PREVENTING MALARIA AND ANEMIA IN PREGNANCY: A CASE-CONTROL STUDY OF INTERMITTENT PREVENTATIVE TREATMENT ON BIOKO ISLAND, EQUATORIAL GUINEA TRAVELING SCHOLARS PROPOSAL JOSEPHINE CZECHOWICZ, SMSI DR. YVONNE MALDONADO DR. LUIS BENAVENTE APRIL 17, 2006 TABLE OF CONTENTS MEDICAL SCHOLARS COVER PAGE 3 RELEVANT EXPERIENCE 4 INVESTIGATORS 5 FIELD SITE 6 LEARNING OBJECTIVES 7 PROPOSAL ABSTRACT 8 SPECIFIC AIMS 9 BACKGROUND AND SIGNIFICANCE 9 EXPERIMENTAL DESIGN 11 INTERPRETATION OF RESULTS 14 POTENTIAL SOURCES OF ERROR 14 RELEVANCE TO MEDICINE 15 JUSTIFICATION FOR AWAY EXPERIENCE 15 BIBLIOGRAPHY 16 APPENDICES APPENDIX I: QUESTIONNAIRES ENGLISH 18 SPANISH TRANSLATIONS 20 APPENDIX II: IRB APPLICATION RECORD 22 APPENDIX III: CONSENT FORMS 23 Please see paper copy for signatures. RELEVANT EXPERIENCE Prior Institutions: Carleton College Major, Concentration: Biology, Biochemistry Minor: Spanish Degree: B.A. June 2004 Research Where and Duration Average Scholarly Publication Topic When in hours Contributions Months per week Synthesis of -Carleton Total of Summer: -Synthesized Abstract and Poster at lead College 10 50h/week substrate American Chemical Society compounds for Department months analogue Conference, 2004 drugs against of Chemistry Academi inhibitors trypanosomes c year: -Summer 10h/week -Tested 2002, 2003 inhibitory kinetics -Throughout 2003 academic year Antibiotic -Center for 12 40-50 -Tested 404 -Abstracts and Posters: resistance of Vaccine weeks hours per isolates of S. Northern California Streptococcus Development week pneumoniae for International Health pneumoniae in Santiago, resistance to 16 Conference, Chilean Santiago, Chile antibiotics Infectious Disease Chile Conference -Summer -Generated 2004 antibiotic -Manuscript in preparation resistance profile for Santiago, Chile Molecular -National 1 year 40-50 -Investigated -Abstract and Poster: Young mechanisms of Cancer hours per role of BAG-3 Investigators Meeting, 2005 ovarian cancer Institute, week protein in metastasis NIH, lab of apoptosis -Presentation: NIH Post- Dr. Elise baccalaureate seminar Kohn series -2004-2005 -Publications: Pharmacogenomics, Women’s Health, manuscript in preparation INVESTIGATORS Protocol Director: Josephine (JoAnn) Czechowicz I am a first-year medical student. My main interests are women’s health, infectious disease, international health and pediatrics. Before coming to Stanford, I did research on drug design, molecular signaling and epidemiology. The project that intrigued me most was a study of antibiotic resistance I conducted as part of a Fogarty International Research Fellowship in Santiago, Chile. My work in Chile ignited my interested in international health. Here at Stanford, I am pursuing a concentration in Women’s Health. I have already taken several classes in the concentration including Women and Health Care (the McGann lecture series) as well as Current Topics and Controversies in Women's Health and Sex-based Biology, Current Issues in Reproductive Health, and Mommies and Babies in the winter. I so enjoyed the Mommies and Babies class that I have applied for the TA position for next year. My interest in women’s health inspired me to found a new student group called “Women and Medicine” focused on educating my peers about major health issues pertinent to women in the US and around the world. Stanford Advisor: Yvonne Maldonado, M.D. Dr. Maldonado is Associate Professor of Pediatric Infectious Disease at Stanford. She has significant expertise in childhood infection and perinatal transmission of disease, most specifically HIV, but also malaria. Additionally, Dr. Maldonado has done a large amount of fieldwork, with field sites in Mexico and Zimbabwe. Dr. Maldonado is the founder and director of the Stanford Infectious Diseases and Immunology Center. She serves on federal, national and international advisory committees relevant to pediatric infectious diseases, pediatric vaccines and international health. On-Site Advisor: Luis Benavente, M.D. Dr. Luis Benavente has over 20 years of experience in public health, as well as maternal and child health. Accredited as a Specialist in Epidemiology, Luis has extensively published in epidemiology of nutritional disorders, nutrition and infection, and micronutrient deficiencies. He served as both Professor and Head of the Department of Public Health at the Universidad Peruana Cayetano Hereida, and worked at the Peruvian Institutes of Health in their Research Center for 13 years. Luis then went on to work with Project HOPE in Guatemala, Nicaragua, Peru and in the US from 1996-2002. Luis currently is the Senior Health Program Officer for Medical Care Development International. He holds a Medical Degree and a Masters of Science Degree in Microbiology and Immunology. FIELD SITE Obstetrics and Family Planning Clinic, Malabo Regional Hospital This facility is the central prenatal facility on Bioko Island, providing prenatal care to over 70% of the island’s pregnant women annually. The clinic staffs three obstetricians and typically sees 40-50 patients per day. The facility has agreed to provide me with access to patients upon check in and a private space for me to conduct malaria and anemia tests, as well interview my subjects. Medical Care Development International (MCDI) and the Bioko Island Malaria Control Project (BIMCP) The government of Equatorial Guinea, Medical Care Development International and Marathon Oil Corporation have developed and are actively engaged in a comprehensive malaria control project for Bioko Island, Equatorial Guinea. This joint effort is expected to contribute significantly to the overall health and quality of life of the people of Equatorial Guinea. The malaria control program will adopt a strategic plan designed around three program goals: Reduce the transmission of the malaria parasite through mosquito control programs and improved preventive measures at the household and the community level Improve the health care delivery systems for malaria cases by establishing malaria treatment centers that will use standardized protocols, diagnosis and referrals Enhance surveillance systems and operational research to strengthen Equatorial Guinea’s capacity to conduct surveys and implement an effective reporting and monitoring system My on-site collaborator in this project, Luis Benavente, is Senior Health Project Officer of MCDI. Our academic inquiry has the potential to positively impact the second and third of the goals of the BIMCP. LEARNING OBJECTIVES To understand the process of community-based research from conception to publication. This objective will be attained through the process of completing the project. At present I have conceived of my project, set up collaboration with a community- based partner, written a research proposal, planned appropriate statistical analysis and filed for IRB approval. Once I arrive in Bioko, I will learn about the obstacles to research in a resource-poor setting and how to overcome them to complete my investigation. Finally, upon my return, I will work with my statistical partners, Dr. Meira Falcovitz-Halpern here at Stanford and Dr. Luis Benavente in Africa, to analyze my data. Finally Drs. Maldonado and Benavente will guide me through the preparation and submission of a manuscript. To gain an inside perspective on the reality of public-private collaboration in humanitarian aid work. Health economists have touted the Bioko Island Malaria Control Project as a model of public-private collaboration in humanitarian development. My research partner in this study, Medical Care Development International, is a major player in this project. Through my work with MCDI researchers, I will see first hand how development projects are planned and implemented in a public-private partnership. To observe what comprises the standard of obstetric care in a resource-poor setting. My data collection will be based at the obstetrics clinic of Malabo Regional Hospital. In addition to collecting data and interviewing patients, I will also have the opportunity to shadow Dr. Gloria Nsteng in clinic and on the labor and delivery ward of the hospital. Dr. Ntseng is the chief obstetrician and a Bioko native. My interactions and conversations with her will give me insight into the quality and delivery of obstetric care in the developing world. PROPOSAL PREVENTING MALARIA AND ANEMIA IN PREGNANCY: A CASE-CONTROL STUDY OF INTERMITTENT PREVENTATIVE TREATMENT ON BIOKO ISLAND, EQUATORIAL GUINEA ABSTRACT Malaria during pregnancy poses great risks to both mother and child, the most common of which is anemia. Anemia increases the mother’s risk for placental abruption, preterm labor and maternal death and puts the developing baby at risk for low birth weight and miscarriage. One dose of intermittent preventative treatment (IPT) with the drug combination sulfadoxine-pyrimethamine during the first 26 weeks of pregnancy has been shown to decrease a woman’s risk of malaria by 85% and anemia by 50%. The life cycle of P. falciparum as well as socio-behavioral factors differ throughout sub-Saharan Africa. In order to optimize IPT delivery, the operational efficacy of IPT in preventing malaria and anemia must be assessed on a local level. This case-control study examines a population of pregnant women in their third trimester on Bioko Island, Equatorial Guinea. We aim to determine whether treatment with at least one dose of IPT during the first two trimesters of pregnancy correlates with reduced proportions of malaria and anemia. 70 participants will be recruited for each of two groups: a study group that previously received at least one dose of IPT in the first two trimesters and a control group that received none. We will determine malaria infection status using an immunochromatographic test and measure hemoglobin levels with a HemoCue detector. Additionally, to better understand contributors to anemia other than malaria, we will gather information with a quantitative survey. The knowledge gained in this study will allow for more effective implementation of malaria prevention measures for pregnant women and ultimately better outcomes for women and children. SPECIFIC AIMS Specific Aim 1: To determine whether pregnant women in Malabo, Equatorial Guinea who have taken Intermittent Preventative Treatment (IPT) with sulfadoxine-pyrimethamine have lower proportions of malaria than those who have not taken IPT. Malaria status will be determined using a rapid Immunochromatographic Test (ICT). Specific Aim 2: To determine whether pregnant women in Malabo, Equatorial Guinea who have taken IPT have higher hemoglobin levels than those who have not taken IPT. Hemoglobin levels will be measured with a rapid HemoCue test. Specific Aim 3: To investigate factors other than malaria that contribute to maternal anemia among pregnant women on Bioko Island using a quantitative survey. Hypothesis: Women who receive IPT with sulfadoxine-pyrimethamine during pregnancy will have lower proportions of malaria and higher average hemoglobin levels than those who do not receive IPT. BACKGROUND AND SIGNIFICANCE Each year in sub-Saharan Africa, approximately 30 million pregnant women are at risk for contracting malaria and suffering its adverse consequences (World Health Organization/UNICEF, 2003). Pregnant women are particularly vulnerable to malaria and are more likely to be infected with the pathological P. falciparum than non-pregnant women . The most common complication of malaria during pregnancy is maternal anemia. P. falciparum infection increases a woman’s risk of anemia by 450% . Anemia secondary to malaria puts pregnant women at greater risk of other morbidities including placental abruption, placenta previa, premature labor and maternal death. Placental malaria, a condition in which parasites infect the placenta, poses further risks, particularly for the developing fetus [3, 4]. Malaria in pregnancy can result in poor fetal outcomes, specifically miscarriage, low birth weight, and neonatal mortality . Pregnancy presents an important opportunity for health-related interventions that can simultaneously improve outcomes for both mother and child. Numerous strategies have been employed to prevent maternal malaria including the use of insecticide-treated bed nets to prevent mosquito bites and indoor residual spraying. Both interventions have been shown to dramatically decrease the risk of malaria [6, 7]. Past pharmaceutical interventions have been controversial. Weekly prophylaxis with chloroquine was effective throughout the 1980s. However, the emergence of chloroquine resistant malaria has decreased the effectiveness of this option. Further, the logistic constraint of weekly drug administration has made chloroquine an unrealistic choice even in areas with little resistance . Intermittent preventative treatment (IPT) with sulfadoxine-pyrimethamine (SP) has been proven to be a safe and effective treatment in many malaria-endemic areas. Three IPT doses of SP in Malawi were shown to decrease a woman’s risk of active parasitemia by 72% . A more recent study conducted in Kenya showed that as little as one dose of SD-IPT in the first two trimesters of pregnancy decreased risk for malaria by 85%. The same study showed a beneficial effect of IPT usage on hemoglobin level, decreasing risk for anema by 50% . In 2000, the WHO recommended that IPT be implemented in malaria endemic regions as the standard of care for prophylaxis during pregnancy (WHO, 2000). However, since the announcement of this policy, there has been little assesment of its effectiveness or implementation . The life cycle of P. falciparum and numerous sociobehvioral parameters differ between different regions and climates, therefore local assessment of the operational efficacy of IPT is essential to determine optimal IPT implementation in a particular community. Equatorial Guinea (EG) is a Central African country located on the Gulf of Guinea (Figure 1) consisting of a continental region and an island region. Bioko Island, 30km from the coast of Cameroon, is home to the EG capital, Malabo. Malaria on Bioko is holo- to hyper-endemic with an infection rate of approximately 50% among children . The infection rate among pregnant women has not been directly measured but is estimated at 25% . P. faliciparum infection is nine times more common on Bioko than infection with P. vivax. The life cycles of P. falciparum and P. vivax differ: P. falciparum infects and then is eliminated while vivax may become dormant and recur within a host . A recent population-based study estimated the maternal anemia prevalence on Bioko to be approximately 75% . Although the anemia rate among pregnant women is high, little research has been done to determine the contribution of malaria to anemia. Examining a possible correlation between IPT use and increased hemoglobin levels may provide insight into the contribution of malaria to the high anemia rate. Surveying the subjects on other possible contributors to anemia, may provide insight into other methods of combating maternal anemia (e.g. iron supplementation) if little correlation between ITP use and hemoglobin level is observed. Figure 1. Relative location of Equatorial Guinea Since 2003, a public-private partnership to eradicate malaria has existed between the EG Ministry of Health and Marathon Oil: the Bioko Island Malaria Control Project (BIMCP). The $8.3 million project has been implemented and assessed by Medical Care Development International (MCDI), a Washington DC- based non-profit organization. The main strategies of the program have been indoor residual spraying and improved prophylaxis distribution among children. The program was implemented in 2003 and has had tremendous success. In just one year, the prevalence of malaria among children fell by 33% . There is a good deal of political will in support of malaria eradication on Bioko. Research in support of IPT would likely result in its implementation by BIMCP. Further, identifying major barriers to IPT access among women would allow for optimization of IPT delivery. EXPERIMENTAL DESIGN Overview: This project is a case-control study to determine whether IPT use correlates with lower proportions of active P. falciparum malaria and reduced hemoglobin levels in pregnant women in the city of Malabo, on Bioko Island, Equatorial Guinea. We will survey participants to investigate contributors to anemia during pregnancy other than malaria, as well as to identify barriers to IPT use. Timeline: 1/1/06– 4/17/06 6/26/06 – 8/11/06 8/14/06-8/31/06 9/1/06-12/1/06 Study design, Data collection; Data entry, Dissemination of results proposal writing, 50 hours per and analysis; to BIMCP; Manuscript IRB approval, week. 150 40 hours per preparation for medical scholars subjects in MRH week submission to peer- application and Obstetrics and reviewed journals; 10 study setup; 10 Family Planning hours per week hours per week Clinic Population: Participants will be recruited from the obstetrics and family planning clinic based at Malabo Regional Hospital. The clinic is the main prenatal care facility in Malabo, providing prenatal care to 70% of the city’s pregnant women. The clinics typically see between 30 and 50 obstetrics patients per day. Data will be collected over a period of seven weeks. Patients that fit the criteria of the study will be asked to participate upon check-in for pre-natal visits. Interviews and sample collection will be performed on site at the clinic. Over 95% of Malabo residents speak Spanish, so Czechowicz, who is fluent, will conduct interviews in Spanish. Inclusion Criteria Pregnant women gestational age 26 weeks or greater (third trimester) Age 18 or older Study Group: Received at least one dose of sulfadoxine-pyrimethamine IPT during the first two trimesters of pregnancy Control Group: Received no SP-IPT during first two trimesters Exclusion Criteria Use of malaria prophylaxis other than SP-IPT during first two trimesters Active malaria at time of conception Severe pregnancy complication Subjects will be sorted into “Study” and “Control” groups based on whether or not they previously received any IPT, as summarized in this table: Study Control Size 70 70 IPT utilization prior Yes No to visit? All patients will be consented according to the Stanford IRB standards for Human Subjects Research (for consent form, see Appendix III) and identifiers will be coded on site. Approval from the Stanford IRB is pending (record of IRB application, Appendix II). Data Collection: Malaria Diagnostic Testing: The subjects’ malaria status will be determined by Immunochromatographic Test (ICT) for P. falciparum (a simple assay with a sensitivity of 100% and specificity of 99.7% relative to the standard lab technique of thick smear microscopy) . ICT requires a finger stick and subsequent collection of less than 100L of blood. A drop of blood is placed on the chromatographic strip, and lines on the strip are visualized in response to P. falciparum antibodies. Based on the results of this test, patients will be classified as either positive or negative for active malaria. Those subjects with active malaria will be informed and encouraged to follow up with their physician. Hemoglobin Concentration Testing: Hemoglobin concentration will be determined using a HemoCue portable hemoglobin meter. Approximately 10m of blood from the original finger stick capillary tube will be tested. The numerical value of the subjects’ hemoglobin concentration will be recorded. Those subjects with hemoglobin concentrations below 10mg/dL (anemic) will be informed of their status and encouraged to follow up with their physician. Identifying anemia risk factors other than malaria: An investigation of factors other than malaria that contribute to low hemoglobin levels will be assessed with a quantitative survey (Appendix I, Part B, “Anemia Questionnaire”). Subjects in both Study and Control groups will be interviewed. Factors to be considered include dietary iron intake and iron supplementation. Subjects will be classified as Low, Moderate or High risk for dietary iron deficiency. Identifying barriers to IPT: Barriers to IPT access in Malabo will be investigated using a qualitative survey (see Appendix I, Part C, “Barriers to IPT Questionnaire”). The survey will be administered to patients in both the Control and Study groups. The survey contains both open and closed ended questions. Power Value: To determine if IPT use correlates with lower proportions of malaria we look to see a difference between study and control groups (i.e. an effect size) of 20% or greater. The prevalence of malaria among pregnant women on Bioko is estimated to be 25% [12, 16, 17]. To achieve a power value of 80% and an alpha of p<0.05, the sample size must be at least 69 subjects in each group of the study. To be convinced that IPT use correlates with higher Hemoglobin levels, we look at see an effect size of 0.75 g/dL or greater. The standard deviation of Hemoglobin concentration on Bioko is 1.7 g/dL [18, 19]. To achieve a power value of 80% and an alpha of p<0.05, the sample size must be at least 64 subjects in each group. Data Analysis: Data will be analyzed in collaboration with Dr. Maldonado’s colleague, Dr. Meira Falkovitz-Halpern, Ph.D. A Two-tailed Fischer’s Exact Test will be used to determine whether the proportion of women who have malaria among IPT users is different than that among those who did not use IPT. The mean hemoglobin concentrations between IPT users and non-users will be compared using a T- test. Proportions of women at Low, Moderate and High risk for dietary anemia will be calculated for both Study and Control groups. Interpretation of Results: If IPT use correlates with lower incidence of malaria and anemia, this will demonstrate that the operational efficacy of the treatment is comparable to its efficacy in randomized clinical trials. If IPT use does not correlate with lower proportions of malaria or anemia, this will suggest that there is an obstacle to operational efficacy specific to Bioko. Maternal anemia is attributable to numerous factors, but malaria is typically its regarded as its primary cause in Bioko. Differences in active malaria proportions between the study and control groups can be attributed to IPT. If we observe lower proportions of malaria and anemia in the IPT group it follows that the reduction in anemia can be proportionately attributed to the reduction in malaria. Our survey of the dietary and behavioral contributors to anemia will help to explain why women who are uninfected with malaria may be anemic. Potential Sources of Error: The following are potential sources of error in this investigation: Clinic-based study. The study is clinic-based and therefore could potentially not represent a cross-section of the population. The subjects could potentially be in better health on average than the general population. However, according to a 2004 BIMCP population-based survey, the vast majority (approximately 90%) of women receive prenatal care at a hospital or clinic, so hospital goers are not an elite subset. Also, since the study does not measure rates of IPT utilization across the population, but rather correlations between IPT and certain health outcomes, this issue is less problematic. HIV and malaria. It is well established that HIV infection increases one’s risk of contracting malaria, and vice versa. Furthermore, HIV positive women who are also infected with malaria are more likely to be anemic than HIV negative women . However, the HIV infection rate among women in Malabo is 3.4%, relatively low compared to other countries in sub-Saharan Africa (CIA world fact sheet, 2001). For this reason, we expect that HIV will be only a minor confounding factor, if a factor at all. Inaccuracies from self-reported data. Because of Recall Bias, subjects are probably more likely to overestimate than to underestimate their use of IPT. Therefore, if a significant correlation between IPT and lower malaria and anemia rates is observed, it is not likely to be undermined by the self- reported nature of the study. RELEVANCE TO MEDICINE Malaria and anemia take a great toll on women and children in sub-Saharan Africa. Pregnancy presents a unique opportunity in which one intervention can improve two lives. The results of this study could have important implications for implementation of IPT in Equatorial Guinea. The Ministry of Health, Marathon Oil, and MCDI began the Bioko Island Malaria Control Project (BIMCP) in 2004. The project’s primary tool has been indoor residual spraying (IRS), which has been implemented with great success. IRS combined with vigorous prophylaxis distribution among children has resulted in a 33% decrease in malarial infection among children (MCDI, unpublished data). The political momentum to eradicate malaria on Bioko is strong. Solid research supporting the effectiveness of IPT in preventing malaria and anemia among pregnant women would likely result in enthusiastic implementation of such measures by BIMCP. Malaria-related anemia during pregnancy contributes to poor outcomes for both the mother and the fetus. The mother has an increased risk of morbidity and mortality, and the child has increased risk of miscarriage, low birth weight, and stillbirth. Understanding the optimal methods of malaria prevention in pregnant women will allow for better planning and outcomes on Bioko and throughout sub- Saharan Africa. JUSTIFICATION FOR AWAY EXPERIENCE This study requires travel to Bioko Island, EG. My project is designed to examine an epidemiological problem unique to pregnant women on Bioko. My collaboration with the BIMCP will result the immediate application of my findings to improve malaria prophylaxis delivery to pregnant women there. Further, my partner in the study, MCDI, is based in Malabo, EG. BIBLIOGRAPHY 1. Brabin, B.J., An analysis of malaria in pregnancy in Africa. Bull World Health Organ, 1983. 61(6): p. 1005-16. 2. Adam, I., A.H. Khamis, and M.I. Elbashir, Prevalence and risk factors for Plasmodium falciparum malaria in pregnant women of eastern Sudan. Malar J, 2005. 4(1): p. 18. 3. Levy, M., et al., Pregnancy outcome following first trimester exposure to chloroquine. Am J Perinatol, 1991. 8(3): p. 174-8. 4. Shulman, C.E., Malaria in pregnancy: its relevance to safe-motherhood programmes. Ann Trop Med Parasitol, 1999. 93 Suppl 1: p. S59-66. 5. Steketee, R.W., et al., The burden of malaria in pregnancy in malaria- endemic areas. Am J Trop Med Hyg, 2001. 64(1-2 Suppl): p. 28-35. 6. Choi, H.W., et al., The effectiveness of insecticide-impregnated bed nets in reducing cases of malaria infection: a meta-analysis of published results. Am J Trop Med Hyg, 1995. 52(5): p. 377-82. 7. Curtis, C.F. and A.E. Mnzava, Comparison of house spraying and insecticide-treated nets for malaria control. Bull World Health Organ, 2000. 78(12): p. 1389-400. 8. van Eijk, A.M., et al., Implementation of intermittent preventive treatment with sulphadoxine-pyrimethamine for control of malaria in pregnancy in Kisumu, western Kenya. Trop Med Int Health, 2004. 9(5): p. 630-7. 9. Schultz, L.J., et al., The efficacy of antimalarial regimens containing sulfadoxine-pyrimethamine and/or chloroquine in preventing peripheral and placental Plasmodium falciparum infection among pregnant women in Malawi. Am J Trop Med Hyg, 1994. 51(5): p. 515-22. 10. Shulman, C.E., et al., Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial. Lancet, 1999. 353(9153): p. 632-6. 11. van Eijk, A.M., Blokland IE, Slutsker L, Odhiambo F, Ayisi JG, Bles HM, Rosen DH, Adazu K, Lindblade KA., Use of intermittent preventive treatment for malaria in pregnancy in a rural area of western Kenya with high coverage of insecticide-treated bed nets. Tropical Medicine and International Health, 2005 10(11): p. 1134-40. 12. Pardo, G., et al., Impact of different strategies to control Plasmodium infection and anaemia on the island of Bioko (Equatorial Guinea). Malar J, 2006. 5: p. 10. 13. Benavente, L., Schwabe, C, Malaria eradication implemented by the Bioko Island Malaria Control Project: Progress Report, unpublished. 2005. 14. Roche, J., et al., Surveillance of in vivo resistance of Plasmodium falciparum to antimalarial drugs from 1992 to 1999 in Malabo (Equatorial Guinea). Am J Trop Med Hyg, 2003. 68(5): p. 598-601. 15. Iqbal, J., et al., Diagnosis of imported malaria by Plasmodium lactate dehydrogenase (pLDH) and histidine-rich protein 2 (PfHRP-2)-based immunocapture assays. Am J Trop Med Hyg, 2001. 64(1-2): p. 20-3. 16. Roche, J., et al., An epidemiological study of malaria in Bioko and Annobon islands (Equatorial Guinea). Ann Trop Med Parasitol, 1991. 85(5): p. 477-87. 17. Martinez, H., et al., [Anemia in women of reproductive age. The results of a national probability survey]. Salud Publica Mex, 1995. 37(2): p. 108-19. 18. Wolmarans, P., et al., Iron status of South African women working in a fruit-packing factory. Public Health Nutr, 2003. 6(5): p. 439-45. 19. van Eijk, A.M., et al., Human immunodeficiency virus seropositivity and malaria as risk factors for third-trimester anemia in asymptomatic pregnant women in western Kenya. Am J Trop Med Hyg, 2001. 65(5): p. 623-30. 20. Brentlinger, P.E., C.B. Behrens, and M.A. Micek, Challenges in the concurrent management of malaria and HIV in pregnancy in sub-Saharan Africa. Lancet Infect Dis, 2006. 6(2): p. 100-11.
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