Folic acid supplementation may potentially alter the efficacy of sulfadoxine-pyrimethamine (SP) treatment in children with malaria. However, there is lack of evidence from randomized controlled trials and effects of folic acid supplementation on clinical efficacy of SP therapy remain moderately understood among children. In a double masked, placebo-controlled trial among preschool children in Pemba Island (Tanzania), iron and folic acid supplementation (Fe/FA) showed an increased risk of hospitalizations and death. In the present paper, we evaluated if folic acid supplementation reduced the efficacy of malaria treatment and thereby contributed to observed adverse effects. During the study, 1648 children had confirmed malarial episodes and received either sulphadoxine-pyrimethamine (SP) treatment and iron folic acid or SP treatment and placebo. These children were evaluated for recovery and incidence of hospitalization during the next 15, 30, and 140 days. Two groups did not differ in malarial episode or hospitalization rate on subsequent 15, 30, and 140 days. Altered efficacy of SP by folic acid was not observed and did not contribute to adverse events in the previous trial. This trial is registered with Controlled-trials.com ISRCTN59549825. 1. Introduction Malaria affects approximately 219 million people each year (range 154–289 million) with an estimated 660,000 deaths. Ninety percent of malaria deaths occur in Africa, where malaria accounts for about one in six of all childhood deaths (http://www.unicef.org/health/index_malaria.html). With widespread emergence of chloroquine resistant P. falciparum infections, drugs targeting the critically important folate metabolism of malarial parasite have been frequently used [1]. In a double masked, placebo-controlled trial among preschool children in Pemba island (Tanzania), iron and folic acid supplementation (Fe/FA) based on earlier WHO guidelines [2] showed an increased risk of hospitalizations and death [3]. Children during this study were receiving sulfadoxine-pyrimethamine (SP), an antifolate antimalarial drug as a first-line treatment for malaria. Sulfadoxine is known to act by inhibition of dihydropteroate synthetase while pyrimethamine competitively inhibits dihydrofolate reductase thereby blocking the endogenous pathway whereby plasmodium parasites produce folate de novo. In addition, it blocks uptake of and/or utilization by malaria parasites of exogenous folic acid that may transiently occur in circulation following ingestion of high supplemental doses. It has been suggested that FA supplementation
References
[1]
J. E. Hyde, “Exploring the folate pathway in Plasmodium falciparum,” Acta Tropica, vol. 94, no. 3, pp. 191–206, 2005.
[2]
R. J. Stoltzfus and M. L. Dreyfuss, “Guidelines for the use of iron supplements to prevent and treat iron deficiency anemia,” in International Nutritional Anemia Consultative Group (INACG), World Health Organization (WHO), United Nations Childrens Fund (UNICEF), pp. 1–39, ILSI Press, 1998.
[3]
S. Sazawal, R. E. Black, M. Ramsan et al., “Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial,” The Lancet, vol. 367, no. 9505, pp. 133–143, 2006.
[4]
J. Y. Carter, M. P. Loolpapit, O. E. Lema, J. L. Tome, N. J. D. Nagelkerke, and W. M. Watkins, “Reduction of the efficacy of antifolate antimalarial therapy by folic acid supplementation,” The American Journal of Tropical Medicine and Hygiene, vol. 73, no. 1, pp. 166–170, 2005.
[5]
P. Wang, Q. Wang, T. V. Aspinall, P. F. G. Sims, and J. E. Hyde, “Transfection studies to explore essential folate metabolism and antifolate drug synergy in the human malaria parasite Plasmodium falciparum,” Molecular Microbiology, vol. 51, no. 5, pp. 1425–1438, 2004.
[6]
J. Krungkrai, H. K. Webster, and Y. Yuthavong, “De novo and salvage biosynthesis of pteroylpentaglutamates in the human malaria parasite, Plasmodium falciparum,” Molecular and Biochemical Parasitology, vol. 32, no. 1, pp. 25–37, 1989.
[7]
R. Ferone, “Folate metabolism in malaria,” Bulletin of the World Health Organization, vol. 55, no. 2-3, pp. 291–298, 1977.
[8]
I. M. Rollo, “Antiplasmodial efficacy of 2,4 diaminopyrimidine sulfonamide combinations, especially against chloroquine resistant malaria,” Canadian Medical Association Journal, vol. 112, no. 13, pp. 50–53, 1975.
[9]
J. D. Chulay, W. M. atkins, and D. G. Sixsmith, “Synergistic antimalarial activity of pyrimethamine and sulfadoxine against Plasmodium falciparum in vitro,” The American Journal of Tropical Medicine and Hygiene, vol. 33, no. 3, pp. 325–330, 1984.
[10]
M. J. Tong, G. T. Strickland, B. A. Votteri, and J. J. Gunning, “Supplemental folates in the therapy of Plasmodium falciparum malaria,” Journal of the American Medical Association, vol. 214, no. 13, pp. 2330–2333, 1970.
[11]
World Health Organization, “Monitoring antimalarial drug resistance,” Report No.: WHO/CDS/CSR/EPH/2002.17, Geneva, Switzerland, 2002.
[12]
M. Mulenga, P. Malunga, S. Bennett et al., “Folic acid treatment of Zambian children with moderate to severe malaria anemia,” The American Journal of Tropical Medicine and Hygiene, vol. 74, no. 6, pp. 986–990, 2006.
[13]
F. K. Dzinjalamala, A. Macheso, J. G. Kublin et al., “Blood folate concentrations and in vivo sulfadoxine-pyrimethamine failure in Malawian children with uncomplicated Plasmodium falciparum malaria,” The American Journal of Tropical Medicine and Hygiene, vol. 72, no. 3, pp. 267–272, 2005.
[14]
A. Mbaye, K. Richardson, B. Balajo et al., “Lack of inhibition of the anti-malarial action of sulfadoxine-pyrimethamine by folic acid supplementation when used for intermittent preventive treatment in Gambian primigravidae,” The American Journal of Tropical Medicine and Hygiene, vol. 74, no. 6, pp. 960–964, 2006.
