Primary Care

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

BMJ 2003; 326 doi: (Published 22 May 2003) Cite this as: BMJ 2003;326:1124

Greater Awareness of Non-anaemic Iron Deficiency Needed

The report by Verdon, et al. showing the effectiveness of iron
supplementation in treating fatigue in non-anaemic women is an important
addition to the evidence that iron deficiency is a significant health
problem in women even apart from its effects on haemoglobin.1 As the
authors note, the results directly confirm those of a clinical trial that
we (Beutler) reported 40 years ago showing reduction of fatigue upon
treatment with iron among non-anaemic women with iron-depleted bone
marrow.2 We are puzzled, however, by their assertion that the trial they
now report was the first controlled one. Our trial design was a classical
double-blind crossover.

In reality, a syndrome of fatigue and other related symptoms
responsive to iron therapy in the absence of anemia has been documented
for more than 150 years [see references 2 and 3 for reviews]. More recent
reports have focused on effects on athletic performance. These studies
have shown that treatment with iron increased aerobic and anaerobic
capacity4 and decreased muscle fatigability5 among subjects having low
levels of serum ferritin and normal levels of haemoglobin at baseline.
Consistent among all of these reports is the relatively small (or absent)
effect of iron treatment on haemoglobin levels.

Further support of the clinical significance of non-anaemic iron
deficiency comes from our recent survey of iron status among a large
cohort of subjects attending a health appraisal center. In this study, a
significantly higher rate of fatigue, ¡°irritability,¡± and headaches was
reported by non-anaemic women with iron deficiency compared to iron-
replete controls (Table). The higher prevalence of these symptoms
persisted when the rather high cut-off for iron deficiency used by Verdon,
et al. (ie, serum ferritin <_50 ug="ug" l="l" was="was" applied.="applied." p="p"/> Although there appears to be consensus regarding the impact and
response to iron treatment, issues surrounding the diagnosis of non-
anaemic iron deficiency continue to be debated. We do not agree, however,
with Verdon et al.¡¯s assertion that their results indirectly support the
claim by Rushton that current reference ranges for haemoglobin and serum
ferritin are too low for women and should be changed to be the same as
that for men.6 We have previously pointed out that even among women with
relatively high levels of serum ferritin (>100 ug/L), mean haemoglobin
levels are 10-15 g/L lower than for iron-replete men, arguing against the
use of male references ranges for women.7

Attempts to refine references ranges for serum ferritin are unlikely
to improve detection of non-anaemic iron deficiency because the
variability of the normal range of this analyte is so great. More likely,
increased recognition and successful treatment of this condition will
result from a heightened awareness among clinicians of iron deficiency
apart from anemia as a possible cause of otherwise unexplained fatigue in
their patients. Thus, iron deficiency might be considered as part of the
differential diagnosis of fatigue, particularly in women with serum
ferritin in the lower end of the reference range, regardless of
haemoglobin levels. A trial of iron therapy for a limited period of time
in these patients would provide the diagnosis as well as the cure, and
seems quite free of risk.

Jill Waalen, MD, MPH*
Vincent Felitti, MD**
Ernest Beutler, MD*
*The Scripps Research Institute, La Jolla, California USA
**Kaiser Permanente, San Diego, California USA

  Table.  Prevalence of symptoms among white women with non-anaemic 
iron deficiency

Symptom	            Subjects with         Controls       p¢Ó

                    non-anaemic           (=10,945)

                    iron deficiency*   


or Severe 
Fatigue	      208 (33.8%)        3,071 (28.1%)  0.0026

Irritability  118 (19.2%)	 1,608 (14.7%)	0.0030

Headaches     155 (25.2%)	 2,104 (19.2%)	0.0004

*Serum ferritin  <_21 ug="ug" l="l" transferrin="transferrin" saturation="saturation" _16="_16" and="and" haemoglobin="haemoglobin" ã="ã" _120="_120" g="g" l.="l." _="_" serum="serum" ferritin="ferritin" ã21="ã21" ã16="ã16" ã120="ã120" ó="ó" chi-square="chi-square" pre="pre"/>


1. Verdon F, Burnand B, Fallab Stubi C-L, Bonard C, Graff M, Michaud
A, et al. Iron supplementation for unexplained fatigue in non-anaemic
women: double blind randomized placebo controlled trial. BMJ 2003;326:1124

2. Beutler E, Larsh SE, Gurney CW. Iron therapy in chronically
fatigued, nonanemic women: a double-blind study. Ann Intern Med

3. Beutler E. History of iron in medicine. Blood Cells Mol Dis

4. Friedmann B, Weller E, Mairbaurl H, Bartsch P. Effects of iron
repletion on blood volume and performance capacity in young athletes. Med
Sci Sports Exerc 2001;33:741-746.

5. Brutsaert TD, Hernandez-Cordero S, Rivera J, Viola T, Hughes G,
Haas JD. Iron supplementation improves progressive fatigue resistance
during dynamic knee extensor exercise in iron-depleted, nonanemic women.
Am J Clin Nutr 2003;77:441-448.

6. Rushton DH, Dover R, Sainsbury AW, Norris MJ, Gilkes JJH, Ramsay
ID. Why should women have lower reference limits for haemoglobin and
ferritin concentrations than men? BMJ 322:1355-1357.

7. Waalen J, Felitti V, Beutler E. Haemoglobin and ferritin
concentrations in men and women: cross sectional study. BMJ 2002;325:137.


This is manuscript number 15905-MEM. Supported by National
Institutes of Health grants DK53505-04 and RR00833 and the Stein Endowment

Competing interests:  
None declared

Competing interests: Table. Prevalence of symptoms among white women with non-anaemic iron deficiencySymptom Subjects with Controls p¢Ó non-anaemic (=10,945) iron deficiency* (n=616)Fatigue or Severe Fatigue 208 (33.8%) 3,071 (28.1%) 0.0026Irritability 118 (19.2%) 1,608 (14.7%) 0.0030Frequent Headaches 155 (25.2%) 2,104 (19.2%) 0.0004*Serum ferritin

28 June 2003
Jill Waalen
Research Associate
Vincent Felitti and Ernest Beutler
The Scripps Research Institute, La Jolla, California USA 92037