Iron supplementation for unexplained fatigue in
non-anaemic women: double blind randomised placebo
F Verdon, B Burnand, C-L Fallab Stubi, C Bonard, M Graff, A Michaud, T Bischoff, M de Vevey,
J-P Studer, L Herzig, C Chapuis, J Tissot, A Pécoud, B Favrat
Objective To determine the subjective response to
iron therapy in non-anaemic women with
Design Double blind randomised placebo controlled
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 ?g/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 ?g/l improved with oral
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.
Prevalence rates of 14% to 27% have been reported in
primary care, and in 1-2% of patients fatigue is the
main reason for consultation.1–6Women were three
times more likely than men to mention fatigue in a
study conducted in general practice.7Although 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. Iron deficiency associated with increased
fatigue was, however, shown in a recent longitudinal
is commonin thegeneral population.
study on women’s health.8In a European study, about
20% of women of childbearing age had a serum ferri-
tin concentration less than 15 ?g/l, and only 4% of
these women had iron deficiency anaemia.9We exam-
ined the effect of iron therapy in women with
unexplained fatigue in the absence of anaemia.
Our study was conducted in a primary care setting: an
academic centre (57 patients) and eight private general
practices (87 patients). 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. Violations of the protocol detected
after randomisation led to exclusion of women only in
a complementary per protocol analysis. Reasons for
these late exclusions had been determined before-
hand: pregnancy diagnosed during the study period,
haemochromatosis, physical or mental disorders iden-
tified after inclusion, and vitamins or iron supplements
taken during the trial.
Randomisation, main outcome, and adherence to
Our study was a pragmatic randomised placebo control-
led trial. Participants received either 80 mg/day oral
long acting ferrous sulphate (Tardyferon; Robapharm,
Boulogne) or placebo for four weeks. Iron and placebo
were identical in appearance and taste and for 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 codes were held by the pharmacist and
remained unbroken until the analyses were completed.
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 admin-
Unit, University of
Lausanne, rue du
Bugnon 44, 1011
M de Vevey
Institute of Social
Clinic, University of
C-L Fallab Stubi
consultant of internal
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BMJ VOLUME 32624 MAY 2003bmj.com
istered questionnaire incorporating eight items for
each of three dimensions (fatigue, anxiety, and depres-
examined as additional outcomes. 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 physi-
cal, psychological, and haemorrhagic events. Serum
ferritin concentration and adherence to treatment
were measured and considered as intervening vari-
ables. A complete blood count was obtained at
baseline, and the serum ferritin concentration was
measured by chemoluminometric immunoassay.Clini-
cians 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 ini-
tial value was ≤ 20 ?g/l.
Adherence to treatment was measured by an
electronic device (MEMS; Aardex Europe, Switzer-
land), which recorded the date and time that the pill
container was opened.11
counted. Adherence was quantified by dividing the
number of times the device was opened by the total
number of days of observation. Patients were asked not
to take over the counter vitamin or iron supplements.
Unused pills were also
An estimated sample size of 63 patients was needed to
detect a one point difference between the groups on
the visual analogue scale. The calculation included an
estimated standard deviation of two points for a two
tailed test (?=0.05, power=0.80). We calculated changes
in symptom levels and scores over time for each
patient by subtracting the results at follow up from
those at baseline.The principal analysis was performed
according to an intention to treat protocol. Tests
performed were two sample t tests, ?2tests, and linear
regression analyses. A per protocol analysis was also
In 366 women, fatigue was the main reason for
consulting; 222 were excluded because of psychiatric
disorders (110 women),physical disorders (61),refusals
(16), or other reasons (35). 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 (figure). The groups had simi-
lar characteristics at baseline (table 1). Low serum fer-
ritin concentrations were common: ≤ 50 ?g/l in 115
(85%) patients and ≤ 20 ?g/l in 69 (51%) patients.
Scores for anxiety and depression were low in both
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 ( − 1.82 (SD 1.7)
v − 0.85 (2.1) points, difference 0.95 points 95% confi-
dence interval 0.32 to 1.62,P=0.004;table 2).By choos-
ing a cut-off point of 50 ?g/l, we found that there was
no quantitatively significant response greater than
50 ?g/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 statisti-
cally different between the two groups ( − 2.1 (6) v − 1
(7) points, P=0.31), whereas a greater decrease in anxi-
ety was observed in the iron group ( − 1.7 (6) v 1.3 (6),
After adjustment for age,initial levels of depression
and anxiety,and serum ferritin concentration in a mul-
tiple 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 haemo-
globin 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
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 inter-
vention, serum ferritin concentrations were highest in
the iron group (21.0 (SD 9.2) v 13.7 (6.9), P < 0.001).
After exclusion of five patients, a per protocol analysis
was no different from the intention to treat analysis.
Table 1 Characteristics of women receiving iron or placebo for unexplained fatigue in
the absence of anaemia. Values are means (standard deviations)
Iron group (n=71)
Serum ferritin concentration (?g/l)
Haemoglobin concentration (g/l)
Fatigue scale (1-10 points)*
Multi-item fatigue questionnaire†
*Visual analogue scale.
†Score of 0 to 40 points.
Patients with fatigue (n=366)
Lost to follow up (n=4)
Lost to follow up (n=3)
Side effects (n=1)
Analyses at one month (n=136)
Iron group (n=75)
Completed trial (n=71)
Placebo group (n=69)
Completed trial (n=65)
Flow of participants through study
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BMJ VOLUME 326 24 MAY 2003bmj.com
To our knowledge this is the first randomised clinical
trial in women of childbearing age (18 to 55 years) 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.12Adolescent females have been shown to
benefit from iron supplementation: iron improved las-
situde, 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.13 14In a non-randomised comparison of
Australian women, fatigue decreased and quality of life
increased with iron supplementation or a diet high in
Women with fatigue often associate their symp-
toms with psychosocial stressors and not a possible
emotional or biomedical cause.4 16 17Conversely, medi-
cal investigatorstend to
emotional causes and more rarely with biomedical
causes.4–6 16 18We found that iron deficiency may be an
under-recognised cause of fatigue in women of
childbearing age. Thus, 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 stres-
sors 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 ?g/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.19One
study compared serum ferritin concentrations with
iron stores in the bone marrow and found that a serum
ferritin concentration of 50 ?g/l was associated with a
50% chance of iron deficiency occurring in the bone
marrow.20The lower reference limits for serum ferritin
and haemoglobin concentrations have been consid-
ered too low for women.21The authors of that study
advocate the adoption of the same reference values for
both men and women that “would be expected to have
fundamental and positive implications for women’s
health and welfare.”Our study indirectly supports their
conclusion by showing that women can benefit from
iron supplementation even if their red blood cell
counts are considered normal.
Iron deficiency even in the absence of anaemia
is associated with decreased activity of iron depend-
ent enzymes and therefore affects the metabolism of
neurotransmitters.22 23In people with iron deficiency
anaemia the related symptoms will disappear more
quickly than the accompanying increase in haemato-
logical indices.24This suggests that some cellular func-
tions are affected by iron treatment independently of
haemoglobin concentration. We did not, however,
measure haemoglobin concentration after exposure
to iron and therefore did not assess whether people
who had low but normal haemoglobin concentrations
had an increase in haemoglobin concentration that
could be associated with a decrease in fatigue.
Limitations of study
Our study has several limitations. 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.14We 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 con-
trol 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.20Finally, 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
Table 2 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
Type of therapy
No of women
Level of fatigue*
Difference (95% CI)P value
0.97 (0.32 to 1.62)0.004
*Measured on visual analogue scale.
page 3 of 4
BMJ VOLUME 326 24 MAY 2003bmj.com
We thank M Burnier for his contribution to the electronic moni- Download full-text
toring 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: FV, BB, CLF, and BF participated in the
conception and design of the study, analysis and interpretation
of data, drafting and revising the manuscript, and inclusion of
patients for BF and FV.CB,MG,AM,TB,MdeV,J-PS,LH,CC,JT,
and AP participated in the conception and design of the study,
inclusion of patients, and drafting and revising the manuscript.
BF will act as guarantor for the paper.
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 20 March 2003)
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