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