Wednesday July 11 2012
Lack of iron linked to fatigue
Taking iron tablets “can reduce tiredness by 50%” even if you’re not anaemic, the Daily Mail has reported.
This is a reasonably accurate, if somewhat optimistic, summary of new research that may help women who feel “tired all the time”. The Mail’s story is based on a study that looked at French women who reported feeling unusually tired (fatigued) and had low levels of iron in their blood without being clinically defined as anaemic.
In the study, half of the women were given a 12-week course of iron tablets while the other half were given placebo tablets. After the 12 weeks, the women answered questions relating to their levels of fatigue so that the researchers could calculate a “fatigue score”.
The researchers found that women on iron tablets had a fatigue score that had reduced by 48% on average, while those on placebo pills had a fatigue score that had dropped 29% by the end of the 12 weeks. While this appears to be a significant difference, it equates to only 3.5 points on a 40-point scale. Despite this, the researchers have argued that iron deficiency could be an often overlooked, but treatable, cause of fatigue in many women.
So, based on this research, should you rush out to buy iron pills if you feel tired? Not before checking with your GP. Iron pills are not safe or suitable for people with certain medical conditions, such as inflammatory bowel conditions. You can also increase your iron levels naturally by eating a lot of green leafy vegetables, as part of a healthy diet.
It’s also worth remembering that the study only involved adult women, so its findings may not apply to anyone else.
Where did the story come from?
The study was carried out by researchers from universities in Switzerland and was sponsored by Pierre Fabre Medicament. However, the researchers worked independently and were financed by their own academic institutions.
The study was published in the peer-reviewed Canadian Medical Association Journal.
The Mail chose to report the 50% reduction figure in their headline, which is rounded up from the 47.7% relative reduction in fatigue score reported in the study. The absolute difference of 3.5 points on a 0 to 40 scale, also reported in the study, was not highlighted in the media. However, this arguably gives us a better sense of how much fatigue was actually reduced in the group taking iron compared with those taking a placebo.
What kind of research was this?
This was a randomised control trial (RCT) that assigned participants (recruited through their GP) to either take iron supplements or to receive a placebo to investigate its potential effect on fatigue.
The research team highlighted previous research suggesting that unexplained fatigue (so-called because there is no obvious medical cause) can be explained by iron deficiency. Hence, this study aimed to test whether iron therapy could improve fatigue and other related measures such as haemoglobin levels, iron stores and quality of life in a subset of women.
A randomised control trial is the gold standard of testing whether a treatment, such as iron supplementation, is effective. Results from well-conducted RCTs are generally regarded as one of the highest levels of evidence available on the effectiveness of medical treatments.
What did the research involve?
Researchers recruited 198 women from 44 private primary care practices in France from March to July 2006. To be included in the study participants had to meet the following criteria:
- be a menstruating woman
- be aged between 18 to 53 years old
- report “considerable fatigue” without obvious clinical causes (measured by scoring higher than six points on a Likert scale, ranging from 1-10)
- not be suffering from anaemia (normal haemoglobin level greater than 12.0 g/dl)
- have low or borderline low ferritin levels (less than 50 micrograms per litre); ferritin stores and helps regulate iron levels in the body
- not have a known disease or condition that could explain the fatigue (such as psychiatric problems or thyroid, liver or cardiovascular disease)
- not be pregnant or breastfeeding
- not have a digestive disorder that interferes with iron absorption
- not be already taking iron supplementation
Eligible women were randomly allocated to receive either tablets containing the equivalent of 80mg of iron a day (102) or placebo (96). Participants were instructed to take either 80mg a day prolonged-release iron tablets or placebo before or after meals for a 12-week period.
The iron and placebo treatments were identical in appearance and taste and the dose regimens were the same. The allocation to treatment or placebo was concealed from the patients, general practitioners, caregivers and the primary researchers until the end of the trial (in other words, the trial was double blinded).
The researchers were mainly interested in the effect of the iron on fatigue. Fatigue was measured at the start of the trial (baseline measurement) and after 12 weeks. To measure fatigue, the researchers used a validated questionnaire called the “Current and Past Psychological Scale” which ranges from 0 to 40 points. This scale covered elements of fatigue (the main focus of the research) as well as anxiety and depression. Quality of life, anxiety and depression were assessed separately.
Blood samples were also taken at baseline, 6 and 12 weeks into the treatment to analyse in detail the constituents of the blood.
The results were analysed appropriately using an “intention to treat” principle. This means that all the results across both groups were analysed (iron versus placebo), irrespective of whether any participants dropped out or stopped taking the treatment half-way through. This gives a more realistic impression of the effect than analysing only those who took the intended treatment.
What were the basic results?
At the start of the study, the group assigned to receive iron had an average fatigue score of 25.4 compared with 25 in the placebo group (on a scale from 0 to 40).
The main finding was that those receiving iron supplementation had a 3.5 point improvement (95% confidence interval 0.3 to 6.7 points) in their fatigue score on the Current and Past Psychological Scale compared with those in the placebo group. On average, those taking iron reduced their fatigue score by 12.2 points while the placebo group reduced their fatigue score by 8.7 in the same 12-week period.
This meant that those receiving iron supplementation had a 47.7% decrease in fatigue, compared with a decrease of 28.8% in the placebo group. Therefore iron gave an 18.9% greater reduction in fatigue relative to placebo.
Iron supplementation did not show any effect on anxiety or depression scores and there was no significant effect on measures of quality of life.
In total, five patients reported a serious adverse event (such as hospital admissions for surgery) but none appeared to be related to taking iron. This is an unusual finding in such a small study of apparently healthy adult women, but it is not likely to significantly affect the results.
The iron supplementation caused significant changes to the blood constituents associated with iron in participants taking the supplements, including increasing the levels of haemoglobin, ferritin and other biochemical indicators associated with iron. These effects were similar when measured at 6 and 12 weeks.
How did the researchers interpret the results?
The researchers concluded: “Iron deficiency may be an under-recognised cause of fatigue in women of child-bearing age. If fatigue is not due to secondary causes [medical conditions], the identification of iron deficiency as a potential cause may prevent inappropriate attribution of symptoms to putative emotional causes or life stressors […], thereby reducing inappropriate pharmacological [drug] treatments”.
This study showed that iron supplementation for 12 weeks decreased fatigue scores by an average of 3.5 points (on a 0 to 40 point scale) compared with placebo in menstruating iron-deﬁcient non-anaemic women with unexplained fatigue and ferritin levels below 50 micrograms.
The well-designed trial provides a good level of evidence that iron supplementation can modestly improve fatigue scores in this subset of women. However, limitations are still present and should be carefully considered when interpreting the findings of this study:
Relative versus absolute differences
The papers chose to report the 50% reduction figure, which has been rounded up from the 47.7% relative decrease in fatigue scores between the iron group and placebo groups. When we look at the absolute difference in fatigue scores on the 0 to 40 point scale used, we see that iron caused only a 3.5 point improvement over placebo. This more realistic figure is not reported in any of the media coverage. The extent to which this 3.5 improvement is clinically or personally significant to those with fatigue merits further consideration.
Possibly ineffective blinding
The authors recognised that a major limitation of their work was that blinding the participants to their treatment allocation (iron versus placebo pill) could not be guaranteed because of the side effects of iron supplementation. People taking iron could notice its effects, such as stool colour and digestive effects, and therefore may have guessed they were not taking a placebo. If this was the case, this could bias the results as those knowing they were taking iron may expect that it is going to benefit them and this expectation could improve their reported fatigue levels. However, the researchers reported that they did not observe any differences in digestive events between the groups because a low dose of iron was used. Therefore, this may not have actually influenced the results of the study.
Subjective measure of fatigue
The measure of fatigue was subjective as it was assessed by participants themselves in the form of a self-administered questionnaire. It is possible that this self-reporting causes error in the measure of fatigue. An objective measure of fatigue would be more beneficial.
Limited ability to generalise the results
The study was performed on iron-deficient women aged 18-53 years old who were still having periods, and who had no identified medical cause for their fatigue or low iron levels. Therefore the findings cannot be generalised to women who have been through the menopause, to men, or to people who have a medical cause for their symptoms. This study did not address the effect of iron on fatigue in these groups.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on twitter.