To Fe, or not to Fe

It would be tempting to assume that, given the surge of recent publications on the topic and generous research funding, concern for iron nutrition in blood donors is a recent development. This is not the case. Fifty-five years ago, the Swiss Red Cross was prescribing iron tablets for those donors who were close to the hemoglobin threshold, which, at the time, was 13 g/dL for women and 14 g/dL for men.1 Even then, issues that call attention today were already being addressed. For example, compliance was recognized as a problem. For this reason, iron prophylaxis was only given for 2 weeks, because it was realized that donors were loath to take medication for longer periods. The farsightedness of the Swiss in their management of these “borderline” donors, especially against the background that there are no current consensus directives on the topic, was also reflected in the decision to defer donors if iron prophylaxis was ineffective after 3 months. These donors were then referred for medical investigation. It is not that the literature has been devoid of publications pointing to a role for iron. For example, in 1981, Simon and coworkers showed that iron did not have to be prescribed as a medication to be effective.2 In their study, when menstruating women were taking iron—most often in a daily vitamin mineral supplement—iron stores were higher across all donation frequencies. The results encouraged the authors to make two proposals to “secure appropriate protection for donors.” The first was measuring iron stores by serum ferritin assay, and the second was iron supplementation, which also, according to the authors, could allow continued donation. Their recommendation was hampered because no commercial ferritin assay was available. This shortcoming is not the case now and innumerable studies have confirmed the 1970 observation by Finch and coworkers that storage iron deficiency can be measured by serum ferritin in blood donors.3 To recognize all of the investigators who have confirmed this finding would demand a bibliography so bulky as to leave scant room for comment by this editorialist. Although more recent contributions to this literature, which have certainly earned the attention of accreditors and regulators, have asked whether storage iron deficiency in the presence of a normal hemoglobin level has deleterious consequences, this concern is not new. The possibility was raised more than 60 years ago, when Beutler and investigators published a small double-blind study in nonanemic women whose fatigue was reversed by iron.4 Since then, others have proposed that iron deficiency, in the absence of anemia, impairs a number of physical and intellectual functions, including exercise capacity, albeit particularly in athletes,5 and, in women, cognition6 and memory.7 Furthermore, the possibility that women of childbearing age could be rendered anemic by donation has raised concerns for their pregnancies, since anemia is associated with premature delivery and low birth weight,8 and there is some evidence that infants born of iron-deficient mothers are at risk of neurodevelopmental abnormalities.9 Others are more circumspect in their belief that there is a role for nonanemic iron deficiency in advancing deleterious health outcomes. With regard to quality of life, for example, the authors of the Danish Blood Donor Study described results from investigations of a link between low iron stores and self-reported health as “ambiguous.”10 In their study, 16,375 nonanemic blood donors with ferritin levels less than 15 ng/mL completed questionnaires asking about their mental and physical health. The authors concluded that there was no relationship between iron stores and health-related quality of life and that “nonanemic donors feel equally healthy whether iron depleted or not.” Supporting evidence for this assessment came from a randomized clinical trial of 154 women between ages 18 and 50 years who were iron deficient but not anemic, when a month-long course of oral iron increased hemoglobin and ferritin concentrations, but had no effect on fatigue or aerobic capacity. Those results prompted the conclusion by the blood transfusion service of the Swiss Red Cross that iron supplementation provided no clinical benefit.11 Consensus is also elusive with regard to recognizing a role for iron in maternal health and infant outcomes. The US Preventive Services Task Force recently concluded that, as far as iron supplementation in pregnancy is concerned, “improvement in maternal and infant outcomes has not been well-demonstrated.”12 Furthermore, a study of 18,483 female blood donors in Quebec who delivered neonates between 2001 and 2011 did not show a higher risk for stillbirth, premature delivery, or low birth weight.13 Although many of the clinical consequences of nonanemic iron deficiency have yet to be confirmed as risks for blood donors, there is no doubt that there are adverse outcomes if iron deficiency progresses to anemia. Against this background, it is not surprising that, given the significant prevalence of iron-deficient erythropoiesis in female donors, as confirmed in the Donor Iron Status Evaluation Study,14 there have been calls for action that include iron replacement.15, 16 Some had anticipated the call. In this issue of TRANSFUSION, Eder and her colleagues describe a study at a center which, in 2005, became an early adopter of an oral iron-supplementation program for donors.17 The investigators report that, not surprisingly, the elevated platelet counts in iron-deficient donors are reduced after iron therapy. While some enthusiasm for giving iron has been to reduce the loss of whole blood donors attributable to low hemoglobin deferrals, the report by Eder and colleagues suggests that an unintended consequence could be seen in platelet apheresis donors when iron replacement reduces the higher platelet yields associated with iron deficiency. For those who consider following in the footsteps of the few blood programs that offer iron supplementation to donors, the words of a recent editorialist in this journal were especially germane when he reminded readers that strategies to mitigate iron deficiency were “our clinical and ethical duty to care.”18 It is, however, easier to pay lip service to these duties rather than regard them as an imperative. Since iron tablets can be bought over the counter and many individuals do so of their own volition, there is the temptation to argue that recommendation to take a supplement carries no additional responsibility on the part of the blood program to be concerned about the future well-being of the donor. What makes this conclusion particularly appealing is the fact that follow-up is managed with the reassessment of that individual's blood donation candidacy, should he or she return to donate again. However, an approach that distances blood programs from a range of possible iron prophylaxis outcomes, restricting the relationship with the donor to no more than an instruction or recommendation to take iron, makes a number of questionable assumptions. The first is that oral iron is inevitably safe, although side effects are common (in one study, 33.8% of those on oral iron had a gastrointestinal symptom11). However, there are important exceptions. Iron is not an idle bystander in terms of its interactions with other oral medications.19 The metal interferes with the absorption of several medications including angiotensin-converting-enzyme (ACE) inhibitors, levothyroxine, and some broad-spectrum antibiotics, such as tetracyclines and quinolones. There is also recent attention to the effects of oral iron on the gut microbiome, in that changes in microflora induced by the metal could have damaging effects on the immune responsiveness of the gut.20 The second assumption that deserves scrutiny is that the iron-deficient donor has his or her donation record to account for that deficiency. This is not a given. Without appropriate follow-up, iron deficiency for other reasons, such as gastrointestinal inflammation or malignancy, gynecological disease, or malabsorption, could be masked and more appropriate diagnosis and therapy delayed. To avoid this risk, tactics have been proposed that could reduce the risk of delaying a diagnosis of iron deficiency that is not attributable to blood donation. Short-term iron replacement in a dose calculated to be equivalent only to the amount of iron lost by the donation is one of the approaches. In this approach, however, donor follow-up to assess response is essential. On the ethical front, although there are any of a number of principles at play in decisions about measurement of iron stores and justification for iron supplementation, the central considerations are nonmaleficence, which embraces the concept of doing no harm, and autonomy, which respects an individual's decisions and, by extension, recognizes the importance of full disclosure of the information needed to make the decisions. The donor circumstances that demand attention to nonmaleficence are not difficult to identify. If iron supplementation is recommended for those whose stores have been depleted by donation, then those individuals who present as first-time donors with depleted stores also deserve identification to avoid a donation that would further reduce their stores. This problem does not affect an insignificant population. In one study, 12% of females who had never donated before had ferritin levels less than 12 ng/mL.2 This observation then begs the question: Should a serum ferritin be a predonation qualifying test? From an ethical point of view, it is not enough to argue that it would be inconvenient to initially recruit donors for a blood test and then expect that those who qualify with adequate stores will actually return when invited. Cumbersome as this procedure would be, it would not be impossible, but it would raise another question: What takes precedence, the adequacy of the blood supply or donor health? It is open to conjecture whether these considerations would even be relevant if a point-of-care test for iron stores, such as zinc protoporphyrin, were available. Those believing that storage iron deficiency has deleterious consequences could identify donors at risk; and, because hemoglobin is not a good measure of iron stores, they could argue that all donors, including those who pass a hemoglobin threshold, should be screened. With regard to the ethical principle of autonomy, donors can only make decisions about their own lives if they are appropriately informed. If donors are to experience a very different relationship with their blood program, one that takes them through diagnosis of iron deficiency and treatment with iron supplementation, then they must be well apprised of the issues. They should clearly understand that iron therapy will certainly benefit the blood program by reducing hemoglobin deferrals and will possibly benefit themselves if iron deficiency without anemia proves to be causative of, rather than merely associated with, grave consequences. For those authorities that hold to a causative relationship of these suggested consequences, including those for cognition, pregnancy outcomes, and quality of life, these issues would need to be clearly spelled out in the informed consent. Given this opportunity to be clairvoyant, it seems likely that accreditors and regulators will decide that there is enough accumulating information to adopt a precautionary approach and recommend steps that will investigate and manage iron balance in donors. Contrarians will ask for evidence from randomized controlled trials that nonanemic iron deficiency has important, clinically significant sequelae, and they will question whether blood programs are suited to the broader public-health role that iron nutritional surveillance and intervention impose. In 2001, the National Heart Lung and Blood Institute, along with the organizations representing blood collectors in the United States, hosted a workshop addressing the maintenance of iron balance in female blood donors.21 The group's recommendations included the suggestion that iron-replacement strategies deserved investigation. Blood centers were encouraged to ensure that donors had input into design of research protocols. Fifteen years later, it would be worth recognizing that, while that opportunity has been lost, inviting donor input now into the protocols that might be developed to address their iron balance would be an appropriately ethical step. The author has no conflicts of interest to declare. Merlyn H. Sayers, MBBCh, PhD MSayers@carterbloodcare.org Carter BloodCare Bedford, Texas Department of Pathology, University of Texas Southwestern Medical Center Dallas, Texas

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