The Perceived Impact of Iron Deficiency and Iron Therapy Preference in Exercising Females of Reproductive Age: A Cross-Sectional Survey Study

Introduction

Iron deficiency (ID) is the most common nutrient deficiency globally, affecting approximately one-third of the population (2 billion people).^1,2 The adverse health complications and symptoms of ID are well documented and include: fatigue, brain fog (reduced concentration), dizziness, headaches, restless legs, hair loss, and muscle weakness or soreness.^3–6 Such symptoms are proposed to reduce both mental and physical health as well as overall patient quality of life.^7,8

Iron deficiency is substantially prevalent in women of reproductive age, due to increased iron loss during menstruation and/or pregnancy.^8–10 The prevalence rates of iron deficiency in exercising females in this age range from various cohort studies have been estimated to be as high as 50%.^11–15 This is due to the combined effect of menstrual blood loss in conjunction with several avenues for iron loss during exercise; which include: food-related energy deficits (purposeful or not), exercise-induced haematuria (blood in urine), gastrointestinal bleeding, sweating, haemolysis, increased inflammation, and transient elevations in hepcidin.^16–19 Research is currently ongoing as to the best strategies to overcome ID in exercising females encountering these issues. Given the inflammatory effects of exercise resulting in increased hepcidin concentrations, iron absorption is compromised in exercising populations, making it difficult to maintain optimal iron stores through diet alone.^20,21 In combination with menstrual blood loss, exercising females often require iron replacement therapy to maintain optimal iron stores.

Oral iron supplementation is the most common treatment method for treating ID. Consumed as tablet or liquid preparations, oral iron supplements are widely used due to the low cost, low risk, and modest efficacy.^20,22 When consumed over an 8 to 12-week period, at a dose of approximately 100 mg of elemental iron per day, exercising populations appear to increase their serum ferritin from 40 to 80%.^18,23 However, due to poor absorption in the gut, the restoration of iron levels can take extended periods of time.²⁴ In addition to the modest magnitude of the response, several potential side effects have been documented with the consumption of oral iron supplements; namely, constipation, heartburn, nausea, vomiting, diarrhoea and abdominal discomfort (gastrointestinal upset).²⁵ Indeed, ferrous sulphate (the most common oral iron supplement) has been associated with 2.6 times the odds of gastrointestinal side effects compared to placebo.^20,25 Further research has demonstrated insufficient adherence to oral iron supplements predominately due to gastrointestinal upset;²⁶ resulting in suboptimal treatment efficacy.

An alternative therapy is intravenous iron therapy with direct injection of iron into the circulation allowing for absorption restrictions at the gut to be bypassed.²⁷ Intravenous iron allows for rapid increases in iron status, studies reporting 200–400% increases in ferritin levels from a dose of 300 to 550 mg of iron.^18,23,27,28 Despite the increased efficacy of treatment, due to the higher cost and more invasive nature of therapy, it is reserved for more severe cases of ID or when oral iron supplements are not tolerated. Adverse reactions to intravenous iron therapies are rare (such as hypersensitivity and anaphylaxis). However, despite being infrequent, they can be life threatening.²⁹ Notwithstanding, newer intravenous iron supplementation formulations have been developed with ongoing advances in pharmaceutical technologies,³⁰ and there has been a rapid increase in parenteral therapies for women of reproductive age in Australia (where intravenous iron is available on Medicare through GP practices).³¹ These preparations have allowed physicians to safely administer a full treatment dose in a clinical setting in 15–30 minutes.³² However, this research is purely from a clinical perspective, in non-healthy individuals (ie individuals with other adverse health complications aside from ID).

Regardless of the supplementation method, where serum ferritin is <40 μg/L, research suggests that there will be significant increases in serum ferritin if some form of intervention is undertaken.^33,34 However, this does not necessarily correlate to improved fatigue and work capacity. Several randomised control trials have been conducted on the topic, with conflicting results. As with the ambivalence found in the clinical trials, differing conclusions exist across systematic reviews and meta-analyses.^34–37 These reviews were highlighted in a recent Cochrane meta-analysis,³⁷ where it was explained that substantial heterogeneity significantly impacted the outcomes, primarily due to the differences in research protocols (ie different definitions of iron deficiency, different participant characteristics, varying supplementation type and dose, inconsistent administration routes). This review was recently updated and suggested that iron therapy may improve fatigue scores; however, this is still supported by very low-quality evidence.³⁸

When examining the literature concerning preference and adherence to these iron therapies, minimal research was found at the individual level. One systematic review, using the Cochrane methodology, has been conducted, comprising 12 studies across 17 countries, majority of which were third world countries. This review used thematic analysis to develop a conceptual framework of social determinants of iron supplementation among women of reproductive age. Several domains emerged; however, they were mainly drivers at the cultural or societal level (such as political circumstances, societal norms and values, education and communication, socio-economic circumstances, community and social support).³⁹

To the best of our knowledge, no study has investigated individual perceptions regarding the efficacy of iron supplementation in healthy, exercising women of reproductive age. Despite the plethora of research investigating iron therapy from a quantitative perspective, there has been a relative inattention to integrating qualitative findings at the individual level, specifically in the case of iron therapies.^39,40 In Australia, where IV iron is readily available and common practice, we wished to assess the perceived impact of ID on training, exercise capacity and recovery and the perceived efficacy of oral iron and IV iron on exercise capacity and recovery.

Methods

Research Design & Participants

A qualitative cross-section survey design was adopted (details below). The inclusion criteria were pre-menopausal females aged between 18 and 65 who were undertaking 3 or more hours of exercise per week. No exclusion criteria was applied to this population. However, individuals were asked if they have/had ID or anaemia, or if they were taking any medications or supplements. This data was recorded, and only those who reported a history of ID or anaemia were asked follow-up open-ended survey questions. Ethics approval to conduct this research was provided by the University of Western Australia (UWA HERC RA/4/20/6465). This research was conducted in compliance with recognised international standards and adheres to the declaration of Helsinki. As such, all individuals were required to provide informed consent prior to participating in the research.

Survey Design

The survey has previously been used and validated^6,41–44 (Appendix 1). Yes/no polar questions were asked to collect information on participant demographics, history of iron supplementation, and average number of hours they exercised each week. Eight open-ended free-text questions were asked. These questions were designed to invite participants to describe – in their own words – the impact of iron deficiency, as well as the perceived efficacy of iron therapies (both oral and intravenous) on exercise training, performance, and recovery (Appendix 1).

Data Analysis

Data were screened, and descriptive characteristics were calculated. Open-ended survey items required two authors (AS, CD) to independently familiarise themselves with the data, initially coding 10% of responses for cross-examination of inter-rater agreement. Once agreement was confirmed, AS coded the remaining responses for each survey item, repeatedly cross-checking with CD to ensure accuracy.

Manifest content (ie literal/semantic meaning of words, as opposed to latent/underlying meaning) in responses to open-ended questions were determined and assigned to categories.⁴⁵ After initial coding, frequency counts were also performed to highlight key terms or phrases used by participants. Finally, we performed a basic manual sentiment analysis to determine whether each response was framed positively (given a score of 1), negatively (given a score of −1), or neutral/ambiguous (given a score of 0), which was then summated to determine an overall participant sentiment (or tone) for each survey item.^46,47 For example, a general sentiment of 0.5 for a question on the impact of oral iron supplementation on performance would indicate that participants (on average) had a moderate positive sentiment about the impact of oral iron supplementation (ie it is generally perceived as having a positive impact). Two authors (JF, HN) independently coded the sentiment of each response, with disagreements settled by a third author (AS). Cohen’s kappa (κ)⁴⁸ coefficients are presented for each survey item as a measure of interrater reliability, with confidence intervals being calculated from standard error values.

Results

Descriptive Characteristics

One thousand and forty-two females completed the questionnaire. Of this sample, a sub-sample of 403 individuals completed the survey, answering all polar questions and at least one open-ended text question (based on their responses to current/history of ID, anaemia, and iron therapy). The average age was 29.84 ± 10.59 years old. The mean height was 166.48 ± 8.8cm and the average weight was 64.80 ± 11.15 kg. The number of hours exercised per week was 7.63 ± 4.29 hours.

In the entire sample, previous history of ID was reported by 338 (83.9%) of participants. Previous history of anaemia was reported by 131 (32.5%) of participants. Of these participants, 354 (87.8%) reported the use of some form of iron supplementation; with 331 (82.1%) reported the previous use of oral iron supplements, and 153 (38%) iron infusions.

Open Ended Survey Items

Across all items, response word counts were low (two to five words on average). A full description of key terms and phrases, sentiment, and reliability analyses is presented in Table 1. Manifest content analyses are presented in three broad topic areas: (1) Participants’ perceptions of the impact of ID symptoms on performance and recovery; (2) participants’ perceptions of the impact of oral iron supplementation on training, performance, and recovery; and (3) participants’ perceptions of the impact of iron infusion treatment on training, performance, and recovery. All codes identified within participants’ text responses (with examples) are presented in Table 2 (topic area 1), Table 3 (topic area 2), and Table 4 (topic area 3), and a schematic presentation of code categories is provided in Figure 1.

Table 1 Key Terms, Overall Sentiment and Interrater Reliability for Sentiment Analyses

Table 2 Content and Examples of Responses on the Impact of Iron Deficiency Symptoms

Table 3 Content and Examples of Responses on the Impact of Iron Tablet Supplementation

Table 4 Content and Examples of Responses on the Impact of Iron Infusion

Figure 1 A graphical presentation of code categories within each domain. Notes: The figure includes all categories of codes for each domain, but does not provide the individual codes within each category. For a full description of codes identified within participants’ responses, see Tables 2–4. The colours included in the figure are for differentiation between domains only (ie, for ease of reading) and are not to be interpreted as providing any information or inferences about the dataset.

Perceived Impact of Iron Deficiency

As expected, there was a strong negative sentiment of ID in regard to exercise performance (sentiment mean −0.94) and recovery (sentiment mean −0.81). Several categories emerged from the manifest content. Both physiological (energy decline, reduced ability to exercise) and psychological (decreases in motivation, increase in cognitive challenges) impacts were reported on exercise performance (Table 2). Longer recovery times were also described, which resultantly inhibited regular exercise routines (Table 2).

Perceived Efficacy of Oral Iron Supplementation

Moderate positive sentiment was observed regarding the perceived efficacy of oral iron supplementation on training (sentiment mean +0.45), performance (sentiment mean +0.47), and recovery (sentiment mean +0.44). Similar categories emerged from the manifest content for the 3 domains (Table 3). Participants commonly reported symptom reduction as well as improved; performance outcomes, energy levels, cognitive abilities, and training load. However, there was also a high number of neutral/ambiguous responses. Participants often described their experience with words such as “no”, “not”, “none”, or “nil”, indicating a perceived lack of benefit. Also, some side effects were frequently noted by participants in all three of the above domains. Most often, these were issues such as stomach aches, constipation, and vomiting.

Perceived Efficacy of Intravenous Iron Supplementation

Strong positive sentiment was observed concerning the perceived efficacy of intravenous iron supplementation on training (sentiment mean +0.79), performance (sentiment mean +0.76), and recovery (sentiment mean +0.74). Several categories emerged from the manifest content regarding the 3 domains, as shown in Table 4. All categories were derived from highly positive identified codes, suggesting a greater preference for intravenous iron supplementation.

Discussion

The present study demonstrates a clear perceived impact of ID in active or habitually exercising women of reproductive age. In accordance with previous research,^6,41 the greatest perceived impact relating to ID was fatigue and energy decline. Specifically, participants reported that they were unable to; perform at optimal levels, that fatigue was a significant barrier to exercise, and consequently, that there was a reduction in their ability to exercise. In terms of recovery, participants reported that they required additional rest between exercise bouts, which inhibited their desired routine (ie keeping up with a structured exercise routine or training schedule). Such outcomes can be detrimental to exercise performance due to a decreased training volume within a specific time frame. Psychological impacts were also commonly reported. For example, participants described decreases in motivation to exercise in conjunction with difficulties in cognition (ability to focus/concentrate), which ultimately affected decision-making. Overall, there was a very strong negative sentiment towards ID both from a physiological and a psychological perspective.

To correct ID, individuals generally engage in iron therapies through oral supplementation or intravenous iron infusions. Both forms of therapy have their advantages and disadvantages, mainly due to tolerability and safety issues.³⁰ For example, oral iron therapy can take several months to correct iron stores⁴⁹ and is typically associated with gastrointestinal side effects, such as: constipation, nausea, vomiting, diarrhoea and abdominal discomfort.²⁵ Nevertheless, the present study has demonstrated a moderate positive sentiment between oral iron supplementation and exercise performance, training, and recovery. Indeed, in response to oral iron supplementation, participants commonly noted exercise performance improvements, symptom reduction and increases in energy levels – typically allowing for a return to desired training/recovery routines. Further, participants described cognitive improvements, such as greater focus and productivity, allowing for better results at competitions. These findings support oral iron as the first line of treatment to correct ID,^20,22 especially considering contemporary research demonstrating more efficient ways to achieve equilibrium between iron absorption and tolerability from oral iron supplement approaches (ie lower dose, enteric coated tablets, alternate day supplementation, etc.).^49–51

In more severe cases of ID (such as iron deficiency anaemia), or when oral iron supplements are not tolerated due to gastrointestinal side effects, other forms of therapy might be considered by the practitioner, such as intravenous iron infusions. Previous research has shown high levels of non-adherence towards oral iron supplements,^26,30 mainly due to gastrointestinal side effects, in addition to weight gain under treatment.²⁶ This could explain, in part, the rapid increase in intravenous iron therapy for women of reproductive age in Australia.³¹ The present study demonstrates a high sentiment towards intravenous iron therapies and exercise performance, training, and recovery, with both physiological and psychological benefits reported from such approaches. Physiologically, participants reported greater energy levels and reduced fatigue, allowing for rapid increases in training loads (some reported as little as 2 days). Further, with regard to recovery, participants commonly described a reduction in post-exercise fatigue, improved sleep, and less soreness, allowing for an easier return to optimal training loads. Psychologically, participants reported higher levels of perceived concentration, improved focus, better reaction time, and improved decision-making. Overall, similar to oral iron supplementation, positive sentiment was generally characterised by participants regarding parenteral iron therapies with respect to exercise performance, training, and recovery. However, unlike oral iron therapy, adverse reactions from IV approaches (such as hypersensitivity and anaphylaxis) can be life-threatening.²⁹ Notwithstanding, newer and safer intravenous iron formulations have been developed with ongoing advances in pharmaceutical technologies,^{29,30,32,52–54} providing further evidence for increased use of intravenous iron. This research, however, is purely from a clinical perspective, in non-healthy individuals (ie individuals with other adverse health complications aside from ID).

Recent research has questioned the rise in intravenous iron therapies in iron deficient individuals who are otherwise healthy, specifically those that are iron deficient without anaemia (IDNA).³¹ Fivefold increased incidence rates have been observed in intravenous iron therapies between 2013 and 2017 for women of reproductive age in Australia.³¹ Although this selection of treatment has been justified in clinical practise,³² the change in popularity of treatment has raised concerns about whether intravenous iron is used appropriately and cost effectively in exercising populations,^31,55 especially given that the literature on the efficacy of intravenous iron therapies on exercise performance in individuals with IDNA is equivocal.^33–36,56 Indeed, studies have shown studies both increases¹⁸ and no change^27,28 to exercise capacity in response to a dose of intravenous iron. A recent review article has highlighted the need for a greater understanding of the increased use of intravenous iron in such populations. It was concluded that qualitative studies would provide important information on the motivating factors for exercising populations to seek intravenous therapies of all kinds, which would inform educational strategies to meet nutritional and performance needs.⁵⁵ The present study demonstrates positive sentiment responses for the efficacy of oral and intravenous iron supplements on exercise performance, training, and recovery; with a greater positive sentiment being observed in intravenous iron therapies. These findings highlight the need for quantitative research investigating physiological evidence on the efficacy of iron supplementations in exercise performance, as the current literature remains divergent.³⁷ Due to the heterogeneity of the current literature, even meta-analysis methodologies cannot reach consensus on this topic.^{33–37,56,57} As such, future research should consider individual patient data meta-analysis techniques in conjunction with highly powered randomised control trials.

The findings of this study should be considered in light of its limitations. First, the average response duration was very short; although we were able to extract meaning from the short responses, more detailed responses may have resulted in a greater understanding of the perspectives of the participants. In the future, researchers should explore methods to elicit more in-depth responses to ID queries. Second, keywords were treated in isolation—that is, direction of the term was not considered (for example, the word “better” in isolation has a different meaning to “it did not get better”). However, we are confident that the data presented in this study accurately represent the general perceptions of the participants, and we provide bigram and trigram data for additional context.

Overall, positive sentiment was demonstrated for both oral iron supplementation and intravenous iron therapy to correct ID and anaemia, with a greater sentiment toward intravenous iron therapies in exercising females of reproductive age. This could explain the rapid increase in intravenous iron use; however, qualitative responses suggest several similarities between the two therapies with respect to their efficacy in treatment, suggesting that the cheaper and safer option should be used as first-line treatment (oral iron supplementation); which corroborates previous research. However, further research is required to determine the efficacy of intravenous iron therapy on exercise performance, particularly in IDNA exercising females of reproductive age.