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

Abstract

SummaryFor decades, folic acid has routinely been given to prevent or treat anaemia in children, pregnant women and people with sickle cell disease. However, there is no conclusive evidence that folate deficiency anaemia constitutes a public health problem in any of these groups. Industrial flour fortification is recommended and implemented in many countries to combat neural tube defects. Dietary folates or folic acid can antagonise the action of antifolate drugs that play a critical role in the prevention and treatment of malaria. Randomised trials have shown that folic acid supplementation increases the rate of treatment failures with sulfadoxine‐pyrimethamine. The efficacy of antifolate drugs against Plasmodium is maximized in the absence of exogenous folic acid, suggesting that there is no safe minimum dose of ingested folic acid. We here review the safety and benefits of interventions to increase folate status in malaria‐endemic countries. We conclude that formal cost‐benefit analyses are required.

Adherence to home fortification with micronutrient powders in Kenyan pre-school children: self-reporting and sachet counts compared to an electronic monitoring device

“…The micronutrient powders were manufactured specifically for this trial by DSM Nutrition Products (Johannesburg, South Africa) and packaged in 1 g sachets. The home fortificant powders for all three groups contained the same multiple micronutrients other than iron (Table 1 ) as recommended by the Home Fortification Technical Advisory Group, except folic acid, which we omitted because of our concerns that it may be utilized by Plasmodium parasites and increase failure risk of antifolate drugs [ 12 ]. We do not believe that exclusion of folic acid from the fortificants affects the generalisability of our results.…”

Metabolic dependency of chorismate in Plasmodium falciparum

“…Altogether, these results suggest that folate or its derivatives may play a role during egress/invasion of merozoites and ring development. Further investigation is required as pABA is the only known metabolite present in adult human plasma at variable concentrations (0.15 -6.56 µM) 26 and increasing folate supplementation in malaria endemic areas 27 has the potential to result in an increased risk of infection and failure of antifolate treatments. It is worth mentioning that all metabolites except pABA are present in the CM at supraphysiological concentrations 28 .…”

Excess micronutrient intake: defining toxic effects and upper limits in vulnerable populations

“…2 Each nutrient is considered systematically, and any judgments or assumptions made are explicitly described in a discussion of the scientific uncertainties involved. 2,33 Risk assessment of nutrients follows four steps: 2 1,7,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] General value is divided by an uncertainty factor (UF), creating a buffer of safety to arrive at the UL (see discussion on NOAELs, LOAELs, CEs, and UFs below). Different ULs are set for different life-stage groups.…”

“…g g Some suggest the UL should take into account folate's interference with antifolate drugs such as those used for malaria control. 13 On the other hand, Wald et al argue that the IOM misinterpreted data when setting the LOAEL and UL for folate and that there is no evidence for a folate UL at all for any ages. Authors assert that the existence of a folate UL has "acted as a barrier to the wider introduction of mandatory fortification of flour with folic acid to prevent No adverse effects of excess folic acid have been confirmed in young children 66 and no UL has been set for infants by any group.…”

“…Some suggest the UL should take into account folate's interference with antifolate drugs such as those used for malaria control . On the other hand, Wald et al .…”