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#79 Iron Supplementation in Non-Anemic Women with Unexplainable Fatigue: Another Tired Theory?

Is iron supplementation a reasonable option in treating non-anemic iron-deficient women with unexplained fatigue?

In female patients with iron deficiency without anemia who have unexplained fatigue, weak evidence suggests small benefit from iron supplementation. If real, about 1 in 4-10 may have improvement in fatigue.

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Four randomized controlled trials (RCTs) of menstruating non-anemic women (mean age mid-30s) with unexplained fatigue 
  • 294 women with serum ferritin <50 µg/L,1 intravenous iron 1000 mg or placebo x1 dose, followed x8 weeks 
    • Iron statistically significantly improved fatigue score by 0.8 points versus placebo (22-point scale) 
      • More patients reported >50% improvement in their fatigue with iron: 33.3% versus 16.4% with placebo, number needed to treat (NNT)=6 
    • Adverse eventsIron 57.2% versus placebo 49% (p=0.16). 
  • 198 women with serum ferritin <50 µg/L,2 oral ferrous sulfate (80 mg elemental iron) or placebo daily x12 weeks 
    • Iron statistically significantly improved fatigue score by 3.5 points versus placebo (40-point scale) 
    • No significant effects on quality of life, depression or anxiety. 
    • Adverse events: Iron 34.3% versus placebo 25% (p=0.20). 
  • 144 women,3 oral ferrous sulfate (80 mg elemental iron) or placebo daily x4 weeks 
    • Iron statistically significantly improved fatigue score by 0.97 points versus placebo (10-point scale) 
    • In subgroup analysis, only benefit if serum ferritin <50 µg/L. 
  • 90 women with serum ferritin <50 µg/L,4 intravenous iron 200 mg or placebo x4 doses in 2 weeks, followed x12 weeks 
    • No statistically significant difference in fatigue score 
      • However, significantly more patients reported “slight or better improvement in fatigue” with iron on a different fatigue questionnaire 
        • Iron 63% versus placebo 34%, NNT=4 
    • Adverse events: Iron 53% versus placebo 66%. 
  • Interpretation is challenged by: 
    • Each study using multiple and differing scales 
    • High placebo response  
    • Small changes in scales with no validated minimal clinically important differences 
      • One study2 later5 provided the number of patients reaching cut-offs of uncertain relevance: None significant (if adequately powered, NNT might be ~10). 
  • Cost: Oral iron costs $20 for a year’s supply;6 one 1000-mg dose of intravenous iron costs ~$300-450.7 
aug 3 2016 Ricky Turgeon BSc(Pharm) ACPR PharmD

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  • Daniel McKennitt MD
  • G. Michael Allan MD CCFP

1. Favrat B, Balck K, Breymann C, et al. PLoS ONE 2014;9:e94217.

2. Vaucher P, Druais PL, Waldvogel S, et al. CMAJ 2012;184:1247-54.

3. Verdon F, Burnand B, Fallab Stubi CL, et al. BMJ 2003;326:1124–7.

4. Krayenbuehl PA, Battegay E, Breymann C, et al. Blood 2011;118:3222-7.

5. Vaucher P. Available at: Last accessed: Dec 6, 2016.

6. Nickonchuk T, Lee J, Allan GM, et al. Available at: Last accessed: Dec 6, 2016.

7. Therapeutics Initiative. Available at: intravenous-iv-iron-for-severe-iron-deficiency/ Last accessed: Dec 6, 2016.

Authors do not have any conflicts of interest to declare.