Malaria in Pregnancy

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Malaria in Pregnancy

• Steve Meshnick, M.D., Ph.D.
• Professor of Epidemiology and Microbiology

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Outline

• The global burden of malaria
• Importance of malaria in reproductive health
• UNC research activities

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Sachs Malaney, Nature, 2002
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Malaria 2004

• 90 of cases and deaths in Africa
• gt300 million cases/year
• Periodic fever, chills, prostration
• 2 million deaths/year, mostly in children lt5
• Cerebral malaria, severe anemia

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Types of malaria

• Plasmodium falciparum
• Most common
• Multi-drug resistant
• Most dangerous
• Plasmodium vivax
• Latin America Asia
• Plasmodium malariae
• Plasmodium ovale

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Geography of malaria

• sub-Saharan Africa
• P. falciparum
• Year-round transmission
• Incidence ?gt1/person/yr
• Adults are immune
• Affects children lt 5 primigravidae

• Asia Latin America
• P vivax gtP. falciparum
• Seasonal transmission
• Incidence is low
• Little or no immunity
• Affects people of all ages and pregnant women of
  all gravidity

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Malaria control toolbox

• Antimalarial drugs
• Prophylaxis
• Case management (treatment)
• Intermittent Preventive Therapy
• Vector control
• Household spraying
• Insecticide-treated bednets
• Vaccine

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Case management

• sub-Saharan Africa
• Low income
• High transmission
• Sulfadoxine- pyrimethamine
• Presumptive therapy

Asia Latin America Middle income Low
transmission Artemisinin Combination
Therapy Microscopy and treatment of
slide-confirmed cases
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Intermittent Preventive Therapy (IPT)

• Areas of high transmission
• Therapeutic doses of SP given periodically to all
  pregnant women or infants at risk
• Takes advantage of
• High utilization by pregnant women of antenatal
  clinics
• High coverage of infants for EPI vaccination
  visits (2, 3, 9 mos)

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Household spraying

• Anophelines rest on walls and ceiling after blood
  meal
• DDT is best
• Affordable, effective, safe
• Requires too much infrastructure for poor
  countries

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Insecticide Treated Nets

• Bednets impregnated with permethrin insecticide
• Need retreatment every 6 months
• New permanets do not need retreatment
• Act as human-baited mosquito traps and are better
  with high coverage
• Should they be socially marketed or freely
  distributed?

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Global efforts to control malaria

• Roll Back Malaria (WHO)
• Set achievable goals
• Individual country plans
• Global Fund for AIDS, TB and Malaria
• Gates Foundation (MMV, GAVI)

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Outline

• The global burden of malaria
• Importance of malaria in reproductive health
• UNC research activities

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Malaria in pregnant women

• gt50 million pregnant women exposed to malaria
  each year
• 3.5 million pregnant women infected
• ?Poor birth outcomes
• ?Poor maternal outcomes

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Placental malaria

• Parasites accumulate and thrive in the placenta
• Only affects primigravidae in areas of high
  transmission

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Gravidity and malaria

• Primigravidae have no pre-existing immunity to
  placental parasites and are highly susceptible
• In high transmission areas, primigravidae develop
  immunity to placental parasites and are protected
  in subsequent pregnancies
• In low transmission areas, multigravidae are
  unexposed and unprotected

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Effects of malaria on pregnant women

• Poor birth outcomes
• Low birth weight due to preterm delivery (PTD)
  and intrauterine growth retardation (IUGR)
• abortions, stillbirths
• Maternal outcomes
• Anemia, maternal mortality

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Poor birth outcomes

• In African studies, malaria accounts for
• 8-14 of all low birth weight
• 3-8 of infant mortality
• (Steketee et al., Am. J. Trop. Med. Hyg, 2001)

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Maternal mortality

• Responsible for 0.5 23 of maternal deaths in
  Africa
• Malaria causes severe anemia and ? platelets can
  predispose to death from hemorrhage
• www.prema-eu.org

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Interventions

• Intermittent Preventive Therapy (IPT)
• sulfadoxine-pyrimethamine (SP)
• Insecticide-Treated Nets (ITNs)
• RBM goals 60 of pregnant women in endemic
  areas should have access to both by 2005

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IPT

• Malawi first to introduce (1993)
• Two therapeutic doses of SP to all pregnant women
  at quickening and at 28-34 wks Inexpensive
  (0.20)
• 2-dose coverage is still low (lt25)
• New recommendations include 4-doses or monthly SP
• Prevents 23-86 of severe maternal anemia

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ITNs

• Cost 4.00
• Reduce malaria, severe anemia and LBW by 30-50
• Socially marketed nets (1.00)
• Low uptake
• Freely distributed nets
• High uptake and well utilized
• Less sustainable

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Malaria is the most common and easily preventable
cause of poor birth outcomes in the world
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Programmatic priorities

• Integration of malaria prevention into
• Reproductive health programs
• Programs to prevent mother-to-child transmission
  of HIV
• Increase uptake of IPT and ITNs
• Make programs sustainable

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Outline

• The global burden of malaria
• Importance of malaria in reproductive health
• UNC research activities

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Malawi

• Population 11 million
• Per capita income 180
• Per capita expenditure on health 10
• Malaria prevalence ?100
• HIV prevalence 15-30
• Life expectancy 41 yrs

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Queen Elizabeth Central Hospital

• QECH provides primary and secondary health
  services for Blantyre.
• Also referral center for Southern Malawi

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Pathologenesis of malaria in pregnancy

• During normal pregnancy, the cellular immune
  response (Th1) is suppressed to prevent fetal
  rejection
• Malaria stimulates the Th1 response ?
  intrauterine growth retardation
• Malaria stimulates expression of an HIV
  co-receptor (CCR5) in the placenta
• Moormann et al., JID, 1999 Tkachuk et al., JID
  2001 Abrams et al., Am. J. Reprod. Immunol., 2004

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Malaria and HIV co-infections during pregnancy

• Up to 10 of pregnant women may be co-infected
  with both HIV and malaria
• HIV-infected pregnant women have more frequent
  and severe malaria
• Malaria infection might increase mother-to-child
  transmission of HIV
• Infant mortality rate for offspring of
  co-infected mothers is 3-8 fold higher than
  singly infected mothers

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Effects of malaria on HIV viral load
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Malaria-HIV in Pregnancy study

• Pre-labor
• Consent
• HIV Counseling Testing
• Blood for malaria, Hb,
• HIV, HIV viral load, CD4 and syphilis.
• Onset of Labor
• Nevirapine to mother
• Delivery
• Nevirapine to baby
• Placental blood and tissue
• Birth outcome

Outcome HIV status by real-time PCR at lt48 hrs,
6 wks, and 12 wks
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Patient characteristics
2364 asked for consent (Dec 2000- June 2002)
1662 (70.3) consented
480 (28.9) HIVve
61 (12.7) Peripheral MPs
342 placental smear done
387 (80.6) delivered
304 Placental histopathology done
39 (11.4) Malaria
303 Malaria -
74 (24.3) Malaria
230 Malaria -
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Association between HIV viral load and malaria
(univariate)
Geometric Mean HIV viral load P-value
Peripheral viral load Malaria positive (n69) Malaria negative (n200) 62,359 24,814 0.0007
Placental viral load Malaria positive (n66) Malaria negative (n196) 14,371 5,631 0.008
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Multivariate analyses

• Malaria is associated with 1.7-fold increase in
  peripheral HIV viral load and a 2-fold increase
  in placental viral load after adjusting for CD4
  cell count and hemoglobin concentrations
• Since a 1-log increase in peripheral viral load
  is associated with a 2.5-fold increase in MTCT,
  then malaria might increase MTCT by 25.
• Mwapasa, et al., AIDS, 2004

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Does malaria promote MTCT of HIV?

• Study on-going, but to date, no association
  between malaria and MTCT seen
• Currently, only 10 power to detect the 25
  difference
• Indirect evidence for an effect on MTCT
• Malaria? viral load? MTCT
• Malaria? fever ? MTCT
• Malaria? LBW ? MTCT

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Public Health Implications

• 500,000 live births/year in Malawi
• ? 100,000 to HIV() women
• ? 20,000 HIV() babies (if nevirapine used)
• 6,000 HIV() babies born to malaria ()
  mothers/yr
• Better malaria prevention could prevent 1,200 new
  infections

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HIV and susceptibility to malaria

• HIV-infected pregnant women have more frequent
  and severe malaria
• Is the effect of HIV on malaria dependent on
  decreasing CD4s or decreasing antibody?

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HIV impairs immunity to malaria
Mount et al., Lancet, 2004
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Important issues in malaria-HIV interactions

• Can prevention or treatment of malaria delay
  progression of HIV disease?
• Does HIV affect susceptibility to malarial
  disease in children?
• Does ART restore immunity to malaria?

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IPT 2004

• 2-dose IPT with SP ineffective in HIV-infected
  women
• SP IPT also losing effectiveness due to drug
  resistance
• What should replace SP?

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Possible alternatives to SP

• SP-artesunate
• SP-azithromycin
• Amodiaquine
• Mefloquine
• Lapdap

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SP vs SP-artesunate vs SP-azithromycin

• Study ongoing
• Expected completion of pilot (120 women) by
  summer 2004

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Can new IPT regimens delay the onset of drug
resistance?

• New low-cost assays to measure malaria resistance
  to
• SP (Alker et al, AAC, in press)
• Quinolines (Purfield et al., Malaria J, in press)

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New drugs for malaria

• DB289 developed by Tidwell group and for
  treatment of African sleeping sickness (supported
  by Gates Foundation)
• Effective in an initial trial against P.
  falciparum in Thailand curing gt90 of patients
  (supported by MMV)

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Summary

• Malaria is an enormous reproductive health
  problem, especially in sub-Saharan Africa
• IPT and ITNs are inexpensive and effective
  interventions
• Investment in malaria control can do the most
  good for the least amount of money

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Acknowledgements