Abstract: This review includes 11 studies with 1074 participants. Outcome metrics for which data were available (haemoglobin concentration, quality-of-life scores, serum ferritin, peak oxygen consumption and mild to moderate adverse effects) were similar across the included studies. The incidence of severe adverse events across all studies was zero. None of the studies measured bacterial infection as a specific outcome metric. Substantial heterogeneity influenced the results of the meta-analysis, arising from differing patient populations, definitions of iron deficiency, iron preparations and dosing regimens, and time to end of follow-up. Consequently, many outcomes are reported with small group sizes and wide confidence intervals, with a subsequent downgrading in the quality of evidence. The level of bias in many included studies was high, further reducing confidence in the robustness of the results. We found that intravenous iron therapy may lead to a small increase in haemoglobin concentration of limited clinical significance compared to placebo (MD 3.04 g/L, 95% CI 0.65 to 5.42; I2 = 42%; 8 studies, 548 participants; low-quality evidence). Quality-of-life scores (Piper Fatigue Scale MD 0.73, 95% CI 0.29 to 1.18; I2 = 0%; studies = 3) and peak oxygen consumption (MD 2.77 mL/kg/min, 95% CI −0.89 to 6.43; I2 = 36%; 2 studies, 32 participants) were associated with very low-quality evidence, and we remain uncertain about the role of intravenous iron for these metrics. We were unable to present pooled estimates for the outcomes of serum ferritin at the end of follow-up or mild to moderate adverse effects due to extreme statistical heterogeneity. Ultimately, despite the results of the meta-analysis, the low- or very low-quality evidence for all outcomes precludes any meaningful interpretation of results beyond suggesting that further research is needed. We performed a Trial Sequential Analysis for all major outcomes, none of which could be said to have reached a necessary effect size. Current evidence is insufficient to show benefit of intravenous iron preparations for the treatment of non-anaemic iron deficiency across a variety of patient populations, beyond stating that it may result in a small, clinically insignificant increase in haemoglobin concentration. However, the certainty for even this outcome remains limited. Robust data for the effectiveness of intravenous iron for non-anaemic iron deficiency is still lacking, and larger studies are required to assess the effect of this therapy on laboratory, patient-centric, and adverse-effect outcomes.

Plain-language summary: We found 11 studies with 1074 participants. A broad range of people were included in these studies, including people with heart failure, elite athletes, people with restless legs syndrome and otherwise fit and well women. We excluded studies that looked at children, pregnant women, and people being treated with erythropoietin (a hormone that stimulates the production of red blood cells). Intravenous iron may lead to a small increase in the level of haemoglobin in the blood. We also assessed the effect of intravenous iron on quality of life, serum ferritin (iron stored in the body), peak exercise capacity, and milder side-effects of iron administration but we were unable to determine whether or not intravenous iron was of benefit for these outcomes. This is because there were many differences between studies in the types of participants studied, the definition of iron deficiency used, the type of intravenous iron preparation prescribed and the length of the studies. We also tried to collect data on severe side effects and bacterial infection after iron infusion, but we were unable to find any studies that measured these effectively. Because of the many differences between the relatively small number of studies included in this review, we are uncertain about the effect of intravenous iron in non-anaemic iron deficiency beyond saying that it might cause an increase in haemoglobin concentration. Furthermore, the starting level of haemoglobin for people included in this review was considered 'normal' prior to their receiving treatment. Therefore, not only is this increase quite small, but the starting level of haemoglobin was considered adequate according to current guidance, and patients may not even notice an improvement in symptoms. We are not suggesting that intravenous iron is not of benefit for adults with non-anaemic iron deficiency, rather that the current quality of evidence is not good enough to be certain about the effects of these drugs. Overall, the evidence for intravenous iron for the treatment of non-anaemic iron deficiency is of low or very low quality. Whilst intravenous iron might cause a small increase in haemoglobin concentration from an already normal level, we are uncertain about its effects in other outcomes that we examined as part of this review. Further research examining the effects of intravenous iron for the treatment of adults with non-anaemic iron deficiency is required to help answer this research question. The evidence is current to October 2019.