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Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: a systematic review of randomised controlled trials
  1. Brett L Houston1,2,
  2. Daryl Hurrie3,
  3. Jeff Graham1,2,
  4. Brittany Perija4,
  5. Emily Rimmer1,2,
  6. Rasheda Rabbani5,6,
  7. Charles N Bernstein7,
  8. Alexis F Turgeon8,9,
  9. Dean A Fergusson10,
  10. Donald S Houston1,2,
  11. Ahmed M Abou-Setta5,6,
  12. Ryan Zarychanski1,2,5,6
  1. 1 Department of Internal Medicine, Section of Medical Oncology and Haematology, University of Manitoba, Winnipeg, Manitoba, Canada
  2. 2 Department of Medical Oncology and Haematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada
  3. 3 Applied Health Sciences, Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg, Manitoba, Canada
  4. 4 Department of Internal Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
  5. 5 George & Fay Yee Centre for Healthcare Innovation, University of Manitoba/Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada
  6. 6 Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
  7. 7 Department of Internal Medicine, Section of Gastroenterology, University of Manitoba, Winnipeg, Manitoba, Canada
  8. 8 Population Health and Optimal Health Practices Research Unit, Trauma—Emergency—Critical Care Medicine, CHU de Québec—Université Laval Research Center, Québec City, Québec, Canada
  9. 9 Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, Faculty of Medicine, Université Laval, Québec City, Québec, Canada
  10. 10 Clinical Epidemiology Program, Ottawa Hospital Research Institute (OHRI); Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  1. Correspondence to Dr Ryan Zarychanski; rzarychanski{at}


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; I2 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; I2 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; 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).

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.

  • iron deficiency
  • iron supplementation
  • fatigue
  • exercise capacity
  • systematic review

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  • Contributors All authors meet ICMJE criteria for authorship. Two researchers (BH and DH) lead and coordinated all aspects of the review, including but not limited to preparation of the literature search, screening relevant material, data analysis and extraction, interpretation of the results of the meta-analytic procedures, bias investigation and preparation of the final report; three second reviewers (JG, ER, BP) conducted independent screening of relevant material, extracted and analysed data and aided in report preparation; one haematologist/ intensivist (RZ), methodologist (DAF) and anaesthetist/intensivist (AFT) with expertise in systematic reviews provided content expertise and methodological input and resolved disagreement among reviewers; one systematic review expert (AMAS) provided methodological input; two haematologists (DSH and ER), one gastroenterologist (CNB) and one statistician (RR) provided content expertise. All authors were involved in the process of study design and manuscript review.

  • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement We are submitting (in our manuscript and supplementary files) all planned data analyses.