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Mark Eakes MD/MPH Student Graduate Program in Public Health Eastern Virginia Medical School

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  1. “Evaluation of the Efficacy of Sulfadoxine-Pyrimethamine in the Prevention of Transmission of Malaria from the Mother to the Infant” Mark Eakes MD/MPH Student Graduate Program in Public Health Eastern Virginia Medical School June 16, 2008 Site Mentor: Leon Mubikayi, MD MPH Academic Advisor: David O. Matson, MD PhD

  2. Overview • Background on malaria and pregnancy in the Democratic Republic of the Congo (DRC) • Presentation of the study • Discussion of study findings and possible future studies

  3. Why An International Practicum? • Expand exposure of international public health topics to students in the EVMS Graduate Program in Public Health • As a small Program, have a “niche”, which for us is modeling for faith-based organizations how international service can be provided in a rigorously evaluated manner

  4. Why the Congo? • The Presbytery of Eastern Virginia (PEVA) has a >100-year relationship with the Presbyterian Church in the Congo. • A Congolese citizen serves PEVA as its Mission Interpreter. • The MPH Program met with the Mission Interpreter to explore possible interactions and met with the Medical Director of The Christian Medical Institute of the Kasai (IMCK), a multi-service health complex located in Tshikaji, nine miles from Kananga, DRC, during his visit to the U.S. • The Medical Director asked our help in determining how well the DRC national recommendation for preventing mother-to-fetus transmission of malaria is working.

  5. Background • Malaria is the disease caused by infection with1 or more of 4 species of Plasmodium: • Plasmodium falciparum • Plasmodium vivax • Plasmodium ovale • Plasmodium malariae • P. falciparum is the most common and most dangerous of these four species. • Each year, malaria causes over 500 million episodes of clinical illness and up to 2.7 million deaths worldwide. • 90% of illness and death attributable to malaria occurs in sub-Saharan Africa, especially among pregnant women and children under 5 yrs. -Rogerson SJ, Expert Rev Anti Infect Ther, 2006. -Yartey JE, Int J Gynecol Obstet, 2006.

  6. Background • Malaria is transmitted by the bite of the female anopheline mosquito. • The parasite has a very complex lifecycle that includes both a liver and blood phase in humans, and other phases in the mosquito.

  7. Background http://www.cdc.gov/malaria/biology/life_cycle.htm; Accessed: December 1, 2007

  8. Background • Pathogenesis of malaria affects multiple organ systems. • Symptoms include fever, chills, headache, body ache, nausea, vomiting, fatigue, dizziness and malaise. • Most individuals in malaria-infected areas are subject to infection every few days throughout the year. • Many have mild bouts of illness, due to acquired immunity. • During pregnancy: 2 key effects • Mother: anemia • Fetus: • Low Birth Weight • Intra Uterine Growth Restriction (IUGR) -Barnett ED, Textbook of pediatric infectious diseases, 2004.

  9. Background • Symptoms vary among the species of infection, with P. falciparum having the most severe symptoms. • If untreated, P. falciparum malaria can lead to coma, renal failure, pulmonary edema and death. • P. falciparum infection has an unique characteristic called sequestration, in which red blood cells containing mature forms of the parasite adhere to the microvascular epithelium, especially in the brain and placenta. -Barnett ED, Textbook of pediatric infectious diseases, 2004. -Crawley J, Semin Pediatr Infect Dis, 2004.

  10. Background • Global impact of malaria includes more than 40% of the world’s population being at some risk of acquiring the disease. • Economic impact on Africa alone is more than $12 billion per year and impedes annual economic growth by as much as 1.3% per year. -Crawley J, Semin Pediatr Infect Dis, 2004.

  11. Background • For pregnant women, the risk of carrying microscopic parasitemia increases substantially. • P. falciparum sequesters in the intervillous spaces of the placenta. • Normal immunity is hindered as the placenta acts as a “privileged site” for parasite multiplication and shields the parasites from being cleared by the spleen. -Rogerson SJ, Expert Rev Anti Infect Ther, 2006 -White NJ, PLoS Med, 2005.

  12. Background • Maternal anemia is the most obvious impact of malaria upon pregnant women. • An estimated 10,000 deaths occur per year in Africa because of severe maternal anemia alone. • While there are other causes of anemia, the fraction of anemia attributable to malaria is 26%. -Desai M, Lancet Infect Dis, 2007. -Yartey JE, Int J Gynecol Obstet, 2006.

  13. Background • The effects of malaria upon the developing fetus can be devastating. • Low Birth Weight (LBW) is the most important risk factor for infant mortality. • Risk of LBW is approximately doubled if mother has placental malaria. • Studies have suggested that 11.4% of neonatal deaths and 5.7% of all infant deaths in areas of endemic malaria are caused by pregnancy-associated LBW. -Desai M, Lancet Infect Dis, 2007. -Yartey JE, Int J Gynecol Obstet, 2006. -Crawley J, Semin Pediatr Infect Dis, 2004.

  14. Background • Malaria-associated LBW and Intra Uterine Growth Restriction (IUGR) result from poor fetal nutrition because of the placental infection by the malaria parasites. • Premature delivery and LBW are associated with reduced infant iron stores, which predisposes the infant to iron-deficiency anemia in the first year of life. • Estimates of adverse birth outcomes attributable to malaria in areas of stable transmission: • 8-36% of premature births • 13-70% of IUGR • 8-14% of LBW • 75,000-200,000 infant deaths per year. -Yartey JE, Int J Gynecol Obstet, 2006. -Crawley J, Semin Pediatr Infect Dis, 2004. -Newman RD, Trop Med Int Health, 2003.

  15. Background • An important feature of malaria in pregnant women in stable transmission areas is the increased risk of adverse outcomes among paucigravid women (in first or second pregnancy) as compared with multigravid women. • A more potent immunity is acquired through consecutive pregnancies and helps protect these women from many of the symptoms of malaria. • Age is also a factor: younger primagravid and multigravid women are at a higher risk than older primagravid and multigravid women. -Desai M, Lancet Infect Dis, 2007.

  16. Background • HIV/AIDS pandemic in malaria endemic areas adds a greater challenge to those associated with the malaria infection alone. • Co-infection of HIV-positive women with malaria greatly increases chances of passing HIV to their babies. • In one study: • 40% of babies born to HIV-positive mothers with malaria became infected with HIV • Only 15% of babies were infected when born to only HIV-positive mothers • HIV infection also eliminates the gravidity-specific correlation, shifting the risk to all gravidities. -Desai M, Lancet Infect Dis, 2007. -Brentlinger PE, Lancet Infect Dis, 2006 -Cohen J, Science, 2003.

  17. Background • Treatment options are based upon several factors: • Type of Plasmodium species • Drug-resistance of that species • Drug availability • Safety of the drug(s) • Therapeutic goals • Therapeutic goals could include: • Treating an acute infection • Prevention of malaria infection (i.e., travelers) • Clearing the parasite from either the blood or liver • Control of malaria in pregnant women

  18. Background • The approach to managing pregnant women differs because of fetal safety concerns. • Malaria chemoprophylaxis was first reported in Nigeria in 1964, using chloroquine throughout the second and third trimesters. • Positive outcomes resulted in the World Health Organization (WHO) recommending all pregnant women in areas of moderate-high malaria transmission be given chloroquine prophylaxis. -Crawley J, Semin Pediatr Infect Dis, 2004.

  19. Background • Another drug used for chemoprophylaxis was pyrimethamine, but a Nigerian study in 1993 reported P. falciparum also resistant to that drug. • In subsequent years, P. falciparum has become resistant to chloroquine. • A study in Senegal in 2001-2002 demonstrated that pregnant women harbored even more chloroquine-resistant parasites than the general population, probably due to increased drug consumption as part of chemoprophylaxis, leading to increased drug pressure and selection of drug-resistant parasites. -Nosten F, Trop Med Int Health, 2003. -Bertin G, J Antimicrob Chemother, 2005 -Oluwu JA, Afr J Med med Sci, 2000.

  20. Background • In the mid-1990’s, Intermittent Preventive Therapy (IPT) replaced chloroquine-based chemoprophylaxis for the prevention of malaria during pregnancy in most endemic African countries. • One of the main drivers of the shift from chemoprophylaxis to IPT was the difficulty in obtaining high compliance with the frequent administration of the drugs needed for chemoprophylaxis. • IPT offered the simplicity of only requiring the administration of the drugs a few times appeared to be efficacious. -ter Kuile FO, JAMA, 2007. -Rogerson SJ, Expert Rev Anti Infect Ther, 2006.

  21. Background • Although there are many drugs available to treat malaria, only a small number have been shown to be relatively safe for both the mother and her fetus. • Sulfadoxine-pyrimethamine (SP) [brand name Fansidar] is the only antimalarial drug currently used for IPT during pregnancy. • A caution: a 2005 study reported recent increases in resistance to SP in Africa. • Resistance to SP in East Africa is exemplified by28-day failure rates between 30-60%. -ter Kuile FO, JAMA, 2007. -Newman RD, Trop Med Int Health, 2003 -White NJ, PLoS Med, 2005. -Nosten F, Trop Med Int Health, 2003

  22. Background • In addition to drugs, there are other tools for preventing malaria. • The Insecticide Treated Net (ITN) is one such tool, hung over beds and slept under at night when the anopheline mosquito is active. • A study in Western Kenya in 1997 reported that ITN’s reduced the effects of malaria during the first four pregnancies in this endemic area, with improved maternal hemoglobin and reduced risk of LBW. -ter Kuile FO, Am J. Trop Med. Hyg., 2003.

  23. Background • In April 2000, a group of African nations adopted the Abuja Declaration during a summit on Roll Back Malaria (RBM). • Regional leaders committed to ensuring 60%of pregnant women in malaria-endemic areas had access to effective prevention programs with the following targets: • Access to prompt, effective medical care • Supported and promoted access to ITN’s • Supported and promoted IPT -World Health Organization, 2004.

  24. Background • In October 2005, the WHO published recommendations on the use of SP for IPT in areas of moderate-to-high resistance to SP in the African region. • The guidance reiterated that 2 doses of SP should be administered after the first trimester and a third dose “significantly reduced” the prevalence of placental malaria in HIV-positive women when compared with 2 doses. -WHO Regional Office for Africa, 2005.

  25. Background • In the DRC, 97% of the population is exposed to endemic malaria, with the remainder in eastern, mountainous areas exposed to epidemic malaria. • In 1998, a National Malaria Control Program (NMCP) was created with four primary control strategies: • Appropriate case management in both community and health infrastructures • Scaling up the use of ITN’s • Providing IPT for pregnant women • Epidemic prevention and control -DRC Ministry of Health, 2006. -Roll Back Malaria Partnership, 2005.

  26. Background • In 2005, the first-line treatment of malaria was changed to amodiaquine-artesunate combination, with quinine being prescribed for the treatment of febrile episodes. • For IPT, SP is still the current drug choice. • A recent DRC survey showed about 70% of pregnant women attend antenatal clinics: an important issue from a national health policy perspective because antenatal clinics are the primary sites implementing the NMCP. -DRC Ministry of Health, 2006. -Roll Back Malaria Partnership, 2005.

  27. Background • The pace of development of new drugs has not kept up with the pace of increasing resistance over the past couple of decades. • A recent systematic review of studies conducted from 1966 to 2006 to assess resistance of malaria to SP found only 6 African countries represented: DRC was not one of them. • The dearth of information in this central sub-Saharan country is a strong motivator to study the question of the efficacy of SP in pregnant women. -Crawley J, Semin Pediatr Infec Dis, 2004. -ter Kuile FO, JAMA, 2007.

  28. Hypothesis/Aims • Hypothesis: the new national recommendation for intermittent treatment of pregnant women in the DRC will result in a significant reduction in malaria transmission to the fetus. • Aims: • Determine the prevalence of malaria parasitemia among pregnant women in Kasai, DRC • Determine the prevalence of malaria parasitemia among newborns in Kasai, DRC • Relate parasitemia to intermittent treatment of the mother, anemia in the mother and the infant, and the infant’s birth outcome

  29. MethodsStudy Setting Official NameDemocratic Republic of the Congo (DRC), formerly Zaire Population66,660,551 Capital CityKinshasa (9.3 million) Largest CitiesKinshasa, Lubumbashi, Mbuji-Mayi, Kolwezi,Kananga CurrencyCongolese Franc (CDF) LanguagesFrench (official), Lingala, Kingwana, Kikongo,Swahili and Tshiluba ReligionsCatholic, Protestant, others http://www.worldatlas.com/webimage/countrys/africa/cd.htm; accessed 9JUNE2008

  30. MethodsStudy Setting • The Christian Medical Institute of the Kasai (IMCK) is a multi-service health complex located in Tshikaji, nine miles from Kananga, the hub of central Congo. • Founded in 1954 by the American Presbyterian Congo Mission, the facilities and services at IMCK now include: • a 160-bed referral/teaching hospital • schools of nursing and laboratory technology • a clinical teaching program for medical school students • a residency program in Family Medicine • …and a range of community health programs. http://www.afdevinfo.com/htmlreports/org/org_54531.html, accessed 8 JUN 2008.

  31. The Christian Medical Institute of the Kasai

  32. Methods • The Academic Advisor and the Student Investigator traveled to the IMCK in July 2007, to assess the ability of the site to implement the treatment protocol and provide quality data for analysis. • The four clinics and two laboratories participating in the study were visited. • A detailed review of the standards of care in regards to the testing and data collection was conducted with the Medical Director of the IMCK. • He and his research coordinator received CITI human protection training and training in EPIINFO, the software used for creation of the analytic database.

  33. Methods • Following the site visit, protocols were submitted and accepted by the national IRB in the DRC and the IRB at EVMS. • The Academic Advisor visited the site in February, 2008, with an external expert in malaria, to review the data handling procedures and ensure the quality of the malaria diagnostics. • The data were collected and were transmitted electronically to the Norfolk investigators. • The data were then analyzed for association and statistical trends.

  34. Methods Following the site visit, protocols were submitted and accepted by the national IRB in the DRC and the IRB at EVMS. The Academic Advisor visited the site in February, 2008, with an external expert in malaria, to review the data handling procedures and ensure the quality of the malaria diagnostics. The data were collected and were transmitted electronically to the Norfolk investigators. The data were then analyzed for association and statistical trends. 35

  35. Methods • The Health Zone of Tshikaji consists of 12 Health Centers and 10 Maternities (antenatal clinics) • The four study sites consisted of three Maternities and The Good Shepherd Hospital: • TSH: Tshikaji Clinic (1 Km from the hospital) • KAL: Kalemba Clinic (7 Km Kananga) • PAX: PAX Clinic in downtown Kananga • HBB: The Good Shepherd Hospital next to Tshikaji (about 14 Km from Kananga) • Women attend the antenatal clinics for routine prenatal care, blood tests, medicine administration, delivery and other related services.

  36. Methods • Women retain their medical records: a pink antenatal card where all of the data are recorded. • For the study, a form was developed to assign each women a unique study number coded by site and to record all of the pertinent data for the study (over 30 variables). Women were asked permission to place the number on their card so data from subsequent visits would be properly recorded in the data forms. • The de-identified data were entered into EPIINFO and then sent to the Norfolk investigators.

  37. Methods • The normal standard of care was followed: • Women presenting for pre-natal care had blood tested for: • Malaria parasitemia (thick smear) • Hematocrit • HIV • Women were questioned about bed net use • SP was administered according to the following criteria/schedule: • Between 16 and 34 weeks gestation • 2 doses, at least one month apart • 3rd dose if HIV-positive

  38. Methods • At delivery, the blood was drawn from the women for: • Malaria parasitemia • Hematocrit • The infant’s cord blood was used to determine: • Malaria parasitemia • Hematocrit • Other infant outcomes measured included: • Birth Weight • Live or Dead • Vaginal or Cesarean delivery • Gender • Some women presented only at delivery with no record of treatment. Provided a “No Treatment” comparison group.

  39. Good Shepherd Hospital, part of the medical complex of the Christian Medical Center of the Kasai.

  40. PAX Clinic, downtown Kananga

  41. Tshikaji Antenatal Health Center

  42. Kalemba Antenatal Health Center

  43. Results Enrollment Data Mothers Enrolled: 1815 Number Deliveries: 674 First Day of Enrollment: July 27, 2007 Last Day of Enrollment: May 17, 2008 Date of First Birth: September 19,2007 Date of Last Birth: May 17, 2008

  44. Results Aim 1: Determine the prevalence of malaria parasitemia among pregnant women in Kasai, DRC ENROLLMENT SitePositive TotalPercent HBB 5 58 8.6 KAL 33 102 32 PAX 405 1021 40 TSH 64 380 17 TOTAL 507 1561 32.5 DELIVERY SitePositive TotalPercent HBB 6 115 5.2 KAL 9 50 18 PAX 83 438 19 TSH 4 71 5.6 TOTAL 102 674 15.1 2 test, p < .001 2 test, p < .001

  45. Results Aim 2: Determine the prevalence of malaria parasitemia among newborns in Kasai, DRC DELIVERY SitePositive TotalPercent HBB 0 115 0 KAL 1 50 2 PAX 8 438 1.8 TSH 2 71 2.8 TOTAL 11 674 1.6 2 test, p = .01