2. Malaria in Pregnancy Steve Meshnick, M.D., Ph.D. Professor of Epidemiology and Microbiology

3. Outline The global burden of malaria Importance of malaria in reproductive health UNC research activities

5. Sachs & Malaney, Nature, 2002

6. 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

7. Types of malaria Plasmodium falciparum –Most common –Multi-drug resistant –Most dangerous Plasmodium vivax –Latin America & Asia Plasmodium malariae Plasmodium ovale

8. Geography of malaria sub-Saharan Africa P. falciparum Year-round transmission Incidence  >1/person/yr Adults are immune Affects children < 5 & primigravidae Asia & Latin America P vivax >P. falciparum Seasonal transmission Incidence is low Little or no immunity Affects people of all ages and pregnant women of all gravidity

9. Malaria control toolbox Antimalarial drugs –Prophylaxis –Case management (treatment) –Intermittent Preventive Therapy Vector control –Household spraying –Insecticide-treated bednets Vaccine

10. 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

11. 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)

12. Household spraying Anophelines rest on walls and ceiling after blood meal DDT is best: –Affordable, effective, safe Requires too much infrastructure for poor countries

13. 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?

14. 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)

15. Outline The global burden of malaria Importance of malaria in reproductive health UNC research activities

16. 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

17. Placental malaria Parasites accumulate and thrive in the placenta Only affects primigravidae in areas of high transmission

18. 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

19. 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

20. 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)

21. 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

22. 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

23. 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

24. 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

25. Malaria is the most common and easily preventable cause of poor birth outcomes in the world

26. 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

27. Outline The global burden of malaria Importance of malaria in reproductive health UNC research activities

28. 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

33. Queen Elizabeth Central Hospital QECH provides primary and secondary health services for Blantyre. Also referral center for Southern Malawi

34. 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

35. 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

36. Effects of malaria on HIV viral load

37. 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 <48 hrs, 6 wks, and 12 wks

38. 480 (28.9%) HIV+ve 387 (80.6%) delivered 304 Placental histopathology done 74 (24.3%) Malaria + 230 Malaria - 342 placental smear done 39 (11.4%) Malaria + 303 Malaria - 61 (12.7%) Peripheral MPs+ Patient characteristics 2364 asked for consent (Dec 2000- June 2002) 1662 (70.3%) consented

39. 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)

40. 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

41. 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

42. 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

43. 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?

44. HIV impairs immunity to malaria Mount et al., Lancet, 2004

45. 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?

46. 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?

47. Possible alternatives to SP SP-artesunate SP-azithromycin Amodiaquine Mefloquine Lapdap

48. SP vs SP-artesunate vs SP-azithromycin Study ongoing Expected completion of pilot (120 women) by summer 2004

49. 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)

50. 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 NH 2 H 2 N N OCH 3 H 3 CO

51. 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

52. Acknowledgements