Daily iron supplementation for improving anaemia, iron status and health in menstruating women.

The Cochrane database of systematic reviews

Apr 2016

DOI: 10.1002/14651858.CD009747.pub2

Citations:164

Influential Citations:10

Systematic Reviews / Meta-Analyses

COI

Enhanced Details

Methods

Randomised controlled trials (RCTs) and quasi-RCTs with either individual- or cluster-randomisation evaluating daily iron supplementation. Participants were menstruating women beyond menarche and before menopause, not pregnant or lactating; most were aged 12–50 years (some younger). Studies conducted across multiple countries (including the USA). Overall, 67 trials enrolled 8,506 women (4,444 in iron arms, 4,064 controls).

Intervention

Daily oral iron supplementation with iron salts (ferrous sulfate, ferrous fumarate, ferrous gluconate, carbonyl iron, ferric pyrophosphate, ferrous carbonate); elemental iron doses range from 1 mg to ~300 mg per day; delivered as tablets (including dispersible forms), capsules, or liquids; duration from about 1 week to 24 weeks; at least 5 days per week; sometimes combined with vitamin C to improve absorption or folic acid for pregnancy-related outcomes; cointerventions allowed only if the same in intervention and control groups.

Results

Iron supplementation significantly reduced anaemia at the end of intervention (RR 0.39; 95% CI 0.25–0.60; 10 trials, 3273 women) and increased haemoglobin by a mean of 5.30 g/L (95% CI 4.14–6.45; 51 trials, 6861 women). It reduced iron deficiency at end (RR 0.62; 95% CI 0.50–0.76; 7 trials, 1088 women) and raised ferritin by 10.27 ng/mL (95% CI 8.90–11.65; 42 trials, 3881 women). Transferrin saturation increased by 5.98 percentage points (95% CI 3.93–8.02; 23 trials, 1637 women). Soluble transferrin receptor decreased (SMD -0.32; 95% CI -0.49 to -0.16; 11 trials, 579 women). Adverse effects were more frequent with higher doses: loose stools/diarrhoea (RR 2.13; 95% CI 1.10–4.11); hard stools/constipation (RR 2.07; 95% CI 1.35–3.17); abdominal pain not clearly increased; nausea not clearly increased. Vitamin C coadministration augmented anemia prevalence reduction (but did not change Hb or ferritin). No consistent cognitive function improvements; fatigue may improve in fatigued individuals; exercise performance (maximal and submaximal) improved. All-cause mortality data were not reported. Malaria data were limited (one trial; no difference). No meaningful differences across iron salts. Duration of 1–3 months yielded larger Hb and ferritin increases than shorter or longer durations. Overall, daily iron supplementation is effective for reducing anaemia and iron deficiency and for increasing Hb and iron stores in menstruating women, with a favorable benefit–risk profile at lower doses (e.g., ≤30 mg elemental iron daily for 1–3 months).

Limitations

Many trials had unclear or high risk of bias across domains (randomisation, allocation concealment, blinding, incomplete data). Substantial heterogeneity in populations, doses, durations, formulations, and outcome reporting. Adherence often underreported; adverse effects variably reported. Limited data on cognitive/psychological outcomes and in malaria-endemic settings; potential publication bias possible; older trials predominate. Only a subset of studies assessed long-term health or functional outcomes.

Abstract

BACKGROUND Iron-deficiency anaemia is highly prevalent among non-pregnant women of reproductive age (menstruating women) worldwide, although the prevalence is highest in lower-income settings. Iron-deficiency anaemia has been associated with a range of adverse health outcomes, which restitution of iron stores using iron supplementation has been considered likely to resolve. Although there have been many trials reporting effects of iron in non-pregnant women, these trials have never been synthesised in a systematic review. OBJECTIVES To establish the evidence for effects of daily supplementation with iron on anaemia and iron status, as well as on physical, psychological and neurocognitive health, in menstruating women. SEARCH METHODS In November 2015 we searched CENTRAL, Ovid MEDLINE, EMBASE, and nine other databases, as well as four digital thesis repositories. In addition, we searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and reference lists of relevant reviews. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs comparing daily oral iron supplementation with or without a cointervention (folic acid or vitamin C), for at least five days per week at any dose, to control or placebo using either individual- or cluster-randomisation. Inclusion criteria were menstruating women (or women aged 12 to 50 years) reporting on predefined primary (anaemia, haemoglobin concentration, iron deficiency, iron-deficiency anaemia, all-cause mortality, adverse effects, and cognitive function) or secondary (iron status measured by iron indices, physical exercise performance, psychological health, adherence, anthropometric measures, serum/plasma zinc levels, vitamin A status, and red cell folate) outcomes. DATA COLLECTION AND ANALYSIS We used the standard methodological procedures of Cochrane. MAIN RESULTS The search strategy identified 31,767 records; after screening, 90 full-text reports were assessed for eligibility. We included 67 trials (from 76 reports), recruiting 8506 women; the number of women included in analyses varied greatly between outcomes, with endpoint haemoglobin concentration being the outcome with the largest number of participants analysed (6861 women). Only 10 studies were considered at low overall risk of bias, with most studies presenting insufficient details about trial quality.Women receiving iron were significantly less likely to be anaemic at the end of intervention compared to women receiving control (risk ratio (RR) 0.39 (95% confidence interval (CI) 0.25 to 0.60, 10 studies, 3273 women, moderate quality evidence). Women receiving iron had a higher haemoglobin concentration at the end of intervention compared to women receiving control (mean difference (MD) 5.30, 95% CI 4.14 to 6.45, 51 studies, 6861 women, high quality evidence). Women receiving iron had a reduced risk of iron deficiency compared to women receiving control (RR 0.62, 95% CI 0.50 to 0.76, 7 studies, 1088 women, moderate quality evidence). Only one study (55 women) specifically reported iron-deficiency anaemia and no studies reported mortality. Seven trials recruiting 901 women reported on 'any side effect' and did not identify an overall increased prevalence of side effects from iron supplements (RR 2.14, 95% CI 0.94 to 4.86, low quality evidence). Five studies recruiting 521 women identified an increased prevalence of gastrointestinal side effects in women taking iron (RR 1.99, 95% CI 1.26 to 3.12, low quality evidence). Six studies recruiting 604 women identified an increased prevalence of loose stools/diarrhoea (RR 2.13, 95% CI 1.10, 4.11, high quality evidence); eight studies recruiting 1036 women identified an increased prevalence of hard stools/constipation (RR 2.07, 95% CI 1.35 to 3.17, high quality evidence). Seven studies recruiting 1190 women identified evidence of an increased prevalence of abdominal pain among women randomised to iron (RR 1.55, 95% CI 0.99 to 2.41, low quality evidence). Eight studies recruiting 1214 women did not find any evidence of an increased prevalence of nausea among women randomised to iron (RR 1.19, 95% CI 0.78 to 1.82). Evidence that iron supplementation improves cognitive performance in women is uncertain, as studies could not be meta-analysed and individual studies reported conflicting results. Iron supplementation improved maximal and submaximal exercise performance, and appears to reduce symptomatic fatigue. Although adherence could not be formally meta-analysed due to differences in reporting, there was no evident difference in adherence between women randomised to iron and control. AUTHORS' CONCLUSIONS Daily iron supplementation effectively reduces the prevalence of anaemia and iron deficiency, raises haemoglobin and iron stores, improves exercise performance and reduces symptomatic fatigue. These benefits come at the expense of increased gastrointestinal symptomatic side effects. show less