Iron Supplements May Cut Fatigue in Some Premenopausal Women

Jenni Laidman

July 13, 2012

July 13, 2012 — Iron supplements cut fatigue nearly in half for nonanemic women in a randomized placebo-controlled trial published online July 9 in the Canadian Medical Association Journal.

Paul Vaucher, DiO, from the Department of Community Medicine and Primary Care, University of Geneva, Switzerland, and colleagues enrolled 198 women between the ages of 18 and 53 years in a double-blind, placebo-controlled randomized trial to receive either 80 mg of oral ferrous sulfate daily (n = 102) or a placebo (n = 96) for 12 weeks. The women were recruited from 44 primary care practices in France. All reported fatigue and had ferritin levels lower than 50(mu)g/L. None of the women had hemoglobin levels of 12 g/dL or less, which would indicate anemia.

Women in this study who received the iron supplements reported a 47.7% decrease in the mean score for fatigue on the Current and Past Psychological Scale. The placebo group saw a reduction in the mean score of 28.8% (-18.9%; 95% confidence interval [CI], -34.5 to -3.2; P = .02). There was no treatment effect for quality of life (P = .2), depression (P = .97), or anxiety (P = .5).

"I think this is a good addition to the body of knowledge we have on the topic," Diane M. DellaValle, PhD, RD, from the Robert W. Holley Center for Agriculture and Health, Cornell University, Ithaca, New York, told Medscape Medical News. Dr. DellaValle has worked on iron levels and fatigue in women.

"This is actually really interesting," James P. McClung, PhD, nutrition biologist, Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, Massachusetts, told Medscape Medical News. Dr. McClung has also published in this area. "There has been a lot of discussion about iron status and fatigue in women. Perhaps this answers some questions."

Iron-deficient anemia is a well-known cause of clinical effects, leading to fatigue and "negative cognitive outcomes," Dr. McClung said. "What's new here is...we knew that people — women especially — who are iron-deficient anemic were likely to have fatigue, diminished work performance, and it is normal to recommend iron to that group of people. We didn't know that women who present with fatigue with normal hemoglobin may also benefit from an iron supplement. This means that perhaps what we'll call iron deficiency without anemia and poor iron stores may be implicated in fatigue. Now physicians may consider screening women for iron status when they present with these symptoms of fatigue."

In a subanalysis, Dr. Vaucher and colleagues compared the 149 women with a hemoglobin reading of 13 g/dL or higher with the 49 women in the trial with a hemoglobin status of less than 13 g/dL and saw a treatment effect in hemoglobin status in the lower-hemoglobin group of 0.97 g/dL (95% CI, 0.54 - 1.40) compared with 0.09 (95% CI, -0.22 to 0.41; P < .001) in the group with higher baseline hemoglobin. The analysis also showed a greater treatment effect in the low-hemoglobin group for soluble transferrin receptor of -0.89 mg/L (95% CI, -1.6 to -0.2), compared with the a treatment effect of &-0.4 (95% CI, -0.6 to -0.1; P = .05) in the higher-hemoglobin group was.

"This is telling me that using 12 g/dL hemoglobin as a clinical cut-off for anemia needs to be reexamined, which has been debated for a long time," Dr. DellaValle said.

Both Dr. McClung and Dr. DellaValle said the study met "the gold standard" of a randomized placebo-controlled trial, but each pointed out weaknesses that they said future studies need to address.

One problem, Dr. DellaValle said, was the reliance on self-report. "In our lab, and in the labs of many others who study iron, we use objective functional outcomes, studying physical activity and sedentary time using physical monitors. We measure local muscle fatigue, and we look at endurance capacity."

Further, Dr. DellaValle pointed out, the group randomly assigned to receive iron supplementation was heavily weighted toward women with lower ferritin levels, with a relative difference from placebo of -37.3%, and women with lower hemoglobin scores, with a relative difference from placebo of -43.6%. "That means their randomization technically didn't work," she said. However, she noted, the authors acknowledged this and adjusted for it in an analysis showing that this baseline imbalance did not alter results.

Dr. McClung called the study sample size "relatively small." Although the researchers randomly assigned nearly 200 people to the groups, just more than 100 fulfilled the trial protocol (55/102 participants originally assigned to the supplement group and 66/96 participants in the placebo group). This required the authors to rely on an intention-to-treat analysis, using incomplete data for those excluded from the trial to maintain the study size of 198.

"It's an acceptable mathematical model for filling in missing data," Dr. McClung said, "but it's not as good as if you really had the data. It leaves some questions, but it's certainly acceptable."

Several study authors received funding from Robapharm and Pierre Babre for a study on the effects of iron supplementation in blood donors. One coauthor is a member of an iron deficiency meeting board sponsored by Vifor Pharma and has lectured and given expert testimony for Pierre Fabre Medicament and Vifor Pharma. One author has received consulting fees from Pierre Fabre Medicament. Dr. McClung and Dr. DellaVella have disclosed no relevant financial relationships.

CMAJ. Published online July 9, 2012. Full text

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