Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis

JAMA Netw Open. 2021 Nov 1;4(11):e2133935. doi: 10.1001/jamanetworkopen.2021.33935.


Importance: Intravenous iron is recommended by many clinical guidelines based largely on its effectiveness in reducing anemia. However, the association with important safety outcomes, such as infection, remains uncertain.

Objective: To examine the risk of infection associated with intravenous iron compared with oral iron or no iron.

Data sources: Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials (RCTs) from 1966 to January 31, 2021. Ongoing trials were sought from ClinicalTrials.gov, CENTRAL, and the World Health Organization International Clinical Trials Search Registry Platform.

Study selection: Pairs of reviewers identified RCTs that compared intravenous iron with oral iron or no iron across all patient populations, excluding healthy volunteers. Nonrandomized studies published since January 1, 2007, were also included. A total of 312 full-text articles were assessed for eligibility.

Data extraction and synthesis: Data extraction and risk of bias assessments were performed according to the Preferred Reporting Items of Systematic Reviews and Meta-analyses (PRISMA) and Cochrane recommendations, and the quality of evidence was assessed using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. Two reviewers extracted data independently. A random-effects model was used to synthesize data from RCTs. A narrative synthesis was performed to characterize the reporting of infection.

Main outcomes and measures: The primary outcome was risk of infection. Secondary outcomes included mortality, hospital length of stay, and changes in hemoglobin and red blood cell transfusion requirements. Measures of association were reported as risk ratios (RRs) or mean differences.

Results: A total of 154 RCTs (32 920 participants) were included in the main analysis. Intravenous iron was associated with an increased risk of infection when compared with oral iron or no iron (RR, 1.17; 95% CI, 1.04-1.31; I2 = 37%; moderate certainty of evidence). Intravenous iron also was associated with an increase in hemoglobin (mean difference, 0.57 g/dL; 95% CI, 0.50-0.64 g/dL; I2 = 94%) and a reduction in the risk of requiring a red blood cell transfusion (RR, 0.93; 95% CI, 0.76-0.89; I2 = 15%) when compared with oral iron or no iron. There was no evidence of an effect on mortality or hospital length of stay.

Conclusions and relevance: In this large systematic review and meta-analysis, intravenous iron was associated with an increased risk of infection. Well-designed studies, using standardized definitions of infection, are required to understand the balance between this risk and the potential benefits.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Administration, Intravenous
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anemia, Iron-Deficiency / drug therapy*
  • Anemia, Iron-Deficiency / microbiology
  • Blood Transfusion / statistics & numerical data
  • Female
  • Hemoglobins / analysis
  • Humans
  • Infections / chemically induced
  • Infections / epidemiology*
  • Iron / administration & dosage
  • Iron / adverse effects*
  • Length of Stay / statistics & numerical data
  • Male
  • Middle Aged
  • Non-Randomized Controlled Trials as Topic
  • Pregnancy
  • Randomized Controlled Trials as Topic
  • Risk Factors
  • Young Adult


  • Hemoglobins
  • Iron