Safety and benefits of interventions to increase folate status in malaria-endemic areas

British Journal of Haematology

Volumn 177, Issue 6, 2017, Pages 905-918

  Verhoef, Hans ^a,b,c   Veenemans, Jacobien ^d,e   Mwangi, Martin N ^c   Prentice, Andrew M ^a,b  

^a MEDICAL RESEARCH COUNCIL   (United Kingdom)

^b MEDICAL RESEARCH COUNCIL LABORATORIES   (Gambia)

^c WAGENINGEN UNIVERSITY   (Netherlands)

^d Admiral De Ruyter Hospital   (Netherlands)

^e AMPHIA HOSPITAL   (Netherlands)

Author keywords

folic acid; folic acid antagonists; malaria; neural tube defects; sulfadoxine pyrimethamine

Indexed keywords

FOLIC ACID; PYRIMETHAMINE PLUS SULFADOXINE; ANTIMALARIAL AGENT; FOLIC ACID ANTAGONIST;

COST BENEFIT ANALYSIS; DIET SUPPLEMENTATION; DISEASE ASSOCIATION; DISEASE COURSE; FOLIC ACID DEFICIENCY; FOLLOW UP; GAMBIA; HUMAN; INTERVENTION STUDY; KENYA; MALARIA FALCIPARUM; OBSERVATIONAL STUDY; PRACTICE GUIDELINE; PREGNANT WOMAN; PRIORITY JOURNAL; REVIEW; RISK FACTOR; ZAMBIA; ADVERSE EFFECTS; DIETARY SUPPLEMENT; DRUG INTERACTION; DRUG RESISTANCE; FEMALE; MALARIA; PHYSIOLOGY; PREGNANCY; PREGNANCY COMPLICATIONS;

ANTIMALARIALS; DIETARY SUPPLEMENTS; DRUG INTERACTIONS; DRUG RESISTANCE; FEMALE; FOLIC ACID; FOLIC ACID ANTAGONISTS; FOLIC ACID DEFICIENCY; HUMANS; MALARIA; PREGNANCY; PREGNANCY COMPLICATIONS;

EID: 85016552505     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.14618     Document Type: Review

References (96)

1. Adjalla, C.E., Amouzou, E.K., Sanni, A., Abdelmouttaleb, I., Chabi, N.W., Namour, F., Soussou, B. & Guéant, J.-L. (2003) Low frequency of mutated methylenetetrahydrofolate reductase 677C–>T and 1298A–>C genetics single nucleotide polymorphisms (SNPs) in Sub-Saharan populations. Clinical Chemistry and Laboratory Medicine, 41, 1028–1032.
2. Allen, L.H. (2012) B vitamins in breast milk: relative importance of maternal status and intake, and effects on infant status and function. Advances in Nutrition, 3, 362–369.
3. Antony, A.C. (2008) Severe anemia in Malawian children. New England Journal of Medicine, 358, 2291.
4. Baggott, J.E. & Morgan, S.L. (2008) Folic acid supplements are good (not bad) for rheumatoid arthritis patients treated with low-dose methotrexate. American Journal of Clinical Nutrition, 88, 479–480.
5. Bailey, L.B. (2004) Folate and vitamin B-12 recommended intakes and status in the United States. Nutrition Reviews, 62, S14–S20.
6. Beaudin, A.E. & Stover, P.J. (2009) Insights into metabolic mechanisms underlying folate-responsive neural tube defects: a minireview. Birth Defects Research. Part A, Clinical and Molecular Teratology, 85, 274–284.
7. Berry, R.J., Bailey, L., Mulinare, J., Bower, C. & Dary, O. (2010) Fortification of flour with folic acid. Food and Nutrition Bulletin, 31, S22–S35.
8. Boele van Hensbroek, M., Morris-Jones, S., Meisner, S., Jaffar, S., Bayol, L., Dackour, R., Phillips, C. & Greenwood, B.M. (1995) Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria. Transactions of the Royal Society of Hygiene and Tropical Medicine, 89, 672–676.
9. Calis, C.J., Phiri, K.S., Faragher, E.B., Brabin, B.J., Bates, I., Cuevas, L.E., De Haan, R.J., Phiri, A.I., Malange, P., Khoka, M., Hulshof, P.J., van Lieshout, L., Beld, M.G., Teo, Y.Y., Rockett, K.A., Richardson, A., Kwiatkowski, D.P., Molyneux, M.E. & van Hensbroek, M.B. (2008) Severe anemia in Malawian children. New England Journal of Medicine, 358, 888–899 [discussion in New England Journal of Medicine, 358, 2291].
10. Carter, J.Y., Loolpapit, M.P., Lema, O.E., Tome, J.L., Nagelkerke, N.J. & Watkins, W.M. (2005) Reduction of the efficacy of antifolate antimalarial therapy by folic acid supplementation. American Journal of Tropical Medicine and Hygiene, 73, 166–170.
11. Charles, D.H., Ness, A.R., Campbell, D., Smith, G.D., Whitley, E. & Hall, M.H. (2005) Folic acid supplements in pregnancy and birth outcome: re-analysis of a large randomised controlled trial and update of Cochrane review. Paediatric and Perinatal Epidemiology, 19, 112–124.
12. Choumenkovitch, S.F., Selhub, J., Wilson, P.W., Rader, J.I., Rosenberg, I.H. & Jacques, P.F. (2002) Folic acid intake from fortification in United States exceeds predictions. Journal of Nutrition, 132, 2792–2798.
13. Christianson, A., Howson, C.P. & Modell, B. (2006) March of Dimes Global Report on Birth Defects: The Hidden Toll of Dying and Disabled Children. March of Dimes Birth Defects Foundation, White Plains, NY. Available at: http://www.marchofdimes.org/materials/global-report-on-birth-defects-the-hidden-toll-of-dying-and-disabled-children-full-report.pdf, accessed 7 November 2016.
14. Chulay, J.D., Watkins, W.M. & Sixsmith, D.G. (1984) Synergistic antimalarial activity of pyrimethamine and sulfadoxine against Plasmodium falciparum in vitro. American Journal of Tropical Medicine and Hygiene, 33, 325–330.
15. Clark, M.A., Goheen, M.M., Fulford, A., Prentice, A.M., Elnagheeb, M.A., Patel, J., Fisher, N., Taylor, S.M., Kasthuri, R.S. & Cerami, C. (2014) Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum. Nature Communications, 5, 4446.
16. Clarke, R., Bennett, D.A., Parish, S., Verhoef, P., Dötsch-Klerk, M., Lathrop, M., Xu, P., Nordestgaard, B.G., Holm, H., Hopewell, J.C., Saleheen, D., Tanaka, T., Anand, S.S., Chambers, J.C., Kleber, M.E., Ouwehand, W.H., Yamada, Y., Elbers, C., Peters, B., Stewart, A.F., Reilly, M.M., Thorand, B., Yusuf, S., Engert, J.C., Assimes, T.L., Kooner, J., Danesh, J., Watkins, H., Samani, N.J., Collins, R. & Peto, R.; MTHFR Studies Collaborative Group. (2012) Homocysteine and coronary heart disease: meta-analysis of MTHFR case–control studies, avoiding publication bias. PLoS Medicine, 9, e1001177.
17. Crider, K.S., Zhu, J.H., Hao, L., Yang, Q.-H., Yang, T.P., Gindler, J., Maneval, D.R., Quinlivan, E.P., Li, Z., Bailey, L.B. & Berry, R.J. (2011) MTHFR 677C->T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. American Journal of Clinical Nutrition, 93, 1365–1372.
18. Daly, L.E., Kirke, P.N., Molloy, A., Weir, D.G. & Scott, J.M. (1995) Folate levels and neural tube defects: implications for prevention. Journal of the American Medical Association, 274, 1698–1702.
19. De Benoist, B. (2008) Conclusions of a WHO technical consultation on folate and vitamin B12 deficiencies. Food and Nutrition Bulletin, 29, S238–S244.
20. De Regil, L.M., Pena-Rosas, J.P., Fernandez-Gaxiola, A.C. & Rayco-Solon, P. (2015) Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Systematic Reviews, 12, CD007950.
21. Desai, M., ter Kuile, F.O., Nosten, F., McGready, R., Asamoa, K., Brabin, B. & Newman, R.D. (2007) Epidemiology and burden of malaria in pregnancy. Lancet Infectious Diseases, 7, 93–104.
22. Dhur, A., Galan, P. & Hercberg, S. (1991) Folate status and the immune system. Progress in Food and Nutrition Science, 15, 43–60.
23. Dixit, R., Nettem, S., Madan, S.S., Soe, H.H., Abas, A.B., Vance, L.D. & Stover, P.J. (2016) Folate supplementation in people with sickle cell disease. Cochrane Database Systematic Review, 2, CD011130.
24. Dzinjalamala, F.K., Macheso, A., Kublin, J.G., Taylor, T.E., Barnes, K.I., Molyneux, M.E., Plowe, C.V. & Smith, P.J. (2005) Blood folate concentrations and in vivo sulfadoxine-pyrimethamine failure in Malawian children with uncomplicated Plasmodium falciparum malaria. American Journal of Tropical Medicine and Hygiene, 72, 267–272.
25. Eichholzer, M., Tonz, O. & Zimmermann, R. (2006) Folic acid: a public-health challenge. The Lancet, 367, 1352–1361.
26. Ferone, R. (1977) Folate metabolism in malaria. Bulletin of the World Health Organization, 55, 291–298.
27. Fishman, S.M., Christian, P. & West, K.P. (2000) The role of vitamins in the prevention and control of anaemia. Public Health Nutrition, 3, 125–150.
28. Fleming, A.F. (1989a) Tropical obstetrics and gynaecology. 1. Anaemia in pregnancy in tropical Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene, 83, 441–448.
29. Fleming, A.F. (1989b) The presentation, management and prevention of crisis in sickle cell disease in Africa. Blood Reviews, 3, 18–28.
30. Fleming, A.F. & De Silva, P.S. (2003) Haematological diseases in the tropics. In: Manson's Tropical Diseases, 21st edn (ed. by G.C. Cook & A.I. Zumla), pp. 169–243. Saunders, Philadelphia, PA.
31. Furness, D.L., Yasin, N., Dekker, G.A., Thompson, S.D. & Roberts, C.T. (2012) Maternal red blood cell folate concentration at 10–12 weeks gestation and pregnancy outcome. Journal of Maternal-Fetal & Neonatal Medicine, 25, 1423–1427.
32. Galloway, P., McMillan, D.C. & Sattar, N. (2000) Effect of the inflammatory response on trace element and vitamin status. Annals of Clinical Biochemistry, 37, 289–297.
33. Geary, T.G., Divo, A.A., Bonanni, L.C. & Jensen, J.B. (1985) Nutritional requirements of Plasmodium falciparum in culture. III. Further observations on essential nutrients and antimetabolites. Journal of Protozoology, 32, 608–613.
34. Gregson, A. & Plowe, C.V. (2005) Mechanisms of resistance of malaria parasites to antifolates. Pharmacological Reviews, 57, 117–145.
35. Guyatt, H.L. & Snow, R.W. (2004) Impact of malaria during pregnancy on low birth weight in sub-Saharan Africa. Clinical Microbiology Reviews, 17, 760.
36. Hoffbrand, A.V., Catovsky, D., Tuddenham, E.G. & Green, A.R. (eds.) (2011) Postgraduate Haematology, 6th edn. Wiley-Blackwell, Chichester.
37. Hubner, R.A., Houlston, R.D. & Muir, K.R. (2007) Should folic acid fortification be mandatory? No. British Medical Journal, 334, 1253.
38. Kalmbach, R.D., Choumenkovitch, S.F., Troen, A.M., D'Agostino, R., Jacques, P.F. & Selhub, J. (2008) Circulating folic acid in plasma: relation to folic acid fortification. American Journal of Clinical Nutrition, 88, 763–768.
39. Kamen, B.A., Wang, M.T., Streckfuss, A.J., Peryea, X. & Anderson, R.G. (1988) Delivery of folates to the cytoplasm of MA104 cells is mediated by a surface membrane receptor that recycles. Journal of Biological Chemistry, 263, 13602–13609.
40. Kelly, P., McPartlin, J., Goggins, M., Weir, D.G. & Scott, J.M. (1997) Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. American Journal of Clinical Nutrition, 65, 1790–1795.
41. Khanna, D., Park, G.S., Paulus, H.E., Simpson, K.M., Elashoff, D., Cohen, S.B., Emery, P., Dorrier, C. & Furst, D.E. (2005) Reduction of the efficacy of methotrexate by the use of folic acid: post hoc analysis from two randomized controlled studies. Arthritis and Rheumatism, 52, 3030–3038.
42. Koury, M.J. & Ponka, P. (2004) New insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annual Review of Nutrition, 24, 105–131.
43. Krungkrai, J., Webster, H.K. & Yuthavong, Y. (1990) Folate and cobalamin metabolism in Plasmodium falciparum. Parasitology Today, 6, 388–391.
44. Lassi, Z.S., Salam, R.A., Haider, B.A. & Bhutta, Z.A. (2013) Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes. Cochrane Database Systematic Review, 3, CD006896.
45. Lengeler, C. (2004) Insecticide-treated bed nets and curtains for preventing malaria. Cochrane Database Systematic Review, 2, CD000363.
46. Levene, M.I., Tudehope, D.I. & Thearle, M.J. (2000) Essentials of Neonatal Medicine. John Wiley & Sons, Hoboken, NJ.
47. Lohner, S., Fekete, K., Berti, C., Hermoso, M., Cetin, I., Koletzko, B. & Decsi, T. (2012) Effect of folate supplementation on folate status and health outcomes in infants, children and adolescents: a systematic review. International Journal of Food Sciences and Nutrition, 63, 1014–1020.
48. Lucock, M., Wild, J., Smithells, R. & Hartley, R. (1989) Biotransformation of pteroylmonoglutamic acid during absorption: implications of Michaelis-Menten kinetics. European Journal of Clinical Nutrition, 43, 631–635.
49. Luzzatto, L. (2010) The rise and fall of the antimalarial Lapdap: a lesson in pharmacogenetics. The Lancet, 376, 739–741.
50. Mahomed, K. (1997) Folate supplementation in pregnancy. Cochrane Database Systematic Review, 3, CD000183.
51. Mbaye, A., Richardson, K., Balajo, B., Dunyo, S., Shulman, C., Milligan, P., Greenwood, B. & Walraven, G. (2006) Lack of inhibition of the anti-malarial action of sulfadoxine-pyrimethamine by folic acid supplementation when used for intermittent preventive treatment in Gambian primigravidae. American Journal of Tropical Medicine and Hygiene, 74, 960–964.
52. Meremikwu, M.M., Donegan, S. & Esu, E. (2008) Chemoprophylaxis and intermittent treatment for preventing malaria in children. Cochrane Database Systematic Reviews, 2, CD003756.
53. Metz, J. (2007) Folic acid metabolism and malaria. Food and Nutrition Bulletin, 28, S540–S549.
54. Metz, J. (2008) A high prevalence of biochemical evidence of vitamin B12 or folate deficiency does not translate into a comparable prevalence of anemia. Food and Nutrition Bulletin, 29, S74–S85.
55. Miller, E.R., Juraschek, S., Pastor-Barriuso, R., Bazzano, L.A., Appel, L.J. & Guallar, E. (2010) Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels. American Journal of Cardiology, 106, 517–527.
56. Mulenga, M., Malunga, P., Bennett, S., Thuma, P., Shulman, C., Fielding, K. & Greenwood, B. (2006) Folic acid treatment of zambian children with moderate to severe malaria anemia. American Journal of Tropical Medicine and Hygiene, 74, 986–990.
57. Nduati, E., Diriye, A., Ommeh, S., Mwai, L., Kiara, S., Masseno, V., Kokwaro, G. & Nzila, A. (2008) Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer. Parasitology Research, 102, 1227–1234.
58. Nzila, A. (2006) Inhibitors of de novo folate enzymes in Plasmodium falciparum. Drug Discovery Today, 11, 939–944.
59. Nzila, A., Ward, S.A., Marsh, K., Sims, P.F. & Hyde, J.E. (2005) Comparative folate metabolism in humans and malaria parasites (part I): pointers for malaria treatment from cancer chemotherapy. Trends in Parasitology, 21, 292–298.
60. Nzila, A., Okombo, J. & Molloy, A.M. (2014) Impact of folate supplementation on the efficacy of sulfadoxine/pyrimethamine in preventing malaria in pregnancy: the potential of 5-methyl-tetrahydrofolate. Journal of Antimicrobial Chemotherapy, 69, 323–330.
61. Nzila, A., Okombo, J. & Hyde, J. (2016) Malaria in the era of food fortification with folic acid. Food and Nutrition Bulletin, 37, 153–163.
62. Oniyangi, O. & Omari, A.A. (2006) Malaria chemoprophylaxis in sickle cell disease. Cochrane Database of Systematic Reviews, 4, CD003489.
63. Ouma, P., Parise, M.E., Hamel, M.J., Ter Kuile, F.O., Otieno, K., Ayisi, J.G., Kager, P.A., Steketee, R.W., Slutsker, L. & Van Eijk, A.M. (2006) A randomized controlled trial of folate supplementation when treating malaria in pregnancy with sulfadoxine-pyrimethamine. PLoS Clinical Trials, 1, e28.
64. Oyediran, A.B., Ddumba, E.M., Ochola, S.A., Lucas, A.O., Koporc, K. & Dowdle, W.R. (2002) A public-private partnership for malaria control: lessons from the Malarone Donation Programme. Bulletin of the World Health Organization, 80, 817–821.
65. Pegoraro, R.J., Chikosi, A., Rom, L., Roberts, C. & Moodley, J. (2004) Methylenetetrahydrofolate reductase gene polymorphisms in black South Africans and the association with preeclampsia. Acta Obstetricia et Gynecologica Scandinavica, 83, 449–454.
66. Piel, F.B., Patil, A.P., Howes, R.E., Nyangiri, O.A., Gething, P.W., Dewi, M., Temperley, W.H., Williams, T.N., Weatherall, D.J. & Hay, S.I. (2013) Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. The Lancet, 381, 142–151.
67. Pietrzik, K., Bailey, L. & Shane, B. (2010) Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clinical Pharmacokinetics, 49, 535–548.
68. Powers, H. (2007) Folic acid under scrutiny. British Journal of Nutrition, 98, 665–666.
69. Quinlivan, E.P. & Gregory, J.F. (2003) Effect of food fortification on folic acid intake in the United States. American Journal of Clinical Nutrition, 77, 221–225.
70. Relton, C.L., Pearce, M.S. & Parker, L. (2005) The influence of erythrocyte folate and serum vitamin B12 status on birth weight. British Journal of Nutrition, 93, 593–599.
71. Rodriguez-Cortes, H.M., Griener, J.C., Hyland, K., Bottiglieri, T., Bennett, M.J., Kamen, B.A. & Buchanan, G.R. (1999) Plasma homocysteine levels and folate status in children with sickle cell anemia. Journal of Pediacatric Hematology and Oncology, 21, 219–223.
72. Rolschau, J., Kristoffersen, K., Ulrich, M., Grinsted, P., Schaumbur, E. & Foged, N. (1999) The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part I. European Journal of Obstetrics, Gynecology and Reproductive Biology, 87, 105–110 [incl. discussion 103–104].
73. Sazawal, S., Black, R.E., Ramsan, M., Chwaya, H.M., Stoltzfus, R.J., Dutta, A., Dhingra, U., Kabole, I., Deb, S., Othman, M.K. & Kabole, F.M. (2006) 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, 367, 133–143.
74. Schalhorn, A. & Kühl, M. (1992) Clinical pharmacokinetics of fluorouracil and folinic acid. Seminars in Oncology, 19, 82–92.
75. Stern, L.L., Bagley, P.J., Rosenberg, I.H. & Selhub, J. (2000) Conversion of 5-formyl-tetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylene-tetrahydrofolate reductase gene. Journal of Nutrition, 130, 2238–2242.
76. Stokstad, E.L. & Jukes, T.H. (1987) Sulfonamides and folic acid antagonists: a historical review. Journal of Nutrition, 117, 1135–1141.
77. Sweeney, M.R., McPartlin, J. & Scott, J. (2007) Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health, 7, 41.
78. Timmermans, S., Jaddoe, V.W., Hofman, A., Steegers-Theunissen, R.P. & Steegers, E.A. (2009) Periconception folic acid supplementation, fetal growth and the risks of low birth weight and preterm birth: the Generation R Study. British Journal of Nutrition, 102, 777–785.
79. Tong, M.J., Strickland, G.T., Votteri, B.A. & Gunning, J.-J. (1970) Supplemental folates in the therapy of Plasmodium falciparum malaria. Journal of the American Medical Association, 214, 2330–2333.
80. Van Eijk, A.M., Ouma, P.O., Williamson, J., Ter Kuile, F.O., Parise, M., Otieno, K., Hamel, M.J., Ayisi, J.G., Kariuki, S., Kager, P.A. & Slutsker, L. (2008) Plasma folate level and high-dose folate supplementation predict sulfadoxine-pyrimethamine treatment failure in pregnant women in western Kenya who have uncomplicated malaria. Journal of Infectious Diseases, 198, 1550–1553.
81. Verhoef, H., West, C.E., Kraaijenhagen, R., Nzyuko, S.M., King, R., Mbandi, M.M., Van Laatum, S., Hogervorst, R., Schep, C. & Kok, F.J. (2002) Malarial anemia leads to adequately increased erythropoiesis in asymptomatic Kenyan children. Blood, 100, 3489–3494.
82. Wald, N.J. & Oakley, G.P. (2007) Should folic acid fortification be mandatory? Yes British Medical Journal, 335, 1252.
83. Wang, W. (1999) Role of nutritional supplement in sickle cell disease. Journal of Pediatric Hematology and Oncology, 21, 176–178.
84. Wang, P., Wang, Q., Sims, P.F. & Hyde, J.E. (2007) Characterisation of exogenous folate transport in Plasmodium falciparum. Molecular Biochemistry and Parasitology, 154, 40–51.
85. WHO. (2010a) Sickle-cell disease: a strategy for the WHO African Region. Report of the Regional Director. Document number AFR/RC60/8. World Health Organization, Regional Office for Africa, Geneva. Available at: http://www.afro.who.int/en/downloads/doc_download/6638-sickle-cell-disease-a-strategy-for-the-who-african-region.html, accessed 7 November 2016.
86. WHO. (2010b) WHO Policy recommendation on Intermittent Preventive Treatment during infancy with sulphadoxine-pyrimethamine (SP-IPTi) for Plasmodium falciparum malaria control in Africa. World Health Organization, Geneva. Available at: http://www.who.int/malaria/news/WHO_policy_recommendation_IPTi_032010.pdf, accessed 7 November 2016.
87. WHO. (2012) WHO Policy Recommendation: Seasonal Malaria Chemoprevention (SMC) for Plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub-region in Africa. World Health Organization, Geneva. Available at: http://www.who.int/entity/malaria/publications/atoz/smc_policy_recommendation_en_032012.pdf, accessed 7 November 2016.
88. WHO. (2013) The use of co-trimoxazole prophylaxis for HIV-related infections among adults, adolescents and children. Supplementary section to the WHO consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, Chapter 8. World Health Organization, Geneva. Available at: http://www.who.int/hiv/pub/guidelines/arv2013/December2014-ARVsupplement-chap8.pdf, accessed 7 November 2016.
89. WHO. (2014) WHO policy brief for the implementation of intermittent preventive treatment of malaria in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP). Document reference WHO/HTM/GMP/2014.4. World Health Organization, Geneva. Available at: http://www.who.int/malaria/publications/atoz/iptp-sp-updated-policy-brief-24jan2014.pdf?ua=1, accessed 7 November 2016.
90. WHO. (2015a) World Malaria Report 2015. World Health Organization, Geneva. Available at: http://apps.who.int/iris/bitstream/10665/200018/1/9789241565158_eng.pdf?ua=1, accessed 7 November 2016.
91. WHO. (2015b) Guideline: Optimal Serum and Red Blood Cell Folate Concentrations in Women of Reproductive Age for Prevention of Neural Tube Defects. World Health Organization, Geneva. Available at: http://apps.who.int/iris/bitstream/10665/161988/1/9789241549042_eng.pdf?ua=1, accessed 7 November 2016.
92. WHO/FAO. (2004) Vitamin and Mineral Requirements in Human Nutrition, 2nd edn. World Health Organization, Geneva.
93. WHO/FAO/UNICEF/GAIN/MI/FFI. (2009) Recommendations on wheat and maize flour fortification. Meeting Report: Interim Consensus Statement. World Health Organization, Geneva. Available at: http://www.who.int/nutrition/publications/micronutrients/wheat_maize_fort.pdf, accessed 7 November 2016.
94. Wilson, A.L., on behalf of the IPTc Taskforce. (2011) A systematic review and meta-analysis of the efficacy and safety of Intermittent Preventive Treatment of malaria in children (IPTc). PLoS ONE, 6, e16976.
95. Yetley, E.A. & Johnson, C.L. (2011) Folate and vitamin B-12 biomarkers in NHANES: history of their measurement and use. American Journal of Clinical Nutrition, 94, 1S–10S.
96. Zhang, K. & Rathod, P.K. (2002) Divergent regulation of dihydrofolate reductase between malaria parasite and human host. Science, 296, 545–547.