What are the risks associated with intravenous iron therapy?

Risks of Intravenous Iron

Intravenous iron carries two main categories of risk: increased infection (approximately 16% relative increase) and acute infusion reactions (occurring in ~4% of patients), with true anaphylaxis being very rare but potentially life-threatening. 1

Infection Risk

The most clinically significant risk is an increased rate of new infections, with a risk ratio of 1.16 (95% CI 1.03-1.29), translating to 16 additional infections per 1,000 treated patients. 1 This represents moderate-quality evidence from a meta-analysis of 154 randomized trials including 32,762 participants. 1

Mechanism and Clinical Implications

• IV iron increases circulating non-transferrin-bound iron, which serves as a substrate for pathogen growth and replication. 2
• This disrupts "nutritional immunity"—the body's natural defense mechanism of withholding free iron during infections to limit bacterial proliferation. 2, 3
• Common nosocomial organisms like Staphylococcus aureus and S. epidermidis possess iron-acquisition systems; exogenous iron can convert benign colonization into virulent infection. 2, 3

Absolute Contraindication

Do not administer IV iron during active severe infection, particularly soft tissue infections or sepsis—defer until infection is completely resolved. 2, 3, 4 If urgent anemia correction is needed during active infection, red blood cell transfusion is the preferred alternative. 3

Acute Infusion Reactions

Complement Activation-Related Pseudo-Allergy (CARPA)

The vast majority of reactions to IV iron are complement activation-related pseudo-allergy (infusion reactions), not true IgE-mediated anaphylaxis, and should be treated as such. 1 These occur in approximately 4.3% of patients. 4

• Symptoms include hypotension, shortness of breath, chills, flushing, nausea, vomiting, chest pain, and dizziness. 4, 5
• Iron dextran (especially high-molecular-weight formulations) carries the highest risk compared to non-dextran preparations like ferric gluconate, iron sucrose, or ferric carboxymaltose. 4, 6

True Anaphylaxis

True anaphylaxis is very rare but potentially life-threatening. 1, 4 Iron dextran carries an FDA boxed warning regarding anaphylaxis risk and requires a mandatory test dose before full administration. 4, 5

Risk Factors for Hypersensitivity

• Previous reaction to iron infusion (highest risk). 6
• Fast infusion rate. 6
• Multiple drug allergies. 6
• Severe atopy. 6
• Possibly systemic inflammatory diseases. 6

Formulation-Specific Risks

• Iron dextran: Highest anaphylactoid risk; requires test dose; FDA boxed warning. 4, 5
• Ferric carboxymaltose: Unique risk of hypophosphatemia requiring phosphate monitoring. 4
• Non-dextran preparations (ferric gluconate, iron sucrose, ferric derisomaltose): Lower hypersensitivity risk. 4, 7

Cardiovascular Complications

Rare but serious cardiovascular events can occur in the context of hypersensitivity reactions, including: 5

• Shock and severe hypotension. 5
• Acute myocardial ischemia with or without myocardial infarction. 5
• In-stent thrombosis. 5
• Fetal bradycardia in pregnant women (particularly second and third trimesters). 5

Pregnancy-Specific Risks

Early pregnancy is a contraindication to iron infusions. 6 Severe hypersensitivity reactions including circulatory failure may have serious fetal consequences such as bradycardia, especially during the second and third trimesters. 5

Mandatory Safety Precautions

Before Administration

• Screen for active infection (absolute contraindication). 2, 4
• Obtain history of prior reactions to parenteral iron. 4
• Ensure resuscitation equipment and emergency medications are immediately available. 4, 6

During Administration

• Monitor vital signs continuously. 4
• Observe for signs of hypersensitivity. 4
• Avoid rapid infusion rates. 6

Post-Administration

• Observe for at least 60 minutes after initial dose. 4
• Monitor phosphate levels when using ferric carboxymaltose. 4
• Monitor transferrin saturation and ferritin to avoid iron overload. 4

Common Pitfalls to Avoid

• Do not confuse CARPA reactions with true anaphylaxis—most reactions are complement-mediated and do not require epinephrine as first-line treatment. 1
• Do not use IV iron in patients with active infection—the infection risk outweighs anemia treatment benefits. 2, 3
• Do not assume all IV iron formulations have identical safety profiles—iron dextran has significantly higher hypersensitivity risk. 4, 6
• Do not underdose—patients often receive less iron than needed, leading to persistent anemia and need for repeat infusions. 8