Varicella-zoster infection in the newborn

INTRODUCTION — Varicella-zoster virus (VZV) is the virus responsible for varicella (chickenpox) and herpes zoster ("shingles"). VZV is a member of the herpesvirus family, along with herpes simplex virus (HSV) types 1 and 2, cytomegalovirus, Epstein-Barr virus, and human herpesvirus (HHV)-6, -7, and -8.

Varicella usually is a mild, self-limited illness in healthy children. Rarely, varicella affects the pregnant or postpartum woman, causing problems for the fetus or newborn. Nosocomial acquisition of VZV also can occur in newborns.

Varicella-zoster infection in the newborn is reviewed here. Chickenpox and VZV infection in pregnancy are reviewed separately. (See "Clinical features of varicella-zoster virus infection: Chickenpox" and "Varicella-zoster virus infection in pregnancy".)

CLINICAL FEATURES

Congenital varicella syndrome — Most cases of congenital varicella syndrome occur in infants whose mothers were infected between 8 and 20 weeks gestation. However, the overall risk of vertical transmission is quite small compared with other viruses acquired during pregnancy. The risk appears to be approximately 2 percent if the infection occurs before 20 weeks and <1 percent if it occurs before 13 weeks [1,2]. On rare occasions, fetal varicella syndrome can occur after 20 weeks gestation [3]. (See "Varicella-zoster virus infection in pregnancy".)

Characteristic findings of affected infants include some or all of the following in order of the frequency of occurrence [4]:

●Intrauterine growth restriction

●Cicatricial (scarring) skin lesions, which may be depressed and pigmented in a dermatomal distribution (picture 1)

●Ocular defects, such as cataracts, chorioretinitis, Horner syndrome, microphthalmos, and nystagmus (see "Cataract in children")

●Limb abnormalities, which often include hypoplasia of bone and muscle

●Central nervous system abnormalities, such as cortical atrophy, seizures, and intellectual disability

●Fetal demise also can result, and mortality after birth in those with clinically apparent lesions has been reported to be 30 percent

Neonatal varicella

Risk of infection — Neonatal varicella is a serious illness associated with a mortality rate up to 30 percent [5]. Newborns born to mothers who are exposed to VZV or have clinical disease manifestations within two weeks of delivery are at the greatest risk for infection. Nosocomial acquisition of VZV also can occur.

The case fatality rate is increased when the mother develops symptoms of varicella infection from five days before to two days after delivery [6,7]. This interval allows insufficient time for the development of maternal IgG and passive transfer of antibody protection to the fetus. Postnatally acquired varicella that occurs between 10 and 28 days after birth usually is mild [8]. However, because of their relative immunologic immaturity, newborns are at greater risk for acquiring severe disease than are older infants or children [9].

Premature infants are at increased risk for nosocomial acquisition of VZV compared with infants born at term because active transfer of maternal IgG antibodies occurs primarily during the third trimester of pregnancy [10]. Postnatal age also is a risk factor because maternally acquired antibody levels decline with age [11,12]. In one report of VZV exposure in a neonatal intensive care unit (NICU), seronegativity occurred frequently in infants older than two months of age [11].

Clinical features — The clinical picture of neonatal varicella is variable, ranging from a mild illness resembling chickenpox in older children to a disseminated infection similar to manifestations seen in immunocompromised hosts. (See "Clinical features of varicella-zoster virus infection: Chickenpox", section on 'Clinical manifestations'.)

Fever may develop within the first days after birth, followed by a generalized vesicular eruption (picture 2). The rash starts as macules and rapidly progresses to papules and then to characteristic vesicular lesions before crusting. It usually appears first on the head and then generalizes. The lesions characteristically are in various stages of development and healing. The generalized involvement and appearance of lesions in different stages of development distinguish varicella from the vesicular rash seen in neonatal herpes simplex virus (HSV), which tends to occur in localized clusters (picture 3). (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Skin, eye, and mouth disease'.)

In mild cases of neonatal varicella, the lesions heal within 7 to 10 days. However, disseminated disease may ensue, with varicella pneumonia, hepatitis, and meningoencephalitis being the most common visceral manifestations. Reports of neonatal herpes zoster in babies born to mothers with varicella during pregnancy are rare [13,14].

Prompt administration of varicella-zoster immune globulin (ie, Varizig) to infants born to women with active varicella infection at delivery may ameliorate neonatal disease. (See 'Postexposure prophylaxis' below.)

DIAGNOSIS — The diagnosis of neonatal varicella can be made clinically based upon the characteristic appearance of generalized vesicular skin lesions in various stages of development and healing (picture 2) in an infant born to a mother exposed to VZV or with clinical symptoms close to the time of delivery. In uncertain and/or severe cases, the diagnosis is confirmed by detection of the virus using polymerase chain reaction (PCR). PCR is the test of choice for diagnosis of neonatal varicella because it is highly sensitive and specific. PCR can detect VZV from vesicular swabs or scrapings, scabs from crusted lesions, tissue from biopsy samples, and/or cerebral spinal fluid [7]. It can also distinguish between wild VZV and vaccine strains. (See "Diagnosis of varicella-zoster virus infection", section on 'Polymerase chain reaction'.)

Direct fluorescent antibody (DFA) on scrapings from active vesicular skin lesions can provide a rapid diagnosis. However, DFA should not be used in lieu of PCR testing, since PCR is more sensitive. (See "Diagnosis of varicella-zoster virus infection", section on 'Direct fluorescent antibody'.)

Viral culture is not helpful in making the diagnosis, since it has a much lower sensitivity compared with PCR and the virus takes several weeks to grow. (See "Diagnosis of varicella-zoster virus infection", section on 'Viral culture'.)

Serologic testing can help establish the diagnosis. However, this approach requires acute and convalescent titers and therefore it is not helpful for rapidly establishing the diagnosis. In neonatal varicella infection, acute and convalescent sera demonstrate a rise in VZV IgG titers. In contrast, uninfected neonates who received passive transfer of maternal antibodies during pregnancy typically have low acute VZV titers and convalescent titers remain low. VZV IgM is insensitive in newborns and false positives can occur. (See "Diagnosis of varicella-zoster virus infection", section on 'Serologic testing'.)

Other diagnostic tests, including fluorescent anti-membrane antibody (FAMA), latex agglutination (LA), enzyme-linked immunosorbent assay (ELISA), and complement-enhanced neutralization, are available but are not recommended in neonates.

Prenatal diagnosis of fetal varicella infection is possible. (See "Varicella-zoster virus infection in pregnancy".)

MANAGEMENT OF EXPOSURE — Management of newborns who are exposed to VZV by maternal infection or contact with affected individuals includes isolation and postexposure prophylaxis. The specific intervention depends upon the timing of exposure, the mother's serologic status, and gestational age. Varicella vaccination, which is used for prevention in older children and adults, has not been tested for this purpose in newborns. (See "Prevention and control of varicella-zoster virus in hospitals".)

Postexposure prophylaxis — Postexposure prophylaxis with varicella-zoster immune globulin (Varizig) can prevent varicella in exposed neonates or ameliorate the disease course in patients in whom the infection was not fully prevented [15]. Varizig is a purified human immune globulin preparation made from plasma containing high levels of anti-varicella antibodies [16]. (See "Post-exposure prophylaxis against varicella-zoster virus infection", section on 'Passive immunoprophylaxis'.)

The American Academy of Pediatrics (AAP), Centers for Disease Control and Prevention (CDC), and the Advisory Committee on Immunization Practices (ACIP), recommend administration of Varizig to newborns who have had a significant exposure to VZV plus one or more of the following [7,17]:

●Maternal symptoms – Neonates whose mothers have signs and symptoms of varicella around the time of delivery (within five days before or two days after) should receive Varizig.

●Preterm infants ≥28 weeks of gestation – Hospitalized preterm infants born at ≥28 weeks of gestation who have had a significant exposure to VZV and whose mothers do not have documented immunization, serologic immunity, or prior documented history of varicella infection should receive Varizig.

●Preterm infants <28 weeks of gestation – Hospitalized premature infants born at <28 weeks of gestation or who weigh <1000 grams at birth who have had a significant exposure to VZV should receive Varizig regardless of maternal history of varicella or vaccination.

Healthy term neonates who are exposed to VZV postnatally (including infants whose mother's rash developed >48 hours after delivery) generally do not require postexposure prophylaxis. This is because postnatally acquired varicella that occurs beyond the immediate newborn period in a term infant generally is mild. However, some experts suggest administering Varizig in this setting (for exposures occurring up to two weeks after birth) if the mother does not have evidence of immunity to VZV [7]. Varizig is given intramuscularly at a dose is 125 units (1 vial) for neonates weighing >2.1 kg to 10 kg and 62.5 units (0.5 vial) for children weighing ≤2 kg [7]. Each vial contains lyophilized powder, which must be reconstituted for intramuscular administration.

When postexposure prophylaxis is indicated, passive immunization with Varizig should be offered as soon as possible. The window of passive immunization with Varizig after varicella exposure is up to 10 days [18]. (See "Post-exposure prophylaxis against varicella-zoster virus infection", section on 'Passive immunoprophylaxis'.)

There are no placebo-controlled clinical trials evaluating the efficacy of Varizig in neonates. Its efficacy is inferred from observational data demonstrating considerably lower transmission rates and milder disease course than would be expected based upon historical data. The supporting evidence is discussed in greater detail separately. (See "Post-exposure prophylaxis against varicella-zoster virus infection", section on 'Target groups'.)

If Varizig is unavailable, intravenous immune globulin (IVIG) or prophylaxis with acyclovir can be considered [7].

Isolation — Isolation for the mother and infant depends upon whether there is active disease or the timing of exposure.

Patients who require isolation include:

●Active disease – A mother with active VZV lesions must be isolated. The infant is isolated from the mother until she is not infectious. If the onset of maternal disease occurred within five days before or two days after delivery, the infant should receive passive immunoprophylaxis. (See 'Postexposure prophylaxis' above.)

Any infant who develops varicella in the nursery or neonatal intensive care unit (NICU) is also isolated.

●Maternal exposure 6 to 21 days before hospitalization – A seronegative mother exposed to VZV 6 to 21 days before hospital admission should be isolated from other patients and the nursery because she may develop varicella while hospitalized. This calculation takes into account the incubation period of varicella that is usually 14 to 16 days but sometimes ranges from 10 to 21 days after exposure [7]. The incubation may be prolonged for as long as 28 days after receipt of Varizig or IVIG, and it may be shortened in immunocompromised patients.

Her infant, if born at term, should be isolated with the mother. The mother and infant should be cared for only by staff with immunity to VZV. Both should be discharged as soon as possible.

Patients who generally do not require isolation include:

●Active disease 21 days before delivery – A mother who has active varicella within 21 days of delivery that resolves before hospitalization does not need to be isolated. However, the newborn should stay in the mother's room and be isolated from other infants. The infant should have passively acquired maternal antibody and therefore does not need to receive passive immunoprophylaxis.

●Maternal exposure within six days of hospitalization – If a seronegative mother was exposed within six days of admission and discharged before 48 hours, isolation is not needed, because varicella would not be expected to develop during the hospital stay.

Nursery exposure — An infant who develops varicella in the nursery or NICU should be isolated. The more common situation is nursery exposure by a visitor or hospital worker who is infectious. In the newborn nursery, exposed infants typically are discharged before they would be infectious.

Postnatally acquired varicella in term infants >10 days old usually is mild. Thus, some clinicians favor providing routine newborn care without administration of Varizig or determination of maternal immune status. However, administration of Varizig may be considered for an infant exposed during the first two weeks after birth if maternal serology is negative [7].

Isolation may be required for the rare infant who remains hospitalized longer than eight days and whose mother is seronegative. (See "Prevention and control of varicella-zoster virus in hospitals".)

Neonatal intensive care unit exposure — Exposed infants in the NICU usually are cohorted. They are isolated from new patients admitted between 8 and 21 days after exposure. Varizig should be given to all exposed NICU patients with seronegative mothers and to all exposed preterm infants <28 weeks gestation or ≤1000 g birth weight regardless of maternal immune status [7,19]. Infants who received Varizig should be isolated from new patients for 28 days [13].

TREATMENT

Acyclovir — Newborns with severe disseminated VZV infection (eg, pneumonia, encephalitis, thrombocytopenia, severe hepatitis) are treated with intravenous acyclovir (60 mg/kg per day in three divided doses) for 10 days [7,20,21].

Antiviral treatment must be started as soon as possible after the onset of symptoms because most viral replication has stopped by 72 hours after appearance of the rash. Evidence supporting use of acyclovir in neonatal varicella is limited to case reports and case series [22,23]. Indirect evidence is provided from the experience in treating varicella in immunocompromised patients. Like immunocompromised patients, neonates with disseminated VZV are at increased risk of severe morbidity and higher mortality compared with older immunocompetent patients. (See "Treatment of varicella (chickenpox) infection", section on 'Immunocompromised hosts'.)

Breastfeeding — Whether VZV is secreted in human milk is uncertain, although VZV DNA has been detected [24]. Breastfeeding is encouraged in newborns exposed to or infected with varicella because antibody in breast milk may be protective [25].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Varicella-zoster virus".)

SUMMARY AND RECOMMENDATIONS

●Transmission – Varicella-zoster viral (VZV) infection in the newborn occurs due to either vertical transmission from the mother during pregnancy or delivery, or acquired after birth from the environment or infected care providers. (See 'Introduction' above.)

●Clinical features

•Congenital infection – Congenital varicella syndrome occurs in infants whose mothers are infected between 8 and 20 weeks gestation. Clinical manifestations vary and include cicatricial (scarring) skin lesions (picture 1), ocular defects (eg, cataracts, chorioretinitis, Horner syndrome, microphthalmos, and nystagmus), and abnormalities of the limb (eg, hypoplasia of bone and muscle) and central nervous system (eg, cortical atrophy, seizures, and cognitive impairment). (See 'Congenital varicella syndrome' above and "Varicella-zoster virus infection in pregnancy", section on 'Clinical features of congenital varicella syndrome'.)

•Perinatal or postnatal infection – Neonatal varicella is a serious illness with a mortality rate as high as 30 percent. Neonates born to mothers with VZV infection, or who were exposed within two weeks of delivery are at risk for neonatal varicella. The risk of mortality is increased when the mother develops symptoms of varicella infection from five days before to two days after delivery because there is insufficient time for the development and transfer of maternal antibody. (See 'Neonatal varicella' above.)

The clinical manifestations of neonatal varicella vary from a mild illness similar to chickenpox in older children to a disseminated disease involving the liver, lung, and central nervous system. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of neonatal VZV infection can be made clinically based upon the characteristic appearance of generalized vesicular skin lesions in various stages of development and healing (picture 2) in an infant born to a mother exposed to VZV or with clinical symptoms close to the time of delivery. In uncertain and/or severe cases, the diagnosis is confirmed by detection of the virus by PCR from vesicular swabs or scrapings, scabs from crusted lesions, tissue from biopsy samples, and/or cerebral spinal fluid. Direct fluorescent antibody (DFA) on scrapings from active vesicular skin lesions can provide a rapid diagnosis. However, DFA should not be used in lieu of PCR testing, since PCR is more sensitive. (See 'Diagnosis' above.)

●Postexposure prophylaxis – For neonates with significant exposure to VZV plus one of the following circumstances, we recommend postexposure prophylaxis with varicella-zoster immune globulin (Varizig) (Grade 1B) (see 'Postexposure prophylaxis' above and "Post-exposure prophylaxis against varicella-zoster virus infection", section on 'Target groups'):

•Neonates whose mothers have signs and symptoms of varicella around the time of delivery (within five days before or two days after)

•Hospitalized preterm infants born at ≥28 weeks of gestation who have had a significant exposure to VZV and whose mothers do not have documented immunization, serologic immunity, or prior documented history of varicella infection

•Hospitalized premature infants born at <28 weeks of gestation or who weigh <1000 grams at birth who have had a significant exposure to VZV regardless of maternal history of varicella or vaccination

●Antiviral therapy for severe disseminated infection – For newborns with severe disseminated VZV infection (eg, pneumonia, encephalitis, thrombocytopenia, severe hepatitis), we recommend antiviral therapy rather than supportive care alone (Grade 1B). These infants are at high risk of morbidity and mortality without antiviral therapy. Treatment consists of a 10-day course of intravenous acyclovir (60 mg/kg per day in three divided doses). (See 'Acyclovir' above.)

●Infection control – Mothers with active disease or those who are seronegative with a history of exposure 6 to 21 days before admission must be isolated from other patients including their infants. The newborn should be isolated from the mother until she is no longer infectious. Any infant who develops varicella must be isolated from other infants. (See 'Isolation' above.)

●Breastfeeding – Breastfeeding is encouraged in infants exposed to or infected with varicella. (See 'Breastfeeding' above.)