Iron supplementation for iron-deficiency anaemia

The global prevalence of anaemia in women of reproductive age (15–49 years) was reported at 29.9% (95% uncertainly interval (UI) 27.0%–32.8%) in 2019, with global prevalence in children under 5 years old reported at 39.8% (95% UI 36.0%–43.8%). Children under 5 years old from Africa were reported to have the highest prevalence of anaemia in this age group at 60.2% (95% UI 56.6%–63.7%) (World Health Organization, 2023). Iron deficiency anaemia (IDA), the most common presentation, accounts for 50% of all anaemias (Warner and Kamran, 2020). The development of IDA increases with advancing age along with an increase in associated morbidity, both physical and psychosocial, with occult bleeding the most common cause amongs older adults (Rockey et al, 2020). Disturbed iron metabolism plays a major role in several conditions associated with older age and adequate correction of iron deficiency may improve disease prognosis (Wawer et al, 2018). Iron deficiency is associated with a number of economic (work capacity, healthcare costs), psychological (reduced quality of life, reduced cognition) and physical effects (restless leg syndrome, fatigue, infertility, chronic heart failure, reactive thrombocytosis etc), even in the absence of anaemia (Jimenez et al, 2015). This review of current literature investigates the use of oral iron supplementation in people with iron deficiency anaemia.

Psychologically, IDA is associated with significant increases in the incidence of anxiety, depression, sleep disturbance and psychotic disorders leading to a reduction in quality of life, cognition and increased healthcare cost (Lee, 2020). This could be because of IDA-induced altered myelination in the brain and impaired monoamine metabolism (Todorich et al, 2009) and neurotransmitter homeostasis (Kim and Wessling-Resnick, 2014). Pathologies leading to and affected by IDA include celiac disease, chronic kidney disease, inflammatory bowel disease, chronic heart failure and certain cancers (Jimenez et al, 2015). IDA can also predispose to venous thromboembolism (VTE) by inducing thrombocytosis (Ezeh et al, 2021). Assessing for and adequately treating IDA with iron supplementation can therefore potentially prevent or reduce the risk of this avoidable risk factor, particularly in patients with recurrent VTE disease (Ezeh et al, 2021).

Individuals with IDA of an unidentified aetiology are often referred for a specialist gastroenterologist assessment as most cases have a gastrointestinal origin. Appropriate care and management of IDA can improve quality of life, relieve associated symptoms, and, in severe cases, decrease the necessity of blood transfusion. Common treatment options include oral tablets, liquid iron, intramuscular injections and intravenous therapy. However, the effectiveness of oral iron tablets is inadequate in many gastrointestinal pathologies, such as celiac disease, autoimmune gastritis and inflammatory bowel disease, because it is dependent on the patient's adherence to medication (Jimenez et al, 2015).

The effectiveness of daily oral iron tablets (with or without additional treatment, ie vitamin c or folic acid) of any dose, compared with placebo, for improving anaemia, iron status and health in menstruating females was reported in a systematic review of 67 randomised, controlled, clinical trials investigating the effect of oral tablet supplements in 8506 women of reproductive age (12–50 years) (Low et al, 2016). Reported outcomes included haemoglobin concentration at the end of the intervention and side effects (Table 1).

Participants receiving oral iron tablets reported a greater plasma concentration of haemoglobin compared to placebo (mean difference (MD) 5.30 g/L, 95% CI 4.14 to 6.45, 51 studies, 6861 women) yet this outcome produced significant heterogeneity. A sensitivity analysis on plasma concentration of haemoglobin maintained the significant mean difference in favour of iron tablets but eliminated heterogeneity. Significant increases in the risk of four side effects were noted with iron supplementation in tablet form (gastrointestinal, diarrhoea, constipation and change in stool colour). These included an almost twofold increase in risk of gastrointestinal side effects (RR 1.99, 95% CI: 1.26 to 3.12, five trials, 521 participants, low-grade evidence), a more than twofold increase in the risk of diarrhoea (RR 2.13, 95% CI: 1.10 to 4.11, six trials, 604 participants, high-quality evidence), a twofold increase in the risk of constipation (RR 2.07, 95% CI: 1.35 to 3.17, eight trials, 1036 participants, high-quality evidence) and a sixfold increase in the risk of stool colour change (RR 6.92, 95% CI: 3.83, 12.52, four trials, 359 participants, high-quality evidence). The risk in abdominal pain (RR 1.55, 95% CI 0.99 to 2.41, seven trials, 1190 participants, low-quality evidence) revealed a trend towards significance, however, this result was reported from low-grade evidence. No significant difference in risk of nausea was reported (RR 1.19, 95% CI 0.78 to 1.82, eight trials, 1214 participants) (Low et al, 2016). Overall, data from this review reported that daily use of oral iron tablets effectively increases plasma haemoglobin levels in this population group. However, this was at the expense of significant increases in risk of gastrointestinal side effects, diarrhoea and constipation (Low et al, 2016).

A recent case study reported on five patients with IDA who had no history of blood transfusions, presenting with epigastric pain, weight loss and fatigue, and who also suffered from various chronic illnesses including arthritis, diabetes, liver cirrhosis and cardiovascular disease (Onorati et al, 2020). Participants had received therapeutic doses of iron supplement tablets and had undergone a diagnostic upper gastrointestinal endoscopy. Endoscopy revealed several gastric panels showing patchy brown mucosal discolourations bordered by moderate haemorrhage and several gastric ulcers and erosions. The concentration effect of the supplemental iron tablets could have been the cause of gastric injury, as similar effects had not been observed in studies where participants used a liquid form of iron. Limitations of this study include size, and therefore generalisability, and a lack of control/comparison group. While the results of this small but pertinent study provide support for liquid form of iron as an alternative option in the management of IDA compared to oral iron tablets. Larger studies are recommended to confirm this finding and inform evidence-based practice.

In an extensive systematic review of literature over three decades, the efficiency and tolerability of iron protein succinylate was evaluated (Martínez Francés and Martínez-Bujanda, 2020). Overall, 54 studies with over 8000 patients were included in the review. Of these studies, 32 compared iron protein succinylate with other iron complexes, six RCTs and one observational study compared it with other presentations of iron protein succinylate and 15 studies did not use a comparator (Figure 1a). Overall, 6450 participants received the liquid form (iron protein succinylate), while the remaining participants received oral tablets (ferrous or ferric complexes). Study treatment duration varied between 23–180 days with a mean duration of 49 days. Pooled efficiency analysis of all participants pre- and post-iron treatment reported increases in haemoglobin and ferritin concentrations in those receiving liquid form of iron (iron protein succinylate n=6450) or oral tablets (ferrous (n=1010) or ferric (n=682) complexes) with no difference between the groups. Figure 1a and b indicate comparable efficacy of the three forms of iron supplementation in treating IDA (Martínez Francés and Martínez-Bujanda, 2020).

Adverse events (AEs) were also reviewed with a total of 924 reports, of which 823 were non-serious gastrointestinal-related events. Use of iron protein succinylate was associated with the lowest rate of AEs, with both oral tablet forms reporting more than three times the rate seen with liquid form (Figure 2a) and six times the rate for treatment-related AEs (Figure 2b) (Martínez Francés and Martínez-Bujanda, 2020).

This review evaluated the existing literature on the efficacy and tolerability of iron protein succinylate supplementation in comparison to oral iron complexes over a period of three decades. The results showed that both iron protein succinylate and iron tablet formulations have comparable efficacy, but iron protein succinylate supplementation was found to have a more favourable tolerability profile, including reduced gastrointestinal side effects. However, the limited reporting of adverse effects in the studies and the poor analysis of these effects limits the ability to generalise these conclusions (Martínez Francés and Martínez-Bujanda, 2020).

Conclusion

Evidence to date suggests that the liquid form of iron supplementation has comparable efficacy to the tablet formulation, but with significantly lower gastrointestinal side effects. The evidence presented here should inform the advice healthcare professionals provide to patients with IDA. As gastric-related adverse effects following oral iron tablet supplementation are common, liquid iron formulation should be considered a superior option to mitigate gastrointestinal side effects and increase treatment adherence and successful management of IDA in primary care.

Key Points

• 70% of people using iron supplementation tablets for IDA experience gastrointestinal side effects
• Liquid and tablet formulations have comparable efficacy, yet liquid formulations have a six times lower incidence of adverse effects from treatment
• Liquid iron is preferable for people who experience gastrointestinal effects from iron tablet formulations

CPD reflective questions

• What are three gastrointestinal pathologies where oral iron tablets may provide suboptimal efficacy?
• What are the most common side effects experienced from oral iron tablet supplementation?
• As a clinician, what factors would you consider when recommending a specific formulation of iron supplementation to a patient?