EVIDENCE-BASED PUBLIC HEALTH

Iron supplementation is unlikely to increase the incidence ofinfectious disease in childrenAbstracted from:GeraT, Sachdev HPS.Effect of iron supplementation on incidence of infectious illness in children: systematic review.BMJ 2002; 325:1142^1151.

BACKGROUND Anaemia is a major public healthissue, a¡ecting up to half of school age children in theworld. Iron supplements can be administered using arange of methods, but the safety of supplementationremains uncertain. There are concerns that ironsupplements may increase the risk of infectiousdisease, especially in developing countries.

OBJECTIVE To assess the relationship between ironsupplementation and the incidence of infectious diseasein children.

METHOD Systematic review with meta-analysis.

SEARCH STRATEGY The authors searchedMEDLINE, the Cochrane Controlled Trials Register,HealthSTAR, IBIS, EMBASE, reference lists ofidenti¢ed studies, bibliographies and reviews and theproceedings of conferences and meetings. Experts anddonor agencies were contacted for additional studies.

INCLUSION/EXCLUSION CRITERIA Ran-domised placebo-controlled trials were eligible if theyassessed iron supplementation in children administeredorally, through formula milk or forti¢ed cereals orparenterally. Non-placebo-controlled trials of irongiven parenterally were also eligible. Twenty-eighttrials with 7892 children were included. Six wereunpublished.

OUTCOMES Total recorded infectious illnesses;incidence of individual illnesses including respiratorytract infection, diarrhoea and malaria; positive smearfor malaria.

MAIN RESULTS Iron supplementation did notincrease the overall risk of infectious illness (incidencerate ratio 1.02, 95% CI 0.96 to 1.08) or the risk ofdeveloping speci¢c diseases such as malaria. Ironsupplementation was associated with an increased riskof diarrhoea, equivalent to about 0.05 episodes per childyear (incidence rate ratio 1.11, 95% CI 1.01 to 1.23).Forti¢ed foods may be the safest method of ironsupplementation. There was signi¢cant unexplainedheterogeneity between trials.

AUTHORS’ CONCLUSIONS Iron supplemen-tation is unlikely to increase the overall incidence ofinfectious illness in children, though it may increasethe risk of developing diarrhoea.

Sources offunding:None speci¢ed.

Correspondence to: HPSSachdevVasantVihar,NewDelhi, India.Email: hpssachdev@hotmail.com

Abstract provided by Bazian Ltd, London

104 Evidence-based Healthcare (2003) 7,104^105 1462-9410/03/$ - see frontmatter & 2003 Published by Elsevier Science Ltd.doi:10.1016/S1462-9410(03)00022-6

Commentary

Relevance

Gera and Sachdev address an important unresolved issue. Irondef|ciency is themajor micronutrient def|ciency world wide.Theinternational communityhaverepeatedlycalled for action to cor-rect this problem. Many countries have implemented strategiesto increase iron consumption or supplement target groups.Safety has been a concern, particularly inmalaria endemic areas.Gera and Sachdev conclude that providing extra iron does notincrease the incidence of infections.These conclusions are consis-tentwith those of another reviewof therisks andbenef|ts of ironsupplementation in malarious areas carried out by INACG in1999. 1Taken together, the f|ndings suggest that iron supplemen-tation is not associated with a signif|cant increase in the risk ofclinical malaria, although it increases the odds of being slide-positive for malarial parasitaemia at the end of the supple-mentation period.Safety concerns are much broader than the incidence of

infections, however. Absorption of orally administered ironis related to the degree of def|ciency, which is translated in thenumber of intestinal iron receptors. Absorption is nevercompletely ‘switched off.’ This means that there is a risk ofiron overload for people carrying the haemochromatosistrait.2 Until now, the importance of this factor has remaineduncertain.Iron is a potent free radical generator.Numerousmechanisms

exist to protect against freeradical damage. 3Only when thebal-ance between free radical generation and protection is upsetdoes damage occur. The best known case is kwashiorkor.4 Pro-tectivemechanismsmay be enzyme-based, whereminerals suchas zinc, manganese and selenium are essential elements, ormoreindirect, using the electron scavenging properties of vitamins Eand A, carotenes or polycyclic molecules (now referred to asantioxidants). Def|ciencies of nutrients that act as antioxidantscan compromise cell-mediated immunity.The varying responsesto iron supplementation found by Gera and Sachdev could be at-tributed to a shortage of factors that protect against free radicaldamage when iron is present. Most of the above-mentioned mi-cronutrients have also been implicated in decreased disease re-sistance in their own right.

Caveats

The authors havebeenmethodologically rigorous and attemptedto limitpublicationbias. As theynote, however, there iswide sta-tistical heterogeneity between studies.This heterogeneity is notsurprising when one considers the important clinical andmetho-dological variations among trials.Differences include setting, riskof infection, age range, route of administration, duration of ironsupplementation and specif|city of case def|nition.Gera and Sachev modelled the heterogeneity using a random

effects analysis. The relevance of pooling results from studieswith such different characteristics is questionable. Some suggestthat random effects analysis is simply a means of combining ‘ap-ples and pears.’ Investigating sources of heterogeneity may bemore informative than pooling. 5 The authors attempted to dothis using stratif|ed analysis and meta-regression. None of thestudy characteristics included in the meta-regression could ex-plain the heterogeneity, although some important covariatessuch as dose or age groupwere not included.On the other hand, the question of heterogeneitymay not be

so important. In the forest plot for incidence rate ratio of ill-nesses, the treatment effect is weak or non-existent in most ofthe individual studies.The treatment effect estimate is close to1for all of the big studies. Thus, the overall conclusion that ironsupplementation is safe seemswarranted.

Dr Patrick Kolsteren andDominique RoberfroidNutrition and Child Health Unit

Institute of Tropical MedicineAntwerp, Belgium

Literature cited

1. The INACGreview is cited in Huffman SL, Zehner ER,HarveyPH et al. Essential Health Sector Actions to Improve MaternalNu-trition in Africa.Washington,DC: LINKAGES, 2001.

2. National Research Council. Recommended Dietary Allowances.Washington,DC:National Academy Press,1989.

3. Halliwell B. Free radicals, antioxidants, and human diseases:curiosity, cause, or consequence? Lancet1994; 344: 721^724.

4. Golden MHN. Free radicals in the pathogenesis of kwashior-kor. ProcNutr Soc1987; 46: 53^68.

5. Thompson SG.Why sources of heterogeneity inmeta-analysisshould be investigated.BMJ1994; 309:1351^1355.

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