Effect of daily iron supplementation on health in children aged 4-23 months: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND About 47% of preschool children worldwide are anaemic. Daily oral iron supplementation is a commonly recommended intervention for treatment and prevention of anaemia, but the efficacy and safety of iron supplementation programmes is debated. Thus, we systematically reviewed the evidence for benefit and safety of daily iron supplementation in children aged 4-23 months. METHODS We searched Scopus and Medline, from inception to Feb 5, 2013, WHO databases, theses repositories, grey literature, and references. Randomised controlled trials that assigned children 4-23 months of age to daily oral iron supplementation versus control were eligible. We calculated mean difference (MD) or standard MD (SMD) for continuous variables, risk ratios for dichotomous data, and rate ratios for rates. We quantified heterogeneity with the I(2) test and synthesised all data with a random-effects model. This review is registered with the International Prospective Register of Systematic Reviews, number CRD42011001208. FINDINGS Of 9533 citations identified by the search strategy, 49 articles from 35 studies were eligible; these trials included 42,306 children. Only nine studies were judged to be at low risk of bias. In children receiving iron supplements, the risk ratio for anaemia was 0·61 (95% CI 0·50-0·74; 17 studies, n=4825), for iron deficiency was 0·30 (0·15-0·60; nine studies, n=2464), and for iron deficiency anaemia was 0·14 (0·10-0·22; six studies, n=2145). We identified no evidence of difference in mental (MD 1·65, 95% CI -0·63 to 3·94; six studies, n=1093) or psychomotor development (1·05, -1·36 to 3·46; six studies, n=1086). We noted no significant differences in final length or length-for-age, or final weight or weight-for-age. Children randomised to iron had slightly lesser length (SMD -0·83, -1·53 to -0·12; eight studies, n=868) and weight gain (-1·12, -1·19 to -0·33) over the course of the studies. Vomiting (risk ratio 1·38, 95% CI 1·10-1·73) and fever (1·16, 1·02-1·31) were more prevalent in children receiving iron. INTERPRETATION In children aged 4-23 months, daily iron supplementation effectively reduces anaemia. However, the adverse effect profile of iron supplements and effects on development and growth are uncertain. Adequately powered trials are needed to establish the non-haematological benefits and risks from iron supplementation in this group. FUNDING Victoria Fellowship (Government of Victoria, Australia); CRB Blackburn Scholarship (Royal Australasian College of Physicans); Overseas Research Experience Scholarship, University of Melbourne.

[1]  E. McLean,et al.  Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993–2005 , 2009, Public Health Nutrition.

[2]  Robert E Black,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 , 2006, The Lancet.

[3]  R. Martorell,et al.  Long-term effects of iron and zinc supplementation during infancy on cognitive function at 9 y of age in northeast Thai children: a follow-up study. , 2011, The American journal of clinical nutrition.

[4]  R. Black,et al.  Iron supplementation in early childhood: health benefits and risks. , 2006, The American journal of clinical nutrition.

[5]  L. Hedges,et al.  Introduction to Meta‐Analysis , 2009, International Coaching Psychology Review.

[6]  A. Prentice,et al.  Effect of Supplementation with Zinc and Other Micronutrients on Malaria in Tanzanian Children: A Randomised Trial , 2011, PLoS medicine.

[7]  H. Stenlund,et al.  A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: interactions between iron and zinc. , 2003, The American journal of clinical nutrition.

[8]  P. Galan,et al.  Effect of daily iron supplementation on iron status, cell-mediated immunity, and incidence of infections in 6–36 month old Togolese children , 2000, European Journal of Clinical Nutrition.

[9]  B. Lozoff,et al.  Iron Deficiency and Child Development , 2007, Food and nutrition bulletin.

[10]  E. Pollitt,et al.  Adverse effect of iron supplementation on weight gain of iron-replete young children , 1994, The Lancet.

[11]  R. Gilbert,et al.  Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia. , 2001, The Cochrane database of systematic reviews.

[12]  R. Martorell,et al.  Maternal and child undernutrition and overweight in low-income and middle-income countries , 2013, The Lancet.

[13]  H. Szajewska,et al.  Effects of iron supplementation in nonanemic pregnant women, infants, and young children on the mental performance and psychomotor development of children: a systematic review of randomized controlled trials. , 2010, The American journal of clinical nutrition.

[14]  E. Özmert,et al.  Short‐term developmental outcome of iron prophylaxis in infants , 2000, Pediatrics international : official journal of the Japan Pediatric Society.

[15]  L. De‐Regil,et al.  Translating research into action: WHO evidence-informed guidelines for safe and effective micronutrient interventions. , 2012, The Journal of nutrition.

[16]  C. Lutter.  Iron deficiency in young children in low-income countries and new approaches for its prevention. , 2008, The Journal of nutrition.

[17]  D. Yahav,et al.  Oral iron supplementation for preventing or treating anaemia among children in malaria-endemic areas. , 2009, The Cochrane database of systematic reviews.

[18]  T. Gera,et al.  Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials , 2005, Public Health Nutrition.

[19]  T. Theander,et al.  Effect of intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial , 2003, The Lancet.

[20]  T. Gera,et al.  Effect of iron supplementation on physical growth in children: systematic review of randomised controlled trials , 2006, Public Health Nutrition.

[21]  Budi Utomo,et al.  Zinc-iron, but not zinc-alone supplementation, increased linear growth of stunted infants with low haemoglobin. , 2007, Asia Pacific journal of clinical nutrition.

[22]  Z. Bhutta,et al.  Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial , 2013, The Lancet.

[23]  V H Talib,et al.  The effect of iron therapy on the growth of iron-replete and iron-deplete children. , 2003, Journal of tropical pediatrics.

[24]  H. Sachdev,et al.  A randomized placebo-controlled trial of iron supplementation in breastfed young infants initiated on complementary feeding: effect on haematological status. , 2004, Journal of health, population, and nutrition.

[25]  U. Yamborisut,et al.  Iron and zinc supplementation improved iron and zinc status, but not physical growth, of apparently healthy, breast-fed infants in rural communities of northeast Thailand. , 2006, The Journal of nutrition.

[26]  F. Viteri,et al.  The effects of short-term oral iron therapy on developmental deficits in iron-deficient anemic infants. , 1982, The Journal of pediatrics.

[27]  Jane Thompson,et al.  Effects of Daily Iron Supplementation in 2- to 5-Year-Old Children: Systematic Review and Meta-analysis , 2013, Pediatrics.

[28]  D. Altman,et al.  Assessing Risk of Bias in Included Studies , 2008 .

[29]  B. Wharton,et al.  Treatment with iron increases weight gain and psychomotor development. , 1986, Archives of disease in childhood.

[30]  M. Akman,et al.  The effects of iron deficiency on infants' developmental test performance , 2004, Acta paediatrica.

[31]  P. Phillips-Howard,et al.  Randomized, controlled trial of daily iron supplementation and intermittent sulfadoxine-pyrimethamine for the treatment of mild childhood anemia in western Kenya. , 2003, The Journal of infectious diseases.

[32]  L. Hooper,et al.  The effects of oral iron supplementation on cognition in older children and adults: a systematic review and meta-analysis , 2010, Nutrition journal.

[33]  J. Beard.  Why iron deficiency is important in infant development. , 2008, The Journal of nutrition.

[34]  T. Gera,et al.  Effect of iron supplementation on incidence of infectious illness in children: systematic review , 2002, BMJ : British Medical Journal.

[35]  J. V. D. van der Meer,et al.  Redistribution of vitamin A after iron supplementation in Indonesian infants. , 2003, The American journal of clinical nutrition.

[36]  E. Pollitt,et al.  Stability, Predictive Validity, and Sensitivity of Mental and Motor Development Scales and Pre-School Cognitive Tests among Low-Income Children in Developing Countries , 1999 .

[37]  C. Seaman,et al.  Randomized, placebo-controlled trial of iron supplementation in infants with low hemoglobin levels fed iron-fortified formula. , 1991, Pediatrics.

[38]  T Walter,et al.  Iron deficiency anemia: adverse effects on infant psychomotor development. , 1989, Pediatrics.

[39]  J. Katz,et al.  Effects of zinc and iron supplementation fail to improve motor and language milestone scores of infants and toddlers. , 2013, Nutrition.

[40]  S. S. Sachdev,et al.  Effect of Iron Supplementation on Haemoglobin Response in Children: Systematic Review of Randomised Controlled Trials , 2007, Journal of pediatric gastroenterology and nutrition.

[41]  Robert E Black,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 , 2006, The Lancet.

[42]  M. Domellöf.  Iron requirements of term, breast-fed infants : a study in Sweden and Honduras , 2001 .

[43]  H. Bauchner,et al.  Daily Multivitamins with Iron to Prevent Anemia in Infancy: A Randomized Clinical Trial , 2001, Clinical pediatrics.

[44]  H. Sachdev,et al.  Effect of iron supplementation on physical performance in children and adolescents: systematic review of randomized controlled trials. , 2007, Indian pediatrics.

[45]  L. De‐Regil,et al.  Intermittent iron supplementation for improving nutrition and development in children under 12 years of age. , 2011, The Cochrane database of systematic reviews.

[46]  H. Stenlund,et al.  A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: effects on growth and development. , 2004, The American journal of clinical nutrition.

[47]  P. Shah,et al.  Efficacy of oral iron therapy in improving the developmental outcome of pre-school children with non-anaemic iron deficiency: a systematic review , 2012, Public Health Nutrition.

[48]  S. Muthayya,et al.  Determinants of Anemia Among Young Children in Rural India , 2010, Pediatrics.

[49]  D. Lien,et al.  Efficacy of combined iron and zinc supplementation on micronutrient status and growth in Vietnamese infants , 2006, European Journal of Clinical Nutrition.

[50]  C. West,et al.  Effects of iron and zinc supplementation in Indonesian infants on micronutrient status and growth. , 2001, The Journal of nutrition.

[51]  E. Ziegler,et al.  Iron status of breastfed infants is improved equally by medicinal iron and iron-fortified cereal. , 2009, The American journal of clinical nutrition.

[52]  E. Pollitt,et al.  Reversal of developmental delays in iron-deficient anaemic infants treated with iron , 1993, The Lancet.

[53]  Juan Pablo Peña-Rosas,et al.  Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age. , 2011, The Cochrane database of systematic reviews.