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

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.The prevalence of fatigue ranges from 14% to 27% among patients in primary care.¹ In addition, 1%–2% of visits to general practices are because of fatigue, and women are three times more likely than men to mention fatigue.¹ Unexplained fatigue can be caused by iron deficiency.² Verdon and coauthors found an improvement in fatigue following iron supplementation in nonanemic women with unexplained fatigue.³ However, the hemoglobin levels of these patients were not available, which may have contributed to the ongoing debate about the appropriateness of reference limits defining anemia in women.^4,5 Thus, the effectiveness of iron supplementation in nonanemic menstruating women with major fatigue without an obvious clinical cause is unknown.⁶ Our main objective was to test the hypothesis that oral iron therapy for a short period may improve fatigue, hemoglobin, iron stores and quality of life in menstruating nonanemic women whose ferritin levels are below 50 μg/L. Our secondary objective was to evaluate whether this effect is dependent on the initial levels of hemoglobin, ferritin or transferrin saturation.