Epidemiology and control of malaria during pregnancy

1. Epidemiology and control of malaria during pregnancy M. James Eliades, MD, MPH Centers for Disease Control and Prevention Division of Parasitic Diseases

2. Objectives of talk • Discuss the epidemiology of malaria during pregnancy in sub-Saharan Africa • Present evidence for current intervention strategies • Mention gaps in our knowledge

3. Epidemiology

4. Malaria during pregnancy: bad news • 50 million women in malaria endemic areas become pregnant each year (UNICEF) • Malaria during pregnancy most widely evaluated in sub-Saharan Africa and estimated to account for: • 400,000 cases of severe anemia in pregnant women (Guyatt 2001) • ~ 35% of preventable low birth weight (Steketee 2001, Guyatt 2004) • 3-8% of infant mortality (Steketee 2001, Guyatt 2001) • 75,000 - 200,000 infant deaths annually (WHO/UNICEF Africa Malaria Report 2003)

5. Where in the World is Malaria Found? Distribution of Malaria

6. Malaria during pregnancy • Maternal and perinatal effects depend on intensity of transmission: Plasmodium falciparum in high transmission areas is most well studied - responsible for most morbidity & mortality

7. “Stable” malaria Prevalence persistently high Transmission can continue with few vectors Collective immunity is high P. falciparum Young children and pregnant women at greatest risk Type: sub-Saharan Africa “Unstable” malaria Variability in space and time Disease fluctuates (inc. epidemics) Collective immunity is low P. vivax, also P. falciparum All ages at risk Type: S.E. Asia Transmission intensity

8. Malaria in Pregnancy • Transmission levels effect consequences of disease • Low transmission/little or no immunity • Symptomatic • Severe malaria • Anemia • Adverse birth outcomes • Moderate to high transmission/immunity • Asymptomatic • Severe anemia • Low birth weight

9. Malaria during pregnancy:stable transmission areas P. falciparum malaria • Acquired immunity - high • 1st & 2nd pregnancies at greatest risk • Prevention essential Asymptomatic infection Placental sequestration Anemia Nutrient transport Low birth weight Risk of infant mortality

10. Malaria during pregnancy:unstable transmission areas • Acquired immunity - low • All pregnancies affected equally P. falciparum malaria Clinical illness • Recognition and case management needed in addition to prevention Severe disease Risk to mother (death) Risk to fetus (stillbirth, abortion)

11. Vulnerable groups among pregnant women • Primigravidae • Adolescents • HIV-positive women • Women in rural areas

12. Placental parasitemia by pregnancy number, Kisumu, Kenya, 1996-98 Parasite density/mm3 % parasitemic 772 402 479 Adapted from Van Eijk et al.

13. Effects on Maternal Health • Severe anemia • Proportion in all gravidities attributable to malaria: 26% • Approximately 400,000 cases per year

14. Effects on Birth Outcome • Low Birth Weight • 20% of LBW deliveries, 35% of preventable LBW • Responsible for at least 100,000 infant deaths • Intrauterine growth retardation (IUGR) • Preterm delivery • Stillbirth • Twice the risk with placental malaria(OR 2.19)

15. Low birth weight

16. Effects on Birth Outcomes: Low Transmission Settings • In Africa • LBW: 9.3% • Preterm delivery: 8.6% • Stillbirths: 3.7% • Outside Africa • LBW: 16.0% • Preterm delivery: 11.0% • Stillbirths: 3.0%

17. ³ 2500 <1500 1500-1999 2000-2499 Neonatal Mortality Rates by BirthweightMangochi, MalawiSeptember 1987 - June 1989 1000 800 800 600 Deaths per 1000 Live Births 400 300 200 49 26 0 1.0 Relative Risk 31 11.7 2.4 Adapted from Steketee et al.

18. Pathophysiology

19. Placenta • Sequestration of parasites in the placenta • Red blood cells infected with P. falciparum attach to placenta • Can be present without peripheral parasitemia • Increased susceptibility of primigravidae

20. Congenital Malaria • Can occur with all four species • Parasites cross the placenta and enter the fetal circulation • Immunity of mother affects severity • Non-immune: stillbirth, perinatal death, fever/anemia/jaundice/splenomegaly up to six weeks post-delivery • Immune: usually asymptomatic; parasties rapidly cleared

21. HIV Among Pregnant Women in sub-Sahara Africa • Estimated 27 million people in Africa living with HIV/AIDS • 55% of sub-Sahara Africa adult HIV infection in reproductive-age women • Estimated increase in MIP attributable to HIV is 5.5% and 18.8% for populations with HIV prevalence of 10% and 40%

22. HIV Seroprevalence Among Women Attending Antenatal Clinics in Urban Areas UNAIDS, Report on the Global HIV/AIDS Epidemic, 2002

23. HIV & Malaria During Pregnancy • HIV+ women have higher prevalences and densities of parasitemia • All parities affected • Risk of infant mortality higher in babies born to mothers co-infected with HIV and placental malaria • Increased vertical transmission of HIV?

24. Study 2. Placental parasitemia by HIV status and pregnancy number, Kisumu, Kenya, 1996-98 Parasite density/mm3 % parasitemic 231 159 197 772 402 479 HIV (+) HIV (-) Total n = 2263 Summary RR = 1.63 (1.41-1.89), p<0.001

25. Intermittent preventive therapy by HIV status and SP efficacy Management

26. Current strategies

27. Options for malaria control during pregnancy • Drugs • Chemoprophylaxis • Intermittent preventive treatment during pregnancy (IPTp) • Febrile case management • Insecticide Treated Nets (ITNs) • Prevention and treatment of anemia • Hematinic supplementation • Nutritional counseling • Vaccines?

28. Chemoprophylaxis: no longer a recommended strategy in high transmission areas • Most regimens require weekly or more frequent dosing • Chloroquine (CQ) is the most commonly used drug • Usefulness limited by: • Difficulty in delivering and sustaining intervention • Poor adherence to regimen • Side effects of CQ (especially itching) • Rising levels of P. falciparum resistance to CQ • Poor program effectiveness of CQ chemoprophylaxis

29. Intermittent Preventive Treatment for pregnancy (IPTp)

30. Intermittent preventive treatment (IPTp): an alternative strategy • Most studied regimen: Sulfadoxine-pyrimethamine (SP) 2 curative courses (3 tablets) • One course during second trimester • One course during third trimester • Inexpensive • Easily deliverable (can be given under direct observation) • Safe • Efficacious

31. Course 2 30-36 wks Course 1 24-28 wks 20 10 30 Conception Birth Intermittent preventive treatment -- the two dose SP strategy Fetal growth velocity  Weeks of gestation

32. Intermittent preventive treatment (IPTp) with SP: results of clinical trials CQ = chloroquine; SP = sulfadoxine-pyrimethamine; CM = case management; LBW Low birth weight NE = not evaluated; NS = not statistically significant (p > 0.05) * Data in thesis; not included in published manuscript)

33. Intermittent preventive treatment (IPTp) with SP: program effectiveness evaluations SP = sulfadoxine-pyrimethamine; Hb Hemoglobin; LBW Low birth weight NS = not statistically significant (p > 0.05)

34. IPTp with SP: summary of evidence and benefits • 2 doses of IPT with SP is associated with: • Reduction in 3rd trimester maternal anemia • Reduction in placental malaria parasitemia • Reduction in low birth weight • At least 2 doses required for optimal benefit • Monthly dosing more beneficial in HIV+ women • Regimen is safe and well tolerated

35. Insecticide treated bed nets (ITNs)

36. ITNs-efficacy in pregnancy: design

37. ITNs during pregnancy • Meta analyses of 5 RCTs (4 from Africa, 1 from Thailand) • In Africa, ITNs reduced • placental parasitemia in all pregnancies (RR=0.79 [0.63-0.98]) • LBW (RR=0.77 [0.61-0.98]) and stillbirths/abortions in G1-4 (RR=0.67 [0.47-0.97])* • In Thailand, ITNs reduced anemia and stillbirth/abortions in all pregnancies Source: Gamble 2006

38. Case management of malaria and anemia

39. Safe drugs Chloroquine Quinine / quinidine Proguanil, chlorproguanil Pyrimethamine Sulfonamides Dapsone (+pyrimethamine= Maloprim) Mefloquine (prophylaxis) Clindamycin (300 mg qid, 5-7 days) Artemisinins (2nd and 3rd) Drugs with questionable safety or insufficient data Mefloquine (treatment dose) Artemisinins (1st) Amodiaquine Azithromycin Lumefantrine (component of coartem/Riamet) Combination therapy Artemisinin derivative with other drugs Lapdap (chlorproguanil-dapsone) Atovaquone-proguanil (Malarone) Amodiaquine-SP Case management of malaria in pregnancy

40. Tetracycline Doxycycline Halofantrine Primaquine Tafenoquine Note: if serious illness, and where limited number of drugs are available, it is necessary to balance the risk of maternal death with the hypothetical risks to the infant Antimalarials contra-indicated in pregnancy

41. Antimalarial drug policy An antimalarial drug policy must balance between: Access Rational use • Equitable access to reduce mortality and morbidity • Emphasis on community management (e.g. use of lay persons for distributing drugs) Reduces development of resistance Emphasis on regulation and controlled use (e.g. prescription only drugs)

42. Interventions depend on level of transmission • High transmission areas • Women don’t feel sick- need prevention of adverse effects • Prevention by IPT and nets • Low transmission areas • IPT will not necessarily keep the woman well • Prevention by nets • Any role for chemoprophylaxis in select areas? • Both areas need prompt appropriate febrile case management

43. The Results of Preventing Infection • Reduce the risk of severe maternal anemia: 38% • Reduce the risk of LBW: 43% • Reduce the risk of perinatal mortality: 27%

44. From Research to Policy to Implementation

45. African summit on Roll Back Malaria (RBM) – Abuja 2000 • At least 60 percent of those at risk of malaria, particularly pregnant women and children under 5 years of age, benefit from the most suitable combination of personal and community protective measures such as insecticide-treated mosquito nets … • At least 60 percent of all pregnant women who are at risk of malaria, especially those in their first pregnancies, have access to intermittent preventive treatment.

46. Malaria during pregnancy: Research to program - a continuous cycle Programmatically relevant research Monitoring & evaluation Program implementation Policy change

47. Status of IPTp policy and implementation in Africa (2001) IPTp policy (5) Very little or no malaria (7) No known IPT policy

48. Rapid assessment of burden of malaria during pregnancy • Survey at antenatal care: • peripheral malaria parasitemia and anemia • Survey at delivery units • Peripheral and placental parasitemia, birth weight, and gestational age • Other modules: severe disease, health facility assessment, rapid ethnographic evaluation

50. Example: Burkina Faso • Joint collaboration of CDC with JHPIEGO and Burkina Faso Ministry of Health • Baseline 2001 rapid assessment examined: rates of peripheral and placental parasitemia, maternal anemia, and low birth weight • >22% of women had placental parasitemia despite widespread use of chloroquine chemoprophylaxis • Pilot intervention of IPTp with 3 doses of SP begun in 2003; ITN distribution through NGO programs • Repeat rapid assessment (program evaluation) conducted in 2004