1. Objectives

To assess the effects of intermittent oral iron supplementation, alone or in combination with other micronutrients, on anaemia and its associated impairments in menstruating women, compared with no intervention, a placebo or daily supplementation

2. How studies were identified

The following databases were searched to May 2011:

• CENTRAL (The Cochrane Library 2011, Issue 2)
• MEDLINE
• EMBASE
• CINAHL
• POPLINE
• Science Citation Index
• BIOSIS Previews
• CPCI-S

Additional searches were performed in the following databases to July 2011:

• SCIELO
• LILACS
• IBECS
• IMBIOMED
• The Networked Digital Library of Theses and Dissertations
• metaRegister
• WHO International Clinical Trials Registry Platform (ICTRP)

Relevant organizations and researchers in the field were also contacted to identify any ongoing and unpublished studies, and reference lists were handsearched

3. Criteria for including studies in the review

3.1 Study type

Randomized or quasi-randomized trials, including cluster-randomized trials

3.2 Study participants

Menstruating women, defined as women beyond menarche and prior to menopause who are not pregnant or lactating and who are free from any conditions that could affect the presence of menstrual periods

(Studies targeting women with conditions affecting iron metabolism, such as chronic renal failure, inflammatory bowel disease, cancer or malabsorptive conditions, were excluded)

3.3 Interventions

Interventions involving intermittent dosage of oral iron alone or with other micronutrients versus placebo or no intervention, or compared with the same supplements provided daily

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

(Studies combining iron supplementation with other co-interventions, such as education or deworming, were included if co-interventions were identical in both intervention and control groups)

3.4 Primary outcomes

• Anaemia (haemoglobin concentration below a study-defined cut-off)
• Haemoglobin (g/L)
• Iron deficiency (as defined by each study using indicators of iron status such as ferritin or transferrin)
• Ferritin (µg/L)
• Iron deficiency anaemia (defined by the presence of anaemia plus iron deficiency)
• All-cause morbidity (the most frequent event associated with the intervention)

Secondary outcomes included diarrhoea, respiratory infections, adverse side effects (nausea, vomiting, constipation, gastrointestinal discomfort), work performance and economic productivity, school performance and cognitive function, depression, adherence, and in malaria settings, malaria incidence and severity

4. Main results

4.1 Included studies

Twenty-one trials enrolling 10,258 women were included in this review:

• Four trials enrolled women with mild to moderate anaemia, and one trial only included severely anaemic women. Remaining trials included both anaemic and non-anaemic women and excluded severely anaemic women
• In three trials iron supplements were given twice a week; one trial compared both weekly and twice weekly supplementation with a placebo; 17 trials provided iron supplements once a week
• Different doses of iron, predominantly in the form of ferrous sulphate, were administered, ranging from 30 mg to 120 mg per dose; none of the trials exceeded 120 mg of elemental iron per week; all supplements were tablets or capsules
• In 11 of the trials women were supplemented for three months or less and the maximum duration of supplementation was six months
• In nine trials, women were supplemented with iron only, in eight trials women received iron plus folic acid, in two trials women received iron plus multiple micronutrients, and two studies trialled both iron plus folic acid and iron plus multiple micronutrients
• Participants were aged between six and 49 years; one trial enrolled premenarchal girls and did not provide separate data for postmenarchal girls

4.2 Study settings

• Bangladesh (2 trials), Brazil, Guatemala, France, Kenya, India (2 trials), Iran (2 trials), Indonesia (3 trials), Mali, Malawi, Mexico, Nepal, Sri Lanka, the United Republic of Tanzania (2 trials), and Peru
• Most studies were conducted in school settings, four studies implemented the intervention in rural or urban communities and villages, and one trial in Bangladesh was conducted amongst garment factory workers
• Five trials were conducted in areas with some degree of malaria endemicity

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. Dichotomous data were pooled using random effects meta-analysis to generate mean risk ratios (RR) and corresponding 95% confidence intervals (CI), while continuous data were pooled to generate mean differences (MD) and corresponding 95% CI. Data from cluster-randomized trials were adjusted for clustering. To investigate sources of heterogeneity, the following subgroup analyses were planned:

• By composition: iron alone, iron plus folic acid, iron plus multiple micronutrients
• By anaemia status at baseline (haemoglobin <120 g/L): anaemic, non-anaemic, mixed/unknown
• By iron status at baseline (as defined by trialists): iron deficient, not iron deficient, mixed/unknown
• By dose of elemental iron per week in the treatment group: ≤60 mg, >60 mg
• By duration of the supplementation: ≤3 months, >3 months
• By malaria endemicity status of the area at the time of the trial: yes; no/unknown.

Results
Intermittent iron supplementation, with or without other micronutrients, versus no supplementation or placebo
Anaemia
In ten trials of 2996 women, treatment with intermittent iron supplementation reduced the risk of anaemia at the end of the intervention by 27% in comparison to controls (RR 0.73; 95% CI [0.56 to 0.95], p=0.019), with substantial heterogeneity detected (I²=79%). In subgroup analyses, many results became non-significant due to smaller sample sizes; however, little variation in effect size across subgroups was observed, with the exception of women anaemic at baseline, whose response to intermittent iron supplementation was greater (RR 0.39, 95% CI [0.30 to 0.52], 1 trial/222 women).

Haemoglobin (g/L)
Women receiving intermittent iron supplementation achieved mean haemoglobin concentrations of 4.58 g/L greater than women in the control group (95% CI [2.56 to 6.59], p<0.00001; 13 trials/2599 women) at the end of the intervention. Little variation was observed across subgroups, although a greater response was observed in women who were anaemic at baseline (MD 8.64 g/L, 95% CI [3.90 to 13.38]).

Iron deficiency
The risk of iron deficiency was reduced by 50% among women treated with intermittent iron, but the results were not statistically significant (RR 0.50, 95% CI [0.24 to 1.04], p=0.062; 3 trials/624 women).

Ferritin (μg/L)
Ferritin concentrations were greater by 8.32 μg/L in the intervention group in comparison to the controls at the end of the intervention (95% CI [4.97 to 11.66], p<0.00001; 6 trials/980 women).

Iron deficiency anaemia
One trial in 97 women reported on this outcome, finding no statistically significant difference between treatment groups (RR 0.07, 95% CI [0.00 to 1.16], p=0.063).

All-cause morbidity

No difference in all-cause morbidity between treatment groups was observed in one trial of 119 women (RR 1.12, 95% [0.82 to 1.52], p=0.47).

Additional outcomes
Reported diarrhoea, other adverse effects, malaria outcomes (parasitaemia, high density parasitaemia, clinical malaria), and adherence were not different between treatment groups, and no data were available for other pre-specified secondary outcomes.

Intermittent iron supplementation versus daily iron supplementation
Anaemia
In six trials with a total of 1492 women, intermittent iron supplementation was associated with a 26% higher risk of anaemia at the end of the intervention in comparison to daily supplementation (RR 1.26, 95% CI [1.04 to 1.51], p=0.017).

Haemoglobin (g/L)
No statistically significant difference in haemoglobin at the end of treatment was found between intermittent and daily iron supplementation groups in eight trials of 1676 women (MD -0.15 g/L, 95% CI [-2.20 to 1.91], p=0.89). In subgroup analyses, women who received ≤60 mg iron/week intermittently showed higher haemoglobin concentrations (MD 1.14 g/L, 95% CI [-0.34 to 2.62]) in comparison to those women who received >60 mg iron/week intermittently (MD -2.41 g/L, 95% CI [-5.24 to 0.42]).

Iron deficiency
In one trial of 198 women, the risk of iron deficiency was non-statistically significantly greater among women receiving intermittent supplementation in comparison to those receiving daily supplementation (RR 4.30, 95% CI [0.56 to 33.20], p=0.16).

Ferritin (μg/L)
Treatment with intermittent iron supplementation resulted in a statistically significant lower ferritin at the end of the intervention in comparison to daily iron supplementation (MD -11.32 μg/L, 95% CI [-22.61 to -0.02], p=0.00006; 3 trials/657 women).

No trials reported on the outcomes iron deficiency anaemia or all-cause morbidity.

Additional outcomes
Adverse effects, including diarrhoea and depression, were not different between treatment groups, and nor was adherence. No other pre-specified secondary outcomes were reported on.

5. Additional author observations*

Few trials were considered to be at low risk of bias for allocation concealment, blinding, or attrition. The overall quality of the evidence judged according to GRADE criteria was low to very low across both comparisons.

On the basis of the evidence reviewed here, intermittent iron supplementation in menstruating women reduces the prevalence of anaemia and improves haemoglobin and ferritin concentrations in comparison to placebo or no intervention. However, intermittent iron supplementation in comparison to daily iron supplementation increases the risk of anaemia. Overall, findings did not differ when iron supplementation was provided weekly or biweekly; nor with the duration of the intervention, dose, anaemia status at baseline, or malaria endemicity.

Further research is needed into the provision of other micronutrients in combination with intermittent iron to menstruating women, including investigating the optimal dose and regimen of intermittent folic acid effective for the prevention of neural tube defects. The effects of intermittent iron regimens on work and productivity outcomes, iron-related side effects and adherence to supplementation should also be further investigated.