1. Objectives

To evaluate intermittent iron supplementation, either alone or in combination with other vitamins and minerals, on nutritional and developmental outcomes in children under 12 years of age compared with daily supplementation, a placebo or no supplementation

2. How studies were identified

The following databases were searched to May/June 2011:

• CENTRAL (The Cochrane Library 2011, Issue 2)
• MEDLINE
• EMBASE
• CINAHL
• POPLINE
• World Health Organization International Clinical Trials Registry Platform (ICTRP)
• SCIELO
• LILACS
• IBECS
• IMBIOMED

Reference lists were also searched, and the authors directly contacted researchers and relevant organizations to identify further studies

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials, quasi-randomized trials, and cluster-randomized trials

3.2 Study participants

Children under the age of 12 years at induction with no specific health problems

(Studies specifically targeting preterm or low birth weight infants or children with severe infectious diseases, such as HIV, were excluded)

3.3 Interventions

Oral iron supplements administered intermittently, either alone or in combination with other vitamins and minerals, in comparison to placebo or no supplementation, or compared with the same supplements provided daily

(Intermittent supplementation is defined as the delivery of iron supplements one, two or three times a week on non-consecutive days)

3.4 Primary outcomes

• Anaemia (as defined by study authors)
• Haemoglobin (g/L)
• Iron deficiency (as defined by study authors using indicators such as ferritin or transferrin)
• Iron status (ferritin, μg/L)
• Iron deficiency anaemia (anaemia in conjunction with iron deficiency)
• All-cause mortality

Secondary outcomes included all-cause morbidity, acute respiratory infection, diarrhoea, adverse effects, adherence, folate status, mental development and motor skill development, school performance, physical capacity, height-for-age Z-scores and weight-for-age Z-scores

4. Main results

4.1 Included studies

Thirty-three trials enrolling 13,114 children were included in this review

• Nineteen studies assessed intermittent iron supplementation against no intervention or placebo; and 21 studies evaluated intermittent versus daily iron supplementation
• Fifteen studies included children from birth to 59 months of age; 11 studies included children ≥60 months of age; and seven studies included children in both age categories
• Nine studies provided supplementation with iron twice a week; two studies provided supplementation with iron every other day (three times a week); and the remaining trials provided supplementation once per week
• The majority of studies provided supplementation with iron alone, however; one study administered iron in combination with 30 mg of vitamin C; five studies provided iron in combination with folic acid; and four studies provided supplements containing multiple micronutrients
• Ferrous sulphate was the most common source of supplemental iron; other iron compounds tested included ferrous polymaltose, ferrous dextran and ferrous fumarate. Total weekly doses ranged from 7.5 mg to 200 mg of elemental iron

4.2 Study settings

• Community settings in Bangladesh, Bolivia (2 trials), Brazil (3 trials), China (2 trials), India (2 trials), Indonesia (3 trials), Iran, Jordan, Kenya (3 trials), Malawi (2 trials), Mali, Mexico, Pakistan, Panama, Philippines, South Africa, the United Republic of Tanzania, Thailand, Turkey (3 trials) and Viet Nam (2 trials)
• Seven studies included only anaemic children; three included only non-anaemic children; and the remaining trials had a baseline prevalence of anaemia ranging from 15% to 90%

4.3 Study settings

How the data were analysed
Two main comparisons were made: i) intermittent iron supplementation versus no supplementation or placebo; and ii) intermittent iron supplementation versus daily iron supplementation. Studies with more than one intervention arm may have been included in both comparisons. Random effects models were utilised to produce pooled estimates of dichotomous data (risk ratios, RR) and continuous data (mean differences, MD) with 95% confidence intervals (CI). To explore potential variation, the following subgroup analyses of primary outcomes were planned:

• By dose of elemental iron per week: ≤25 mg; >25 mg to 75 mg; >75 mg
• By duration of supplementation: ≤3 months; >3 months
• By type of iron supplement: ferrous sulphate; ferrous fumarate; other
• By anaemia status at baseline: anaemic; non-anaemic; mixed or not reported
• By supplementation regimen: one supplement a week; other intermittent regimen
• By sex: males; females; mixed or not reported
• By micronutrient composition: iron alone; iron plus folic acid; iron plus other micronutrient; iron multiple plus micronutrients

Results
Intermittent iron supplementation versus no supplementation or placebo
Anaemia
Children provided with intermittent iron supplementation were significantly less likely to be anaemic at follow-up compared with those receiving no intervention (RR 0.51, 95% CI [0.37 to 0.72], p<0.0001; 10 studies/1824 children), although heterogeneity was high (I²=81%). This finding remained statistically significant in subgroup analyses, except where total iron supplementation was >75 mg per week (RR 0.71, 95% CI [0.48, to 1.04]); where the intervention lasted more than three months (RR 0.37, 95% CI [0.14 to 1.02]); when restricted to children with anaemia at baseline (RR 0.30, 95% CI [0.07 to 1.38]), or without anaemia at baseline (RR 0.78, 95% CI [0.27 to 2.31]); and when restricted to boys only (RR 0.81, 95% CI [0.66 to 1.00]).

Haemoglobin concentrations (g/L)
Haemoglobin concentrations were on average 5.20 g/L higher in children receiving intermittent iron supplementation compared to those receiving no intervention or placebo (95% CI [2.51 to 7.88], p=0.00015; 19 studies/3032 children). In subgroup analyses, this finding became non-statistically significant where total iron supplementation was 25 mg or less per week (MD 8.19 g/L, 95% CI [-4.01 to 20.38]); for “other” types of iron compound (MD 2.03 g/L, 95% CI [-0.26 to 4.33]; among children without anaemia at baseline (MD 2.00 g/L, 95% CI [-2.46 to 6.46]); and when iron was provided with zinc (MD -1.60 g/L, 95% CI [-8.09 to 4.89]).

Iron deficiency
Overall, children that were provided intermittent iron supplementation were 76% less likely to have iron deficiency at the end of the intervention compared with those receiving no intervention or placebo (RR 0.24, 95% CI (0.06 to 0.91), p=0.036; 3 studies/431 children).

Iron status as measured by ferritin (μg/L)
In pooled analysis, ferritin concentrations were on average 14.17 μg/L higher in children receiving intermittent iron supplementation compared to those receiving no intervention (95% CI [3.53 to 24.81], p<0.01; 5 studies/550 children). This was finding was rendered non-significant in subgroup analyses where total iron supplementation was 25 mg or less per week (MD 4.60 μg/L, 95% CI [-0.89 to 10.09]); the intervention lasted three months or less (MD 15.80 μg/L, 95% CI [-1.23 to 32.83]); for “other” types of iron compound (MD 2.46 μg/L, 95% CI [-14.37 to 19.29]); when children were anaemic at baseline (MD 2.46 μg/L, 95% CI [-14.37 to 19.29]); when iron was provided with zinc (MD 5.50 μg/L, 95% CI [-3.91 to 14.91]), or multiple micronutrients (MD 3.80 μg/L , 95% CI [-4.96 to 12.56]); and in children aged zero to 59 months (MD 13.15 μg/L, 95% CI [-2.28 to 28.59]).

For the outcomes iron deficiency anaemia and all-cause mortality, no trials reported data.

Additional outcomes
Motor quality was assessed in one study (Baqui et al., 2003), in which the MD between treatment groups was 15.60 (95% CI [7.66 to 23.54]). In this study, the psychomotor development index was also greater among those treated with intermittent iron (MD 6.90, 95% CI [1.35 to 12.45]). However, in a separate study (Sungthong et al., 2002), intelligence quotient was significantly lower by 3 points (95% CI [-5.96 to -0.04]), Thai language ability was reduced (MD -0.30, 95% CI [-0.50 to -0.09]), and mathematic ability was reduced (MD -0.27, 95% CI [-0.44 to -0.10]) with intermittent iron supplementation. For all other secondary outcomes, either no trial reported any data or no statistically significant findings were observed.

Intermittent iron supplementation versus daily iron supplementation
Anaemia
Overall, children that were provided iron supplements intermittently were more likely to have anaemia at follow up compared to those receiving daily iron supplements (RR 1.23, 95% CI [1.04 to 1.47], p=0.017; 6 studies/980 children). This finding became non-significant in subgroup analyses by total iron dose per week; when the intervention lasted three months or less (RR 1.24, 95% CI [0.55 to 2.77]); among children anaemic at baseline (RR 0.96, 95% CI [0.50 to 1.82]); when only one supplement was provided per week (RR 1.18, 95% CI [0.97 to 1.43]); when iron was provided alone (RR 1.17, 95% CI [0.97 to 1.42]) or in combination with multiple micronutrients (RR 1.31, 95% CI [0.31 to 5.57]); and among children aged over 60 months (RR 0.95, 95% CI [0.47 to 1.91]).

Haemoglobin concentrations (g/L)
Haemoglobin concentrations were on average 0.60 g/L lower in children receiving intermittent iron supplementation compared to those receiving daily iron supplementation; however, this result was not statistically significant (95% CI [-1.54 to 0.35]; 19 studies/2851 children). In the following subgroup analyses the difference in haemoglobin concentrations became statistically significant: where 25 mg of iron or less was provided per week to the intermittent group (MD -2.42 g/L, 95% CI [-4.18 to -0.66]), where the intervention lasted more than three months (MD -1.14 g/L, 95% CI [-2.07 to -0.22]), and where iron was provided with folic acid (MD -2.26 g/L, 95% CI [-4.30 to -0.22]).

Iron deficiency
In one study of 76 children (Yang et al., 2004), those provided with intermittent iron supplementation were more likely to have iron deficiency at follow-up compared with those receiving daily supplementation (RR 4.00, 95% CI [1.23 to 13.05], p=0.022).

Iron status measured by ferritin (μg/L)
Ferritin concentrations were on average 4.19 μg/L lower in children receiving intermittent iron supplementation compared to those receiving daily supplementation; however, the findings were not statistically significant (95%CI [-9.42 to 1.05]; 10 studies/902 children).

For the primary outcomes iron deficiency anaemia and all-cause mortality, no trials reported data.

Additional outcomes
In one study (Sungthong et al., 2002), intelligence quotient was significantly lower by 3 points (95% CI [-5.96 to -0.04]), Thai language ability was reduced (MD -0.30, 95% CI [-0.50 to -0.09]), and mathematic ability was reduced (MD -0.27, 95% CI [-0.44 to -0.10]) with intermittent iron supplementation in comparison to daily supplementation. For all other secondary outcomes, either no trial reported any data or no significant findings were observed.

5. Additional author observations*

The overall methodological quality of the trials included in this review was poor, with two-thirds of studies being at risk of bias. Most trials were conducted in Asia, Africa and Latin America, in populations with a moderate to high prevalence of anaemia. Therefore, it is unclear whether the findings of this study can be applied to high-income settings.

Overall, intermittent supplementation with iron was beneficial in improving haemoglobin and ferritin concentrations and in reducing the prevalence of anaemia among children less than 12 years of age, although children receiving daily iron supplements were less likely to be anaemic at follow-up.

As there were a lack of data on adverse effects, and neurocognitive, developmental, and growth outcomes, further research is required. Future studies should also assess cost effectiveness, adherence, and further examine the effect of providing other nutrients in combination with intermittent iron.