Most cases are related to varicella infection between 13^th and 20^th week of pregnancy. Transplacental transfer of the virus results in fetal viremia and subsequent cutaneous dissemination. The virus then spreads along the cutaneous sensory nerves in a retrograde manner to reach the dorsal root ganglion satellite cells. Due to the lack of cell mediated immunity before 20 weeks of gestation, the virus remains latent only for a short period of time. Following reactivation, the virus with its neurotropic nature causes further neuronal damage that include necrosis of nerve cells and affection of axons. Considering the pathogenesis of the fetal varicella syndrome, some have suggested that it better be referred to as fetal varicella-zoster syndrome (16,20,21).

The criteria recommended for the diagnosis of FVS include maternal varicella during pregnancy, the presence of congenital skin lesions that correspond to dermatomal distribution & immunological evidence of in-utero varicella-zoster infection (22). The latter could be proved by either the demonstration of specific IgM antibodies to VZV after birth or persistence of IgG after 6 months of age. These methods have their limitations, since in some characteristic cases of FVS, IgM may not be detectable at birth and in some of them IgM may not be persist for 6 months. As far as antenatal detection is concerned, major abnormalities, including limb hypoplasia and microcephaly can be diagnosed by ultrasound scan; but often these defects are not present until late in pregnancy. This could be due to the fact that virus is not reactivating until a few months after the primary infection. It has been suggested that if suspicious signs have been seen on ultrasound, cordocentesis could be used to check for fetal IgM or placental villi could be sampled for VZV DNA detection (16,23).

Perinatal varicella infection

The second important pattern that concerns neonates is the varicella infection occurring in the mother during late pregnancy. Late onset maternal varicella either may have no effect on the fetus or causes a potentially fatal disseminated infection with widespread cutaneous and visceral affection. The attack rate is estimated to be 24% to 50% (1) and the severity of neonatal disease seems to be dependent on the timing of maternal illness. If mother develops rash five or more days prior to delivery, the infection follows a milder course in her neonate. However, the risk of neonatal death increases if the mother develops rash within four days prior to or up to two days after the delivery (24). These differences reflect that the presence or absence of specific maternal antibody titre is not realized until about the fifth day of her own exanthem. Maternal varicella 5 to 21 days pre-delivery usually results in benign neonatal chickenpox as the baby is protected by transplacentally acquired maternal antibody (14,25,26). If, however, varicella infection occurs too close to delivery, the fetus receives the virus but does not receive the protective antibodies.

The incubation period in congenital varicella, defined as the interval between onset of rash in the mother and that in the fetus or neonate, is usually 9 to 15 days. The interval is slightly shorter than the usual postnatal incubation period, suggesting that the infecting transplacental dose of virus may be higher than that, which occurs postnatally. The manifestations observed in an infected neonate when mother has developed varicella close to delivery are similar to those seen in immunocompromised children and adults. These neonates develop widespread cutaneous and visceral lesions and develop respiratory distress due to varicella pneumonia. The mortality in such cases could exceed 30%, if left untreated.

Neonatal infection

Neonatal varicella could occur due to transplacental infection (as already discussed above) or though postnatal exposure to an infected person, usually from a sibling or a parent. A mother who has never been infected with chickenpox does not have anti-VZV antibodies. Her neonate too therefore, does not have these protective antibodies and is susceptible to acquire the infection postnatally. Such a baby may be at a slightly increased risk of severe infection. The risk is difficult to quantify because of selective reporting and in fact, the American Academy of Pediatrics believe that there is no greater risk of complications in neonates who acquire the infection postnatally (27).