The micronutrient, iron, has an essential role in the transport and storage of oxygen as well as cellular and mitochondrial respiration (1, 2). Further, iron is vital for healthy immune function in conjunction with cell growth (1). Consequently, both excessive and scarce iron levels are associated with various adverse health complications (1, 3). In athletic populations, previous literature has categorised ID into three stages of severity, each with varying impacts on exercise performance (4). These include:
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Iron Depletion (Iron deficiency non anaemia stage I): Iron stores in the bone marrow, liver, and spleen are depleted (serum ferritin: < 35 µg/L; Hb: > 115 g/dL; Transferrin Saturation: > 16%).
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Iron Deficient Erythropoiesis (Iron deficiency non anaemia stage II): Erythropoiesis diminishes as the iron supply to the erythroid marrow is reduced (serum ferritin: < 20 µg/L; Hb: > 115 g/dL; Transferrin Saturation: < 16%).
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Iron Deficient Anaemia: haemoglobin production falls, resulting in anaemia (serum ferritin: < 12 µg/L; Hb: < 115 g/L; Transferrin Saturation: < 16%).
Iron deficiency (ID) is the most common nutrient deficiency globally, affecting approximately one third of the population (2 billion people) (5, 6). Iron deficiency can present itself through an array of symptoms, or can be asymptomatic (7). The most commonly reported symptoms include physical and mental fatigue, brainfog (the inability to think clearly), shortness of breath, heart palpitations, alopecia (hair loss), and pica (the desire to eat non-foods such as dirt) (7–9). Further to this, evidence in mouse models suggest that iron deficiency negatively affects physical endurance, being responsible for decreases in mitochondrial complex I activity of oxidative skeletal muscle (10). Recent research in human participants has also highlighted impaired skeletal muscle metabolism in the presence of iron deficiency, however, no impairment of muscle oxidative phosphorylation was observed (11). Rather, disturbed blood lactate kinetics were demonstrated, appearing to promote a shift towards anaerobic glycolysis, which could explain, in-part, the negative impact seen on aerobic capacity and fatigue scores (11–13).
Without treatment, ID can progress in severity, resulting in states of iron deficiency anaemia (IDA); characterised by exhausted iron stores, a reduction in erythrocyte production, and a decrease in haemoglobin concentration (14). Consequently, oxygen carrying capacity to the working muscle is compromised, inevitably decreasing V̇O2max (15). Such states are linked to even greater declines in work capacity and quality of life (5, 6, 16–22).
The strong causal relationship between IDA and exercise capacity has brought about a plethora of research to determine the best strategies to replenish iron stores. To date, the most common iron supplementation methods include oral supplementation, and in persistent, severe, and/or unresponsive cases, intravenous (IV) iron therapy (23–25).
Iron supplementation methods
Oral iron therapy
Oral iron therapy is generally consumed in either tablet or liquid preparations, commonly available in ferrous or ferric forms. Typically, only ~ 10% of intestinal iron is absorbed (26) meaning the restoration of iron levels via the gut can take extended periods of time (27). Despite this, research has demonstrated modest efficacy in iron store replenishment, with increases of serum ferritin ranging between 40–80% in healthy populations (28, 29) following recommended daily doses of ~ 100-200mg of elemental iron per day over a 6–8 week period (23, 25). Regardless, it should be noted that oral iron therapy has been shown to be ineffective at replenishing iron stores in cases of ID caused by chronic inflammation (functional ID). This is due to a reduced dietary iron absorption and failure of cellular iron export into circulation in the presence of inflammation, thus, reducing iron availability despite the presence of adequate iron stores (30). Consequently, alternative methods of iron repletion should be considered here.
Intravenous iron therapy
Over the last decade, the use of intravenous (IV) iron therapy has increased considerably due to improvement in availability as well as increased safety of modern preparations (30). Modern IV iron preparations are made up of an iron core (ferric hydroxide particles) within a carbohydrate shell for the purposes of delaying iron release (23). Unlike oral iron supplementation, IV iron therapy restores iron levels within approximately 24 hours (31), with direct injection of iron into the circulation allowing for absorption restrictions at the gut to be bypassed (32). Such a prospect allows for rapid increases in iron status, with research in healthy populations reporting 200–400% increases in ferritin levels from a 300 to 550mg dose of iron (28, 29, 32, 33). Although previous reviews have demonstrated no association between IV iron therapy and serious adverse events (34), current guidelines still only recommend its use in severe cases, where appropriate equipment and staff can be utilised to avoid and or manage hypersensitivity reactions (7).
Efficacy of oral and IV iron supplementation on ID individuals
In states of IDA, whereby oxygen carrying capacity is compromised due to decreased haemoglobin concentrations, the benefits of iron therapy on physical capacity have been well demonstrated (35, 36). This is simply due to the correction of haemoglobin concentration allowing for an increased oxygen carrying capacity. In contrast, states of ID without anaemia (IDNA), whereby oxygen carrying capacity is not compromised, the evidence is equivocal. Studies specifically utilising oral supplementation routes have seen both increases (37–42) and no change (29, 43, 44) in physical capacity. Similar ambiguity has been documented in studies involving IV iron therapy, where increases (29) and no change (32, 33) to physical capacity are also shown. Of note, it has been suggested that the divergence of findings is due to major statistical and methodological heterogeneity across studies (45) coupled with the challenge of separating the effects of ID from the consequences of potential anaemia (11).
The aforementioned divergence has been highlighted by several systematic reviews and meta-analyses (45–48). As with the ambivalence found in the clinical trials, differing conclusions also exist across the review papers. One such review, conducted by Rubeor and colleagues (48), involved 12 studies (9 oral, 1 IV, and 2 intramuscular interventions) with 283 participants, where half of the included studies (6 studies; 146 participants) showed performance improvements in IDNA athletes that were treated. Of note, it should be mentioned that all of these studies used a ferritin level cut-off of ≤ 20 µg/L for treatment. Therefore, it was concluded that iron supplementation could improve physical capacity when serum ferritin is ≤ 20 µg/L (48). It should be noted that this study did not define non-anaemia, with the inclusion criteria stating “participants defined by the study authors as having IDNA or low ferritin without anaemia” (48).These finding has been both corroborated (46) and refuted (47) by other meta-analyses, and therefore, it can be concluded that conventional meta-analysis techniques (i.e., aggregate data) have failed to provide clear consensus regarding the efficacy of iron supplementation, both oral and IV, in IDNA individuals (45).
Heterogeneity of literature
A recent Cochrane review (45), also investigating the efficacy of iron supplementation (IV only) in IDNA individuals, explained that substantial heterogeneity significantly impacted the outcomes, primarily due to the aforementioned differences in current research protocols (i.e. different definitions of iron deficiency, different participant characteristics, inconsistent administration routes, and varying research protocols), which consequently results in analyses of limited clinical significance due to low quality evidence (45). Furthermore, very low-quality evidence from the included studies in relation to V̇O2max and quality of life measures meant that appropriate analysis could not be conducted accurately. As such, different methods (such as meta-analysis by individual patient data) should be explored to control for such heterogeneity.
Serum ferritin thresholds for defining iron deficiency
Due to the and lack of consensus for serum ferritin values to define iron deficiency across studies, conventional meta-analysis techniques may not be effective on the basis that the studies aren’t comparable. The current serum ferritin thresholds for defining iron deficiency (serum ferritin < 15ug/L) determined by the World Health Organisation (WHO) are based on expert opinion and are supported by a low to very low certainty of evidence (49, 50). The WHO have acknowledged their guidelines and ferritin cut off values are based on expert opinion, not on published data (51). Due to this, higher threshold recommendations are commonly adopted to increase the sensitivity of ferritin to detect iron deficiency (for example, the Australian Medical Association defines ID as a serum ferritin < 30µg/L). Although these higher ferritin thresholds have increased the sensitivity to detect iron deficiency, there is still little to no evidence justifying them (52).
Despite being widely accepted, the rationale concerning the quantitative values lack empirical support and are still being based upon expert opinion or serum ferritin distributions of varying populations. Physiologically based ferritin thresholds for iron deficiency in conjunction with other blood markers (such as transferrin saturation, soluble transferrin receptor, hepcidin concentration, and haemoglobin concentration) would allow for better informed research (49, 52). For instance, Mei and colleagues (49) aimed to identify the ferritin concentration at which soluble transferrin receptor concentration rises and haemoglobin concentration begins to decline in children and non-pregnant women. The association between the two independent indicators of iron-deficient erythropoiesis (i.e., haemoglobin and soluble transferrin receptor concentration), identified ferritin concentration thresholds of ~ 20 µg/L and ~ 25 µg/L to define iron deficiency in children and non-pregnant women, respectively.
The need for meta-analysis of individual patient data
An individual patient data (IPD) meta-analysis, which summates the raw data from relevant studies, would allow for the standardisation of the inclusion criteria. Thus, enabling the comparison between studies with a single (physiologically derived) ferritin cut-off value for the definition of iron deficiency (53). Resultantly, subject- and study-level sources of heterogeneity are taken into account, which may assist in exploring effect modification as well as adjusting for confounding variables (54). For this reason, the IPD meta-analysis methodology has become increasingly common and is regarded as a ‘gold standard’ meta-analysis compared to conventional meta-analysis techniques (55).
Aim
Overall, when considering cases of extreme heterogeneity in estimates of relative treatment effect, a weighted average may no longer be informative (54). Consequently, synthesising aggregate data may be ineffective and produce conflicting results (as evidenced above), suggesting that alternative approaches should be considered. For this reason, the aim of the present study is to assess, using IPD meta-analysis methodology, the efficacy of iron supplementation (both oral and IV) on physical capacity, quality of life and fatigue scores in IDNA individuals.