Varicella zoster virus in pregnancy

1
Varicella zoster virus in pregnancy

• Mike McKendrick
• Department of Infection and Tropical Medicine
• Royal Hallamshire Hospital
• Sheffield, UK
• Hon. Professor
• Department of Genomic Medicine
• University of Sheffield

2
VZV in pregnancy

• Chickenpox
• Consequences to mother
• Consequences to child
• Intervention post exposure
• Prevention - Intervention pre exposure
• Herpes zoster

3
VZV infection effects to mother

• Primary infection
• Typical chickenpox in adult
• Complications
• Usually none
• Pneumonitis most common complication
• secondary bacterial infection
• (encephalitis)
• Reactivation
• Typical herpes zoster in adult

4
Is risk severe chickenpox increased in pregnancy?

• Confidential enquiry into maternal deaths UK
• 1985-1987 4 deaths
• 1988-1990 3 deaths
• All in second half pregnancy - ? immunotolerance
• Nathwani et al J Infection 199836S59-71
• No maternal deaths reported in last two reports
• Maternal varicella five times more likely to be
  fatal than non pregnant women
  Drug and Therapeutic Bulletin 2005 4369-72
• Review of adult deaths in VZV concluded no
  increase due to pregnancy
  Miller et al Reviews in Med Micro
  19934222-230
• 5 years in Sheffield 19 cases - no severe
  complications
• McKendrick et al J Infection 20075564-67

5
VZV infection in pregnant woman

• Conclusion
• No definite evidence that varicella more likely
  to be fatal in pregnant women than in the non
  pregnant adult

6
Herpes zoster in pregnancy

• No evidence to indicate increased severity in
  pregnancy.
• Theoretical risk if uterine dermatomes D10 to L1
  are involved no reports.

7
Primary infection in pregnancy effects on
foetus (and baby)

• No infection
• Infection
• Serological only
• Clinical
• minor varicella lesions
• Major - Foetal varicella syndrome
• Neonatal varicella (if delivery lt5 days after
  maternal rash)
• Infant herpes zoster

8
Foetal varicella syndrome

• Involves
• Single organ eg eye or skin
• Skin, neural system and GIT, GU tract, eyes,
  muscles and other organs
• Multiple lesions and malformations may lead to
  fetal death
• Due to reactivation of latent virus in neural or
  other tissue in utero
• Identification of non productive latency like VZV
  in non neuronal cell types demonstrated in
  aborted 12 week foetus Nikkels et al JID
  2005191250-4

9
Transmission to foetus

• Prospective study UK and Germany
• 1739 cases up to 36 weeks gestation
• 1373 varicella
• 366 zoster
• Detailed follow up of outcome
• Enders et al Lancet 1994 343 1548-1551

10
Transmission to foetus

• 9 cases fetopathy
• 2 at lt13 weeks risk 0.4 (95 CI0.05-1.5)
• 7 at 13-20 weeks risk 2 (95CI 0.8-4.1)
• 0 at gt 20 weeks
• 10 cases infant herpes zoster (probable
  underreporting)
• 13-24 weeks risk 0.8
• 25-36 weeks risk 1.7
• Enders et al Lancet 1994 343 1548-1551

11
Is FVS underdiagnosed? probably not.

• 347 pregnancies with varicella
• 140 first trimester
• 1 case foetal death 9 wks after infection
• 1 case foetal hydrops 12 weeks after infection
• 122 second trimester
• 100 third trimester
• One case FVS (maternal infection at wk 24) with
  typical skin scars and left retinal macular
  lesion.
• all babies actively followed up to 30 months to
  detect abnormalities of eyes, hearing and
  physical and developmental features
• Harger et al Obstet Gynecol 2002100260-5

12
Gestational age and risk of FVS

• Risk probably continues up to 28 weeks based on
  evidence from 9 cohort studies. Additionally 4
  further case reports of FVS after 20 weeks
  identified from 1979 to 2005.
• Drug and Therapeutic Bulletin 20054394-5

13
Maternal management post exposure to chickenpox

• Check VZV immunity
• Consider
• Prevention of chickenpox VZIG
• However in Sheffield, 50/87 (60) women with
  chickenpox contact did not seek advice from GP or
  hospital in timeframe to facilitate intervention.
  McKendrick et al J Infection
  20075564-67
• Antiviral during incubation period not in any
  guidelines
• Treatment of chickenpox with antiviral
• Counselling of mother and close foetal monitoring

14
Maternal management non immune mother post
exposure

• VZIG
• Biological product
• Must be given early
• modest protection against infection and/or severe
  disease
• Aim to protect mother from chickenpox
• ? Reduce FVS no definite evidence
• no cases in 97 women receiving VZIG but not
  sufficient power to reach significance.
• Enders et al Lancet 1994 343 1548-1551
• documented case of FVS despite VZIG
• VZIG expensive
• UK Health Protection Agency
• Annual cost c. 1million (2 million)
• 75-80 use in pregnant women
• Miller E, Health Protection Agency personal
  communication

15
Management - antivirals

• Aciclovir
• Valaciclovir
• Famciclovir

16
Antivirals - UK

• British National Formulary
• Aciclovir not known to be harmful
  manufacturers advise use only when potential
  benefit outweighs risk
• Valaciclovir see aciclovir
• Famciclovir see aciclovir

17
Antivirals second and third trimesters- IHMF

• The use of oral aciclovir (800 mg five times
  daily) for pregnant women who contract varicella
  in their second or third trimester is
  recommended. It is important to note that this
  recommendation is based on anecdotal evidence,
  and that patients should be advised that
  antiviral drugs are not licensed for use during
  pregnancy.
• The roles of valaciclovir and famciclovir for
  the treatment of varicella infection in the
  pregnant woman remain to be evaluated in clinical
  trials
• IHMF - management of varicella in
  immunocompetent host

18
Antivirals - IHMF first trimester

• It is recommended that further investigation be
  conducted to assess whether pregnant women who
  contract varicella during the first trimester of
  pregnancy should be administered intravenous
  aciclovir (10 mg/kg every 8 hours). There is
  currently no evidence that this treatment results
  in fetal malformations (Research need
  recommendation)
• IHMF - management of varicella in
  immunocompetent host

19
International aciclovir pregnancy registry
1984-1999

• 1234 pregnancies with 1246 outcomes
• Birth defects with first trimester exposure 19
  out of 256 (3.2 95CI, 2.0-5.0)
• Conclusion
• The observed rates and types of birth defects
  for pregnancies exposed to aciclovir did not
  differ significantly from those in the general
  population
• Stone et al. Birth Defects Research (Part A),
  Clinical and Molecular Teratology 2004
  70 201-207

20
Changing epidemiology

• Increase adults at risk
• Upward trend in adult chickenpox in last 20 years
  in UK (E Miller et al 1993) and USA (Gary GC et
  al 1990)
• Adult seropositivity
• Western countries c 90
• London Tower Hamlets
• British women 93
• Bangladeshi women 86
• Talukder et al Epidemiol Infect
  2007 april 10 1-10 Epub
• 54 in Pakistan Akram et al SE Asian J Trop
  Med Pub Health 200031646-649
• 56 in Sri Lanka Liyanage et al Indian J
  Med Sci 200761128-134
• 81 in Italy Alfonsi et al
  Vaccine 2007 256086-8
• Increased population movement will increase
  numbers at risk in Western countries

21
What is impact of childhood varicella
immunisation against chickenpox in pregnancy?

• Less chickenpox in children should reduce cases
  in pregnancy
• Majority had no identifiable exposure - European
  study Enders et al Lancet 1994 343
  1548-1551
• 58 (11/19) in Sheffield acquired infection from
  child at home McKendrick et al J
  Infection 20075564-67
• CDC (USA) and Centre for Infection (UK) have no
  data available on epidemiology of varicella in
  pregnancy

22
Cost effectiveness of antenatal screening and
post partum vaccination of susceptibles Pinot de
Moira A et al Vaccine 2006241298-1307

• UK versus Bangladeshi women
• Assumptions
• VZIG 54 protection (100 v severe dis. or
  death)
• Vaccine efficacy in adults (2 doses) 75
• Cost of congenital varicella syndrome - 420K
• Model
• A) -Serological screening only if no history
  chickenpox
• B) -Serological screening all

23
Cost effectiveness of antenatal screening and
post partum vaccination of susceptibles Pinot de
Moira A et al Vaccine 2006241298-1307

• A verbal and selective screening - savings
• UK women - 149,000 per 100,000 screened
• Bangladeshi - 257,000 per 100,000 screened
• B universal screening cost to NHS
• UK women gt1million per 100,000 screened
• Bangladeshi 780,000 per 100,000 screened

24
Immunisation strategies post partum

• Will fail to protect chickenpox in first
  pregnancy
• Five year retrospective review of chickenpox in
  pregnancy in Sheffield
• Five of nineteen women (26) had chickenpox in
  first pregnancy
• McKendrick et al J Infection 20075564-67

25
Immunisation strategies post partum

• Can live vaccine be used post partum?
• Immunisation not generally recommended by
  manufacturers ACIP post partum immunisation for
  non immune including breast feeding mothers
  second dose at 6-8 weeks
• ACIP no contraindication to breast feeding
• Virus not present in breast milk and no
  transmission to babies
• study at gt6 weeks post partum
• Bohlke K et al Obs and Gynae 2003102970-7
• Manufacturers - avoid pregnancy for 3 months
  after dose ACIP avoid pregnancy for 1 month
  after dose

26
Vaccine strategies prepartum

• Protective for the individual
• Selective
• Unreliable
• Probably inequitable as a policy

27
Vaccine strategies - childhood

• Universal immunisation in childhood as per USA
• generation before immunised reach child bearing
  age
• Duration of immunity
• ? Booster doses, ? Frequency
• Effects of childhood immunisation on maternal
  exposure

28
Vaccine strategies

• Adolescent
• Introduction of papilloma virus vaccine will
  facilitate health intervention at this age.
• Selective immunisation only for those with no
  history of chickenpox would reduce costs though
  the wild virus will still circulate and pose risk
  to non immune adults.
• ? Might be used in countries with no childhood
  immunisation and/or in conjunction with childhood
  immunisation

29
Summary

• Chickenpox may be serious for pregnant woman and
  foetus
• Increasing numbers of seronegative women could
  result in increase in chickenpox in pregnancy in
  some countries
• Strategies for immunisation to protect pregnant
  women from chickenpox needs careful
  consideration.
• Vaccine strategy should aim to protect all non
  immune adults and not just women of child bearing
  age in view of severity of infection in adults.