[e-med] (2) Paludisme: donner systématiquement du fer aux jeunes enfants serait dangereux

["Marc Dixneuf" <marc.dixneuf@sante.gouv.fr>]

Bonjour,

Les articles et le commentaire sont accessbles gratuitement sur le site du Lancet www.lancet.com. Pour avoir accès aux articles, il suffit de s'enregistrer, c'est simple et gratuit. L'opération est proposée quand on essaie d'avoir accès aux articles).
Ci-dessous le résumé de l'étude et le commentaire des deux papiers.

Marc Dixneuf
Remed/e-med

***********
RESUME

The Lancet 2006; 367:133-143
DOI:10.1016/S0140-6736(06)67962-2

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

Sunil Sazawal (a), Robert E Black(a), Mahdi Ramsan(b), Hababu M Chwaya (c) , Rebecca J Stoltzfus(d) , Arup Dutta(a), Usha Dhingra(a), Ibrahim Kabole(b), Saikat Deb(a) , Mashavi K Othman(b) and Fatma M Kabole(b)

Background
Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa. However, there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful.

Methods
We did a randomised, placebo-controlled trial, of children aged 1â35 months and living in Pemba, Zanzibar. We assigned children to daily oral supplementation with: iron (12Â5 mg) and folic acid (50 Îg; n=7950), iron, folic acid, and zinc (n=8120), or placebo (n=8006); children aged 1â11 months received half the dose. Our primary endpoints were all-cause mortality and admission to hospital. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59549825.

Findings
The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24â076 children contributed a follow-up of 25â524 child-years. Those who received iron and folic acid with or without zinc were 12% (95% CI 2â23, p=0Â02) more likely to die or need treatment in hospital for an adverse event and 11% (1â23%, p=0Â03) more likely to be admitted to hospital; there were also 15% (â7 to 41, p=0Â19) more deaths in these groups.

Interpretation
Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. In the presence of an active programme to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation. However, supplementation of those who are not iron deficient might be harmful. As such, current guidelines for universal supplementation with iron and folic acid should be revised.
Affiliations

a Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA b Public Health Laboratory-Ivo de Carneri, Wawi, Chake-Chake, Pemba, Zanzibar, Tanzania c Ministry of Health and Social Welfare, Government of Zanzibar, Zanzibar, Tanzania d Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA


*********************************************************************************
  
COMMENTAIRE

The Lancet 2006; 367:90-91

DOI:10.1016/S0140-6736(06)67939-7

Iron and folic acid supplementation and malaria risk
Mike English  a   and   Robert W Snow a

See Articles
See Articles

This week's Lancet reports on studies by Sunil Sazawal and James Tielsch, and their respective colleagues,1,2 that are important to the international public-health community. The parallel studies done in Pemba, Tanzania, and Nepal recruited children aged less than 3 years to carefully designed cluster-randomised double-masked intervention trials. Enrolled children received carefully supervised at-home supplementation with iron plus folic acid, zinc, iron plus folic acid plus zinc, or placebo in a factorial design, and were followed up for an average of about a year. The data from each site are from three of the four arms of the trials, with results describing the effect of zinc awaited. The studies aimed to provide definitive evidence on the risks or benefits of these interventions in settings where iron deficiency is common and child mortality, largely attributable to infectious diseases, is high. A key difference between the two settings, however, is mortality risk from malaria. WHO currently recommends routine supplementation with haematinics for children in such settings.

Both studies were carefully designed to address a mortality endpoint and involved fieldwork of a scale few groups working in low-income settings have the capacity to manage. Such studies are rare and the study teams are to be applauded. Can the results be reduced to a reliable public-health soundbite? Sazawal and colleagues are relatively cautious, saying that âRoutine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and deathâ. Tielsch and colleagues conclude that âdaily supplementation of young children in southern Nepal with iron and folic acid with or without zinc has no effect on their risk of deathâ. However, both papers are far superior to any previous examination of the survival benefits and risks of supplementation with iron and folate and might never be superceded. If these are the best current data what is the evidence-based policy implication? The conclusion must be that the risks of death or severe illness of routine iron plus folic acid supplementation (in doses similar to those recommended by WHO) in young children exposed to high rates of malaria infection seem to outweigh any immediate benefits. In areas of no malaria risk, the absence of survival benefit or risk suggests decisions on supplementation should be made according to benefits on growth, physical performance, and, probably most importantly, cognitive performance. There is perhaps one caveat to this conclusion. In the Nepal setting it seems likely, on the basis of the lower than expected child mortality, that children had access to a reasonably well functioning primary health-care system, a factor that the Pemba sub-study results suggest may change the balance of risk and benefit with iron and folic acid.

How should we define a high rate of exposure to malaria? The children in the studies represent two ends of a spectrum; those in Nepal are not exposed to any significant malaria risk, while those in Pemba are exposed to about 400 infective bites each year. Africa can support transmission ranging from exceptionally low risks with less than one infective bite a year to over 1000 infective bites a year.3 In very high transmission settings, such as Pemba, severe malaria morbidity and mortality are concentrated in the first 18 months of life (figure).4 Where malaria transmission is substantial but less intense, half of the life-threatening disease risk is found in children aged over 2 years (figure). As such, Sazawal and colleagues' results are not necessarily generalisable to all malaria settings. How much, and which regions of the world have a similar malaria disease ecology to Pemba? We do not know, which is a further challenge to the public-health communityâto provide a framework to target interventions with sound epidemiological criteria.


Are threats to health associated with iron plus folic acid supplementation mainly related to malaria? The two studies suggest a major malaria-specific effect, although the hierarchical method used for assigning cause of death and/or hospital admission in the Pemba study, with malaria listed first in the hierarchy, might contribute to this interpretation. Thus malaria accounted for about 45% of all severe adverse events. However, it can be difficult to distinguish malaria deaths from deaths from other serious bacterial infections, notably meningitis and bacteraemia,5,6 and it is possible that, in a setting where neither lumbar puncture nor blood culture were possible, cause of death could be misclassified.

What biological mechanisms make iron plus folic acid supplementation unsafe? There are experimental, laboratory, and field observations that point the finger of suspicion firmly at iron.7,8 However, the supplement given in the studies was iron and folic acid in a setting in Pemba where the first line antimalarial treatment was with an antifolate combination of sulfadoxine and pyrimethamine. The addition of folate to iron plus sulfadoxine and pyrimethamine for the treatment of malaria results in a biologically and statistically significant delay in parasite clearance and parasitological (but not clinical) cure.9 While the dose of folic acid was an order of magnitude higher in this treatment trial,9 it is possible that, in an area where sulfadoxine and pyrimethamine efficacy was declining rapidly, as was likely in Pemba at the time of the study, folic acid supplementation contributed to the malaria-related adverse health outcomes of those receiving iron plus folic acid.

We now have by far the best evidence on the consequences of introducing iron plus folic acid supplementation in early childhood in low-income settings. Supplementation was associated with an increase in the combined outcome of severe illness episodes and death in a high malaria-transmission setting but no apparent mortality risk in an area with no malaria. For those who feel that there are important benefits from universal supplementation with iron alone or iron plus folic acid which have not been captured by these studies, the challenge is to prove it. There might be benefits in settings with a high prevalence of anaemia, lower malaria transmission, and an effective primary-care system, conditions that might arise with high levels of insecticide-treated bed net coverage combined with good access to effective malaria case-management with artemisinin-based combination therapies. We would argue that the current trials, while a significant advance, represent data from two ends of the spectrum of malaria ecologies and do not yet provide adequate evidence for global policy. To adopt a new international policy to promote use of insecticide-treated bed nets, a range of large-scale mortality trials in different malaria epidemiological settings were needed.10

For now, it would appear that in low-income areas where iron deficiency is common and malaria absent, routine iron plus folic acid supplementation does no harm and is likely to have long-term benefits. In areas where malaria is endemic, targeted iron plus folic acid or iron therapy given to anaemic children, and strengthening the systems for delivery of case management (eg, through the Integrated Management of Childhood Illness approach),11 seem sensible, although the effectiveness of the targeted management approach requires further evaluation.

We declare that we have no conflict of interest.

References
1. Sazawal S, Black RE, Ramsan M, 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. Lancet 2006; 367: 133-143. Abstract | Full Text | PDF (170 KB)

2. Tielsch JM, Khatry S, Stoltzfus RJ, et al. Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial. Lancet 2006; 367: 144-152. Abstract | Full Text | PDF (134 KB)

3. Hay SI, Rogers DJ, Toomer JF, Snow RW. Annual Plasmodium falciparum entomological inoculation rates (EIR) across Africa: literature survey, internet access and review. Trans R Soc Trop Med Hyg 2000; 94: 113-127. MEDLINE | CrossRef

4. Snow RW, Omumbo J, Lowe B, et al. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 1997; 349: 1650-1654. Abstract | Full Text | PDF (54 KB) | MEDLINE | CrossRef

5. Snow RW, Armstrong JRM, Forster D, et al. Childhood deaths in Africa: uses and limitations of verbal autopsies. Lancet 1992; 340: 351-355. MEDLINE | CrossRef

6. Berkley JA, Lowe BS, Mwangi I, et al. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med 2005; 352: 39-47. CrossRef

7. Oppenheimer S. Iron and its relation to immunity and infectious disease. J Nutr 2001; 131: 616S-635S. 

8. Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. BMJ 1978; 2: 1113-1115. 

9. Carter J, Loolpapit M, Lema O, Tome J, Nagelkerke N, Watkins W. Reduction of the efficacy of antifolate antimalarial therapy by folic acid supplementation. Am J Trop Med Hyg 2005; 73: 166-170. MEDLINE

10. Lengeler C. Insecticide-treated bed nets and curtains for preventing malaria. Cochrane Database Syst Rev 2000; 2:CD000363.. 

11. Armstrong Schellenberg JRM, Adam T, Mshinda H, et al. Effectiveness and cost of facility-based Integrated Management of Childhood Illness (IMCI) in Tanzania. Lancet 2004; 364: 1583-1594. Abstract | Full Text | PDF (222 KB) | CrossRef

Back to top

Affiliations

a Kenya Medical Research Institute/Wellcome Trust Collaborative Programme, Nairobi, Kenya