Iron
Evidence Fact Sheet
Iron is an essential trace mineral and cofactor for haemoglobin, myoglobin, and respiratory-chain and DNA-synthesis enzymes. Supplements (ferrous sulfate, gluconate, fumarate, bisglycinate) are used to correct deficiency. Meta-analyses cover fatigue, restless legs, child cognition, and pregnancy; EFSA-authorized, US GRAS.
Also known as: Fe · Ferro · Ferrous sulfate · Ferrous gluconate · Ferrous fumarate · Ferric pyrophosphate · Iron bisglycinate · Heme iron polypeptide
Overview
Iron is an essential trace mineral that the body incorporates into haemoglobin (via ferrochelatase) and myoglobin for oxygen transport and storage, and uses as a cofactor for mitochondrial respiratory-chain enzymes, ribonucleotide reductase (DNA synthesis), and monoamine-synthesis enzymes. Systemic levels are governed by the hepcidin-ferroportin axis, so large single doses raise hepcidin and blunt further absorption — the rationale behind emerging alternate-day single-morning regimens. Common supplemental forms include ferrous sulfate, ferrous gluconate, ferrous fumarate, iron bisglycinate, and heme iron polypeptide. Research doses range from the adult RDA (8-27 mg/day depending on sex and pregnancy) up to therapeutic repletion of roughly 30-120 mg elemental iron daily or alternate-day, with a US tolerable upper intake level of 45 mg/day from all sources. Regulatory status: iron salts are FDA-affirmed GRAS, supplements carry the mandated pediatric-overdose warning under 21 CFR 101.17(e), iron holds multiple EFSA-authorized Article 13 health claims, and it is authorized under ANVISA IN 28/2018 in Brazil and as a nutrient fortifier under GB 14880-2012 in China.
Mechanism of Action
Haemoglobin synthesis (incorporation of Fe2+ into protoporphyrin IX via ferrochelatase to form heme) · Myoglobin synthesis for muscle oxygen storage · Cofactor for cytochrome c oxidase and other respiratory chain Fe-S cluster enzymes (oxidative phosphorylation) · Cofactor for ribonucleotide reductase (DNA synthesis, cell division) · Cofactor for tyrosine hydroxylase and tryptophan hydroxylase (dopamine and serotonin synthesis) · Cofactor for myeloperoxidase and NADPH oxidase in neutrophils (innate immunity) · Hepcidin-ferroportin axis regulates systemic iron homeostasis; high-dose iron raises hepcidin and blunts subsequent absorption
Body systems: Blood & Hematopoiesis · Cardiovascular · IMMUNITY · Neurological & Cognitive · MUSCULOSKELETAL
Evidence-Based Benefits
Each benefit below is anchored to a specific PubMed-indexed study. Effect sizes, sample sizes, and p-values are reported as published; no values are inferred. Honest negatives and null results are kept alongside the positive findings, and disease-research populations are described as such — Iron is not characterized as a treatment for any disease.
Fatigue in Iron Deficiency Without Anaemia
Meta-analysis supported- 0.33pooled effect · 6 RCTs
- 95% CI 0.17, 0.48P<0.0001
- 0.10cross-sectional · NS
In a meta-analysis of six randomized controlled trials, iron supplementation produced a significant reduction in fatigue among people with iron deficiency but no anaemia (low ferritin, normal haemoglobin). Notably, the same paper found that the cross-sectional association between iron deficiency without anaemia and fatigue in the general population was not statistically significant — so the benefit was seen in the treatment trials, not in the observational correlation.
Reported effect: RCT pooled effect size 0.33 (95% CI 0.17, 0.48; I²=0.0%; P<0.0001); cross-sectional pooled effect size 0.10 (95% CI -0.11, 0.31; I²=57.4%; P=0.362, not significant)
“In the meta-analysis of the six RCT, we identified a significant therapeutic effect of Fe in fatigue patients with IDNA (pooled effect size 0·33; 95 % CI 0·17, 0·48; I 2=0·0 %; P<0·0001). In the meta-analysis of the six cross-sectional studies, the association between IDNA and fatigue was not significant (pooled effect size 0·10; 95 % CI -0·11, 0·31; I 2=57·4 %; P=0·362).”
Source: PMID 28625177 · Yokoi 2017 · Br J Nutr
Intravenous Iron in Non-Anaemic Iron Deficiency (Physical Function and Fatigue)
Meta-analysis supported- MD 1.77 mL/kg/minpeak VO2 · 95% CI 0.57–2.97
- SMD 0.30fatigue improvement
An abridged Cochrane review pooling 21 randomized controlled trials (3,514 participants) found that intravenous iron improved physical function (higher mean peak oxygen consumption) and reduced fatigue versus comparator in non-anaemic iron-deficient adults. Quality of life showed no overall difference, and the authors flagged that most outcomes rested on low-certainty evidence.
Reported effect: Peak oxygen consumption mean difference 1.77 mL/kg/min (95% CI 0.57 to 2.97); fatigue standardized mean difference 0.30 (95% CI -0.52 to -0.09); quality of life MD 0.15 (95% CI -0.01 to 0.31, no difference)
“mean peak oxygen consumption (mean difference [MD] 1.77 mL/kg/min, 95% CI 0.57 to 2.97); ... fatigue (standardized MD 0.30, 95% CI -0.52 to -0.09); ... quality of life (MD 0.15, 95% CI -0.01 to 0.31).”
Source: PMID 36321348 · Dugan 2022 · J Cachexia Sarcopenia Muscle
Restless Legs Syndrome
Meta-analysis supported- −3.55IRLSS · 95% CI −5.41,−1.68
- RR 2.16improvement · 95% CI 1.56–2.98
A systematic review and meta-analysis of ten randomized controlled trials found that iron supplementation significantly lowered restless legs syndrome severity (International RLS Study Group rating scale) and more than doubled the proportion of patients reporting symptomatic improvement compared with no iron.
Reported effect: IRLSS decreased by -3.55 points (95% CI -5.41 to -1.68); relative risk of IRLSS improvement 2.16 (95% CI 1.56-2.98)
“Iron therapy was associated with a significant decrease of the IRLSS of -3.55 [95% CI (-5.41) - (-1.68)] ... an increase in the percentage of patients with improvement of the IRLSS score, RR of 2.16 [95% CI 1.56-2.98].”
Source: PMID 30798983 · Avni 2019 · Eur J Intern Med
Cognitive Development in School-Age Children
Meta-analysis supported- SMD 0.46intelligence · 95% CI 0.19,0.73
- SMD 0.79anemic subgroup · IQ
- SMD 0.06school achievement · NS
A systematic review and meta-analysis of randomized trials in school-age children found that iron supplementation significantly improved intelligence, attention/concentration, and memory, with the largest intelligence gains in children who were anemic at baseline (SMD 0.79). Honest limit: there was no significant effect on actual school achievement.
Reported effect: Intelligence SMD 0.46 (95% CI 0.19, 0.73; P<0.001); attention/concentration SMD 0.44 (95% CI 0.07, 0.81; P=0.02); memory SMD 0.44 (95% CI 0.21, 0.67; P<0.001); anemic-at-baseline intelligence SMD 0.79 (95% CI 0.41, 1.16; P=0.001); school achievement SMD 0.06 (95% CI -0.15, 0.26; P=0.56, not significant)
“iron supplementation significantly improved intelligence (SMD 0.46, 95%CI: 0.19, 0.73, P<0.001), attention and concentration (SMD 0.44, 95%CI: 0.07, 0.81, P = 0.02) and memory (SMD 0.44, 95%CI: 0.21, 0.67, P <0.001) ... no significant effect of iron supplementation on school achievement (SMD 0.06, 95%CI: -0.15, 0.26, P = 0.56) ... anemic at baseline had better outcomes of intelligence (SMD 0.79, 95%CI: 0.41, 1.16, P = 0.001).”
Source: PMID 37368919 · Gutema 2023 · PLoS One
Prophylactic Oral Iron in Non-Anaemic Pregnancy
Meta-analysis supported- RR 0.50anaemia risk · 95% CI 0.34–0.74
- MD 6.95 g/lhaemoglobin · 95% CI 4.81–9.09
A systematic review and meta-analysis of 23 studies (4,492 non-anaemic pregnant women) found that prophylactic oral iron raised haemoglobin and ferritin and halved the risk of developing anaemia, with a number needed to treat of 10. It found no difference in birth weight, preterm birth, or caesarean rate, and the authors stressed that reporting on harms was inconsistent with insufficient evidence to link iron to any negative outcome.
Reported effect: Haemoglobin mean difference 6.95 g/l (95% CI 4.81-9.09); ferritin mean difference 12.22 ng/ml (95% CI 6.92-17.52); anaemia relative risk 0.50 (95% CI 0.34-0.74), NNT 10; no difference in birth weight, preterm birth, or caesarean section
“higher haemoglobin [mean difference = 6.95 g/l, 95% CI: 4.81-9.09] ... ferritin [mean difference = 12.22 ng/ml, 95% CI: 6.92-17.52] ... lower risk of anaemia (relative risk = 0.50, 95% CI: 0.34-0.74) ... no difference in birth weight, preterm birth, and rate of caesarean section.”
Source: PMID 39834271 · Watt 2025 · Family Practice
Dosage (research context · not a recommendation)
Adult RDA (US): 8 mg/day men and post-menopausal women, 18 mg/day pre-menopausal women, 27 mg/day pregnancy. Tolerable Upper Intake Level (UL, US IOM): 45 mg/day elemental iron from all sources in adults (gastrointestinal tolerance limit). Therapeutic supplementation for iron deficiency: 30-120 mg elemental iron daily or alternate-day; emerging evidence (Stoffel 2017) supports alternate-day single morning dosing to maximize fractional absorption. Pregnancy: WHO recommends 30-60 mg elemental iron daily where anaemia prevalence is high.
Regulatory Status · 4 Markets
- US · FDA
- No FDA-authorized Significant Scientific Agreement (SSA) health claim exists for iron under 21 CFR Part 101 Subpart E (the SSA program covers only twelve specified nutrient-disease relationships and iron is not among them). Iron supplements are marketed under DSHEA (Dietary Supplement Health and Education Act of 1994) using structure/function claims (e.g., "supports red blood cell formation", "helps maintain healthy oxygen transport") accompanied by the DSHEA disclaimer "This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease" per 21 CFR 101.93. Solid-oral-dosage-form dietary supplements containing iron or iron salts must carry the warning statement required by 21 CFR 101.17(e): "WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately." The 1997 unit-dose packaging requirement for iron supplements containing 30 mg or more per dose was vacated by the court in Nutritional Health Alliance v. FDA (3d Cir. 2003) and the corresponding regulation was removed by FDA in 68 FR 59714 (October 17, 2003); only the warning-statement portion of 21 CFR 101.17(e) remains in force. Iron salts including ferrous sulfate are FDA-affirmed GRAS direct food substances for nutrient use (21 CFR 184.1315; elemental iron 21 CFR 184.1375).
- EU · EFSA
- Iron has multiple EU-authorized health claims under Commission Regulation (EU) No 432/2012 establishing the Union list of permitted health claims pursuant to Regulation (EC) No 1924/2006 Article 13(1). All authorized iron claims share a single condition of use: "The claim may be used only for food which is at least a source of iron as referred to in the claim SOURCE OF [NAME OF VITAMIN/S] AND/OR [NAME OF MINERAL/S] as listed in the Annex to Regulation (EC) No 1924/2006." This corresponds to at least 15% of the Nutrient Reference Value supplied by 100 g/100 mL/per portion. Authorized claim functions: cognitive function, energy-yielding metabolism, formation of red blood cells and haemoglobin, oxygen transport in the body, function of the immune system, reduction of tiredness and fatigue, and role in the process of cell division.
- CN · China
- Approved in China as an SAMR health-food nutrient raw material and as a nutrient fortifier under GB 14880-2012, with existing health-food registrations for the 'improvement of nutritional anaemia' function as precedent. Nutrient-supplement filing supports 'iron supplementation'; specific SAMR health-function claims require the registration pathway.
- BR · ANVISA
- Iron (ferro) is listed as an authorized constituent of dietary supplements (suplementos alimentares) in Brazil under ANVISA Instrucao Normativa IN 28/2018 Anexos I, III and IV (minimum and maximum daily limits for the population groups defined therein), with complementary labeling rules in RDC 243/2018 and RDC 269/2005 (IDR reference values). Authorized functional claims for iron appear in IN 28/2018 Anexo V (lista de alegacoes autorizadas para uso na rotulagem dos suplementos alimentares). ANVISA also operates the Programa Nacional de Suplementacao de Ferro (PNSF, Ministerio da Saude) for public-health iron supplementation of children and pregnant women — that program is a public health intervention, not a labeling claim, and is therefore not represented as a labeled functional claim.
Authorized Claims
ANVISA — “O ferro auxilia na formação das células vermelhas do sangue.” (ANVISA Instrução Normativa IN 28/2018 Anexo V)
Safety
Common adverse effects: nausea, epigastric pain, constipation, dark stools (dose-dependent). High single doses raise serum hepcidin and reduce absorption of subsequent doses, supporting alternate-day regimens for non-pregnant adults. Iron overload risk in hereditary haemochromatosis (HFE C282Y homozygotes), transfusion-dependent thalassemia, and other iron-loading disorders — supplementation contraindicated without medical supervision. Pediatric accidental overdose is a leading cause of fatal poisoning in children under 6; keep iron-containing supplements out of reach of children (FDA-mandated warning per 21 CFR 101.17(e)). Iron reduces absorption of levothyroxine, tetracyclines, fluoroquinolones, bisphosphonates, and levodopa — separate by at least 2-4 hours. Calcium, polyphenols (tea, coffee), and phytates inhibit non-heme iron absorption; ascorbic acid enhances it.
Related
Goals: athletic-performance
Lifestyles: pregnancy
References
PubMed-indexed citations anchoring the benefit findings above. Effect sizes are reported as published.
- PMID 28625177 · Yokoi 2017 · Br J Nutr — Fatigue in Iron Deficiency Without Anaemia
- PMID 36321348 · Dugan 2022 · J Cachexia Sarcopenia Muscle — Intravenous Iron in Non-Anaemic Iron Deficiency (Physical Function and Fatigue)
- PMID 30798983 · Avni 2019 · Eur J Intern Med — Restless Legs Syndrome
- PMID 37368919 · Gutema 2023 · PLoS One — Cognitive Development in School-Age Children
- PMID 39834271 · Watt 2025 · Family Practice — Prophylactic Oral Iron in Non-Anaemic Pregnancy
Frequently Asked Questions
1. Does iron help fatigue even when someone is not anaemic?
In treatment trials, yes. A meta-analysis of six randomized controlled trials found a significant therapeutic effect on fatigue in people with iron deficiency without anaemia (pooled effect size 0.33; PMID 28625177). Interestingly, the same paper found the population-level cross-sectional association between iron deficiency without anaemia and fatigue was not statistically significant (effect size 0.10), so the benefit showed up when iron was actually given, not in the observational correlation. A separate Cochrane review of intravenous iron in non-anaemic iron-deficient adults also reported reduced fatigue and improved physical function (PMID 36321348). This is research-finding context, not medical advice.
2. What does the evidence show for iron in restless legs syndrome?
A systematic review and meta-analysis of ten randomized controlled trials found iron supplementation significantly reduced restless legs syndrome severity on the IRLSS scale (−3.55 points) and more than doubled the proportion of patients reporting improvement (relative risk 2.16; PMID 30798983). These are pooled research findings in studied populations, not a recommendation to self-treat.
3. Does iron improve children's cognition?
A meta-analysis of randomized trials in school-age children found iron supplementation significantly improved intelligence (SMD 0.46), attention/concentration, and memory, with the largest intelligence effect in children anemic at baseline (SMD 0.79; PMID 37368919). An honest caveat from the same analysis: there was no significant effect on actual school achievement (SMD 0.06). This describes research findings, not individual guidance.
4. Is iron in pregnancy supported by evidence, and what about safety?
A meta-analysis of 23 studies in non-anaemic pregnant women found prophylactic oral iron raised haemoglobin and halved the risk of developing anaemia (relative risk 0.50, number needed to treat 10), with no difference in birth weight, preterm birth, or caesarean rate (PMID 39834271). On safety generally, the card notes iron supplements carry a mandated US warning because accidental overdose is a leading cause of fatal poisoning in children under 6, and supplementation is contraindicated without supervision in iron-loading disorders such as hereditary haemochromatosis. This is evidence reporting, not clinical or dosing guidance.
Last evidence review: 2026-06-04