BMJ  2003;326:1124 (24 May), doi:10.1136/bmj.326.7399.1124

Primary care

Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial

¹ General Practice Unit, University of Lausanne, rue du Bugnon 44, 1011 Lausanne, Switzerland, ² Health Care Evaluation Unit, Institute of Social and Preventive Medicine, University of Lausanne, ³ Medical Outpatient Clinic, University of Lausanne

Abstract

Objective To determine the subjective response to iron therapy in non-anaemic women with unexplained fatigue.

Design Double blind randomised placebo controlled trial.

Setting Academic primary care centre and eight general practices in western Switzerland.

Participants 144 women aged 18 to 55, assigned to either oral ferrous sulphate (80 mg/day of elemental iron daily; n=75) or placebo (n=69) for four weeks.

Main outcome measures Level of fatigue, measured by a 10 point visual analogue scale.

Results 136 (94%) women completed the study. Most had a low serum ferritin concentration; 20 µg/l in 69 (51%) women. Mean age, haemoglobin concentration, serum ferritin concentration, level of fatigue, depression, and anxiety were similar in both groups at baseline. Both groups were also similar for compliance and dropout rates. The level of fatigue after one month decreased by - 1.82/6.37 points (29%) in the iron group compared with -0.85/6.46 points (13%) in the placebo group (difference 0.95 points, 95% confidence interval 0.32 to 1.62; P=0.004). Subgroups analysis showed that only women with ferritin concentrations 50 µg/l improved with oral supplementation.

Conclusion Non-anaemic women with unexplained fatigue may benefit from iron supplementation. The effect may be restricted to women with low or borderline serum ferritin concentrations.

Introduction

Although the symptom of fatigue is related to iron deficiency anaemia, evidence is lacking for any association between iron deficiency and tiredness in the absence of anaemia. In a European study, about 20% of women of childbearing age had a serum ferritin concentration less than 15 µg/l, and only 4% of these women had iron deficiency anaemia.¹ We examined the effect of iron therapy in women with unexplained fatigue in the absence of anaemia.

Methods

Our study was conducted in a primary care setting. Participants were recruited from December 1997 to March 2000. Women aged 18 to 55 were included if their main reason for consulting was fatigue. We excluded women with anaemia (haemoglobin concentration < 117 g/l), other obvious physical or psychiatric cause for fatigue, or chronic fatigue syndrome. Reasons for late exclusions had been determined beforehand: pregnancy diagnosed during the study period, haemochromatosis, physical or mental disorders identified after inclusion, and vitamins or iron supplements taken during the trial.

Randomisation, main outcome, and adherence to treatment
Our study was a pragmatic randomised placebo controlled trial. Participants received either 80 mg/day oral long acting ferrous sulphate (Tardyferon; Robapharm) or placebo for four weeks. Iron and placebo were identical in appearance and taste and dose regimen. Randomisation took place at an independent pharmacy, according to a pre-established list. Patients, caregivers, and investigators were blinded to treatment assignment until the end of the trial. Each drug package was coded with a unique number according to the randomisation schedule and then posted to the relevant practice.

The main outcome was the level of fatigue perceived by patients, assessed at baseline and after one month on a 10 point visual analogue scale, ranging from 1 (no fatigue at all) to 10 (very severe fatigue). Also used was a validated 24 item self administered questionnaire incorporating eight items for each of three dimensions (fatigue, anxiety, and depression).² Each item was scored on a visual analogue scale. A cumulative score was obtained for each dimension by adding the eight item scores (range 0-40). The patients were asked about any potential side effects and intercurrent physical, psychological, and haemorrhagic events. Serum ferritin concentration and adherence to treatment were measured and considered as intervening variables. A complete blood count and serum ferritin concentration were obtained at baseline. Clinicians could order other tests to rule out any disorder to explain the fatigue. Serum ferritin concentration was measured after one month in those patients whose initial value was 20 µg/l.

Adherence to treatment was measured by an electronic device, which recorded the date and time that the pill container was opened.³ Unused pills were also counted. Patients were asked not to take over the counter vitamin or iron supplements.

Statistical analysis
We calculated changes in symptom levels and scores over time for each patient. The principal analysis was performed according to an intention to treat protocol. Tests performed were two sample t tests, ² tests, and linear regression analyses.

Results

Of the 144 patients enrolled, 136 (94%) completed the intervention, seven (5%) were lost to follow up, and one withdrew because of nausea and vomiting. The iron group and the placebo group had similar characteristics at baseline. Low serum ferritin concentrations were common: 50 µg/l in 115 (85%) patients and 20 µg/l in 69 (51%) patients. Scores for anxiety and depression were low in both groups.

The mean decrease in the overall intensity of fatigue between zero and one month was higher in the iron group than in the placebo group (table). By choosing a cut-off point of 50 µg/l, we found that there was no quantitatively significant response greater than 50 µg/l (P=0.64). The iron group showed the largest decrease in the cumulative score for fatigue (- 7.5 (8.0) v - 4.6 (7.5) points, difference 3.0 points, 0.3 to 5.6, P=0.03). The difference for depression was not statistically different between the two groups (- 2.1 (6) v - 1 (7) points, P=0.31), whereas a greater decrease in anxiety was observed in the iron group (- 1.7 (6) v 1.3 (6), P=0.003).

View this table: [in this window] [in a new window]   Change in level of fatigue after one month in women receiving iron or placebo for unexplained fatigue in absence of anaemia. Values are means (standard deviations) unless stated otherwise

 

After adjustment for age, initial levels of depression and anxiety, and serum ferritin concentration in a multiple linear regression analysis, iron supplementation was the most important variable to be associated with the decrease in the overall intensity of fatigue, an effect corresponding to - 1 point on the visual analogue scale. Younger age was also associated with a larger decrease in the intensity of fatigue.

A multiple linear regression analysis in the iron group showed that age, initial levels of depression and anxiety, serum ferritin concentration, and haemoglobin concentration were not predictive of the mean decrease in the overall intensity of fatigue. The best predictor of response was the amount of pills consumed in the iron group, but this was not so in the placebo group.

Compliance and dropout rates were similar in both groups: 95% (12) v 98% (9), P=0.25) for compliance and 4 of 75 (5%) v 4 of 69 (6%) for dropout rates in the iron arm and placebo arm, respectively. After the intervention, serum ferritin concentrations were highest in the iron group (21.0 (SD 9.2) v 13.7 (6.9), P < 0.001).

Discussion

To our knowledge this is the first randomised clinical trial in women of childbearing age to show that iron supplementation could have an effect on fatigue in the absence of anaemia. The effect may, however, be restricted to women with low or borderline serum ferritin concentrations. One trial found that 35 women with lassitude or poorly defined symptoms but without anaemia benefited from iron rather than placebo.⁴ Adolescent females have been shown to benefit from iron supplementation: iron improved lassitude, ability to concentrate in school, and mood in one study, and in another study supplementation with 260 mg elemental iron daily improved verbal learning and memory.^{5 6} In a non-randomised comparison of Australian women, fatigue decreased and quality of life increased with iron supplementation or a diet high in iron.⁷

Identifying iron deficiency without anaemia as a potential cause of fatigue is important. It may avoid the inappropriate attribution of symptoms to putative emotional causes or life stressors and thereby reduce unnecessary use of healthcare resources. Instituting iron therapy early may also improve quality of life.⁸

We found a significant response only in the patients with a baseline serum ferritin concentration 50 µg/l. This suggests that iron deficiency could be present even with a "normal" concentration of serum ferritin. Indeed, the lower limit for serum ferritin concentration is controversial: iron stores in the bone marrow may serve as a better indicator of iron deficiency.⁹ The lower reference limits for serum ferritin and haemoglobin concentrations have been considered too low for women and it has been suggested should be the same as for men.¹⁰

Iron deficiency even in the absence of anaemia is associated with decreased activity of iron dependent enzymes and therefore affects the metabolism of neurotransmitters.^{11 12} In people with iron deficiency anaemia the related symptoms will disappear more quickly than the accompanying increase in haematological indices.¹³ We did not, however, measure haemoglobin concentration after exposure to iron.

Limitations of study
Firstly, blinding for group assignment is an important issue, especially with iron, because of the side effects. It was not possible to correct for the change in stool colour by adding bismuth to the placebo because bismuth is an active substance. To minimise the side effects we used a low dose iron sulphate taken with breakfast. Participants in both groups were also told that their drug could colour stools. We did not ask the participants to guess their group assignment. In a recent placebo controlled trial no significant differences in guesses about treatment were found between iron and placebo groups despite the elemental iron dose used being three times that of our study.⁶ We found no difference in compliance between the two groups suggesting that the patients did not recognise that they had been assigned to placebo. Secondly, we did not have a procedure to control recruitment of all consecutive eligible patients, because this would have been difficult to apply in a busy clinical practice. Thirdly, ferritin concentration was the only measure of iron status in the study because it is considered the best non-invasive indicator of iron storage.¹⁴ Finally, our primary outcome focused on fatigue, a patient centred subjective measure.

What is already known on this topic Unexplained fatigue is common in young women Iron deficiency is highly prevalent among women of childbearing age Iron therapy is a well established treatment for fatigue in the presence of iron deficiency anaemia but not in the absence of anaemia What this study adds Iron supplementation may benefit women aged 18 to 55 years with unexplained fatigue in the absence of anaemia The effect may, however, be restricted to women with low or borderline serum ferritin concentrations

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This is an abridged version; the full version is on bmj.com

We thank M Burnier for his contribution to the electronic monitoring of patient compliance and for his critique of the manuscript and W Ghali (University of Calgary, Alberta, Canada) for his comments on the revised manuscript.

Contributors: See bmj.com

Funding: This study was sponsored by Robapharm. The sponsor was not involved in the analysis of the results nor in writing or correcting the manuscript.

Competing interests: FV and BF received financial support from Robapharm for producing a preliminary report of the study.

Ethical approval: The study was approved by the ethical review committee for clinical research of the Department of Internal Medicine, University of Lausanne.

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(Accepted March 20, 2003)

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