Adolescent fatigue: Is intravenous iron a better solution?
Authors: Michael Auerbach, Richard Derman
Journal: American Journal of Hematology (2016)

The western standard for uncomplicated iron deficiency is oral iron. In those unusual conditions when it is well tolerated, oral iron is inexpensive, effective and convenient. Estimates are a year of therapy is necessary to correct the anemia, the deficiency and stores. No oral formulation has been shown to be superior to any other with regard to efficacy, safety or tolerability 1. Newer oral formulations, at markedly increased costs, may show some improvement in absorption, but to date no decrement in adverse events compared to ferrous sulfate has been reported in appropriately done head to head trials. In a recent comprehensive systematic review and meta-analysis of gastrointestinal side effects of oral iron supplementation, Tolkien et al reported up to 70% of those to whom it is prescribed complain of significant gastrointestinal toxicities including nausea, flatulence, abdominal pain, diarrhea, constipation and black or tarry stools 2. This observation is certainly consistent with our experience in thousands who have presented to our offices with iron deficiency with or without anemia. In adolescent girls, it is therefore not a credible expectation to anticipate adherence to therapy. Iron deficiency is well known to cause symptoms independent of hemoglobin levels 3. In addition to fatigue, observed symptoms may include pagophagia (ice craving) or other forms of pica, and restless legs syndrome interfering with sleep, both of which impair performance. In 2009, Krayenbuehl et al, in a randomized, placebo controlled double blind study of 90 non-anemic, iron deficient symptomatic women, using validated tools, reported significant benefits in energy, activity, fatigue and quality of life 4. Most of the subjects were intolerant of, or unresponsive to, oral iron. A single dose of 1,000 mg of ferric carboxymaltose, rapidly and consistently resulted in amelioration of symptoms. In this issue of the American Journal of Hematology, Sharma et al, aptly corroborate these findings in a prospective, observational, single institution clinical study in a small number of subjects (twenty-two) 5. This provocative study builds upon a base of previously published work suggesting an improvement in quality of life and fatigue scores, most of who were suffering from heavy menstrual bleeding and all of whom were intolerant of, or had failed oral iron. While appropriately pointing out that causes of fatigue are multidimensional and can include elements of depression (not uncommon in this age group), no attempt was made to utilize instruments that might capture data on depression and life quality. Additionally, the symptoms associated with heavy menstrual bleeding are protean in nature and presentation. Since half the population was not rescreened at 3 and 6 months, the possibility of placebo remains. Symptom scores change depending on whether menstruating women are actively menstruating, or are in the proliferative or secretory phase of their cycles 6. Additionally, it is unclear why parents of affected individuals were screened and what the explanation for their improvement might be. The inclusion of this data may have shed a brighter light on the explanation for the improvement of symptoms. Nonetheless, the authors appropriately and importantly point out, that the time to require inclusion of only those who have failed, or are intolerant of oral iron therapy is long over. The risks-benefit ratio gleaned from this and multiple prior studies should inform the conduct of larger placebo controlled trials to finally put to rest lingering questions as to who might best be appropriate candidates for first line intravenous iron therapy. The authors are to be congratulated to be the first to study a pediatric (post-menarchal adolescent females) cohort evaluating the fatigue reducing effects of intravenous for iron deficiency with or without anemia and fatigue. Whereas the western standard to administer oral iron as front line therapy remains, it is unlikely that a medication rife with gastrointestinal side effects and non-adherence to prescribed therapy could provide enough iron to keep up with losses. In such conditions, intravenous iron is the preferred route of administration. The availability of safe, easy to administer, efficacious and convenient parenteral formulations, with carbohydrate cores binding elemental iron more tightly 7 and allowing complete replacement doses in 15–60 min has made treatment far more felicitous. We believe it is unfortunate that the investigators were forced to use iron sucrose for this study, as clearly pointed out in the manuscript, it was the only formulation available at their institution. While we agree with the authors that iron sucrose is a safe and effective parenteral formulation, four infusions were necessary to complete treatment, quadrupling the likelihood of minor infusion reactions, additional visits with their associated costs, extravasations and nursing time, without any benefit in safety or efficacy 8. This criticism is supported by multiple prospective and observational studies using low molecular weight iron dextran, ferumoxytol and ferric carboxymaltose, all of which can be administered as a single total dose infusion over 15–60 min in one visit. A few pertinent examples are low molecular weight iron dextran administered as 1,000 mg in 1 h in 888 patients with a host of conditions associated with iron lack 9, low molecular weight iron dextran in 74 pregnant women with iron deficiency intolerant of oral iron 10, the relative safety of the different iron formulations at the Harvard Medical School Hospitals 11, a comparison of ferumoxytol with iron sucrose for iron deficiency anemia after oral iron intolerance 12, a comparison of low molecular weight iron dextran to ferric carboxymaltose in iron deficient gravidas 13 and a prospective study of 1,020 mg of ferumoxytol administered as a 15 min infusion 14. That being said, we should be grateful to the authors for elucidating the benefit of an improved method of treating such a common malady in a population never before evaluated. The results of this study support a litany of new evidence suggesting intravenous iron deserves a place close to front line in the treatment paradigm of iron deficiency with or without anemia. These data further call for larger prospective studies to compare intravenous iron to oral iron in oral iron naïve individuals as well as properly powered comparisons of the still very popular iron sucrose to formulations which can be administered as a total dose infusion. If such admonitions occur, we look forward to a new, improved, more efficacious, less toxic and more convenient treatment for an extremely common problem in young women.