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Position statement

The management of varicella-zoster virus exposure and infection in pregnancy and the newborn period

Anne-Marie Heuchan and David Isaacs, on behalf of the Australasian Subgroup in Paediatric Infectious Diseases of the Australasian Society for Infectious
Med J Aust 2001; 174 (6): 288-292.

MJA 2001; 174: 288-292

Abstract - Recommendations 1A - Recommendations 1B - Recommendations 2 - Recommendations 3 - Recommendations 4 - References - Authors' details
- - More articles on Obstetrics & gynaecology and women's health


Abstract

  • Zoster immunoglobulin (ZIG) should be offered to pregnant, varicella-seronegative women with significant exposure to varicella-zoster virus (VZV) (chickenpox) infection.
  • Oral aciclovir prophylaxis should be considered for susceptible pregnant women exposed to VZV who did not receive ZIG or have risk factors for severe disease.
  • Intravenous aciclovir should be given to pregnant women who develop complicated varicella at any stage of pregnancy.
  • Counselling on the risk of congenital varicella syndrome is recommended for pregnant women who develop chickenpox.
  • ZIG should be given to a baby whose mother develops chickenpox up to 7 days before delivery or up to 28 days after delivery.
  • Intravenous aciclovir should be given to babies presenting unwell with chickenpox, whether or not they received ZIG.
  • Breastfeeding of babies infected with or exposed to VZV is encouraged.
  • A mother with chickenpox or zoster does not need to be isolated from her own baby.
  • If siblings at home have chickenpox, a newborn baby should be given ZIG if its mother is seronegative.
  • The newborn baby does not need to be isolated from its siblings with chickenpox, whether or not the baby was given ZIG.
  • After significant nursery exposure to VZV, ZIG should be given to seronegative babies and to all babies born before 28 weeks' gestation.


Varicella-zoster virus (VZV) (chickenpox) infection can cause severe morbidity in the pregnant woman, the fetus, and the newborn baby.

1. Management of VZV infection in pregnancy

The implications of primary VZV infection in pregnancy for the mother and for the fetus vary with the period of gestation. For the mother, the risk of adverse effects is greatest in the third trimester, whereas for the fetus the risk is greatest in the first and second trimesters.

A. Maternal risk In normal adults, the mortality and morbidity of primary VZV infection is greater than in children. Only about 2% of all cases occur in adulthood, but they account for 25% of all VZV-related deaths.1 Pneumonitis is 25 times more common in adults.1,2

A 1995 Australian study assessed VZV seronegativity in women presenting to antenatal clinics and found 22% of women aged 14-19 years, 14% of those aged 20-24 years, 5% of those aged 25-29 years and 2% of those aged 30 years and over had not had previous exposure and were therefore susceptible to VZV infection.3

Anecdotally, chickenpox infection in pregnancy is more severe than in non-pregnant adults, but there is scant supporting evidence.4 A survey of 164 000 pregnancies in the United Kingdom described 98 women with chickenpox, of whom seven developed severe illness and two died.5 The UK confidential inquiry into maternal deaths from 1985 to 1997 reported only seven deaths associated with VZV in pregnancy, all of which occurred in the second half of pregnancy. Other reports have also suggested increased severity of illness in the second half of pregnancy.6

Zoster immunoglobulin (ZIG), given prophylactically at the time of exposure, is known to prevent or reduce the severity of chickenpox.7-9

Aciclovir, an antiviral agent, shortens the duration of illness in young adults if administered during the incubation period or within 24 hours of the onset of the rash.10,11 When administered prophylactically (7 to 9 days after family exposure) it may be up to 84% protective against infection and able to modify the illness in the remaining family members.12

Although aciclovir is not licensed for use in pregnancy (because of concerns about adverse fetal effects), there have been no reports of adverse effects among hundreds of cases over several years of monitoring.13

Management algorithms (Boxes 1 and 2) have been devised for varicella exposure in pregnancy.

Recommendations 1A

Zoster immunoglobulin (ZIG) (Box 3)

  • All pregnant women who have significant exposure to VZV infection (defined as "living in the same household as a person with active chickenpox or herpes zoster or face-to-face contact with a person with chickenpox or uncovered zoster for at least 5 minutes"), who have no history of chickenpox and who are seronegative (or serological testing is not readily available), should be offered ZIG.4-6 (E3)

  • ZIG should be administered within 72 hours of exposure for maximal effect, although it may provide some benefit up to 96 hours after exposure for immunocompromised subjects.14 (E3)

  • ZIG is ineffective, and should not be given, once clinical illness is established.15 (E4)

Aciclovir (Box 3)

There is no high level evidence on the use of aciclovir in pregnancy. Based on consensus view, we recommend:

  • Consideration should be given to using oral aciclovir prophylaxis for susceptible pregnant women with significant exposure (defined above) who have not received ZIG, or who have any underlying risk factors, such as chronic lung disease, cigarette smoking,16 systemic corticosteroid treatment,17 impaired immunity,18 or are in the second half of pregnancy (Box 3). (E4)

  • Intravenous aciclovir should be given for varicella pneumonitis or other complications at any stage of pregnancy.4,6,19 These complications include respiratory symptoms, neurological symptoms, haemorrhagic rash and/or continued fever or appearance of new lesions after 6 days.4 (E4)

  • Extrapolation from data in children suggests that patients receiving systemic corticosteroid therapy or those with underlying immunodeficiency should be treated with intravenous aciclovir at the earliest sign of chickenpox.18,20,21 (E4)

Management of delivery of the baby

  • There is no evidence that ending the pregnancy speeds maternal recovery. Expedited delivery should only be considered for fetal compromise or if the gravid uterus is thought to be critically impairing maternal ventilation.

 
B. Fetal risk Chickenpox in pregnancy may result in fetal varicella which is usually benign and self-limiting.1 Occasionally, it produces a characteristic pattern of abnormalities known as "congenital varicella syndrome" (CVS).22,23 CVS very occasionally follows maternal zoster infection.5 The risk of CVS after first-trimester maternal chickenpox was estimated from prospective studies as 2.2% (range, 0-9%; 95% CI, 0-4.6%).24-26 In a large prospective European study, the incidence of CVS was 0.4% after maternal chickenpox in the first 12 weeks of pregnancy, rising to 2% between weeks 13 and 20.24 After 20 weeks the risk is far lower, although isolated cases have been reported.3 The incidence of CVS in Australia is 1 in 107 000 pregnancies.27 The congenital defects are usually severe, causing cicatricial skin lesions, limb hypoplasia or paresis, microcephaly and ophthalmic lesions.22,24,28 It is hypothesised that these lesions result from virus reactivation in utero or disseminated zoster infection.2,29 Herpes zoster (shingles) occurs in early childhood in about 1% of otherwise asymptomatic infants exposed to maternal varicella during the second or third trimester.24

At present, there is no reliable marker of in-utero virus reactivation or the predicted development of CVS. Serological tests are an insensitive marker of fetal VZV infection and subsequent fetal damage.24 The polymerase chain reaction (PCR) has been used to detect VZV in amniotic fluid: a negative PCR is associated with a favourable outcome, but a positive PCR correlates poorly with the development of CVS.26 As amniocentesis carries a risk of fetal loss, amniotic fluid PCR has a limited role.

While ZIG may prevent or modify the course of chickenpox in pregnancy, it may not abolish the risk of fetal infection. Therefore, close ultrasound monitoring for the development of fetal abnormalities after maternal chickenpox or administration of ZIG in pregnancy is recommended.

Recommendation 1B

  • Counselling on the risk of congenital varicella syndrome is recommended for women who develop chickenpox during pregnancy. (E4)



2. Management of babies of mothers with perinatal chickenpox

Maternal chickenpox in the peripartum period poses a risk of severe neonatal varicella, with a mortality rate up to 30%.30,31 The increased peripartum severity is attributed to a large transplacental inoculum of virus in the absence of protective maternal antibody. The timing of maternal infection in relation to delivery determines the risk to the infant.31

  • Infection with onset more than seven days before delivery ensures adequate transplacental passage of specific anti-VZV antibody to protect the infant.32

  • Infection with onset 7 days or less before delivery puts the infant at risk of severe neonatal varicella. Passive immunisation of the baby by giving ZIG immediately after delivery prevents or attenuates neonatal varicella and is essential.7,33

Maternal varicella starting 1-2 days after delivery is also associated with an increased risk of severe neonatal varicella from transplacental spread of the virus.30 However, babies of seronegative mothers exposed postnatally to varicella in the first 28 days after delivery apparently have increased risk of severe illness compared with older infants.33 If the mother develops chickenpox postnatally, her baby is evidently seronegative. Therefore, ZIG is recommended for seronegative babies up to 28 days old exposed to varicella.34,35

Recommendations 2

  • ZIG is indicated for the baby if maternal varicella develops up to 7 days before delivery or if the mother develops chickenpox up to 28 days after delivery.7,15,31-33 (E3)

  • ZIG should be given to the baby as early as possible after delivery or exposure, but must be within 72 hours.31,32 (E4)

  • Maternal herpes zoster is not an indication for ZIG administration to the baby. (E4)

  • Clinical follow-up of infants receiving ZIG is essential and they should be admitted to hospital if any rash develops, because severe varicella can still occur despite passive immunisation.35,36 (E4)

  • Intravenous aciclovir should be administered (a) to babies presenting with chickenpox who are unwell (eg, poor feeding, tachypnoea), whether or not they received ZIG; (b) to any high risk neonate who develops chickenpox and who inadvertently did not receive ZIG prophylaxis or for whom it was delayed beyond 24 hours; and (c) to immunocompromised neonates who develop chickenpox, including those who are premature or being treated with corticosteroids.18,21 (E4)

  • Routine aciclovir prophylaxis in conjunction with ZIG is not currently recommended in the neonatal population, due to lack of evidence. (E4)

  • Breastfeeding of infected or exposed babies is encouraged. (E4)

  • A mother and/or her baby with active vesicles should be isolated from other mothers and babies, but an infected mother does not need to be isolated from her own baby. (E4)


3. Management of neonates exposed to VZV infection on the postnatal wards or at home

The commonest neonatal exposure to VZV is when one or more siblings develops chickenpox in the weeks after delivery. The risk of the newborn developing severe disease from postnatal exposure is considerably less than from transplacentally acquired varicella, but some babies with postnatal exposure will develop severe disease.34 The risk to the newborn baby is determined primarily by the presence or absence of transplacentally acquired maternal IgG antibody.

If the mother has had chickenpox, the risk from siblings is negligible. If not, the baby should be given ZIG, which will minimise the risk.34,35

Recommendations 3

  • ZIG should be administered to a baby up to 28 days old exposed to VZV if the mother is seronegative, her serostatus can not be determined, or if the infant was born at or before 28 weeks' gestation.15,37 (E3)

  • A newborn baby does not need to be isolated from its siblings with chickenpox, whether or not the baby was given ZIG. (E4)

  • Parents should be advised that medical attention should be sought if any signs of chickenpox develop. (E4)

  • Admit to hospital for aciclovir treatment if baby becomes unwell (eg, poor feeding, tachypnoea). (E4)

  • The role of prophylactic aciclovir is unproven.



4. Management of VZV exposure within the neonatal unit

VZV poses a particular threat in this setting, because babies born prematurely are relatively deprived of the usual third-trimester transfer of transplacental antibodies.37-39 Spread of VZV is primarily by the respiratory route, so isolation in a separate room is desirable for babies with pneumonitis, and essential if they require artificial ventilation. Staff handwashing is important in reducing spread of the virus.

VZV vaccines are now available in Australia, and immunisation of susceptible staff is strongly recommended.35

A significant exposure in the neonatal unit or on the postnatal ward is defined as:10,15

  • patient sharing the same open ward as a person with chickenpox or zoster;

  • face-to-face contact with a person with chickenpox or zoster for at least 5 minutes; and

  • contact for one hour or more with person (staff or patient) with chickenpox lesions or who developed lesions up to 48 hours later.

All staff who have had significant exposure to an index case (see above) and who do not have a history of previous chickenpox infection or of VZV vaccination should have serological tests. If they are VZV antibody negative, they should be removed from clinical duties from days 7-21 after exposure (days 7-28 if they receive ZIG).

Recommendations 4

  • Infants born after 28 weeks' gestation15 should only be given ZIG if they have had significant exposure (defined above) and serological tests show the mother to be seronegative. (E4)

  • All infants born at or before 28 weeks' gestation or born weighing under 1000 g11,37,38 with significant exposure should be given ZIG regardless of the results of serological testing of the mother. (E4)

  • Quarantine of cases should continue until all lesions have crusted.15 (E3)

  • Quarantine of contacts should be from days 7-21 after exposure, and from days 7-28 after exposure if they received ZIG.15 (E3)

  • Although quarantine of cases and those considered to have significant contact is recommended, this should not compromise medical and nursing care of a sick infant. (E4)

  • Infants with pneumonitis requiring ventilation must be isolated. Where isolation facilities are unavailable, cases should be transferred to a unit with isolation facilities. (E4)

  • Aim to discharge all patients requiring quarantine from hospital as soon as possible. (E4)

Background and evidence basis of recommendations

This position statement was circulated to all members of the Australasian Subgroup in Paediatric Infectious Diseases (ASPID) for comments. The comments were analysed by the authors, discussed with colleagues, and subsequent versions incorporating the comments were re-circulated to all ASPID members.
The recommendations of ASPID on the management of VZV exposure and infection in pregnancy and the neonatal period are endorsed by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

The recommendations are based on the following levels of evidence (simplified from the NHMRC's "Quality of evidence ratings")40

E1 Level I Systematic review or meta-analysis of all relevant randomised controlled trials (RCTs)
E2 Level II Well-designed RCTs
E3 Level III Well-designed cohort or case-control studies
E4 Level IV Consensus opinion of ASPID members

References

  1. Joseph CA, Noah ND. Epidemiology of chickenpox in England and Wales, 1967-85. BMJ 1988; 296: 673-676.
  2. Centers for Disease Control. Varicella-zoster immune globulin for the prevention of chickenpox. MMWR Morb Mortal Wkly Rep 1984; 33: 84-90.
  3. Chant KG, Sullivan EA, Burgess MA, et al. Varicella-zoster virus infection in Australia. Aust N Z J Public Health 1998; 22: 413-418.
  4. Gilbert GL. Chickenpox during pregnancy. BMJ 1993; 306: 1079-1080.
  5. 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 1998; 36 Suppl 1: 59-71.
  6. Smego RA Jr, Asperilla MO. Use of acyclovir for varicella pneumonia during pregnancy. Obstet Gynecol 1991; 78: 1112-1116.
  7. Brunell PA, Ross A, Miller LH, Kuo B. Prevention of varicella by zoster immune globulin. N Engl J Med 1996; 280: 1191-1194.
  8. Gershon AA. Prevention and treatment of varicella zoster virus infection. Pediatr Infect Dis J 1984; 3 (Suppl): 34-36.
  9. Bose B, Kerr M, Brookes E. Varicella zoster immunoglobulin to prevent neonatal chickenpox. Lancet 1986; 1: 449-450.
  10. Lin TY, Huang YC, Ning HC, Hsueh C. Oral acyclovir prophylaxis after intimate contact. Pediatr Infect Disease J 1997; 16: 1162-1165.
  11. Balfour HH Jr, Rotbart HA, Feldman S, et al. Aciclovir treatment of varicella in otherwise healthy adolescents. The Collaborative Aciclovir Varicella Study Group. J Pediatr 1992; 120: 627-633.
  12. Azano Y, Yoshikawa T, Suga S, et al. Postexposure prophylaxis of varicella in family contact by oral acyclovir. Pediatrics 1993; 92: 219-222.
  13. Andrews EB, Yankasksas BC, Cordero JF, et al. Aciclovir in pregnancy registry: 6 years' experience. The Acyclovir in Pregnancy Registry Advisory Committee. Obstet Gynecol 1992; 79: 7-13.
  14. US Department of Health and Human Services. Prevention of Varicella: Recommendations of the Advisory Committee on Immunisation Practices. MMWR Morb Mortal Wkly Rep 1996; 45 (RR-11): i-36.
  15. American Academy of Pediatrics. Varicella-zoster infection. In: Peter G, editor. 2000 Red Book: Report of the Committee of Infectious Diseases, 25th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2000: 624-638.
  16. Grayson ML, Newton-John H. Smoking and varicella pneumonia. J Infect 1988; 16: 312.
  17. Rice P, Simmons K, Carr R, Banatvala J. Near fatal chickenpox during prednisolone treatment. BMJ 1994; 309: 1069-1070.
  18. Balfour HH. Intravenous acyclovir therapy for varicella in immunocompromised children. J Pediatr 1984; 104: 134.
  19. Haake DA, Zakowski PC, Haake DL, Bryson YJ. Early treatment with acyclovir for varicella pneumonia in otherwise healthy adults. Rev Infect Dis 1990; 12: 788-797.
  20. Feldman S, Hughes WT, Daniels CB. Varicella in children with cancer: 77 cases. Pediatrics 1975; 56: 388-397.
  21. Reiches NA, Jones JF. Steroids and varicella. Pediatrics 1993; 92: 288-289.
  22. La Foret, Lynch LL. Multiple congenital defects following maternal varicella. N Engl J Med 1947; 236: 534-537.
  23. Scharf A, Scerr O, Enders G, Helftenbein E. Virus detection in the fetal tissue of a premature delivery with congenital varicella syndrome. A case report. J Perinat Med 1990; 18: 317-322.
  24. Enders G, Miller E, Cradock-Watson J, et al. Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet 1994; 343: 1548-1551.
  25. Pastuszak A, Levy M, Schick B, et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N Engl J Med 1994; 330: 901-905.
  26. Mouly F, Mirlesse V, Meritet J, et al. Prenatal diagnosis of fetal varicella zoster virus infection with polymerase chain reaction of amniotic fluid in 107 cases. Am J Obstet Gynecol 1997; 177: 894-898.
  27. Forrest JM, Mego S, Burgess MA. Congenital and neonatal varicella in Australia. J Paediatr Child Health 2000; 36: 108-113.
  28. Higa K, Dan K, Manabe H. Varicella-zoster virus infections during pregnancy: hypothesis concerning the mechanisms of congenital malformations. Obstet Gynecol 1987; 69: 214-222.
  29. Birthistle K, Carrington D. Fetal varicella syndrome -- a reappraisal of the literature. A review prepared for the UK Advisory Group on Chickenpox on behalf of the British Society for the Study of Infection. J Infect 1998; 36 Suppl 1: 25-29.
  30. De Nicola LK, Hanshaw JB. Congenital and neonatal varicella. J Pediatr 1979; 94: 175-176.
  31. Erlich RM, Turner JAP, Clarke M. Neonatal varicella. J Pediatr 1958; 53: 139-147.
  32. Miller E, Cradock-Watson JE, Ridehalgh MKS. Outcome of newborn babies given anti-varicella zoster immunoglobulin after perinatal maternal infection with varicella zoster virus. Lancet 1989; 2: 371-373.
  33. Hanngren K, Grandien M, Granstrom G. Effect of zoster immunoglobulin for varicella prophylaxis in the newborn. Scand J Infect Dis 1985; 17: 343-347.
  34. Rubin L. Disseminated varicella in the neonate and implications for immunoprophylaxis in neonates exposed to varicella. Pediatr Infect Dis J 1986; 56: 100-102.
  35. Australian Technical Advisory Group on Immunisation, Commonwealth Department of Health and Aged Care. The Australian immunisation handbook. 7th edition. Canberra: NHMRC/AGPS, 2000: 231-238.
  36. Reynolds L, Struik S, Nadel S. Neonatal varicella: varicella zoster immunoglobulin (VZIG) does not prevent disease. Arch Dis Child Fetal Neonatal Ed 1999; 81: F69-F70.
  37. Linder N, Waintraub I, Smetana Z, et al. Placental transfer and decay of varicella-zoster virus antibodies in preterm infants. J Pediatr 2000; 137: 85-89.
  38. Conway SP, Dear PRF, Smith I. Immunoglobulin profile of the preterm baby. Arch Dis Child 1985; 60: 208-212.
  39. Wang E, Prober C, Arvin A. Varicella zoster virus antibody titres before and after administration of zoster immune globulin to neonates in an intensive care nursery. J Pediatr 1985; 103: 113-114.
  40. National Health and Medical Research Council. How to use the evidence: assessment and application of scientific evidence. Table 1.3. <http://www.health.gov.au/nhmrc/publicat/pdf/cp69.pdf> (accessed February 2001).



Authors' details

King George V Hospital, Sydney, NSW.
Anne-Marie Heuchan, MB, MRCP, Fellow in Neonatal Medicine.

The Children's Hospital at Westmead, Sydney, NSW.
David Isaacs, MD, FRACP, FRCPCH, Paediatric Infectious Diseases Physician; and Clinical Professor, University of Sydney.

Reprints will not be available from the authors.
Correspondence: Professor D Isaacs, Department of Immunology and Infectious Diseases, The Children's Hospital at Westmead, PO Box 4001, Westmead, NSW 2145.
davidiATchw.edu.au


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1: Management of significant exposure* to varicella zoster virus (VZV) during pregnacy (Algorithm 1)
Box 1



*Significant exposure is defined as living in the same household as a person with active chickenpox or herpes zoster or face-to-face contact with a person with chickenpox or zoster for at least 5 minutes. †Risk factors for severe maternal VZV infection are second half of pregnancy, underlying lung disease, immunocompromised, and smoker. See Box 3 for dosage of zoster immunoglobulin (ZIG) and aciclovir. Recommendations based on consensus view.
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2: Management of chickenpox in pregnancy (Algorithm 2)
Box 2



*Complications: respiratory symptoms, haemorrhagic rash, persistent fever >6 days, and new lesions developing >6 days.
†At high risk are those women in the second half of pregnancy with underlying lung disease, who are immunocompromised, and who smoke.
See Box 3 for doses of aciclovir.
Recommendations based on consensus view.
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3: Administration and dosage of zoster immunoglobulin (ZIG) and aciclovir

Zoster immunoglobulin

  • High-titre ZIG is available from the Red Cross Blood Transfusion Service in Australia on a restricted basis for the prevention of VZV infection in high-risk subjects. Each vial contains 2mL (16% solution of gammaglobulin fraction of human plasma from donors with high titre of varicella antibodies + thiomersal 0.01% w/v).
  • The recommended dose is 2mL for children 0-5 years, 4mL for children 6-12 years and 6mL for adults.32
  • Administration is by intramuscular injection, with few adverse effects other than local discomfort reported. This can be lessened if the ZIG is at room temperature when administered.
  • ZIG should never be given intravenously.36

Aciclovir

  • Aciclovir appears to be a safe and relatively well tolerated drug, although it may impair renal function if given to patients who are not adequately hydrated.17 It is not licensed for use in pregnancy but appears to be safe12 and its use is indicated in the high-risk situations outlined.
  • The recommended intravenous dose for treating VZV infection in adults and infants is 10-20mg/kg every 8 hours.
  • The oral dose for adults is 800mg five times daily.
  • The use of oral aciclovir in neonates is not recommended.
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Anne-Marie Heuchan
David Isaacs
on behalf of the Australasian Subgroup in Paediatric Infectious Diseases of the Australasian Society for Infectious