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Cited by 163Iron Metabolism and DisordersErythropoietin and Anemia TreatmentHemoglobinopathies and Related Disorders

Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: A randomized controlled trial

Open access
Vaucher, Paul, Druais, Pierre-Louis, Waldvogel, Sophie, Favrat, Bernard·2012·Canadian Medical Association Journal
DOI 10.1503/cmaj.110950PMC PMC3414597
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Abstract

BACKGROUND: The true benefit of iron supplementation for nonanemic menstruating women with fatigue is unknown. We studied the effect of oral iron therapy on fatigue and quality of life, as well as on hemoglobin, ferritin and soluble transferrin receptor levels, in nonanemic iron-deficient women with unexplained fatigue. METHODS: We performed a multicentre, parallel, randomized controlled, closed-label, observer-blinded trial. We recruited from the practices of 44 primary care physicians in France from March to July 2006. We randomly assigned 198 women aged 18-53 years who complained of fatigue and who had a ferritin level of less than 50 ug/L and hemoglobin greater than 12.0 g/dL to receive either oral ferrous sulfate (80 mg of elemental iron daily; n=102) or placebo (n=96) for 12 weeks. The primary outcome was fatigue as measured on the Current and Past Psychological Scale. Biological markers were measured at 6 and 12 weeks. RESULTS: The mean score on the Current and Past Psychological Scale for fatigue decreased by 47.7% in the iron group and by 28.8% in the placebo group (difference -18.9%, 95% CI -34.5 to -3.2; p=0.02), but there were no significant effects on quality of life (p=0.2), depression (p=0.97) or anxiety (p=0.5). Compared with placebo, iron supplementation increased hemoglobin (0.32 g/dL; p=0.002) and ferritin (11.4 μg/L; p<0.001) and decreased soluble transferrin receptor (-0.54 mg/L; p<0.001) at 12 weeks. INTERPRETATION: Iron supplementation should be considered for women with unexplained fatigue who have ferritin levels below 50 μg/L. We suggest assessing the efficiency using blood markers after six weeks of treatment. Trial registration no. EudraCT 2006-000478-56.

AI snapshot

Written from the paper’s full text.

TL;DR

In a 12-week randomized placebo-controlled trial among nonanemic menstruating women with unexplained fatigue and ferritin <50 µg/L, oral iron (80 mg/d prolonged-release ferrous sulfate) reduced fatigue scores significantly more than placebo. Iron also improved hemoglobin and iron-status markers, with no significant effect on anxiety, depression, or quality of life.

Key findings

  • Intention-to-treat analysis showed the CAPPS fatigue score decreased by 12.2 points with iron vs 8.7 with placebo; adjusted treatment effect was −3.46 points (95% CI −6.7 to −0.3), corresponding to a 47.7% vs 28.8% decrease (treatment effect −18.9%, 95% CI −34.5 to −3.2).
  • Iron significantly improved the MAF global fatigue index (treatment effect −4.0, 95% CI −7.6 to −0.4; p = 0.03) and MAF severity index (−0.87, 95% CI −1.5 to −0.08; p = 0.03), but had no significant effect on anxiety or depression scores or quality-of-life indicators.
  • At 6 weeks, iron significantly changed hemoglobin (0.3 g/dL; p = 0.001), ferritin (6.8 µg/L; p < 0.001), mean corpuscular volume (1.2 fL; p = 0.01), hematocrit (0.8%; p = 0.03), soluble transferrin receptor (−0.4 mg/L; p < 0.001), and transferrin saturation (6.6%; p < 0.001); results were similar at 12 weeks.
  • Adverse events were reported by 59/198 patients (29.8%): 35/102 (34.3%) in the iron group vs 24/96 (25.0%) in the placebo group (χ² = 2.1, p = 0.2); gastrointestinal disorders occurred in 12 (11.8%) vs 10 (10.4%), and 5 serious adverse events occurred, none related to treatment.

Methods

  • Design: 12-week multicentre, double-blind, placebo-controlled, parallel-group, pragmatic randomized trial with 1:1 allocation, conducted in 44 private general practices in France; 243 patients were screened and 198 were randomized (iron n = 102, placebo n = 96), with 91 and 87 completing the study, respectively.
  • Participants: menstruating women aged 18–50 years with fatigue >6 on a 1–10 Likert scale, no anemia (hemoglobin ≥12.0 g/dL), ferritin <50 µg/L, no known pathology explaining fatigue, not pregnant or breastfeeding, no digestive disorder altering absorption, and not already taking iron; intervention was oral 80 mg/d prolonged-release ferrous sulfate or placebo for 12 weeks.
  • Outcomes and analysis: primary outcome was the CAPPS fatigue score (0–40); secondary outcomes included MAF, SF-12 vitality, quality of life, and blood markers at baseline, 6, and 12 weeks. Intention-to-treat analysis used hot-deck imputation with 10 imputations and generalized estimating equations adjusted for baseline values and physician clustering; ferritin stratification was per-protocol, hemoglobin analysis was amended, and transferrin saturation analysis was post-hoc. Sample size was powered to detect a 1.8 vs 0.8 point decrease (SD 2.0), with power 0.9 and alpha 0.05, requiring 85 per group, increased by 30% to 240.

Limitations

  • Stated: blinding could not be totally assured because iron side effects (e.g., stool colour, digestive effects) could differentiate it from placebo, although no differences in digestive events were observed and participants were not asked to guess assignment; heterogeneity of responses made responder subgroups difficult to determine; imputation methods require data missing at random, which cannot be totally assumed; and fatigue is a subjective, patient-centred measure, though three fatigue measures and laboratory surrogates increased internal validity.
  • Evident from the text: baseline imbalances existed—more patients in the iron group had hemoglobin <13.0 g/dL and ferritin <15 µg/L—though adjustment for these did not alter results; the per-protocol analysis had smaller groups (55 iron, 66 placebo) and its CAPPS treatment-effect CI crossed zero (−2.6 to 6.7); and the study was sponsored and funded by Pierre Fabre Médicament, which designed the study and was responsible for collecting and managing data, with authors reporting funding and conflicts.

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Integrity signals

Registry

Crossref · 10.1503/cmaj.110950

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 19 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Effects on outcomes

    After six weeks, hematocrit increased significantly (0.8%; p=0.03).

    “After six weeks of iron treatment, there were significant effects on hemoglobin (0.3 g/dL; p = 0.001), ferritin (6.8 µg/L; p < 0.001), mean corpuscular volume (1.2 fL; p = 0.01), hematocrit (0.8%; p = 0.03), soluble transferrin receptor (-0.4 mg/L; p < 0.001) and transferrin saturation (6.6%; p < 0.001).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Effects on outcomes

    Iron supplementation had no significant effect on depression scores (CAPPS) compared with placebo.

    “Iron supplementation did not have any effect on anxiety or depression scores (Table 2).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Ferritin <50 µg/L indicates low or borderline iron stores in nonanemic menstruating women.
  • Findingown data
    § Effects on outcomes

    Iron supplementation had no significant effect on anxiety scores (CAPPS) compared with placebo.

    “Iron supplementation did not have any effect on anxiety or depression scores (Table 2).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Ferritin <50 µg/L indicates low or borderline iron stores in nonanemic menstruating women.
  • Findingown data
    § Effects on outcomes

    Iron supplementation reduced global fatigue index (MAF) compared with placebo (p=0.03).

    “Iron also had significant effects on the global fatigue index from the Multidimensional Assessment of Fatigue Scale (p = 0.03) and its severity index (p = 0.03).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Ferritin <50 µg/L indicates low or borderline iron stores in nonanemic menstruating women.
  • Findingown data
    § Effects on outcomes

    After six weeks, soluble transferrin receptor decreased significantly (-0.4 mg/L; p<0.001).

    “After six weeks of iron treatment, there were significant effects on hemoglobin (0.3 g/dL; p = 0.001), ferritin (6.8 µg/L; p < 0.001), mean corpuscular volume (1.2 fL; p = 0.01), hematocrit (0.8%; p = 0.03), soluble transferrin receptor (-0.4 mg/L; p < 0.001) and transferrin saturation (6.6%; p < 0.001).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Ferritin <50 µg/L indicates low or borderline iron stores in nonanemic menstruating women.
  • The quote only partly states this claim. 3
  • May combine two claims. 11
  • Classified as probably not a substantial claim. 11

  • The quote only partly states this claim.

    Findingown data
    § Effects on outcomes

    After six weeks of iron treatment, hemoglobin increased significantly compared with placebo (0.3 g/dL; p=0.001).

    “After six weeks of iron treatment, there were significant effects on hemoglobin (0.3 g/dL; p = 0.001), ferritin (6.8 µg/L; p < 0.001), mean corpuscular volume (1.2 fL; p = 0.01), hematocrit (0.8%; p = 0.03), soluble transferrin receptor (-0.4 mg/L; p < 0.001) and transferrin saturation (6.6%; p < 0.001).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Adverse events

    During the study, 29.8% of patients reported at least one adverse event, with no significant difference between iron (34.3%) and placebo (25.0%) groups (χ2=2.1, p=0.2).

    “During the study, 59/198 patients (29.8%) reported at least one adverse event: 35/102 (34.3%) in the iron group and 24/96 (25.0%) in the placebo group (χ 2 = 2.1, p = 0.2).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data
    § Effects on outcomes

    Iron supplementation had no significant effect on quality of life indicators (SF-12 and CAPPS total) compared with placebo.

    “There were no significant effects on the indicators of quality of life.”
    • Also stated in: § Interpretation · plain
      “Iron supplementation did not have a significant effect on measured indicators of quality of life apart from those directly related to fatigue.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Ferritin <50 µg/L indicates low or borderline iron stores in nonanemic menstruating women.

  • May combine two claims.

    Findingown data
    § Adverse events

    No serious adverse events appeared to be related to the study treatment, and no deaths were reported.

    “No deaths were reported, and none of the serious adverse events appeared to be related to the study treatment.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data
    § Effects on outcomes

    Iron supplementation for 12 weeks reduced CAPPS fatigue score compared with placebo by 3.5 points (95% CI 0.3 to 6.7) in nonanemic menstruating women with low ferritin and unexplained fatigue.

    “Intention-to-treat analysis showed that patients receiving the iron supplement had a 3.5 point improvement (95% confidence interval [CI] 0.3 to 6.7) in their fatigue score on the Current and Past Psychological Scale compared with those in the placebo group”
    • Also stated in: § Interpretation · plain
      “We found that iron supplementation for 12 weeks decreased fatigue by almost 50% from baseline, a significant difference of 19% compared with placebo, in menstruating iron-deficient nonanemic women with unexplained fatigue and ferritin levels below 50 µg/L.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Ferritin <50 µg/L indicates low or borderline iron stores in nonanemic menstruating women.

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

    Findingown data
    § Adverse events

    Gastrointestinal disorders were reported by 11.8% in iron group and 10.4% in placebo group.

    “Twelve (11.8%) patients in the iron group and 10 (10.4%) in the placebo group reported gastrointestinal disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning
    § Strength and limitations

    We did not observe any differences in constipation, stomach ache, diarrhea or other digestive events between groups.

    “However, we did not observe any differences in constipation, stomach ache, diarrhea or other digestive events between groups because a low dose of prolonged-release ferrous sulfate was used.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data
    § Statistical analysis

    Missing data were accounted for using a hot-deck method with 10 imputations.

    “To account for missing data, we used a hot-deck method with 10 imputations randomly selecting data within each group.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Data are missing at random.

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

    Study design and conductcitation
    § Outcomes and follow-up

    The CAPPS fatigue questionnaire is a validated 24-item self-administered questionnaire with three subscales.

    “This questionnaire is a validated 24-item self-administered questionnaire with three subscales (fatigue, anxiety and depression), each with eight items.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given
    § Randomization and interventions

    Iron and placebo treatments were identical in appearance and taste, and dose regimens were the same.

    “The iron and placebo treatments were identical in appearance and taste, and the dose regimens were the same.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § Interpretation

    The effect size in our study was similar to that in Verdon et al., except for hemoglobin, which was not measured after treatment.

    “Their study was shorter in duration (one month) and did not limit inclusion to severe fatigue; nevertheless, the effect size was similar to that in our study, except for hemoglobin, which was not measured after treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • Rests on an assumption: Ferritin <50 µg/L indicates low or borderline iron stores in nonanemic menstruating women.

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

    Study design and conductown data
    § Randomization and interventions

    The statistician remained blinded to treatment allocation during analyses.

    “During the analyses, the statistician remained blinded as to what treatment each group received.”
    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
    § Abstract

    The study was registered with EudraCT and approved by an independent ethics committee before initiation.

    “The study was registered on Feb. 20, 2006, with EudraCT (no.2006-000478-56) and was approved by an independent ethics committee (Comité Consultatif pour la Protection des Personnes se prêtant à des Recherches Biomédicales, Saint-Germain-en-Laye) before its initiation (protocol no.L00008CP301).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given
    § Randomization and interventions

    Allocation remained concealed to patients, general practitioners, caregivers and principal investigators until the end of the trial.

    “The allocation remained concealed to patients, general practitioners, caregivers and principle investigators until the end of the trial.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § Statistical analysis

    Generalized estimating equations were used to compare changes between groups after adjustment for baseline values and clustering effects between physicians.

    “We compared changes in outcomes between baseline and 12 weeks follow-up and between placebo and iron (ferrous sulfate, FeSo 4 ) groups using generalized estimating equations to calculate an averaged least-squares mean between groups after adjustment for baseline values and clustering effects between physicians.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data
    § Abstract

    The study was a 12-week multicentre, double-blind, placebo-controlled, parallel group, pragmatic randomized trial with 1:1 allocation.

    “We performed a 12-week multicentre, doubleblind, placebo-controlled, parallel group, pragmatic 7,8 randomized trial with a 1:1 allocation ratio.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • Rests on an assumption: More than one month is needed to enlarge the erythropoietic marrow and obtain a change in red blood cell indices, particularly among nonanemic people.

  • Classified as probably not a substantial claim.

    Study design and conductnone given
    § Statistical analysis

    Intention-to-treat analysis was used for all analyses.

    “We used intention-to-treat analysis for all analyses.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data
    § Randomization and interventions

    The clinical pharmacy department generated a simple random allocation sequence without restriction.

    “The clinical pharmacy department of the sponsor (Pierre Fabre) generated a simple random allocation sequence without restriction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § Interpretation

    Our study confirms and adds to the findings of Verdon et al.

    “Our study confirms and adds to the findings of the randomized placebo-controlled clinical trial of oral iron supplementation by Verdon and colleagues.3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • Rests on an assumption: Ferritin <50 µg/L indicates low or borderline iron stores in nonanemic menstruating women.

  • May combine two claims.

    Interpretationown data
    § Interpretation

    Our results confirm that some women with 12.0 g/dL or higher hemoglobin concentrations have increased erythropoiesis following iron supplementation, suggesting that they were iron deficient.

    “Our results confirm that some women with 12.0 g/dL or higher hemoglobin concentrations have increased erythropoiesis following iron supplementation, suggesting that they were iron deficient.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Interpretation

    The effect size for quality of life appears smaller than for fatigue alone; thus, our study was underpowered to reveal a significant effect.

    “However, the effect size for quality of life appears to be smaller than for fatigue alone; thus, our study was underpowered to reveal a significant effect.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Ferritin <50 µg/L indicates low or borderline iron stores in nonanemic menstruating women.
21 of 21

  • The paper relies on this without support.

    Ferritin <50 µg/L indicates low or borderline iron stores in nonanemic menstruating women.

    “(e) have a low or borderline ferritin level (< 50 µg/L)”

  • The paper relies on this without support.

    More than one month is needed to enlarge the erythropoietic marrow and obtain a change in red blood cell indices, particularly among nonanemic people.

    “The length of the treatment period was justified on a physiologic basis because more than one month is needed to enlarge the erythropoietic marrow and obtain a change in red blood cell indices, particularly among nonanemic people.”

  • The authors state this as an assumption.

    Data are missing at random.

    “Furthermore, imputation methods require data to be missing at random, which we cannot totally assume.”
3 of 3

Claims other papers make about this one

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Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Roland M, Torgerson DJ. What are pragmatic trials? BMJ 1998; 316: 285.

Cited by

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Related

Authors
Vaucher, P., Druais, P.-L., Waldvogel, S., & Favrat, B.
Affiliations
University of Geneva (CH)
ORCID
Venue
Canadian Medical Association Journal
Publisher
CMA Impact Inc.
Published
2012-07-09
Volume
184
Issue
11
Pages
1247-1254
ISSN
  • 0820-3946 (ISSN-L)
  • 1488-2329
DOI
10.1503/cmaj.110950
PMC
PMC3414597
OpenAlex
W2151456468
Semantic Scholar
c8b94eca2a945e78508c0e3ac899b957a41ed0c9
Cited by
163
References
35
Citations by year
2026: 14 · 2025: 7 · 2024: 16 · 2023: 11 · 2022: 13 · 2021: 10 · 2020: 13 · 2019: 11 · 2018: 9 · 2017: 6 · 2016: 11 · 2015: 14 · 2014: 11 · 2013: 12 · 2012: 5
FWCI
8.06
Type
journal article
Language
en
Open access
Locations
  • Canadian Medical Association Journal (publishedVersion)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
  • PubMed Central (submittedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders
  • Les Laboratories Pierre Fabre
  • Vifor Pharma
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, fatigue, iron deficiency, ferritin, menstruating women, ferrous sulfate, hemoglobin, soluble transferrin receptor, quality of life, depression, anxiety, unexplained fatigue
MeSH terms
Adolescent, Adult, Fatigue, Female, Ferritins, Ferrous Compounds, Hemoglobins, Humans, Iron, Menstruation, Middle Aged, Quality of Life, Single-Blind Method, Dietary Supplements, Young Adult

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