VIMS Journal: December 2016

Review Article

Varicella Zoster Virus Infection in Pregnancy: Current Thoughts

Dr. Krishnendu Gupta, Dr. M.M. Samsuzzoha, Dr. Arunava Das, Dr. Bijit Chowdhury

Introduction :
The varicella zoster virus (VZV) is a highlycontagious DNA herpes virus responsible fortwo illnesses. Primary infection results inchickenpox and its associated complications ofvaricella pneumonia, hepatitis and encephalitis.Reactivation of latent virus results in zoster('shingles') and complications such aspostherpetic neuralgia and ophthalmic zosterwith central nervous system (CNS)involvement[1]. When primary infection occursduring pregnancy, the virus may rarely betransmitted to the fetus, resulting in defectsknown as the congenital varicella syndrome.Maternal chickenpox with onset within five daysbefore and two days after delivery can causesevere disease and death in the newborn.

Pathogenesis :
Varicella develops in approximately 85% ofsusceptible household contacts. The virus spreadsfrom person to person via respiratory dropletsas well as by direct contact with vesicularfluids.The primary infection is characterized byfever, malaise and pruritic rash in the form ofcrops of maculopapules, that become vesicularand ultimately crust over before healing. Theincubation period of the infection is 10-21 days.However, the infectivity of the disease starts 48hours before the rash appears and continues tobe so till the vesicles crust over [2].
Chickenpox, a common childhood disease isusually manifested as mild infectionbut giveslife long immunity. Over 90% of individualsover 15 years of age in England and Wales areseropositive for VZV immunoglobulin G (IgG)antibody[3]. It is estimatedthat >90% of theantenatal population are seropositivefor VZVIgG antibody[4] and therefore almostinvariablyimmune to infection. As a result ofthis higher frequency of immunity, the incidenceofchicken pox in pregnancy is estimated tocomplicate up to 2 to 3 of every 1000 pregnanciesonly[5]. Following the primary infection, thevirus remains dormant in sensory nerve rootganglia but can be reactivated to cause a vesicularerythematous skin rash in a dermatomaldistribution known as herpes zoster, also called'zoster' or 'shingles'. In normal immunecompetentpatients, herpes zoster in pregnancyis not associated with viraemia and does notappear to cause any ill effects on the fetus.

Possible Sequelae of Varicella Infection inPregnancy :
Although varicella infection is less common inadults than children, it is associated with highermortality and morbidity. The associated mortalityrate in adults is said to be 15 times higher thanthat of children[6]. The main morbidities inpregnancy are pneumonia, hepatitis andencephalitis. The incidence of pneumoniacomplicating varicella in pregnancy has beenquoted in different case series as 5-10%[7], however more recently in a prospective caseseries Haergeret all documented the incidenceas 5%[8].

Chicken pox in the first trimester does not seemto increase risk of spontaneous miscarriage [9].Fetal Varicella Syndrome (FVS) is characterisedby one or more of the following: skin scarringin a dermatomal distribution; eye defects(microphthalmia, chorioretinitis or cataracts);hypoplasia of the limbs; and neurologicalabnormalities (microcephaly, cortical atrophy,mental retardation or dysfunction of bowel andbladder sphincters). Although most of the FVSfound in first half of pregnancy it can happenfrom 3rd to 28th weeks of gestation[10,11]. Rate ofinfection is lower in the first than second trimester(approximately 0.4% before 13 weeksvs. 2%between 13 and 20 weeks)[9,10].

Diagnosis :
Varicella usually presents as a typical skin rashthatappearsin crops beginning as red papules, thatprogress through vesicles and then become cloudypustules, which subsequently dry to form crustedlesions. The lesions are intensely pruritic. Adultpatients usually will have moderately severesystemic manifestations such as malaise, fatigue,and fever. Tachypnea and dyspnea may signalthe onset of varicella pneumonia that can becomplicated by a superimposed bacterialinfection. The presence of headache andphotophobia suggests the possibility ofencephalitis. Acute varicella infection is usuallydiagnosed on the basis of clinical findings alone.However, in difficult cases, varicella-zosterserology can be performed to confirm thediagnosis.

FVS can be diagnosed by ultrasound andtherefore, the affected antenatal women shouldbe referred to a fetal medicine specialist for adetailed anatomy scan at 16-20 weeks or 5weeks after infection, for diagnosis anddiscussion [12]. The ultrasound findings of FVSinclude musculoskeletal abnormalities likeasymmetric limbshortening or malformations,chest wall malformations, intestinal and hepaticechogenic foci, intrauterine growthrestriction,poly-hydramnios, fetal hydrops, or fetal demiseas well as cerebral anomalies likeventriculomegaly, hydrocephalus, microcephalywith polymicrogyria, and porencephaly[9,10]. Thepresence of VZV DNA detected by amnioticfluid PCR has a high sensitivity but a lowspecificity for the development of FVS. Thenegative predictive value of the combination ofamniotic fluid PCR testing and ultrasound isgood but the positive predictive value is poor.Nevertheless, women who develop varicellainfection during pregnancy should be counseledabout the risks versus benefits of amniocentesisto detect varicella DNA by polymerase chainreaction (PCR). However, amniocentesis shouldnot be performed before the skin lesion iscompletely healed [12].

Prevention and Treatment :
All patients should be carefully questioned abouthistory of chicken pox in their first prenatalvisit. More than 90% of pregnant women areimmune to varicella, and they are not at risk forsecond infections. If a pregnant woman has nohistory or is uncertain about prior infection, avaricella-zoster IgG antibody assay can beoffered to her. Postpartum vaccination shouldbe offered if she is found to be seronegative.A detailed history of timing, duration andcloseness of contact is necessary to ascertain asignificant exposure before considering postexposureprophylaxis. Significant exposure isdefined by more than 15 minutes face to face contact in the same room or in a large open ward.If a susceptible pregnant woman hassignificantexposure to chickenpox or shingles, she shouldbe offered prophylaxis by VZIG as soon aspossible or at the very latest within 10 days ofthe exposure ie. within 10 days of appearance ofthe rash in the case of continuous householdexposures[13]. The most well studied method ofprophylaxis is administration of varicella zosterimmune globulin (VZIG). Administration ofVZIG has been shown to prevent and attenuatechickenpox in non-immune individualsas wellas to reduce the risk of development of FVS[14].Because VZIG may prolong the incubation ofthe virus for at least one week, a patient whoreceives this agent should be observed closelyfor possible infection for at least 28 days afterreceipt of VZIG. If VZIG is not immediatelyavailable, prophylaxis with acyclovir (800 mgorally 5 times daily for 7 days) should beconsidered.

Oral acyclovir is also recommended to treatpregnant women with chickenpox if they presentwithin 24 hours of the onset of the rash[12]. It hasbeen reported that oral acyclovir therapy (800mg five times a day for 7 days) commencedwithin 24 hours of appearance of rash reducesthe duration of fever and symptomatology ofvaricella infection both in adults and children.The patient should be hospitalized and treatedwith intravenous acyclovir therapy in case ofsevere maternal infection including pneumonia,encephalitis and severe disseminated infection,or if she is immunosuppressed. The optimumdosage for parenteral acyclovir is 10 mg per kgevery 8 hours for 10 days. In obese patients,ideal body weight should be used to calculatethe dose of acyclovir. Acyclovir has not beenshown to increase the risk of major fetalmalformation. A Danish registry-based cohortstudy between 1996 and 2008 showed nosignificant difference of birth defectsbetweenthe exposed (acyclovir, valacyclovir orfamcyclovir) group (2.2%) and non-exposedgroup (2.4%) [Adjusted prevalence odds ratio0.89, 95% CI 0.65–1.22]. The same study alsoshowed that among 1561 pregnancies exposedto acyclovir, 32 babies (2.0%) had a majoranomaly compared with 2.4% of controls [15].

Delivery :
It is desirable to give a 7-day gap between theappearance of rash and delivery unless it isneeded to facilitate assisted ventilation in casesof varicella pneumonia complicated byrespiratory failure. In this case a multidisciplinaryteam involvement is necessary that includesachest physician and an intensivist for peripartumcare. Delivery during the viraemic period withactive chickenpox vesicles may be extremelyhazardous due to the risks of maternalhaemorrhage and/or coagulopathy due tothrombocytopenia or hepatitis. There is also ahigh risk of varicella infection of the newbornwith significant morbidity and mortality[16].It is extremely important to involve a senioranaesthesiologist for optimum method ofanaesthesia when delivery is required bycaesarean section. General anaesthesia mayexacerbate the respiratory compromise associatedwith varicella pneumonia. On the other hand,spinal anaesthesia may pose a theoretical riskof transmitting the varicella-zoster virus fromskin lesions to the central nervous system. Inthis situation, an epidural anaesthesia may besafer as the dura is usually intact minimizingthe risk of transmitting the virus to the centralnervous system. Nonetheless, the larger needlerequired for epidural anaesthesia may carry the risk of transferring a greater viral load from theskin to the epidural space. A site free of cutaneouslesions should therefore be chosen for needleplacement[17].

Neonatal Varicella Infection :
The newborn infant is at considerable risk fordeveloping neonatal varicella when maternalinfection occur less than 5 days prior to and 2days after delivery[18]. Some reports also statedthat babies who are born to mothers who havehad chickenpox within the period 7 days beforeto 7 days after delivery are in significant risk ofsevere form chickenpox[19]. These newborn shouldbe isolated from the mother until all her lesionshave crusted and dried and they should also betreated immediately with either VZIG with orwithout acyclovir therapy. Breastfeeding is notcontraindicated if the mother is well enough todo so except in the presence of active chickenpoxlesions close to the nipple, when breast milkshould be expressed. The expressed breast milkmay be fed to the baby who is receiving treatmentwith VZIG and/or acyclovir.

Vaccination :
Varicella vaccine contains live attenuated virusderived from the Oka strain of VZV. Susceptiblewomen in reproductive age group should beoffered the varicella vaccine at the time of theirannual examination or preconception counselingappointment. Similarly, susceptible pregnantwomen should be offered the vaccine immediatelyafter delivery. Two doses of the vaccine separatedby 4-6weeks are required for optimum protection.Women should be advised to avoid pregnancyfor 4 weeks after completion of second dose ofvaccination[20]. Nevertheless, there have been noreported cases of FVS or any increased risk offetal abnormality above the background risk incase of inadvertent exposures to the vaccine inpregnancy[21]. Adverse reactions to the vaccineare uncommon. The principal ones include mildfever, inflammation and pain at the injectionsite, and a rash.

Key Recommendations[22] :
1. Varicella vaccination should be offered towomen who are not immune to chickenpoxand are planning a pregnancy or receivinginfertility treatment.
2. If a woman is identified as being nonimmuneto chickenpox during pregnancyshe can be offered vaccination followingdelivery.
3. All women should be asked if they haveever had varicella at the time of booking.For women who give a definite history ofvaricella infection or 2 doses of varicellavaccine, it is not necessary to test forvaricella IgG and she can be considered tobe immune. Laboratories may choose totest all patients for convenience but thisshould be determined at a local level withrespect to cost effectiveness and clinicalimpact.
4. Women who are immunosuppressed shouldbe discussed individually with the localmicrobiologist or infectious diseasephysician as they may have impairedimmunity and require VZIG irrespective ofa previous history of varicella infection orvaccine.
5. Many maternity units test for immunity toVZV at booking. If varicella IgG is detectedin the booking serum, the woman can bereassured that should contact with thedisease occur, her antibodies should protecther and the baby from infection. If varicellaIgG is not detected in the booking serum,the woman should be advised to avoid contact with chickenpox and shingles duringpregnancy and should inform healthcareworkers of potential exposure without delay.
6. If immunity to VZV has not been checkedat booking, or the woman has not bookedfor antenatal care, her susceptibility toinfection can be determined from her history(see below). If a woman reports that she hashad chickenpox before, she can beconsidered as immune.
7. When contact occurs with chickenpox orshingles, a careful history must be taken toconfirm the significance of the contact andthe susceptibility of the patient. If the contactis significant and the pregnant woman is notimmune to VZV, she should be offered VZIGas soon as possible. VZIG iseffective whengiven up to 10 days after contact, but ideallywithin 96 hours.
8. A pregnant woman who develops the rashof chickenpox should immediately contacther GP or maternity hospital and should beisolated from other pregnant women whenshe attends a general practice surgery or ahospital for assessment.
9. Oral acyclovir should be prescribed forpregnant women with chickenpox if theypresent within 24 hours of the onset of therash and if they are more than 20 weeks ofgestation. Acyclovir should be used withcaution in early pregnancy and the risks andbenefits should be discussed with the woman.
10. Intravenous acyclovir should be given to allpregnant women with severe chickenpox,irrespective of when the rash developed.
11. The pregnant woman with chickenpoxshould be asked to contact her doctorimmediately if she develops respiratorysymptoms or any other deterioration in hercondition. Women who develop thesymptoms or signs of severe chickenpoxshould be referred immediately to hospital.A hospital assessment should be consideredin woman at high risk of severe orcomplicated chickenpox even in the absenceof concerning symptoms or signs.
12. Women hospitalised with varicella shouldbe nursed in isolation, under airborneprecautions, away from other babies orpotentially susceptible pregnant women ornonimmune staff.
13. The timing and mode of delivery of thepregnant woman with chickenpox must beindividualised. Appropriate treatment shouldbe decided in consultation with amultidisciplinary team i.e. an obstetricianor fetal medicine specialist, a clinicalmicrobiologist/ Infectious Disease specialistand a neonatologist.
14. Women should be advised that the risk ofspontaneous miscarriage does not appearto be increased if chickenpox occurs in thefirst trimester. If the pregnant womandevelops varicella or shows serologicalconversion in the first 28 weeks ofpregnancy, she has a small risk of fetalvaricella syndrome and she will need to beinformed of the implications.
15. Women who develop chickenpox inpregnancy should be referred to a fetalmedicine specialist at 16-20 weeks or 5weeks after infection for discussion anddetailed ultrasound examination. Womenwho develop varicella infection duringpregnancy should be counselled about therisks versus benefits of amniocentesis todetect varicella DNA by polymerase chainreaction (PCR). Amniocentesis should not be performed before the skin lesions havecompletely healed.
16. The neonatology team should be informedof the birth of all babies born to womenwho have had chickenpox at any gestationduring pregnancy.

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