malaria in pregnancy
DESCRIPTION
Malaria in Pregnancy. Steve Meshnick, M.D., Ph.D. Professor of Epidemiology and Microbiology. Outline. The global burden of malaria Importance of malaria in reproductive health UNC research activities. Sachs & Malaney, Nature, 2002. Malaria 2004. 90% of cases and deaths in Africa - PowerPoint PPT PresentationTRANSCRIPT
Malaria in Pregnancy
Steve Meshnick, M.D., Ph.D.
Professor of Epidemiology and Microbiology
Outline
• The global burden of malaria
• Importance of malaria in reproductive health
• UNC research activities
Sachs & Malaney, Nature, 2002
Malaria 2004
• 90% of cases and deaths in Africa
• >300 million cases/year• Periodic fever, chills, prostration
• ~2 million deaths/year, mostly in children <5– Cerebral malaria, severe anemia
Types of malaria
• Plasmodium falciparum– Most common– Multi-drug resistant– Most dangerous
• Plasmodium vivax– Latin America & Asia
• Plasmodium malariae• Plasmodium ovale
Geography of malaria
sub-Saharan AfricaP. falciparum
Year-round transmission
Incidence >1/person/yr
Adults are immune
Affects children < 5 & primigravidae
Asia & Latin AmericaP vivax >P. falciparum
Seasonal transmission
Incidence is low
Little or no immunity
Affects people of all ages and pregnant women of all gravidity
Malaria control toolbox• Antimalarial drugs
– Prophylaxis– Case management (treatment)– Intermittent Preventive Therapy
• Vector control– Household spraying– Insecticide-treated bednets
• Vaccine
Case management
sub-Saharan AfricaLow income
High transmission
Sulfadoxine- pyrimethamine
Presumptive therapy
Asia & Latin AmericaMiddle income
Low transmission
Artemisinin Combination Therapy
Microscopy and treatment of slide-confirmed cases
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)
Household spraying
• Anophelines rest on walls and ceiling after blood meal
• DDT is best: – Affordable, effective, safe
• Requires too much infrastructure for poor countries
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?
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)
Outline
• The global burden of malaria
• Importance of malaria in reproductive health
• UNC research activities
Malaria in pregnant women
• >50 million pregnant women exposed to malaria each year
• ~3.5 million pregnant women infected
Poor birth outcomes
Poor maternal outcomes
Placental malaria
• Parasites accumulate and thrive in the placenta
• Only affects primigravidae in areas of high transmission
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
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
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)
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
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
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 (<25%)
• New recommendations include 4-doses or monthly SP
• Prevents 23-86% of severe maternal anemia
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
Malaria is the most common and easily preventable cause of poor birth outcomes in the world
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
Outline
• The global burden of malaria
• Importance of malaria in reproductive health
• UNC research activities
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
Queen Elizabeth Central Hospital
• QECH provides primary and secondary health services for Blantyre.
• Also referral center for Southern Malawi
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
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
Effects of malaria on HIV viral load
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
OutcomeHIV status by real-timePCR at <48 hrs, 6 wks, and 12 wks
480 (28.9%) HIV+ve
387 (80.6%) delivered
304 Placental histopathology done
74 (24.3%) Malaria +
230Malaria -
342 placental smear done
39 (11.4%)Malaria +
303Malaria -
61 (12.7%) Peripheral MPs+
Patient characteristics2364 asked for consent (Dec 2000- June 2002) 1662 (70.3%) consented
Geometric Mean
HIV viral load
P-value
Peripheral viral load
Malaria positive (n=69)
Malaria negative (n=200)
62,359
24,814
0.0007
Placental viral load
Malaria positive (n=66)
Malaria negative (n=196)
14,371
5,631
0.008
Association between HIV viral load and malaria (univariate)
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
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
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
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 CD4’s or decreasing antibody?
HIV impairs immunity to malaria
Mount et al., Lancet, 2004
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?
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?
Possible alternatives to SP
• SP-artesunate
• SP-azithromycin
• Amodiaquine
• Mefloquine
• Lapdap
SP vs SP-artesunate vs SP-azithromycin
• Study ongoing
• Expected completion of pilot (120 women) by summer 2004
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)
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 >90% of patients (supported by MMV)
O N
N H 2H 2N
NOCH3
H3CO
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
Acknowledgements