title: Intermittent iron supplementation for improving nutrition and development in children under 12 years of age.
abstract: BACKGROUND
  Approximately 600 million children of preschool and school age are anaemic worldwide. It is estimated that half of the cases are due to iron deficiency. Consequences of iron deficiency anaemia during childhood include growth retardation, reduced school achievement, impaired motor and cognitive development, and increased morbidity and mortality. The provision of daily iron supplements is a widely used strategy for improving iron status in children but its effectiveness has been limited due to its side effects, which can include nausea, constipation or staining of the teeth. As a consequence, intermittent iron supplementation (one, two or three times a week on non-consecutive days) has been proposed as an effective and safer alternative to daily supplementation.
  
  
  OBJECTIVE
  To assess the effects of intermittent iron supplementation, alone or in combination with other vitamins and minerals, on nutritional and developmental outcomes in children from birth to 12 years of age compared with a placebo, no intervention or daily supplementation.
  
  
  METHODS
  We searched the following databases on 24 May 2011: CENTRAL (2011, Issue 2), MEDLINE (1948 to May week 2, 2011), EMBASE (1980 to 2011 Week 20), CINAHL (1937 to current), POPLINE (all available years) and WHO International Clinical Trials Registry Platform (ICTRP). On 29 June 2011 we searched all available years in the following databases: SCIELO, LILACS, IBECS and IMBIOMED. We also contacted relevant organisations (on 3 July 2011) to identify ongoing and unpublished studies.
  
  
  METHODS
  Randomised and quasi-randomised trials with either individual or cluster randomisation. Participants were children under the age of 12 years at the time of intervention with no specific health problems. The intervention assessed was intermittent iron supplementation compared with a placebo, no intervention or daily supplementation.
  
  
  METHODS
  Two authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies and assessed the risk of bias of the included studies.
  
  
  RESULTS
  We included 33 trials, involving 13,114 children (˜49% females) from 20 countries in Latin America, Africa and Asia. The methodological quality of the trials was mixed.Nineteen trials evaluated intermittent iron supplementation versus no intervention or a placebo and 21 studies evaluated intermittent versus daily iron supplementation. Some of these trials contributed data to both comparisons. Iron alone was provided in most of the trials.Fifteen studies included children younger than 60 months; 11 trials included children 60 months and older, and seven studies included children in both age categories. One trial included exclusively females. Seven trials included only anaemic children; three studies assessed only non-anaemic children, and in the rest the baseline prevalence of anaemia ranged from 15% to 90%.In comparison with receiving no intervention or a placebo, children receiving iron supplements intermittently have a lower risk of anaemia (average risk ratio (RR) 0.51, 95% confidence interval (CI) 0.37 to 0.72, ten studies) and iron deficiency (RR 0.24, 95% CI 0.06 to 0.91, three studies) and have higher haemoglobin (mean difference (MD) 5.20 g/L, 95% CI 2.51 to 7.88, 19 studies) and ferritin concentrations (MD 14.17 µg/L, 95% CI 3.53 to 24.81, five studies).Intermittent supplementation was as effective as daily supplementation in improving haemoglobin (MD -0.60 g/L, 95% CI -1.54 to 0.35, 19 studies) and ferritin concentrations (MD -4.19 µg/L, 95% CI -9.42 to 1.05, 10 studies), but increased the risk of anaemia in comparison with daily iron supplementation (RR 1.23, 95% CI 1.04 to1.47, six studies). Data on adherence were scarce and it tended to be higher among those children receiving intermittent supplementation, although this result was not statistically significant.We did not identify any differential effect of the type of intermittent supplementation regimen (one, two or three times a week), the total weekly dose of elemental iron, the nutrient composition, whether recipients were male or female or the length of the intervention.
  
  
  CONCLUSIONS
  Intermittent iron supplementation is efficacious to improve haemoglobin concentrations and reduce the risk of having anaemia or iron deficiency in children younger than 12 years of age when compared with a placebo or no intervention, but it is less effective than daily supplementation to prevent or control anaemia. Intermittent supplementation may be a viable public health intervention in settings where daily supplementation has failed or has not been implemented. Information on mortality, morbidity, developmental outcomes and side effects, however, is still lacking.
authors.affiliation: Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, 20 Avenue Appia, Geneva, Switzerland, 1211.
authors.forename: Luz Maria
authors.initials: LM
authors.lastname: De-Regil
authors.forename: Maria Elena D
authors.initials: ME
authors.lastname: Jefferds
authors.forename: Allison C
authors.initials: AC
authors.lastname: Sylvetsky
authors.forename: Therese
authors.initials: T
authors.lastname: Dowswell
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D002648:Child; D002657:Child Development / Q000187:drug effects*; D002664:Child Nutritional Physiological Phenomena / Q000187:drug effects; D002675:Child, Preschool; D019587:Dietary Supplements; D004334:Drug Administration Schedule; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D019266:Iron, Dietary / Q000008:administration & dosage*; D008297:Male; D016032:Randomized Controlled Trials as Topic; D014131:Trace Elements / Q000008:administration & dosage; D014815:Vitamins / Q000008:administration & dosage
chemical_list: D006442:Glycated Hemoglobin; D019266:Iron, Dietary; D014131:Trace Elements; D014815:Vitamins