Risks of Intravenous Iron Transfusion
Intravenous iron carries a 4.3% risk of infusion-related adverse events, with acute hypersensitivity reactions being the most concerning but rare complication, while infection risk remains controversial and formulation-dependent differences in safety profiles exist. 1
Acute Infusion Reactions
Hypersensitivity Reactions
- All forms of IV iron may cause acute adverse events including anaphylactoid reactions, hypotension, shortness of breath, and chills, though true anaphylaxis occurs in fewer than 1 in 200,000 administrations 1
- The primary mechanism is complement activation-related pseudo-allergy (CARPA), not IgE-mediated anaphylaxis, caused by labile free iron released from iron carbohydrate nanoparticles 2, 3
- Hypersensitivity reactions occur in 2.1% to 8.7% of administrations depending on the formulation used 4
Formulation-Specific Risk Differences
- Iron dextran (especially high-molecular-weight) causes more frequent and severe anaphylactoid reactions compared to non-dextran formulations like ferric gluconate or iron sucrose 1
- Ferric carboxymaltose demonstrates a 75% lower risk of hypersensitivity reactions compared to iron isomaltoside-1000 (2.1% vs 8.7%) 4
- Ferric derisomaltose shows significantly lower incidence of serious/severe hypersensitivity reactions (0.14%) compared to ferric carboxymaltose (1.08%) 5
Respiratory Manifestations
- Respiratory symptoms include shortness of breath, transient cough, bronchospasm, and stridor, typically occurring as part of CARPA rather than isolated pulmonary disease 2
- Moderate reactions present with transient cough and dyspnea, while severe reactions include stridor, bronchospasm, and angioedema 2
- Patients with severe asthma, eczema, mastocytosis, or prior IV iron reactions face higher risk for respiratory complications 2
Infection Risk
Evidence Summary
- A 2021 meta-analysis of randomized controlled trials found a 26% increased risk of infection with IV iron (RR 1.26,95% CI 1.09-1.44) 1
- However, randomized trials in hemodialysis patients have not consistently demonstrated increased infection rates, though observational studies show associations between ferritin levels >4500 ng/ml and infections 1
- The biological plausibility exists as iron is required for pathogen growth and IV iron increases non-transferrin-bound iron, which impairs T-cell and neutrophil function 1
Clinical Implications
- IV iron should be used with caution or avoided entirely in patients with active infection, as animal studies suggest harm in the presence of severe infection 1
- No increased infection risk has been observed in cancer patients receiving IV iron in controlled trials 1
Other Significant Risks
Hypophosphatemia
- Treatment-emergent hypophosphatemia occurs in 2.1% of adult patients and 13% of pediatric patients receiving ferric carboxymaltose 6
- Hypophosphatemic osteomalacia has been reported in post-marketing surveillance 6
Cardiovascular Effects
- Hypotension occurs during infusions, particularly with rapid administration 1
- Tachycardia and chest discomfort have been reported 6
- Concomitant administration with cardiotoxic chemotherapy should be avoided 1
Injection Site Complications
- Injection site reactions occur in 3-8% of administrations 6
- Extravasation occurs in 0.2-2% of cases 6
- Injection site discoloration can occur in 1.4% of patients and may persist for weeks to months 7, 6
Pregnancy-Specific Risks
- Severe hypersensitivity reactions may cause fetal bradycardia, especially in the second and third trimesters 6
- Early pregnancy is considered a contraindication to iron infusions 3
Risk Factors for Adverse Reactions
Patient-Specific Factors
- Previous reaction to IV iron infusion 3
- Multiple drug allergies 3
- Severe atopy 3
- Systemic inflammatory diseases 3
- Presence of comorbidities increases hypersensitivity risk by a factor of 3.6 regardless of iron formulation 4
Administration-Related Factors
- Fast infusion rates increase risk of adverse reactions 1, 3
- The form, dose, and rate of infusion all influence adverse event risk 1
Safety Monitoring Requirements
Pre-Infusion Assessment
- IV iron should only be administered by staff trained to evaluate and manage anaphylactic reactions with resuscitation facilities immediately available 1
- Pre-infusion assessment should evaluate infusion reaction risks 1
During and Post-Infusion
- Patients require close observation for hypersensitivity symptoms for at least 30 minutes following each administration 1
- Vital signs monitoring is essential, particularly during the first 10 minutes 2
- Proper IV line placement must be ensured to prevent extravasation 2, 7
Rechallenge Considerations
- Re-administration after a previous adverse reaction is plausible in over 80% of cases when the initial reaction was mild to moderate 8
- Rechallenge depends on the nature and severity of the prior reaction, with consideration of alternative formulations 8
- Rechallenge after severe hypersensitivity or anaphylaxis with the same product has not been reported in safety studies 8
Long-Term Safety Concerns
Oxidative Stress and Inflammation
- IV iron induces oxidative stress and generates pro-inflammatory substances in animal models, potentially related to free iron toxicity 1
- The long-term clinical significance of these observations in patients remains uncertain 1
Vascular Access
- Frequent IV iron infusion may jeopardize future vascular access options, particularly relevant in hemodialysis patients 1