Varicella Infection In Pregnancy - Consequences For Foetus And Neonate

Abstract

Varicella is usually a benign and common childhood febrile exanthematous viral disease. But varicella infections can be serious, especially in adults including pregnant women and newly born infants. Maternal infection in pregnancy presents several management problems for clinicians. Unrecognized and unprotected maternal infection may cause severe pneumonia for the mothers and may lead to in-utero transplacental fetal transmission (Congenital varicella syndrome) and/or causing severe varicella disease and even death soon after birth (Neonatal varicella). A timely diagnosis of varicella in pregnant women is important to initiate earlier prophylactic and therapeutic measures in order to minimize varicella related maternal and neonatal complications.

Keywords: Maternal varicella, Pregnancy, Pneumonia, Congenital, Neonatal varicella, immediate immunoprophylaxis, Prevention.

Overview

Varicella-Zoster Virus (VZV) infection is a member of the Herpesviridae family that causes primary varicella infection, known as chickenpox which may also be called by its International Committee on Taxonomy of Viruses (ICTV) name, as human herpesvirus 3 (HHV-3). After primary varicella infection, the virus becomes latent in the dorsal root ganglia and may reactivate later as herpes zoster or shingles.

Varicella is now a vaccine-preventable disease by routine childhood immunization. Varicella occurs in sero-susceptible individuals especially in adults including pregnant women is often complicated and life-threatening. In general, more than 90% of the antenatal population is seropositive and possess protective VZV IgG antibodies. Women from tropical and subtropical areas are more likely to be seronegative for VZV IgG and are, therefore, more susceptible to the development of severe and complicated chickenpox. In these clinical settings, varicella infection affects three or more of every 1000 pregnancies (Observational data; KIMS Hospital Thiruvananthapuram, India 2017). Varicella pneumonia in pregnancy must be regarded as a medical emergency.

Maternal infection:

However, infants who are exposed to VZV in utero beyond 28 weeks of gestation, and more than 5 days before delivery (peripartum), generally are protected from severe infection by the transplacentally derived maternal IgG antibodies. Some of these infants may develop asymptomatic varicella infection in utero and may develop reactivated zoster manifestation in early childhood,

In contrast, neonatal or peripartum varicella, pregnant women when develops varicella rash around the time of delivery (i.e. onset of rash less than 5 days before delivery or within 2 days after delivery) often results in severe disseminated varicella in the newborn infant, which has substantial mortality.

Varicella complication in pregnant mothers:

Pneumonia has been reported to complicate 10 to 14% of chickenpox infections in pregnancy and the severity of pneumonia seems to be increased in later gestation. More recent literature reports mortality of 0-14%, a reduction that has been attributed to antiviral therapy and improvements in ICU care facilities

Fetal and neonatal consequences of maternal varicella are:

CVS: is an extremely rare disorder in which affected infants have distinctive abnormalities at birth (congenital). The highest risk (2%) occurs when mothers are infected during weeks 13 to 20 of gestation. Rarely, cases of CVS have been reported in infants of women infected after 20 weeks of pregnancy, the latest occurring at 28 weeks gestation. The CVS has also been designated as fetal varicella syndrome, varicella embryopathy, or varicella fetopathy.

The typical features of CVS include a characteristic scarring skin lesion known as a cicatrix (in >60% of cases) that occurs often in a dermatomal distribution. Other clinical manifestations include hypoplastic limb cataract, cortical atrophy, or mental and developmental delays.

Neonatal Varicella:

Diagnosis of maternal varicella:

Laboratory diagnosis of chickenpox usually is not required. Varicella is a clinical diagnosis because of the characteristic vesicular rash and its distribution. Also, a recent exposure and/or absence of prior varicella history is helpful

In doubtful cases, the diagnosis of varicella rash can be confirmed by swabbing the base of the skin lesion or sending vesicle fluid for VZV PCR. Maternal serology testing can also be helpful and a positive VZV IgG antibodies in a single serum sample is supportive of the maternal immunity status

Diagnosis of Congenital and perinatal Infection

Definitive diagnosis of the CVS syndrome can be difficult. VZV-specific IgM is diagnostic but is not consistently detected. PCR and in situ hybridization also can be used if tissue is available. Women who develop varicella during pregnancy should be counseled about the fetal risks versus benefits of amniocentesis to detect VZV by polymerase chain reaction (PCR). Amniocentesis should not be performed before the skin lesions have completely healed. VZV-specific IgM is diagnostic but is not consistently detected. VZV DNA has a high sensitivity but low specificity for the development of fetal varicella syndrome.

Prenatal diagnosis is possible using a detailed ultrasound examination. A time lag of at least 5 weeks after the primary infection is advised because ultrasound performed at 4 weeks has failed to detect the deformities. Fetal MRI imaging can be useful to look for morphological details of fetal abnormalities.

Management: varicella in Pregnant women & their Newborn:

Pregnant women:

Prevention of maternal varicella through vaccination is key to the prevention of maternal and neonatal complications. Varicella exposed mothers should have their susceptibility test (IgG VZV antibody Elisa test). done as soon as possible. But the Varicella vaccine should not be administered to pregnant women, because the possible effects on fetal development are unknown.

Should consider post-exposure prophylaxis with intramuscular VariZIG (Varicella zoster antibody-rich IgG) for mothers found to be seronegative for varicella antibodies. VariZIG is a purified immune globulin preparation made from pooled human plasma containing high levels of anti-VZV antibodies (IgG). To decrease the risk of severe maternal complications of infection, IM variZig should be given as soon as possible. It is ideal to administer within 72 to 96 hours of exposure and may be useful if given up to 10 days post-exposure. IM VariZIG has not been proven to prevent CVS or neonatal varicella infection, but it is given

If IM variZIG is not available, IVIG (intravenous polyclonal Immunoglobulins) or Intravenous varicella antibody-rich products (Biotest Pharma GmbH) that are used in Europe, can prevent or modify the course of the disease. The recommended IVIG dose for post-exposure prophylaxis of varicella is 400 mg/kg, administered once intravenously. The immune globulin preparations are not effective treatment once the disease is established. Dosing of post-exposure immune and chemoprophylaxis is given in table 1.

Intravenous human zoster immunoglobulin: Contains 25 IU/ml solution (Biotest Pharma GmbH). Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the fetus and the neonate are to be expected. Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the neonate.

Dosing: 1 ml (25 IU) per kg of body weight. For post-exposure prophylaxis, it should be administered as soon as possible and not later than 96 h after exposure.

Antiviral therapy:

Acyclovir may be indicated, especially for severe maternal disease or varicella pneumonia develops. Acyclovir is a category B drug and oral acyclovir should be prescribed for pregnant women if they present within 24 hours of the onset of the rash and if they are more than 20 weeks of gestation. Acyclovir can be used with caution in early pregnancy and the risks and benefits should be discussed. Some experts recommend oral acyclovir or valacyclovir for pregnant women, especially during the second and third trimesters.

Intravenous acyclovir is recommended to all pregnant women with severe complications of varicella, irrespective of when the rash developed.

Dosing of anti-viral in pregnant women:

Acyclovir: 20 mg/kg per dose, administered 4 times per day, with a maximum daily dose of 3200 mg) Valacyclovir: 20 mg/kg per dose, administered 3 times per day, with a maximum daily dose of 3000 mg)

A 7-day course of acyclovir or valacyclovir also may be given to adults without evidence of immunity if the vaccine is contraindicated.

Varicella infected mothers should be referred to a Fetal Medicine and Infectious Disease Consultant 5 weeks after infection for discussion and detailed ultrasound examination. The risks versus benefits of amniocentesis to detect varicella DNA by PCR should be discussed. Amniocentesis should be planned only after the skin lesions have completely healed.

Newborns exposed to maternal varicella during the time of delivery:

Infants should be given IM variZIG immediately after birth even if maternal variZIG was administered. IVIG is an alternative if variZIG is unavailable. These infants should be observed closely because many will still develop chickenpox infection. however, their risk of severe infection will be decreased.

IM variZIG is indicated for post-exposure prophylaxis for preterm born less than 28 weeks' gestation, or who have a birth weight 1000 g or less. Also, preterm infants born more than 28 weeks gestation to susceptible mothers, should receive IM variZIG because these mothers will not have passed protective antibody to their infants

Postnatally exposed healthy term infants are generally protected by maternally derived IgG antibody. Therefore, post-exposure immunoprophylaxis is not generally indicated for full term-born infants. However, some would give variZIG to babies in the first 2 weeks of life whose mothers are not varicella immune by serology testing.

IV acyclovir may be useful for the treatment of severe infection or potentially severe infection in an infant with chickenpox. Famciclovir is available for the treatment of VZV infections in adults, but its efficacy and safety have not been established for children.

Isolation of exposed or varicella infected patients is of critical importance, especially on labor in delivery units, and in neonatal care units. Airborne and contact isolation procedures need to be instituted for babies born to mothers with acute varicella for the first 21 days of life and continued for 28 days if the baby received VariZIG. However, should a woman develop zoster during the period from 5 days before, until 2 days after delivery, there is no additional risk to the newborn as there is no hematogenous spread of the virus.

Table 1: Dosing of IM Varicella Zoster Immune Globulin Based on Weight

Varicella Infection - In summary

Post-exposure immunoglobulin prophylaxis (ZIG and VariZIG) has been recommended over- decades for newborn and other varicella susceptible high-risk patients including pregnant women. Efficacy is increased if prophylaxis is given as soon as possible after exposure

Women who develop varicella in early pregnancy should be referred to a Fetal Medicine and Infectious Diseases specialist. VariZIG has no therapeutic benefit once chickenpox has developed and should therefore not be used in pregnant women who have already developed varicella vesicles.

Neonatal varicella resulting from a maternal infection near the time of delivery or immediately postpartum exposure may result in a devastating clinical outcome. Therefore, it is vital that the neonate receives variZIG immunoprophylaxis as soon as possible with or without acyclovir.