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Cited by 126Iron Metabolism and DisordersErythropoietin and Anemia TreatmentHemoglobinopathies and Related Disorders

Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: a systematic review of randomised controlled trials

Open access
Houston, Brett L, Hurrie, Daryl, Graham, Jeff, Perija, Brittany, Rimmer, Emily, Rabbani, Rasheda, Bernstein, Charles N, Turgeon, Alexis F +4 more·2018·BMJ Open
DOI 10.1136/bmjopen-2017-019240PMC PMC5892776
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Abstract

Objective Iron supplementation in iron-deficiency anaemia is standard practice, but the benefits of iron supplementation in iron-deficient non-anaemic (IDNA) individuals remains controversial. Our objective is to identify the effects of iron therapy on fatigue and physical capacity in IDNA adults. Design Systematic review and meta-analysis of randomised controlled trials (RCTs). Setting Primary care. Participants Adults (≥18 years) who were iron deficient but non-anaemic. Interventions Oral, intramuscular or intravenous iron supplementation; all therapy doses, frequencies and durations were included. Comparators Placebo or active therapy. Results We identified RCTs in Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health, SportDiscus and CAB Abstracts from inception to 31 October 2016. We searched the WHO’s International Clinical Trials Registry Platform for relevant ongoing trials and performed forward searches of included trials and relevant reviews in Web of Science. We assessed internal validity of included trials using the Cochrane Risk of Bias tool and the external validity using the Grading of Recommendations Assessment, Development and Evaluation methodology. From 11 580 citations, we included 18 unique trials and 2 companion papers enrolling 1170 patients. Using a Mantel-Haenszel random-effects model, iron supplementation was associated with reduced self-reported fatigue (standardised mean difference (SMD) −0.38; 95% CI −0.52 to −0.23; I 2 0%; 4 trials; 714 participants) but was not associated with differences in objective measures of physical capacity, including maximal oxygen consumption (SMD 0.11; 95% CI −0.15 to 0.37; I 2 0%; 9 trials; 235 participants) and timed methods of exercise testing. Iron supplementation significantly increased serum haemoglobin concentration (MD 4.01 g/L; 95% CI 1.22 to 6.81; I 2 48%; 12 trials; 298 participants) and serum ferritin (MD 9.23 µmol/L; 95% CI 6.48 to 11.97; I 2 58%; 14 trials; 616 participants). Conclusion In IDNA adults, iron supplementation is associated with reduced subjective measures of fatigue but not with objective improvements in physical capacity. Given the global prevalence of both iron deficiency and fatigue, patients and practitioners could consider consumption of iron-rich foods or iron supplementation to improve symptoms of fatigue in the absence of documented anaemia. PROSPERO registration number CRD42014007085 .

AI snapshot

Written from the paper’s full text.

TL;DR

In non-anaemic iron-deficient adults, iron supplementation reduced self-reported fatigue but did not improve objective physical capacity. It increased haemoglobin and ferritin, with evidence graded moderate for fatigue and low for physical capacity.

Key findings

  • From 11,580 citations, the review included 18 unique trials and 2 companion papers enrolling 1170 patients. Iron supplementation reduced self-reported fatigue (SMD −0.38; 95% CI −0.52 to −0.23; I² 0%; 4 trials; 714 participants).
  • Iron did not significantly improve objective physical capacity: VO₂ max (SMD 0.11; 95% CI −0.15 to 0.37; I² 0%; 9 trials; 235 participants), 15 km time trial (SMD −0.09; 95% CI −0.53 to 0.35; I² 0%; 2 trials; 79 participants), or time to exhaustion (SMD 0.25; 95% CI −0.22 to 0.73; I² 0%; 4 trials; 69 participants).
  • Iron significantly increased serum haemoglobin (MD 4.01 g/L; 95% CI 1.22 to 6.81; I² 48%; 12 trials; 298 participants) and serum ferritin (MD 9.23 µmol/L; 95% CI 6.48 to 11.97; I² 58%; 14 trials; 616 participants). Adverse events were sparsely reported; adherence did not differ (RR 1.0; 95% CI 0.99 to 1.01; I² 0%; 12 trials; 958 participants).

Methods

  • Systematic review and meta-analysis of randomised controlled trials in adults (≥18 years) who were iron deficient but non-anaemic, comparing oral, intramuscular, or intravenous iron with placebo or active therapy; outcomes assessed at least 28 days after starting therapy.
  • Searched Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health, SportDiscus, and CAB Abstracts from inception to 31 October 2016, plus trial registries and forward searches.
  • Used Mantel-Haenszel random-effects meta-analysis, mean difference or standardised mean difference for continuous outcomes, I² for heterogeneity, Cochrane Risk of Bias tool, and GRADE; PROSPERO registration CRD42014007085.

Limitations

  • Stated by the paper: search was limited to English studies; dietary iron fortification studies were excluded; masking oral iron was difficult due to predictable gastrointestinal side effects and stool colour changes; healthy women comprised the population in 15 of 18 trials; follow-up was relatively short (mean 57 days; range 28–112 days); adverse events were sparsely reported; most trials were at unclear risk of bias; publication bias could not be assessed for fatigue because of the low number of included trials.
  • Evident from the text: subgroup analyses for biological sex, athletic status, and risk of bias were often unevaluable because contributing trials enrolled women of uncharacterised athletic status and were of unclear risk of bias; the fatigue outcome was subjective and potentially vulnerable to imperfect blinding.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/bmjopen-2017-019240

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

3 of 8 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In trials where a proportion of participants were anaemic at enrolment, iron supplementation has previously been associated with improved maximal and submaximal exercise performance.

    “In trials where a proportion of participants were anaemic at enrolment and with the knowledge that anaemia results in decreased physical capacity, iron supplementation has previously been associated with improved maximal and submaximal exercise performance.5–8”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [5] source
    • cites [6] Eichner, 2001, Fatigue of anemia, Nutr Rev source
    • cites [7] source
    • cites [8] Haas, 2001, Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship, J Nutr source
  • Findingown data

    Iron supplementation does not significantly improve physical capacity in time-to-exhaustion tests (SMD 0.25; 95% CI −0.22 to 0.73; I2 0%; 4 trials; 69 participants).

    “In four trials23 26 27 34 (69 participants) that used time-to-exhaustion tests, iron supplementation did not significantly improve physical capacity (SMD 0.25; 95% CI −0.22 to 0.73; I2 0%) (figure 3B).”
    Quote in the paperSubstantial claim
  • Findingown data

    Iron supplementation is associated with reduced self-reported fatigue in IDNA adults (SMD −0.38; 95% CI −0.52 to −0.23; I2 0%; 4 trials; 714 participants).

    “Using a Mantel-Haenszel random-effects model, iron supplementation was associated with reduced self-reported fatigue (standardised mean difference (SMD) −0.38; 95% CI −0.52 to −0.23; I2 0%; 4 trials; 714 participants)”
    • Also stated in: § Primary outcomes · plain
      “Iron supplementation was associated with a reduction in subjective measures of fatigue when assessed by either the Piper Fatigue Scale,28 the Current and Past Psychological State scale,32 visual analogue scale33 or Brief Fatigue Inventory questionnaire (BFI)31 (SMD −0.38; 95% CI −0.52 to −0.23; I2 0%) (figure 2).”
    • Also stated in: § Conclusion · plain
      “In IDNA adults, iron supplementation is associated with reduced subjective measures of fatigue but not with objective improvements in physical capacity.”
    Quote in the paperSubstantial claim
  • Findingown data

    Iron supplementation is not associated with improved exercise capacity in 15 km time trials (SMD −0.09; 95% CI −0.53 to 0.35; I2 0%; 2 trials; 79 participants).

    “In two trials (79 participants) that used 15 km time trials,22 25 iron supplementation was not associated with improved exercise capacity (SMD −0.09; 95% CI −0.53 to 0.35; I2 0%) (figure 3A).”
    Quote in the paperSubstantial claim
  • Findingown data

    Subgroup analyses based on method of iron administration and duration of follow-up demonstrated no statistically significant differences in subjective fatigue.

    “Subgroup analyses based on method of iron administration and duration of follow-up demonstrated no statistically significant differences in subjective fatigue (see online supplementary appendix 6).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Premisecitation

    Two systematic reviews including pregnant women, blood donors and children concluded benefit of iron supplementation, although in the review by Yokoi and Konomi, the benefit was limited to randomised controlled trials.

    “Two systematic reviews included studies of pregnant women, blood donors and children and included data from both randomised and non-randomised trials.38 39 These studies concluded benefit of iron supplementation, although in the review by Yokoi and Konomi39, the benefit was limited to randomised controlled trials.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [38] Pratt, 2016, Non-anaemic iron deficiency—a disease looking for recognition of diagnosis: a systematic review, Eur J Haematol source
    • cites [39] Yokoi, 2017, Iron deficiency without anaemia is a potential cause of fatigue: meta-analyses of randomised controlled trials and cross-sectional studies, Br J Nutr source

      The Study selection and characteristics section reports six randomised controlled trials and six cross-sectional studies, including an RCT involving blood donors. The Meta-analysis section reports a significant benefit of iron treatment for fatigue in the RCTs. This paper does not establish that its included studies involved pregnant women or children, and its cross-sectional studies were observational studies, not non-randomised trials. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In a systematic review of healthy menstruating women, iron supplementation, irrespective of iron status or anaemia, improved haemoglobin and measures of iron stores.

    “In a systematic review of healthy menstruating women, iron supplementation, irrespective of iron status or anaemia, improved haemoglobin and measures of iron stores.37”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Low, 2016, Daily iron supplementation for improving anaemia, iron status and health in menstruating women, Cochrane Database Syst Rev source

      The Discussion (Summary of main results; page unavailable) reports increased haemoglobin and iron stores among women receiving iron. But the Subgroup analysis (page unavailable) says iron did not improve haemoglobin in iron-replete women, so the claim's ‘irrespective of iron status’ qualification is not supported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    From 11,580 citations, the review included 18 unique trials and 2 companion papers enrolling 1170 patients.

    “From 11 580 citations, we included 18 unique trials and 2 companion papers enrolling 1170 patients.”
    • Also stated in: § Trial characteristics and study populations · plain
      “Of the 11 580 citations identified, we included 18 unique trials and 2 companion papers,17 18 enrolling 1170 subjects (figure 1; table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In one trial using the BFI score, fatigue was not significantly different between groups after 12 weeks, although it was improved in the subgroup of participants with the lowest iron stores (ferritin ≤15 ng/mL or transferrin saturation ≤20%).

    “In one trial using the BFI score, fatigue was not significantly different between groups after 12 weeks, although it was improved in the subgroup of participants with the lowest iron stores (ferritin ≤15 ng/mL or transferrin saturation ≤20%).31”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    All trials were placebo controlled.

    “All trials were placebo controlled.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Among all studies, the mean duration of iron therapy was 46 days (±30 days; range 1-112 days), and mean duration of follow-up was 57 days (±24 days; range 28-112 days).

    “Among all studies, the mean duration of iron therapy was 46 days (±30 days; range 1–112 days), and mean duration of follow-up was 57 days (±24 days; range 28–112 days).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    Physical capacity was reported in 10 trials (291 participants).

    “Physical capacity was reported in 10 trials19 20 22–27 30 34 (291 participants)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The review identified only 18 trials enrolling 1170 adults, representing a minute fraction of affected individuals.

    “Despite rigorous and systematic methodology, we were only able to identify 18 trials enrolling 1170 adults, representing a minute fraction of affected individuals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Biological sex, athletic status and risk of bias could not be evaluated in subgroup analyses for fatigue because all trials contributing data enrolled women of uncharacterised athletic status and were of unclear risk of bias.

    “Biological sex, athletic status (athlete vs non-athlete) and risk of bias could not be evaluated as all trials contributing data to the meta-analyses enrolled women of uncharacterised athletic status and were of unclear risk of bias.28 31–33”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Biological sex, duration of follow-up and risk of bias were unevaluable in subgroup analyses for physical capacity because all trials enrolled women with follow-up of less than 2 months and all were of unclear risk of bias.

    “Biological sex, duration of follow-up and risk of bias were unevaluable as all trials enrolled women with follow-up of less than 2 months and all were of unclear risk of bias.19 22–27 30 34”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In trials using oral iron, the mean daily elemental iron dose was 86.9 mg (±49.1 mg; range: 16-200 mg).

    “In trials using oral iron,19–26 29 30 32 33 35 36 the mean daily elemental iron dose was 86.9 mg (±49.1 mg; range: 16–200 mg).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    Constipation was reported in one trial and diarrhoea in two trials.

    “Constipation was reported in one trial18 and diarrhoea in two trials18 31 (see online supplementary appendix 10).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The WHO cut-off for anaemia was used by nine studies, whereas seven studies used lower values ranging from >110 to <120 g/L, and baseline haemoglobin concentration was not provided in two trial reports.

    “The WHO cut-off for anaemia (haemoglobin concentration > 130 g/L (males) and > 120 g/L (females)) was used by nine studies,19 22–25 30–32 35 whereas seven studies used lower values ranging from > 110 to <120 g/L,20 21 27 28 33 34 36 and baseline haemoglobin concentration was not provided in two trial reports.26 29”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Nausea was significantly increased in two trials using intravenous administration of iron, whereas nausea was not increased in patients who received iron by oral administration.

    “Nausea was reported in four trials18 28 31 33; two trials28 31 using intravenous administration of iron reported significantly increased nausea, whereas nausea was not increased in patients who received iron by oral administration.18 33”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Adherence with the study intervention was reported in 13 trials.

    “Adherence with the study intervention was reported in 13 trials.18 19 22–29 32 33 35”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Gastrointestinal intolerance was significantly increased in one trial using intramuscular iron administration but not in the two trials that used oral administration.

    “Gastrointestinal intolerance was reported in three trials23 29 32 and was significantly increased in one trial29 using intramuscular iron administration but not in the two trials23 32 that used oral administration.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    10 trials (55%) adequately incorporated blinded outcome assessment.

    “Likewise, 10 trials (55%) adequately incorporated blinded outcome assessment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In 13 of 18 trials (72%), blinding of participants and personnel was considered adequate.

    “In 13 of 18 trials (72%), we considered the blinding of participants and personnel to be adequate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The mean daily elemental iron dose (86.9±49.1 mg) reflects a recommended 'treatment' for patients with iron-deficiency anaemia.

    “While the duration of follow-up in most studies was modest, the mean daily elemental iron dose (86.9±49.1 mg) reflects a recommended ‘treatment’ for patients with iron-deficiency anaemia.41”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    One trial was considered to have a low risk of bias.

    “One trial29 was considered to have a low risk of bias (table 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The review used a comprehensive search strategy including electronic databases, trial registries and forward searches.

    “The strengths of this review include the comprehensiveness of the search strategy, which included electronic databases, trial registries and forward searches.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The review used an a priori published protocol and followed established methodological guidelines (PRISMA, GRADE).

    “We used a comprehensive search strategy, an a priori protocol and adhered to established methodological (eg, Preferred Reporting Items for Systematic Reviews and Meta-Analyses, Grading of Recommendations Assessment, Development and Evaluation) guidelines.”
    • Also stated in: § Discussion · plain
      “We used an a priori published protocol and followed established methodological guidelines concerning the conduct and reporting of this review.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The remainder of the trials were considered unclear risk of bias due to unclear processes of randomisation (12 trials) or allocation concealment (13 trials).

    “The remainder of the trials were considered unclear risk of bias due to unclear processes of randomisation (12 trials19–27 30 33 34) or allocation concealment (13 trials19–27 30 31 34 35).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The difficulty masking oral iron due to predictable gastrointestinal side effects and changes in stool colour, and the impact of imperfect blinding on subjective measures of fatigue, is a potential weakness of the review.

    “A potential weakness our systematic review is the difficulty masking oral iron due to predictable gastrointestinal side effects and changes in stool colour and the impact of imperfect blinding on subjective measures of fatigue.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The duration of follow-up was relatively short (57 days; range 28-112 days) and perhaps too brief to expect significant changes in muscle metabolism or function.

    “The duration of follow-up was relatively short (57 days; range 28–112 days) and perhaps too brief to expect significant changes in muscle metabolism or function.”
    Quote in the paperSubstantial claim
25 of 25

  • The paper relies on this without support.

    It is unclear whether iron supplementation affects fatigue and physical capacity in iron-deficient but non-anaemic individuals.

    “While iron replacement can normalise haemoglobin concentration, restore work capacity and improve fatigue in iron-deficiency anaemia, it is unclear if supplementation affects fatigue and physical capacity in iron-deficient but non-anaemic (IDNA) individuals.”

  • The paper relies on this without support.

    The use of iron supplements is common in the general population and routinely recommended to high performance athletes to enhance performance.

    “In the absence of compelling efficacy data on well-being or muscle function, the use of iron supplements is common in the general population and are routinely recommended to high performance athletes to enhance performance.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Oral-iron trial described as using intramuscular iron

    Major

    The adverse-events section describes trial 29 as using intramuscular iron, but Table 1 identifies Flink et al (trial 29) as using oral iron.

  • Not all trials had placebo controls

    Minor

    The statement that all trials were placebo controlled conflicts with Table 1, which lists zinc gluconate as the control for Donangelo et al.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Hurrie D , Graham J , Rimmer E , et al . Efficacy of iron replacement therapy on fatigue and work capacity in non-anemic adults with iron depletion: a systematic review of randomized controlled trials. PROSPERO International prospective register of systematic reviews, 2014.

Cited by

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Related

Authors
Houston, B. L., Hurrie, D., Graham, J., Perija, B., Rimmer, E., Rabbani, R., Bernstein, C. N., Turgeon, A. F., Fergusson, D. A., Houston, D. S., Abou-Setta, A. M., & Zarychanski, R.
Affiliations
  • CancerCare Manitoba (CA)
  • University of Manitoba (CA)
  • Winnipeg Regional Health Authority (CA)
  • Université Laval (CA)
  • University of Ottawa (CA)
Corresponding author
Zarychanski, Ryan
ORCID
Venue
BMJ Open
Publisher
BMJ
Published
2018-04
Volume
8
Issue
4
Pages
e019240
ISSN
2044-6055 (ISSN-L)
DOI
10.1136/bmjopen-2017-019240
PMC
PMC5892776
OpenAlex
W2796265630
Semantic Scholar
8c1c95bc5457146c9432f1a5ac8b1bb28520eeaa
Cited by
126
References
41
Citations by year
2026: 12 · 2025: 16 · 2024: 20 · 2023: 13 · 2022: 16 · 2021: 17 · 2020: 15 · 2019: 13 · 2018: 4
FWCI
2.89
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • BMJ Open (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, other-oa)
  • PubMed Central (submittedVersion, cc-by-nc)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
Keywords
iron supplementation, iron deficiency anemia, fatigue, physical capacity, VO2max, exercise testing, serum ferritin, oral iron, intramuscular iron, intravenous iron, adverse effects, iron deficiency in pregnancy, iron deficiency in children
MeSH terms
Iron Deficiencies, Adult, Fatigue, Female, Ferritins, Humans, Iron, Male, Randomized Controlled Trials as Topic

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