Questions and answers on iron deficiency treatment selection and the use of intravenous iron in routine clinical practice.

The treatment goal is to refill iron stores and in cases of anaemia, normalize Hb concentration. Oral iron supplements are absorbed across the small intestinal epithelium, mainly in the duodenum, via iron transporters (DMT1 and ferroportin) on the apical and basolateral surface of enterocytes ( Figure 1 ). Only ∼10% of intestinal iron is absorbed on average [ 18 ]. Thus, of the common therapeutic oral dose of 60–180 mg elemental iron, less than 20 mg is absorbed per day, meaning that theoretically 10–30 days of continuous iron supplementation may be required to achieve a 10 g/L increase in Hb, and as long as 6 months to fully normalize Hb levels and replenish iron stores in anaemic patients. When given orally, residual iron supplement remains largely unabsorbed in the digestive tract, which can injure intestinal surfaces and alter the composition of the gut microbiome, leading to gastrointestinal side-effects. Intravenous iron preparations bypass gastrointestinal absorption and their iron–carbohydrate complexes are processed by macrophages in order to release iron [ 19 ]. This is primarily performed by macrophages in the liver, spleen and bone marrow, but the mechanism of the uptake and subsequent degradation of the complex is incompletely understood. Once iron is released into the cytoplasm, it can be stored within ferritin or exported by ferroportin into plasma ( Figure 1 ). Depending on the specific intravenous iron preparation, the total amount of iron that can be administered through a single infusion may range from 62.5 mg to >1500 mg. Therefore, for those preparations delivering a large amount of iron, even a single dose can be sufficient for the complete replacement of iron deficit in patients. Ferroportin, the transporter required for iron export into plasma from both duodenal enterocytes and macrophages, is regulated by the hormone hepcidin ( Figure 1 ). Hepcidin occludes and degrades ferroportin; hence, elevated hepcidin impairs oral iron absorption and decreases the release of iron from macrophages [ 20 ]. Hepcidin is homeostatically regulated by multiple signals, including circulating iron and erythropoietic factors. In iron deficiency, hepcidin levels are low, allowing efficient export of iron from enterocytes and macrophages. During iron loading or in inflammatory conditions, hepcidin is elevated and prevents iron flow into plasma. Theoretically, intravenous iron may partially overcome the hepcidin-mediated block of macrophage iron release by increasing intracellular iron levels, which stimulates macrophage ferroportin translation via the iron responsive element–iron regulatory protein (IRE–IRP) system [ 21 ].

Overall the rates of drug-related adverse events with intravenous iron are extremely low, occurring at a rate of approximately 38 events per million doses, as reported in a historical analysis of United States Food and Drug Administration(FDA) data [ 63 ]. Serious hypersensitivity reactions (anaphylaxis) with modern intravenous iron are now rare, occurring at a rate of 24 per 100,000 persons (95% CI, 20.0–29.5) for non-dextran intravenous iron products at first exposure in a large observational studyof non-dialysis USMedicare patients ( n  = 688,183) [ 64 ]. Overall, results comparable to most other intravenous drugs and therapies [ 65 ]. A meta-analysis of 103 trials involving intravenous iron therapy conducted by the Mayo Clinic found no increased risk of serious adverse events compared with controls (relative risk [RR], 1.04; 95% confidence interval [CI], 0.93‒1.17) [ 66 ]. The indications and reasons for an iron infusion should be explained clearly to patients following a full consultation and examination. The indication for intravenous iron should be confirmed and a plan made to address the underlying cause including investigation and management for any cause for bleeding where appropriate. We would also recommend that patients have time to read an information sheet or online resource independently, prior to their treatment visit, which should include the potential risks of side-effects or complications that patients may experience. Consent for intravenous iron should be documented. The preparation, dosing and administration of intravenous iron varies between products and should be checked against corresponding prescribing information and country-specific guidance. Administration should always take place in appropriately equipped practices, clinics or infusion centres. Most adverse events occurring with intravenous iron can be anticipated by their nature and according to when they typically occur ( Figure 2 ). Recommended strategies to manage common events are described below. Adverse events associated with the administration of intravenous iron. Adverse events occurring with intravenous iron can be anticipated according to when they typically occur. Educational material and institutional training should prepare patients and staff for their occurrence, minimizing the need to unnecessarily withhold or abandon administration and reducing the need for subsequent patient visits. Anxiety: Any intervention is a concern for patients. This is normal in most scenarios but may be exacerbated since iron deficiency itself can affect cognitive function and cause physical symptoms such as anxiety, palpitations, chest pain and shortness of breath. Careful explanation combined with empathetic well-trained staff in a well-organized and relaxed environment can help ensure patients are reassured and able to undergo treatment [ 67 ]. Appropriate training of supporting staff can also reduce the chances of their own anxiety being transferred to patients. Tattooing: Staining can occur from iron either within the vein itself or more significantly from extravasation of iron, leading to tattooing [ 68 ]. In preparation, ensure patients are well hydrated and warm before attempting the intravenous cannula (a large hot drink is an easy solution). In difficult cases, consider using ultrasound-guided cannula placement. The intravenous cannula should be flushed with a minimum of 10 mL N/saline (or even a separate 100 mL bag of saline)to confirm placement before the infusion starts. The cannula should be well secured and checked during the infusion. At completion, disconnect the iron infusion and undertake a further10 mL N/saline flush to ensure there is no residual iron in the cannula that could leak out and stain the vein or skin on removal. Stains may resolve over time, but this can take up to 2 years and is not guaranteed, therefore referral to dermatology for laser therapy may be considered [ 69 ]. Flushing and Fishbane reaction: An initial slower rate of infusion is recommended over the first couple of minutes of an intravenous iron administration as some patients may experience flushing with associated light-headedness, dizziness or nausea. This is believed to be caused by unbound labile iron interacting with the endothelium leading to the release of nitric oxide, referred to as a “Fishbane reaction” [ 70 ]. These acute effects are self-limiting, typically lasting a couple of minutes. Management is to stop the infusion for several minutes, reassure the patient, and provide a glass of water. The iron infusion can then be restarted slowly and usually completed. Patients should made aware of the possibility of flushing reactions prior to administration and advised to arrive well hydrated. Intravenous irons should also be prepared in the prescribed volume of saline (100–250 mL) and not over diluted as this may increase the free or labile iron during infusion. Hypersensitivity reactions: The rate of hypersensitivity reactions with intravenous iron is less than 0.1% [ 71 ]; the risk is enhanced for patients with known allergies, a history of severe asthma, eczema or other atopic allergy, and patients with immune or inflammatory conditions. In this latter high-risk group, premedication with a steroid injection can be considered (e.g. hydrocortisone 200 mg), we would not suggest intravenous Piriton (chlorphenamine maleate) as the side-effects of the medication are often mistaken or worse than any effects of the iron infusion [ 72 , 73 ]. From a clinical perspective, reactions may start within seconds of commencing the infusion and often be confused with a flushing reaction. Some hypersensitivity reactions can occur in the30-minute period of observation after completion of the infusion (so it is advisable to leave the cannula in situ). Diagnosis and treatment depends on the relevant clinical picture and the severity of the response. In most cases, hypersensitivity reactions are limited with flushing, itching and urticarial rash. Management in mild cases is to stop the infusion and monitor the patient as symptoms pass and settle in about 10 minutes, after which time the infusion can be recommenced at a reduced rate and finished (providing no further symptoms occur) [ 74 , 75 ]. In moderate cases, a steroid injection can be considered (e.g. hydrocortisone 200 mg), with or without a 500 mL fluid bolus according to the patient’s observations. Patients who experience symptoms should be monitored for further progression. Serious hypersensitivity reactions (anaphylaxis) are rare and typically characterized by a sudden onset of symptoms or progressive worsening in some cases. Extensive guidance on risk minimization and protocols for management of hypersensitivity reactions were published by other consensus groups [ 76 , 77 ]. Staff should be familiar with these protocols and trained in the management of severe hypersensitivity reactions including access to resuscitation facilities. Management in mild cases is to stop the infusion and monitor the patient as symptoms pass and settle in about 10 minutes, after which time the infusion can be recommenced at a reduced rate and finished (providing no further symptoms occur) [ 74 , 75 ]. In moderate cases, a steroid injection can be considered (e.g. hydrocortisone 200 mg), with or without a 500 mL fluid bolus according to the patient’s observations. Patients who experience symptoms should be monitored for further progression. Serious hypersensitivity reactions (anaphylaxis) are rare and typically characterized by a sudden onset of symptoms or progressive worsening in some cases. Extensive guidance on risk minimization and protocols for management of hypersensitivity reactions were published by other consensus groups [ 76 , 77 ]. Staff should be familiar with these protocols and trained in the management of severe hypersensitivity reactions including access to resuscitation facilities. Post-infusion flu: Patients often report flu-like symptoms 2–5 days after receiving an iron infusion. These include; myalgia, aching, bone pain and, in some cases, increased temperature [ 78 , 79 ]. These types of symptoms may be more common than most institutions document, affecting up to one-third of all patients [ 80 ]. Symptoms are self-limiting and typically last 24–48 hours; however, this can be alarming to affected patients. The condition should not be confused with an “allergic reaction” or hypersensitivity, which is rare once an infusion is completed. Patients should be reminded of the possibility of symptoms before leaving the institution and advised to stay well hydrated and take ibuprofen if needed. Hypophosphataemia: One potential consequence of intravenous iron recognized recently is a fall in serum phosphate with several formulations, particularly ferric carboxymaltose [ 81 ]. Concentrations fall below the normal range in up to 40% of cases and relate to release of a hormone, fibroblast growth factor-23 (FGF-23), from osteocytes [ 81–83 ]. This prompts receptor-mediated renal phosphate excretion, a reduction in circulating parathyroid hormone levels, and indirectly reduces gut phosphate absorption through an FGF-23-mediated reduction in 1,25-di-OH vitamin D [ 83 ]. The effect is usually asymptomatic and reaches a nadir between 1 and 2 weeks [ 81 ]. In most cases, phosphate concentrations have returned to baseline by 12 weeks [ 82 , 84 ]. Isolated case reports, often in the setting of other metabolic disorders and mostly in patients receiving multiple infusions, have shown a potential association between longer periods of hypophosphataemia and osteomalacia and fractures [ 83 , 85 ]. These events are extremely rare and there are currently no intravenous iron-related clinical trial data that report an association between clinical adverse events and low phosphate levels [ 82 , 86 ]. Patient management should be based on an assessment of risk. There is a strong consensus that patients with IBD should be checked for micronutrient deficiencies on a regular basis (regardless of iron administration), with specific deficits appropriately corrected [ 3 , 87 ]. Monitoring of serum phosphate levels may be indicated in patients at risk for low serum phosphate who require a repeat course of treatment [ 88 , 89 ]. In summary, clarification over the sequence of events and likely risks following an iron infusion is important for both staff and patients to ensure that intravenous iron is administered in the safest manner for patient benefit. Given that iron deficiency and the acute but non-life-threatening side-effects of intravenous iron are both associated with an array of generalized symptoms, it is possible that concerns over hypersensitivity and hypophosphataemia may be misconstrued with more common symptomatic events, such as anxiety, Fishbane reactions, and post-infusion flu-like symptoms. Reassurance and knowledge of the clinical trial data are important, where adverse events are well-documented and independently adjudicated, to inform staff and patients of the benefits and potential risk of intravenous iron.

Heavy menstrual bleeding (HMB) is a symptom that should be defined by patients themselves as “…excessive menstrual blood loss which interferes with physical, social, emotional and/or material quality of life” [ 51 , 52 ]. Women can be unaware that their menstrual bleeding is abnormal [ 53–55 ], while others suppress symptoms [ 56 ] or present to providers who seem to normalize the symptoms, which remain untreated [ 57 , 58 ]. Iron deficiency and anaemia is common in this population [ 1 ] Management of women with the symptom of HMB and associated iron deficiency, with or without anaemia, requires dual therapy – interventions directed at the cause of the HMB and treatment designed to correct the iron deficiency and anaemia. Causes of abnormal uterine bleeding in the reproductive years are classified by PALM-COEIN: Polyps, Adenomyosis, Leiomyoma, Malignancy and hyperplasia, Coagulopathy, Ovulatory disorders, Endometrial causes, Iatrogenic, and Not otherwise classified) [ 59 , 60 ]. Interventions require a structured approach to diagnosis and determination of appropriate options with consideration of; costs, anticipated effectiveness, associated morbidity, desire for future fertility, cultural norms, and personal preferences. Treatment of iron deficiency with oral iron therapy should be the initial approach. Unfortunately, 20–40% of non-pregnant women ingesting oral iron preparations experience nausea, vomiting, constipation and/or an undesirable metallic taste, and often stop oral iron therapy [ 1 , 61 ]. These side-effects may be reduced with changes in formulation, the addition of stool softeners for constipation, or by alternate-day administration. With this in mind, women should be reassessed and failure of treatment (defined by Hb rise <10 g/L in one month or ferritin <30 µg/L at 3 months) should trigger the use of intravenous iron, which has seen a considerable increase in use in this setting over the last decade [ 62 ]. In summary, we recommend that intravenous iron should be used in girls and women with iron deficiency anaemia: Who do not tolerate or are inappropriate for the use of oral iron. Who have failed to respond to an appropriate dose, formulation and schedule of oral iron administration within 30 days as defined by an increase in Hb of at least 10 g/L (or 1 g/L). Who are scheduled for elective gynaecologic surgery and who, in the opinion of the surgeon, are unlikely to achieve a Hb of at least 110 g/L (11 g/dL) by the day of surgery using oral formulations. Who do not tolerate or are inappropriate for the use of oral iron. Who have failed to respond to an appropriate dose, formulation and schedule of oral iron administration within 30 days as defined by an increase in Hb of at least 10 g/L (or 1 g/L). Who are scheduled for elective gynaecologic surgery and who, in the opinion of the surgeon, are unlikely to achieve a Hb of at least 110 g/L (11 g/dL) by the day of surgery using oral formulations.

The use of intravenous iron has grown substantially in the past decade due to heightened awareness of the impact of iron deficiency on clinical outcomes and quality of life. Current intravenous iron preparations are indicated for the treatment of iron deficiency when oral preparations are ineffective or cannot be used [ 1 ]. They have a wide range of applicability in clinical contexts including; nutritional deficiency, malabsorption, disorders associated with chronic blood loss, and chronic inflammatory conditions [ 2–5 ]. The availability of modern preparations allows rapid iron repletion in just one or two doses facilitating ease of treatment [ 6 , 7 ]. Intravenous iron preparations are approved with broad labels and the clinical trials testing efficacy span many indications and disease groups, this has led to a proliferation of guidelines and consensus statements. However, there remains a need for more practical “how to” guidance on intravenous iron administration as patients and staff may express concerns over potential side-effects, adverse events, reactions and complications, or contra-indications, which may be confused or misperceived. Here, we aim to support healthcare professionals by summarizing the current recommendations for intravenous iron, alongside practical advice on their administration and informed opinion on the anticipated risks versus expected benefits of treatment.

Intravenous iron repletion is a transformative therapy that can have a major bearing on clinically relevant outcomes and overall well-being. Treating physicians should always aim to establish the underlying cause of bleeding, address it with appropriate therapy when possible, and understand the impact of inflammation and chronic disease on iron deficiency. Intravenous iron has a significant role to play in patients’ health but it is important to be well informed of potential adverse events and timing thereof to help staff and patients ensure treatment is administered safely and efficiently.