What are the risks of intravenous iron therapy?

Risks of Intravenous Iron Therapy

Intravenous iron increases the risk of infection by 16% compared to oral iron or no iron, and this risk must be weighed against the benefits of treating anemia, particularly in patients with active infections or high infection burden. 1

Primary Risk: Infection

• IV iron administration is associated with a 16% increased relative risk of infection (RR 1.16; 95% CI 1.03-1.29) based on a meta-analysis of 154 randomized trials including 32,762 participants. 1

• In absolute terms, this translates to 16 additional infections per 1,000 patients treated (95% CI: 3-29 additional cases). 1, 2

• The evidence quality is moderate according to GRADE criteria, meaning this finding is reasonably reliable. 1

Mechanism of Infection Risk

• IV iron increases circulating non-transferrin-bound iron, which is directly available for pathogen growth since nearly all human pathogens require iron for replication. 1, 2, 3

• This disrupts "nutritional immunity"—the body's natural defense mechanism of sequestering free iron during infections to starve bacteria. 2

• Common nosocomial pathogens like Staphylococcus aureus and Staphylococcus epidermidis have evolved iron acquisition mechanisms and can convert from benign colonizers to virulent pathogens when exogenous iron is available. 1, 2

High-Risk Populations for Infection

• Inflammatory bowel disease patients show the highest infection risk (RR 1.73; 95% CI 1.11-2.71). 1

• Patients with active soft tissue infections should have IV iron deferred until infection is completely resolved. 2

• Settings with high endemic infection burdens may see neither effectiveness nor safety with IV iron supplementation. 1, 2

• The lung is the most common anatomical site for infections following IV iron. 1

Hypersensitivity and Anaphylactic Reactions

• Anaphylactic-type reactions, including fatalities, can occur with IV iron products, particularly iron dextran. 4

• The FDA mandates that resuscitation equipment and trained personnel must be immediately available during all IV iron administrations. 4

• A test dose of 0.5 mL is required before the first therapeutic dose of iron dextran, with at least one hour of observation, though fatal reactions have occurred even when test doses were tolerated. 4

Risk Factors for Hypersensitivity

• Previous reaction to IV iron infusion is the strongest predictor. 5, 6

• Fast infusion rates significantly increase risk. 5, 6

• Multiple drug allergies, severe atopy, asthma, and urticaria elevate risk. 5, 6

• Concomitant ACE inhibitor use may increase reaction risk. 4

• Early pregnancy is an absolute contraindication to IV iron infusions. 5

Mechanism of Hypersensitivity

• Most reactions represent complement activation-related pseudo-allergy (CARPA) triggered by iron nanoparticles rather than true IgE-mediated anaphylaxis. 5, 7

• Different formulations have varying capacities to saturate transferrin: iron gluconate > iron sucrose > iron dextran for direct transferrin saturation. 3

• Head-to-head trials show no clinically significant differences in serious hypersensitivity rates (0.2%-1.7%) among modern IV iron formulations, contradicting the "dextran vs non-dextran" classification. 8

Delayed Reactions

• Large IV doses produce delayed reactions in 24-48 hours, characterized by arthralgia, backache, chills, fever, headache, malaise, myalgia, nausea, and vomiting. 4

• Symptoms typically subside within 3-4 days, though the etiology remains unknown. 4

• Maximum daily dose should not exceed 2 mL undiluted iron dextran to minimize delayed reactions. 4

Acute Organ Injury

• IV iron sucrose produces acute oxidative stress with increased plasma malondialdehyde (lipid peroxidation marker) occurring earlier than peak free iron levels, suggesting direct oxidative effects. 3

• Endothelial dysfunction occurs acutely, peaking before serum free iron levels rise. 3

• Acute kidney injury manifests as increased urinary albumin, N-acetyl-beta-glucosaminidase (tubular enzyme), and monocyte chemoattractant protein-1 (inflammatory cytokine). 3

Contraindications and High-Risk Conditions

• Acute phase of infectious kidney disease is a contraindication. 4

• Serious liver impairment requires extreme caution. 4

• Pre-existing cardiovascular disease may be exacerbated by adverse reactions to IV iron. 4

• Patients with ferritin >700 ng/mL have conflicting safety data, though some hemodialysis data suggest tolerability up to this threshold. 1

Potential Carcinogenesis Risk

• Iron-carbohydrate complexes produce sarcomas at injection sites in animal models (rats, mice, rabbits) with repeated dosing. 4

• Several case reports describe tumors at human injection sites following intramuscular iron-carbohydrate injections, though the long latency period makes accurate human risk assessment impossible. 4

Clinical Context: Balancing Risks and Benefits

While IV iron increases infection risk, it also provides measurable benefits:

• Hemoglobin increases by 0.57 g/dL (95% CI 0.50-0.64) compared to oral iron or no iron. 1

• Red blood cell transfusion requirements decrease (RR 0.83; 95% CI 0.76-0.89). 1

• No impact on short-term or long-term mortality was observed. 1

Practical Risk Mitigation

• Defer IV iron until active infections are completely resolved and treated. 2

• For symptomatic anemia during active infection, consider RBC transfusion instead if anemia is severe. 2

• Use slow infusion protocols to minimize hypersensitivity reactions. 7

• Ensure meticulous observation during and for at least one hour after infusion with immediate access to resuscitation equipment. 4, 5

• The infection risk appears independent of baseline ferritin, hemoglobin, transferrin saturation, or iron formulation type. 1