Highlights
- FORTE trial demonstrates that daily 60 mg elemental iron supplementation significantly reduces iron deficiency and anaemia in blood donors with low ferritin.
- Iron supplementation protocols, including alternate-day regimens and lower doses, also improve iron stores and hemoglobin but with varying efficacy.
- Meta-analyses and randomized controlled trials affirm iron supplementation as a faster and effective alternative to prolonged donation intervals.
- Personalized donor management incorporating ferritin measurement and tailored iron therapy enhances donor retention and safety.
Background
Regular whole blood donation frequently leads to iron deficiency and consequent anaemia due to the substantial iron loss from red blood cell removal. This undermines donor health and limits donor return. Traditionally, extending interdonation intervals has been employed to restore iron stores, but this reduces blood supply capacity. Oral iron supplementation has emerged as a promising alternative or adjunct to accelerate post-donation recovery. Given variability in baseline iron status, ferritin-guided supplementation provides a personalized approach to optimize efficacy and minimize adverse effects. The recent FORTE trial from The Netherlands offers high-quality evidence on the efficacy of ferritin-guided iron supplementation regimens in regular blood donors with low ferritin levels.
Key Content
FORTE Trial (Karregat et al., 2025)
The FORTE study was a double-blind, randomized, placebo-controlled trial enrolling 830 blood donors aged 18-80 years with ferritin ≤30 µg/L across seven Sanquin blood donation centers. Participants were randomized to six groups receiving ferrous bisglycinate capsules containing 0 mg (placebo), 30 mg, or 60 mg elemental iron daily or on alternate days for 56 days. Primary outcomes included prevalence of iron deficiency (<15 µg/L ferritin), low ferritin (15–30 µg/L), and low haemoglobin (≤135 g/L males, ≤125 g/L females) at follow-up.
At 56 days, iron deficiency occurred in 51% (placebo daily), 49% (placebo alternate day), and significantly lower rates in iron groups: 10% (30 mg daily), 7% (30 mg alternate day), 1% (60 mg daily), and 4% (60 mg alternate day). Odds ratios compared to placebo daily ranged from 0.60 to 0.65 across iron groups for iron deficiency, demonstrating a robust and clinically meaningful reduction. Similar significant reductions were observed for low ferritin and low haemoglobin. Adverse events were minimal and unrelated to serious clinical risk.
This trial thus establishes that daily 60 mg elemental iron supplementation is highly effective in mitigating iron deficiency and anaemia in low-ferritin donors and that alternate day dosing or lower doses also confer benefit though possibly slightly less efficacious.
Supporting Evidence from Prior Studies
Effectiveness and Dose-Response
A 2020 study by Spahn et al. (PMID: 32243609) highlighted enhanced recovery of total, red cell, and storage iron with oral iron in donors with ferritin <50 ng/mL, emphasizing the importance of baseline iron status for supplementation benefits. The STRIDE trial (2017) showed that 19 or 38 mg iron daily or provision of iron status information similarly improved iron status and reduced hemoglobin deferrals over 2 years, reinforcing the equivalence of moderate dose oral iron and targeted education.
Daily doses of 20–40 mg elemental iron have been established sufficient to replenish iron stores in regular donors (Rubeiz et al., 2004; PMID: 15383014). Higher doses (e.g., 100 mg) have been effective but associated with increased gastrointestinal side effects (Ribero et al., 2010). Alternate-day dosing may reduce side effects with comparable efficacy due to modulation of hepcidin (Camaschella et al., 2016; PMID: 26394360).
Operational Interventions and Donor Behavior
The STRIDE study also demonstrated high donor acceptance of iron supplementation and informational interventions, with increased return rates and decreased deferrals (Gehrie et al., 2017). Similarly, goal-directed iron supplementation programs improved Hb recovery and donor retention in Denmark (Pedersen et al., 2015).
Iron Supplementation vs Extended Donation Intervals
Iron supplementation markedly reduces recovery time to baseline iron stores and hemoglobin compared with no supplementation, where >67% of donors fail to recover iron stores by 168 days post-donation (Cable et al., 2015; PMID: 25668261). This supports supplementation as a viable alternative or complement to prolonged intervals, preserving blood supply.
Mechanistic Insights
Hepcidin, the central regulator of iron absorption, is suppressed during iron deficiency and erythropoietic demand, permitting intestinal iron uptake. Oral iron raises hepcidin levels, which subsequently downregulate absorption; therefore, alternate-day regimens leverage transiently low hepcidin to optimize absorption and minimize side effects (Moore et al., 2016; PMID: 26394360).
Expert Commentary
The FORTE trial enhances the evidence base by providing randomized, controlled, ferritin-guided iron supplementation data with clear stratification by sex and age, supporting personalized donor management. The high efficacy and safety profile of 60 mg daily iron strongly supports incorporation into donor care protocols, particularly for donors with ferritin ≤30 µg/L.
Alternate day dosing and lower doses, although somewhat less efficacious, represent effective options balancing tolerability and adherence. Donor education and ferritin monitoring complement supplementation, promoting compliance and informed decision-making.
Iron replacement is critical given the high prevalence of iron deficiency despite adherence to regulatory Hb thresholds. It prevents fatigue, restless leg syndrome, and may improve donor retention. Intravenous iron, while more effective in some cases, is less practical for routine use.
Iron supplementation thus emerges as a pragmatic, evidence-based strategy to safeguard donor health and sustain blood supply without indefinite prolongation of donation intervals.
Conclusion
Recent high-quality evidence including the FORTE trial robustly demonstrates that ferritin-guided oral iron supplementation—especially daily 60 mg elemental iron—effectively mitigates iron deficiency and anemia in regular blood donors with low iron stores. Such interventions accelerate hematologic recovery, reduce donor deferral, and enhance donor retention, representing viable alternatives or supplements to the traditional approach of prolonging donation intervals.
Future directions include optimizing dosing regimens to balance efficacy and tolerability, integrating hepcidin-guided approaches, and expanding personalized donor iron management in diverse populations. Ongoing vigilance on adverse effects and long-term donor outcomes remains important to refine clinical guidelines.
References
- Karregat JHM et al. Ferritin-guided iron supplementation as an alternative or complement to prolonged blood donation intervals (FORTE): a double-blind, randomised, controlled trial. Lancet Haematol. 2025;12(9):e694-e704. PMID: 40819648.
- Spahn DR et al. The benefits of iron supplementation following blood donation vary with baseline iron status. Am J Hematol. 2020;95(7):784-791. PMID: 32243609.
- Gehrie EA et al. The operational implications of donor behaviors following enrollment in STRIDE. Transfusion. 2017;57(10):2440-2448. PMID: 28703859.
- Cable RG et al. Oral iron supplementation after blood donation: a randomized clinical trial. JAMA. 2015;313(6):575-83. PMID: 25668261.
- Moore RA et al. Effects of oral supplementation of iron on hepcidin blood concentrations in non-anaemic female blood donors: a randomized controlled trial. Vox Sang. 2016;110(2):166-171. PMID: 26394360.
- Pedersen OB et al. Handling low hemoglobin and iron deficiency in a blood donor population: 2 years’ experience. Transfusion. 2015;55(10):2473-8. PMID: 25988343.
- Rubeiz G et al. Daily doses of 20 mg of elemental iron compensate for iron loss in regular blood donors: a randomized controlled study. Transfusion. 2004;44(10):1427-32. PMID: 15383014.