Obstetrics and Gynecology

Varicella-Zoster virus during pregnancy

Varicella-Zoster Virus During Pregnancy

1. What every clinician should know

A. Clinical features and incidence

Varicella zoster virus (VZV), a double-stranded DNA herpes virus, causes clinical infection with the development of primary infection, chicken pox, or reactivation, herpes zoster (shingles).Although the morbidity of infection is significantly greater within the adult population, most of the primary infections occur during childhood. Over the past two decades, a dramatic decline in disease incidence - with concomitant increase in immunity - has been seen with the implementation of routine childhood varicella vaccinations. Taken together, childhood infection or immunization has resulted in serologic evidence of immunity in 95% of adults and translates into only 0.1-0.4 cases per 1,000 pregnant women each year in the United States.

Regardless of the high prevalence of serologic immunity, primary VZV infection is the most contagious viral infection complicating pregnancy, with 60-95% of exposures resulting in infection. Herpes zoster arises as a reactivation of dormant virus particles within the dorsal root ganglia following prior exposure. More than 300,000 cases of zoster occur annually in the United States, but mostly in elderly and immunocompromised patients; pregnancy is not recognized as an antecedent event. No evidence supports pregnancy worsening severity or frequency of herpes zoster in the healthy, pregnant patient population.

Varicella-zoster virus primary infection, chicken pox, can present at any stage of the disease process, with many patients presenting later in the course of disease with a "rash." A patient often reports a 1-2 day prodrome of flu-like symptoms, including fever, malaise, headache and myalgia prior to the eruption of the rash. The characteristic pruritic vesicular lesions initially appear along the head and trunk , then spread sporadically to the lower abdomen and extremities. These lesions begin as papules and rapidly progress to superficial clear vesicles surrounded by a halo of erythema. The lesions typically are at all stages at any one time during the disease. As a clinical marker, once all of the lesions have crusted, the patient is no longer considered infectious.

Reactivation of VZV, shingles, is typically localized to 1-3 sensory nerve dermatomes, with systemic disease extremely rare (Figure 1). Pain precedes the development of the rash by days to weeks, with reported deep aching or burning pain, altered sensitivity to touch (paresthesias) that may be painful (dysesthesia), exaggerated responses to stimuli (hyperesthesia), or electric shock-like pains. The lesions develop as erythematous papules which develop into vesicles that coalesce, rupture and crust over.

Figure 1.

Pruritic vesicular lesions consistent with Varicella reactivation presenting postpartum along the unilateral posterior flank (lumbar dermatomal distribution). Image courtesy of Dr. Mary Jane Pearson.

Fetal and neonatal clinical disease presentation is related to the timing of infection. Congenital varicella syndrome is typically identified following maternal infection between 12-20 weeks gestation. Congenital varicella syndrome features include limb abnormalities, chorioretinitis, microphthalmia, cerebral cortical atrophy, microcephaly, growth restriction, hydronephrosis, seizures and mental retardation. Specific limb abnormalities include cutaneous scarring, limb hypoplasia and muscle atrophy.

Fortunately, the risk of congenital varicella syndrome is relatively low, with an expected rate of 0.4-2% when maternal infection occurs at 20 weeks or less gestation, and rarely thereafter. Additionally, no reports of congenital varicella infection have been reported in the setting of maternal zoster infection at any point in gestation. Neonatal infection due to intrapartum exposure is associated with a 25-50% attack rate. Neonatal varicella infection can present with pneumonia, disseminated mucocutaneous lesions, visceral infection, fever and as previously mentioned, results in death in 25% of cases.

Women seronegative for VZV are at risk for developing a primary VZV infection. Women at higher risk of VZV reactivation include those in an immune-compromised state; therefore, a review of HIV/AIDS status, immune-modulating medication use and medical history should be completed.

2. Diagnosis and differential diagnosis

Establishing the diagnosis

When a clinical suspicion of VZV arises, important historical elements should be sought to elucidate the etiology of the disease process. Initially, a determination of prior VZV exposure and/or immunization should be obtained as primary VZV infection - chicken pox - differs in presentation, management, and outcome from reactivated VZV - herpes zoster or shingles. If the patient denies prior exposure to VZV or previous immunization, then a presumptive diagnosis of primary VZV must be applied. Fortunately, the clinician can be cautiously reassured that at least 70% of women reporting a "negative" history are actually seropositive, and thus immune from a primary VZV infection and its associated effects.

VZV infection, primary or reactivation, is typically diagnosed based on clinical exam with identification of the characteristic lesions. If the diagnosis is uncertain or a possible chicken pox or zoster exposure has occurred, laboratory testing can confirm maternal infection status. The varicella virus can be isolated from a scraping of the base of an active lesion during the acute phase of infection with subsequent Tzank smear, tissue culture or direct fluorescent antibody testing (DFA testing).

Nucleic acid amplification tests are available with increasing sensitivity and specificity. Seroconversion can be identified with the use of an antibody assay identifying acute and convalescent sera. VZV lgM may be detected within days after VZV symptoms are present and remains positive for 4-5 weeks. If maternal VZV infection is confirmed, fetal infection can be assessed using DNA amplification techniques on amniotic fluid. In addition to invasive testing, limited reports of antenatal diagnosis have been described using ultrasound to identify limb abnormalities.

Differential diagnosis

Several other dermatologic disorders in pregnancy may present with a clinical picture similar to chicken pox. Dermatology consultation may be useful if laboratory testing excludes VZV. A localized Herpes Simplex Virus (HSV) outbreak in the "boxer-short" distribution can present similarly to shingles. HSV culture or nucleic acid amplification testing will help differentiate between these two herpesviridae infections. Shingles is also usually limited to one dermatome while HSV may cross dermatomes.

3. Management

Prevention strategies are paramount in the management of this disease. Screening prior to conception or at the initial prenatal visit with historical report of prior varicella exposure and/or vaccination should be obtained on all patients considering pregnancy, as this information will be useful in the setting of an exposure incident. Within the clinic setting, all healthcare workers in contact with pregnant patients should be screened and vaccinated, or identified as susceptible, to permit redeployment to nonpatient areas.

Once maternal varicella infection is suspected, the affected individual should be isolated from other pregnant women due to the highly contagious virus and severity of disease associated with pregnancy. A detailed history and physical exam should be performed to delineate the current disease status as to either primary or reactivation (see above). Meticulous hygiene and skin care should be stressed in the prevention of secondary skin infection. Pruritus can be decreased with topical dressings, tepid water baths and wet compresses, or by administering antipruritic drugs.

Uncomplicated maternal infection is typically self-limited and does not require treatment. Evidence of maternal compromise with dehydration, pulmonary involvement with pneumonia, or extracutaneous involvement with neurologic, hepatic or ocular disease may require hospitalization and medical therapy.

Acyclovir, a synthetic nucleoside analogue of guanine which is highly specific for cells infected with VZV, is the drug of choice. Once ingested, acyclovir is converted to acyclovir di- and tri-phosphate by other cellular enzymes. Acyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA. Intravenous acyclovir dosing recommendations are 500 mg/m2 or 10-15 mg/kg every 8 hours.

Exposure of a susceptible pregnant woman to a contact with VZV should prompt maternal lgG testing as soon as possible. If she is seronegative, she should be offered Varicella Zoster Immune Globulin (VariZIG). VariZIG is a human globulin fraction previously produced in the United States as VZig until discontinuation in 2005. Currently, the therapy is available as investigational VariZIG, produced by the Cangene Corporation (Winnipeg, Canada) distributed by FFF Enterprises (Temecula, California).

The investigational VariZIG is made from plasma containing high levels of anti-varicella antibodies (immunoglobulin class G [lgG]). The recommended dose is 125 units/10 kg body weight, up to a maximum of 625 units. Although previously recommended to be administered within 96 hours after exposure, in May 2011 the Food and Drug Administration (FDA) approved administration of VariZIG for up to 10 days following exposure. Despite this expanded window of treatment, VariZIG is expected to provide maximum benefit when administered as soon as possible after exposure. Prevention of congenital varicella syndrome with the use of VariZIG is unknown, but unlikely to be tested due to ethical issues.

Two live, attenuated varicella zoster virus-containing vaccines are available in the United States for prevention of varicella: VARIVAX and ProQuad. VARIVAX, a single-antigen varicella vaccine (VARIVAX, Merck & Co., Inc., Whitehouse Station, New Jersey), was licensed in the United States in 1995 for use among healthy children aged 12 months or more, adolescents, and adults; while ProQuad, a combination measles, mumps, rubella, and varicella vaccine (ProQuad, Merck & Co., Inc., Whitehouse Station, New Jersey), was licensed in the United States in 2005 for use among healthy children aged 12 months-12 years.

Vaccination results in 97% seroconversion; however, vaccine induced immunity diminishes over time with resultant breakthrough infection rate of 5% at 10 years. These live, attenuated vaccines are not recommended in pregnancy, and pregnancy should be avoided within 3 months of administration. Data from a registry established in March 1995 through March 2012 and co-sponsored by Merck & Co., Inc (manufacturer of Varivax and ProQuad, see above) with the Centers for Disease Control and Prevention (CDC) did not identify any cases of congenital varicella syndrome or increased prevalence of other birth defects associated with inadvertent varicella vaccination during pregnancy in more than 900 women vaccinated within 3 months before or during pregnancy. Consequently, the CDC currently recommends that unintentional vaccination of varicella in pregnancy does not imply a need for termination. Postpartum breast feeding should not be disrupted as these vaccines are not excreted into breast milk if vaccination is administered postpartum.

4. Complications

Maternal systemic complications in pregnancy are similar to those seen in the non-pregnant population. The most common infectious complication is secondary bacterial superinfection of the skin and soft tissues from excoriation of the lesions with resultant infection with common skin flora, such as Staphylococcus aureus. Extracutaneous involvement of the infection can also include the central nervous system, myocarditis, corneal lesions, nephritis, arthritis, bleeding diatheses, acute glomerulonephritis, pneumonia and hepatitis. Central nervous system manifestations include aseptic meningitis, encephalitis, transverse myelitis and Guillain-Barré syndrome.

Varicella pnuemonia is the most severe complication associated with VZV infection. According to Harger et al. 5.2% of women with varicella were diagnosed with pneumonia. Risk of disease is further increased in adulthood and more so in pregnancy. As the gestation advances, the risk of pneumonia is increased, possibly due to displacement of the diaphragm by the enlarging gravid uterus.

Additional risk factors include current tobacco use and greater than 100 chicken pox skin lesions, indirectly indicating more severe, disseminated infection. Symptoms develop 2-4 days following the onset of the rash with cough, dyspnea and tachypnea. As respiratory symptoms can be mild, a chest x-ray with fetal radiographic shielding is recommended for all pregnant patients presenting with varicella. Radiographic findings include nodular infiltrates similar to those seen with other viral pneumonias. This condition was often lethal, with early reports of 40% mortality.

Fortunately, mortality rates associated with pneumonia have drastically improved to less than 2 percent with improvement of supportive care and aggressive medical therapy with antiviral medication. Resolution of pulmonary issues typically follows the time course of skin lesions, however, compromised pulmonary function could persist up to several weeks.

Acyclovir is recommended for the treatment of complicated VZV infection. The Acyclovir Pregnancy Registry, designed to assess pregnancy outcomes in women exposed to the antiviral medication, was closed in 1999. The advisory committee concluded that there was no increase in the number of birth defects in exposed patients when compared to the general unexposed population.

5. Prognosis and outcome

Pregnant women diagnosed with uncomplicated VZV primary or reactivation disease have a self-limited course that usually resolves without maternal sequelae. Complications such as Varicella pneumonia are uncommon but potentially fatal if unrecognized, as discussed above. Shingles is unusual in the reproductive age group. The most common complication of shingles is postherpetic neuralgia - the patient experiences severe pain in the area of the shingles outbreak, even when the shingles rash itself has resolved. This is usually seen in patients 60 years of age and is rare in pregnancy.

6. What is the evidence for specific management and treatment recommendations?

Lamont, RF, Sobel, JD, Carrington, D. "Varicella-zoster virus (chicken pox) infection in pregnancy". BJOG. vol. 118. 2011 Sep. pp. 1155-1162.

(Congenital varicella syndrome, maternal varicella-zoster virus pneumonia and neonatal varicella infection are associated with serious morbidity and in some cases mortality. Vaccination can prevent the disease, and maternal varicella-zoster immunoglobulin administration before rash development, with or without antiviral medication, can modify the progression of the disease.)

Nathwani, D, Maclean, A, Conway, S, Carrington, D. "Varicella infections in pregnancy and the newborn. A review prepared for the UK Advisory Group on Chickenpox on behalf of the British Society for the Study of Infection". J Infect. vol. 36. 1998 Jan. pp. 59-71.

(A detailed review of maternal and infant susceptibilities and consequences of varicella infection, including risk factors and clinical symptomatology.)

"A new product (VariZIG) for postexposure prophylaxis of varicella available under an investigational new drug application expanded access protocol". MMWR. vol. 55. 2006c. pp. 209.

(Beginning in February 2006, an investigational [not licensed] VZIG product, VariZIG™ [Cangene Corporation, Winnipeg, Canada] became available under an investigational new drug application [IND] submitted to the Food and Drug Administration. This product can be requested from the sole authorized U.S. distributor, FFF Enterprises [Temecula, California], for patients who have been exposed to varicella and who are at increased risk for severe disease and complications.)

"Updated Recommendations for Use of VariZIG — United States, 2013". MMWR. vol. 62. July 19. 2013. pp. 574-576.

"FDA approval of an extended period for administering VariZIG for postexposure prophylaxis of varicella". MMWR Morb Mortal Wkly Rep. vol. 61. 2012. pp. 212.

(VariZIG (Cangene Corporation, Winnipeg, Canada) is the only varicella zoster immune globulin preparation available in the United States for postexposure prophylaxis of varicella in persons at high risk for severe disease who lack evidence of immunity to varicella and are ineligible for varicella vaccine. Limited data suggest that the incidence of varicella is com­parable among persons who receive varicella zoster immune globulin within 4 days of exposure and those who receive it more than 4 days (up to 10 days) after exposure and attenuation of disease might be achieved with administration of varicella zoster immune globulin up to 10 days after exposure. In May 2011, the Food and Drug Administration (FDA) approved an extended period for administering VariZIG. The period after exposure to varicella zoster virus during which a patient may receive VariZIG, which had been 96 hours (4 days), is now 10 days. VariZIG should be administered as soon as possible after exposure.)

"Prevention of varicella. Recommendations of the Advisory Committee on Immunization Practices (ACIP)". MMWR. vol. 56. 2007e.

(In 2006, the Initial Advisory Committee on Immunization Practices adopted recommendations regarding the use of live, attenuated varicella vaccines for prevention of varicella that include regimens for children and recommendations for routine vaccination of all healthy persons over 13 years of age without evidence of immunity. Additional recommendations included prenatal assessment and postpartum vaccination.)

Marin, M, Willis, ED, Marko, A, Rasmussen, SA, Bialek, SR, Dana, A. "Closure of varicella-zoster virus-containing vaccines pregnancy registry - United States, 2013". MMWR Morb Mortal Wkly Rep. vol. 63. 2014 Aug 22. pp. 732-3.

(Data from a registry established in March 1995 through March 2012 and co-sponsored by Merck & Co., Inc (manufacturer of Varivax and ProQuad) with the Centers for Disease Control and Prevention did not identify any cases of congenital varicella syndrome or increased prevalence of other birth defects associated with inadvertent varicella vaccination during pregnancy in more than 900 women vaccinated within 3 months before or during pregnancy. Due to the low rate of exposure of varicella-susceptible women of childbearing age to VZV-containing vaccines, in addition to the rarity of the outcome, it was recognized that the registry would not contribute more robust data on risk for congenital varicella syndrome. Given feasibility concerns and in coordination with the Food and Drug Administration, the registry was closed with new patient enrollment discontinued October 16, 2013.)

Plourd, DM, Austin, K. "Correlation of a reported history of chickenpox with seropositive immunity in pregnant women". J Reprod Med. vol. 50. 2005. pp. 779.

(A study of 940 patients with a reported positive verbal history of prior chickenpox infection were evaluated with an enzyme-linked immunosorbent assay IgG antibody test to identify an overall seronegativity rate of 4.1%. Thus, there is a strong correlation between a reported history of chickenpox and serum immunity.)

Harger, JH, Ernest, JM, Thurnau, GR. "Risk factors and outcome of varicella-zoster virus pneumonia in pregnant women". J Infect Dis. vol. 185. 2002. pp. 422.

(A case-control analysis in which 18 pregnant women with VZV pneumonia were compared with 72 matched control subjects to determine the factors associated with an increased risk of developing varicella-zoster virus (VZV) pneumonia during pregnancy. Women with VZV pneumonia were significantly more likely to be current smokers and to have more than 100 skin lesions.)

Enders, G, Miller, E, Cradock-Watson, J. "Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases". Lancet. vol. 343. 1994. pp. 1548.

(A prospective study in Germany and the United Kingdom between 1980 and 1993 identifying 1,373 women with varicella and 366 with herpes zoster during the first 36 weeks of gestation. Congenital varicella syndrome was identified in nine cases with the highest risk observed during maternal infection between 13-20 weeks. In 97 pregnant women, varicella occurred after post-exposure prophylaxis with anti-varicella-zoster immunoglobulin; however, no cases of congenital varicella syndrome or zoster in infancy occurred in this group.)

Mendelson, E, Aboundy, Y, Smetana, Z. "Laboratory assessment and diagnosis of congenital viral infections: Rubella, cytomegalovirus (CMV), varicella-zoster virus (VZV), herpes simplex virus (HSV), parvovirus B19 and human immunodeficiency virus (HIV)". Reprod Toxicol. vol. 21. 2006. pp. 350.

(Laboratory assessment of maternal VZV infection is based on serology [both IgG and IgM], and on virus detection in skin lesions, but there are no fully reliable methods to assess fetal infection and damage. Fetal IgM and virus detection in amniotic fluid are used, but false negative results are common and positive results do not necessarily correlate with fetal damage.)

Paryani, SG, Arvin, AM. "Intrauterine infection with varicella-zoster virus after maternal varicella". N Engl J Med. vol. 314. 1986 June 12. pp. 1542-6.

(A prospective study of 43 pregnancies complicated by varicella and 14 pregnancies complicated by herpes zoster; nine of 43 pregnant women with varicella had associated morbidity--pneumonia [4 women], death [1], premature labor [4 of 42], premature delivery [2 of 42], and herpes zoster [1]. Varicella during pregnancy was associated with maternal morbidity and evidence of fetal infection, but that herpes zoster was not.)

"Cytomegalovirus, parvovirus B19, varicella zoster, and toxoplasmosis in pregnancy". Practice Bulletin No. 151. Obstet Gynecol. vol. 125. 2015. pp. 1510-25.

(American College of Obstetricians and Gynecologists' Practice Bulletin published in June 2015 replacing the prior bulletin from 2000 developed to aide practitioners in making decisions about appropriate obstetric care in women at-risk or affected with varicella infection near conception or during pregnancy.)
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