A comparative analysis of heme vs non-heme iron administration: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background and purpose: Bioavailability studies and observational evidence suggest that heme iron (HI) may have greater impact on iron status indicators compared with non-heme iron (NHI). This systematic review and meta-analysis aimed to review the current evidence on the effect of the administration of HI compared with NHI for improving iron status in non-hospitalized population groups. Methods: We searched Pubmed, CENTRAL, Scopus, Web of Science, and LILACS from inception to July 2024. There was no language restriction or exclusion based on age or iron status. Only randomized controlled trials comparing HI with NHI were considered. A random-effects meta-analysis was performed to compare the effect of treatments for iron status indicators and total side effects (including gastrointestinal side effects). We measured the certainty of the evidence (CoE) using GRADE assessment. Results: After screening 3097 articles, 13 studies were included. Most of the interventions used HI in low doses combined with NHI. The meta-analysis showed higher hemoglobin increases in children with anemia or low iron stores receiving HI (MD 1.06 g/dL; 95% CI: 0.34; 1.78; CoE: very low). No statistically significant difference between interventions were found for any iron status indicator in the other population subgroups (CoE: very low). Participants receiving HI had a 38% relative risk reduction of total side effects compared to NHI (RR 0.62; 95% CI 0.40; 0.96; CoE: very low). Conclusion: The current evidence comparing HI with NHI is very limited, preliminary findings suggest that interventions using HI may result in fewer side effects and may be superior in children with iron deficiency or anemia. However, given the very low certainty of the evidence, these results need further investigation through high-quality clinical trials. Protocol registration: CRD42023483157.