Do Iron Supplements Work? Conclusions From 24 Research Papers

Introduction

The question of iron supplementation is so important that I am going to answer the question here in the introduction and then justify/elaborate on the answer in the rest of the article.

Iron supplementation is not an amateur sport. Unlike other supplements or vitamins, the body does not regulate iron homeostasis well. This means that the body has difficulty eliminating excess iron from the body. Excess iron can lead to damage to a range of organs including the liver, skin and pancreas. Excess iron may also be related to cancer, heart disease and Alzheimer’s Disease.

Simply put, taking iron supplements in the absence of iron depletion is dangerous. Iron supplements should only be taken under medical supervision and when a diagnosis of iron deficiency has been made. Iron replacement therapy is a good thing. Iron supplementation to try to game nature is a very bad idea.

What Is Iron?

Iron is the sixth most abundant element in the universe. The chemical symbol for iron is Fe which comes from the Latin word for iron, Ferrum. The atomic number for iron is 26.

Iron is not just ubiquitous in nature, it is also an essential mineral for humans. Iron is intrinsic to the oxygen carrying capacity of red blood cells. It also plays a key role in producing adenosine triphosphte (ATP) which is our main energy source.

Low levels of iron in the body can cause anemia which can present as fatigue, shortness of breath, dizziness. High levels of iron in the body is seen in a medical condition known as hemochromatosis which can cause liver dysfunction and diabetes.

Hemochromatosis can be primary i.e. an inherited genetic disorder linked to the HFE gene. I spent three months as an intern doing therapeutic blood-letting in patients with hemochromatosis where we drained off a unit of blood on a regular basis. This meant that the body had to make new blood which helped to use up the iron stores. Essentially we were overriding the lack of homeostasis of the body for iron.

Hemochromatosis can also be a secondary condition linked to excessive iron intake. This is particularly a risk if iron is taken with vitamin C as vitamin C increases the absorption of iron. As mentioned above, there may be an association between high iron stores and risks of heart disease, cancer and dementia.

Unlike many other nutrients and supplements, excess iron cannot be excreted from the body. Iron supplements should not be taken (just because some blogger says that it is good for you) without checking first with your own doctor that you actually need and can handle an iron supplement. Again think iron replacement and not iron supplementation.

Dietary sources of iron can be divided into two main categories: heme and non heme.

  • Heme iron is more readily available for absorption and can be sourced from red meat, poultry, liver and organ meats.
  • Non-heme iron is less readily available for absorption and can be sourced from peas, nuts and dark green leafy vegetables.

Some foods are fortified with iron which increases the iron content of the food. Two additional ways to increase iron absorption from food sources include taking iron with vitamin C or using iron pots for cooking.

Available forms of oral iron supplementations include:

  • ferrous fumarate
  • ferrous succinate
  • ferrous gluconate
  • ferrous lactate
  • ferrous glutamate
  • ferric ammonium citrate and
  • ferrous glycine.

Intravenous iron therapy is also available for severe anaemia where rapid replacement of iron is required. Intramuscular iron is available but is painful and so if not used commonly. Transdermal iron options are being developed but are not yet available for routine use.

There are over 2000 iron supplements available for sale on Amazon and cost in the order of $0.04 for 65 mg of iron.

Is There Any Research?

There are 84,904 scholarly publications related to iron which includes almost 5000 human clinical trials. This is a pretty good research track record. It outperforms vitamin C which has 61,000 publications and 3,000 clinical trials.

Do Iron Supplements Boost Hemoglobin formation and Treat Anemia?

The answer here is yes, sometimes. Iron supplements correct iron deficiency anaemia and can boost hemoglobin. However, iron supplementation will not really help if there is a cause of anemia other than iron deficiency e.g. B12 or folate deficiency.

Bottom Line

Iron replacement therapy can reverse anemia and boost hemoglobin in iron deficiency.

Do They Improve Muscle Function?

A total of 22 volleyball players from two Spanish First National League teams were randomized to either no treatment or iron sulphate 325mg daily for 11 weeks (1).

There was a statistically significant increase in overall strength and specific strength assessments such as power clean and clean and jerk. The authors concluded that oral iron supplementation prevents iron loss and enhances strength in female volleyball players during the competitive season.

A second study was done at the Department of Anthropology, University of Albany and looked at tissue-level iron depletion and progressive fatigue of the quadriceps during dynamic knee-extension exercise in young women (2).

A total of twenty iron-depleted but  non-anemic women  received iron or placebo for 6 weeks in a randomized, double-blind trial. The study outcome measurement involved  2-3 maximal voluntary static contractions with dynamic knee extensions to assess fatigue. The study found that iron supplementation was associated with a significant improvement in muscle fatigability.

Bottom Line

Preliminary data shows that iron supplementation can help with muscle function in athletes. Athletes have a high turnover of cells and have a higher iron requirement than the general population. These studies were short-term studies and do not show us if  iron supplementation was safe in the longterm.

Do They Treat Restless Leg Syndrome?

Restless leg syndrome is a medically recognised condition in which people feel compelled to move their legs. This is especially troublesome at night and can significantly impact on sleeping and quality of life. Low blood iron levels are associated with the restless leg syndrome. Additionally low cerebrospinal ferritin levels are seen in the restless leg syndrome (3).

There are a number of studies looking at the effect of iron supplementation on the restless leg syndrome. A study just published this year looked at 39 women with restless leg syndrome plus iron deficiency (4).

Other causes of the restless leg syndrome (edema, arthritis, venous stasis) were ruled out. The women were given iron supplementation for three months to achieve normalization of iron stores. The women were the followed for 2 and 1/2 years.

On follow-up, 15/39 women reported no symptoms of restless leg syndrome while 24/39 women continued to complain of symptoms. Approximately, one third of women responded, while two-thirds did not respond to iron therapy. Sub- analysis found that persistence of symptoms was more likely to occur in people with prolonged symptoms prior to treatment.

Another study looked at 18 participants with low ferritin and restless leg syndrome (5). Study participants received either 12 weeks of oral iron therapy or matched placebo. They found that there was a significant decrease in the severity of the restless leg syndrome as compared to a control group.

A third study gave intravenous iron to 60 participants for a period of 12 months and found that 68% of patients had a greater than 50% decrease in their restless leg syndrome symptoms score (6).

A 2012 Cochrane review looked at the effect of iron for restless leg syndrome (7). A total of 6 studies involving 192 subjects were included in the review. The review found that iron therapy was as well tolerated as placebo. However there was insufficient evidence to ascertain whether iron therapy can benefit restless leg syndrome.

Bottom Line

There are mixed results on the use of iron supplementation in restless leg syndrome. The Cochrane review is the most robust of the publications and did not confirm a role for iron in restless legs syndrome.

Do They Improve Brain Function?

This is a huge topic and below are a section of the most informative studies in a range of study populations.

Low birth weight infants were randomised to either iron or placebo from 6 weeks to 6 months of age (8). The study showed that iron supplementation does not affect IQ but does  significantly affect behavioural problems in low birth weight infants.

French investigators undertook a comprehensive assessment of the relationship between iron and cognition in 1431 pre/perimenopausal women, 962 post menopausal women and 1539 men (9). This was a cross-sectional study which assessed iron stores and cognitive function. They noted an inverse correlation between iron status and subsequent cognitive function in perimenopausal women

No association was noted in male study participants

In postmenopausal women, an inverse association was found between ferritin and phonemic fluency (ability to differentiate small units of sound).

A study in 818 older individuals studied over 3 years found that iron parameters do not show a straightforward relationship with cognitive functioning (10). The study correlated iron parameters with a battery of neuropsychological tests.

A trial in 149 women examined the relationship between iron status and cognitive function (11). The study found that women with adequate iron stores outperformed women who were iron deficient on cognitive testing.

All women were randomly assigned to receive iron supplements or placebo for 16 weeks. At the end of the study, improvements in ferritin were associated with improved cognitive functioning and higher haemoglobin improved speed of competing cognitive tasks.

A study in Rwanda found that iron biofortified beans improved cognitive performance in college students with low iron status as compard to control beans (12). There intervention took place over 18 weeks. There was a 7 fold improvement in speed and a 2 fold improvement in the specificity  of memory retrieval in the fortified arm of the study

Bottom Line

There definitely seems to be some relationship between iron and cognition. However, as one study said ‘the relationship is not straightforward’. Baseline iron status and hormonal factors seem to play a key role in the affect of iron on cognition. Correcting iron deficiency (which is the standard medical practice) would be a smart thing to do  but supercharging iron stores to try boost cognitive function would not be a good plan.

Do They Eliminate Fatigue?

Australian researchers found that 4 weeks of intravenous iron supplementation reduced perceived fatigue and mood disturbances in 14 long distance runners during 6 weeks of training as compared to placebo (13).

The athletes had no evidence of iron deficiency at baseline. The study involved injection of iron or normal saline at weeks 0, 2, 4 and 6 weeks.  The iron supplementation was not associated with any improvements in oxygen transport of athletic performance.

Swiss researchers enrolled 144 women who were non-anemic with unexplained fatigue to either daily iron of placebo for 4 weeks (14). Over half of the study participants had low ferritin at baseline.

Women who took the iron supplementation were more likely to experience improvements in their level of fatigue. Sub-group analysis showed that the benefit of iron supplementation in non-anemic women with fatigue may be restricted to women with low ferritin.

Iron supplementation was shown to improve general health and fatigue in Australian women with iron deficiency (15). Iron replacement was done using iron capsules or an iron rich diet. Both interventions improved fatigue in this study.

Danish investigators found that a single dose of intravenous iron was associated with a statistically significant reduction in fatigue related to postpartum hemorrhaghe (16). The study design compared intravenous to oral iron and found that the intravenous formulation outperformed the oral formlulation in terms of fatigue.

Finally, iron supplementation improved unexplained fatigue in 198 menstruating women who were not anaemic but who had low serum ferritin levels (17). Iron supplementation was associated with a statistically significant increase in haemoglobin and ferritin and a significant reduction in fatigue.

Bottom Line

My take on these studies is that iron reduces fatigue in people with a high demand for iron or people who are iron deficient. People who have a normal haemoglobin but a low ferritin may benefit from iron as they may be considered to have a borderline iron status.

Boost The Immune System?

A total of 24 dialysis patients were assigned to either a single parenteral dose of iron or saline (18). The impact of the injection on the immune system were assessed.

Intravenously administered iron is taken up by monocytes and leads to short-term activation of the nuclear factor kappa-B pathway. However, increased circulating ferritin levels are associated with an impaired immune response of monocytes. Following intravenous iron administration, there was a transient increase in TNF-alpha and IL-6 as compared to controls.

A study in the Czech Republic showed that iron deficiency was associated with immunodeficiency in neonatal piglets (19). Randomly interesting but totally unhelpful.

Bottom Line

There is too little published on the relationship of iron to immunity to even hazard a guess as to how iron might impact the immune system.

Does it Treat Insomnia?

There are 24 hour variations in iron and transferrin saturation levels and peak levels are noted during sleep. This has led to interest in the possibility that iron can somehow help with sleep (20).

Infants in Nepal and Zanzibar were given iron-folic acid supplementation plus/minus zinc daily for one year (21). A total of 876 children from Zanzibar and 567 children from Nepal participated in the study. The mean haemoglobin level was 9.6gm/dl in Zanzibar and 10.1 gm/dl in Nepal. Supplemental iron was consistently associated with a longer nights sleep and total sleep duration.

A Canadian study looked at 33 children with a diagnosis of an autism spectrum disorder (22). This was an 8-week open-label pilot treatment trial with oral iron supplementation. At baseline, 77% of the children had restless sleep, two thirds of pre-schoolers and one third of school age children had insufficient iron intake.

Ferritin stores increased in these children with appropriate iron replacement. There was a statistically significant improvement in sleep patterns once the iron stores had been replaced.

Bottom Line

There is some preliminary data in specialised populations suggesting that iron may help with sleep in people who are iron deficient. However, there are no studies in the general population and iron cannot be recommended for sleep (especially given the risks of iron overload).

Does Iron Treat ADHD?

There is some overlap between the symptoms of iron deficiency and the clinical presentation of ADHD. Preliminary data suggests that iron supplementation may be of benefit to children with ADHD who are iron deficient. It would not be safe to just do a therapeutic trial of iron in someone with ADHD without first establishing their iron stores (23).

Bottom Line

Iron cannot be recommended for ADHD at this time.

Iron: Are You Deficient? Ask your doctor. Don’t guess.

Iron deficiency is diagnosed when serum ferritin is less than 10mcg/L and when transferring saturation is <20%. Ferritin is a little complex as it is an acute phase reactant. This means that ferritin levels rise in the setting of acute infections or serious diseases. This can lead to a falsely high ferritin which may not reflect the true iron status of the patient. There is currently ongoing research into the use of the reticulocyte count and hepcidin (a liver peptide) for the assessment of iron stores in patients with acute illnesses.

Some people with iron deficiency may be asymptomatic while others may be symptomatic. Common symptoms include weakness, headache, impaired exercise tolerance, easy fatiguability, irritability and low mood. As you can see many of these symptoms are non-specific.

There are many possible causes of these non-specific symptoms (including day to day life itself) which is the reason that it is not safe to self-diagnose and self-mediate for iron deficiency. As mentioned above, excess iron cannot be excreted by the body and can lead to tissue damage.

Other clinical manifestations include:

  • neurodevelopmental delay
  • picca and pagophagia (ice cravings)
  • beeturia (red urine after eating beetroot) and
  • restless leg syndrome.

The causes of iron deficiency can be divided into categories as follows:

  • dietary insufficiency
  • impaired absorption
  • pregnancy
  • bleeding
  • chronic kidney injury
  • congenital disorders  eg hereditary hemorrhagic telangiectasia and renal pulmonary syndrome and
  • malignancy.

Common causes of a lack of a response to iron therapy:

  • poor compliance i.e. not taking the iron
  • reduced absorption
  • excessive blood loss compared to iron replacement therapy
  • dual diagnoses i.e. iron plus folate deficiency or iron plus vitamin B12 deficiency
  • ongoing inflammatory diseases.

Is Iron Supplementation Safe?

Iron supplementation is safe for someone who is iron deficient and needs iron replacement.

The most common side effects of iron supplementation relate to issues to do with the digestive tract. People often complain of stomach upset, nausea, heartburn, metallic taste, diarrhea, abdominal pain, itch but the number one complaint is constipation. Iron supplements can also result in dark bowel motions.

Side effects can sometimes can be managed by lowering the dose of iron or changing to an alternate formulation of iron.

As an infectious diseases physician, one of the main concerns relating to iron replacement relates to the risks of exacerbating infections (24). Iron is a growth factor for bacterial infections. In general we do not replace iron during sepsis unless absolutely necessary. Intravenous iron therapy can cause allergy and even anaphylaxis.

Iron poisoning is the leading cause of accidental poisoning in children and it is improtant to keep iron supplements (and all supplements out of the reach of small children).

Conclusion

Iron replacement therapy can help with health and wellness and should be done under medical supervision.

Random iron supplementation as an attempt to game nature and become ‘Iron John’ is not supported by the medical literature and may have dangerous consequences.

References

1. Iron supplementation prevents a decline in iron stores and enhances strength performance in elite female volleyball players during the competitive season.
Mielgo-Ayuso J, Zourdos MC, Calleja-González J, Urdampilleta A, Ostojic S.
Appl Physiol Nutr Metab. 2015 Jun;40(6):615-22. doi: 10.1139/apnm-2014-0500. Epub 2015 Feb 10

2. Iron supplementation improves progressive fatigue resistance during dynamic knee extensor exercise in iron-depleted, nonanemic women.
Brutsaert TD1, Hernandez-Cordero S, Rivera J, Viola T, Hughes G, Haas JD
Am J Clin Nutr. 2003 Feb;77(2):441-8.

3. Iron for restless legs syndrome.
Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome.
Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP.

4. Symptom Persistence after Iron Normalization in Women with Restless Legs Syndrome.
Bang YR, Jeon HJ, Park HY, Yoon IY.
Psychiatry Investig. 2018 Feb 28. doi: 10.30773/pi.2017.08.21. [Epub ahead of print]

5. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study.
Wang J, O’Reilly B, Venkataraman R, Mysliwiec V, Mysliwiec A.
Sleep Med. 2009 Oct;10(9):973-5. doi: 10.1016/j.sleep.2008.11.003. Epub 2009 Feb 18

6. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome.
Grote L, Leissner L, Hedner J, Ulfberg J.
Mov Disord. 2009 Jul 30;24(10):1445-52. doi: 10.1002/mds.22562

7. Iron for Restless Legs
Trotti LM, Bhadriraju S, Becker LA.
Cochrane Database Syst Rev. 2012 May 16;(5):CD007834. doi: 10.1002/14651858.CD007834.pub2. Review

8. Effects of iron supplementation of LBW infants on cognition and behavior at 3 years.
Berglund SK, Westrup B, Hägglöf B, Hernell O, Domellöf M.
Pediatrics. 2013 Jan;131(1):47-55. doi: 10.1542/peds.2012-0989. Epub 2012 Dec 10

9. Midlife iron status is inversely associated with subsequent cognitive performance, particularly in perimenopausal women.
Andreeva VA, Galan P, Arnaud J, Julia C, Hercberg S, Kesse-Guyot E.
J Nutr. 2013 Dec;143(12):1974-81. doi: 10.3945/jn.113.177089. Epub 2013 Oct 2

10. Serum iron parameters, HFE C282Y genotype, and cognitive performance in older adults: results from the FACIT study.
Schiepers OJ, van Boxtel MP, de Groot RH, Jolles J, de Kort WL, Swinkels DW, Kok FJ, Verhoef P, Durga J.
J Gerontol A Biol Sci Med Sci. 2010 Dec;65(12):1312-21. doi: 10.1093/gerona/glq149. Epub 2010

11. Iron treatment normalizes cognitive functioning in young women.
Murray-Kolb LE, Beard JL.
Am J Clin Nutr. 2007 Mar;85(3):778-87
12. Consumption of Iron-Biofortified Beans Positively Affects Cognitive Performance in 18- to 27-Year-Old Rwandan Female College Students in an 18-Week Randomized Controlled Efficacy Trial.
Murray-Kolb LE, Wenger MJ, Scott SP, Rhoten SE, Lung’aho MG, Haas JD.
J Nutr. 2017 Nov;147(11):2109-2117. doi: 10.3945/jn.117.255356. Epub 2017 Sep 27

13. Four weeks of IV iron supplementation reduces perceived fatigue and mood disturbance in distance runners.
Woods A, Garvican-Lewis LA, Saunders PU, Lovell G, Hughes D, Fazakerley R, Anderson B, Gore CJ, Thompson KG.
PLoS One. 2014 Sep 23;9(9):e108042. doi: 10.1371/journal.pone.0108042. eCollection 2014

14. Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial.
Verdon F, Burnand B, Stubi CL, Bonard C, Graff M, Michaud A, Bischoff T, de Vevey M, Studer JP, Herzig L, Chapuis C, Tissot J, Pécoud A, Favrat B.
BMJ. 2003 May 24;326(7399):1124.

15. Dietary and supplement treatment of iron deficiency results in improvements in general health and fatigue in Australian women of childbearing age.
Patterson AJ, Brown WJ, Roberts DC.
J Am Coll Nutr. 2001 Aug;20(4):337-42

16. Single-dose intravenous iron infusion or oral iron for treatment of fatigue after postpartum haemorrhage: a randomized controlled trial.
Holm C, Thomsen LL, Norgaard A, Langhoff-Roos J.
Vox Sang. 2017 Apr;112(3):219-228. doi: 10.1111/vox.12477. Epub 2017 Feb 15

17. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial.
Vaucher P, Druais PL, Waldvogel S, Favrat B.
CMAJ. 2012 Aug 7;184(11):1247-54. doi: 10.1503/cmaj.110950. Epub 2012 Jul 9

18. Impact of iron treatment on immune effector function and cellular iron status of circulating monocytes in dialysis patients.
Sonnweber T, Theurl I, Seifert M, Schroll A, Eder S, Mayer G, Weiss G.
Nephrol Dial Transplant. 2011 Mar;26(3):977-87. doi: 10.1093/ndt/gfq483. Epub 2010 Sep 8

19. Impairment of the peripheral lymphoid compartment in iron-deficient piglets.
Svoboda M, Drabek J, Krejci J, Rehakova Z, Faldyna M.
J Vet Med B Infect Dis Vet Public Health. 2004 Jun;51(5):231-7

20. Influences of sleep and the circadian rhythm on iron-status indices.
Ridefelt P, Larsson A, Rehman JU, Axelsson J.
Clin Biochem. 2010 Nov;43(16-17):1323-8. doi: 10.1016/j.clinbiochem.2010.08.023. Epub 2010 Aug 26

21. The effects of iron and/or zinc supplementation on maternal reports of sleep in infants from Nepal and Zanzibar.
Kordas K, Siegel EH, Olney DK, Katz J, Tielsch JM, Kariger PK, Khalfan SS, LeClerq SC, Khatry SK, Stoltzfus RJ.
J Dev Behav Pediatr. 2009 Apr;30(2):131-9. doi: 10.1097/DBP.0b013e31819e6a48

22. Children with autism: effect of iron supplementation on sleep and ferritin.
Dosman CF, Brian JA, Drmic IE, Senthilselvan A, Harford MM, Smith RW, Sharieff W, Zlotkin SH, Moldofsky H, Roberts SW.
Pediatr Neurol. 2007 Mar;36(3):152-8

23. Iron and attention deficit/hyperactivity disorder: What is the empirical evidence so far? A systematic review of the literature.
Cortese S, Angriman M, Lecendreux M, Konofal E.
Expert Rev Neurother. 2012 Oct;12(10):1227-40. doi: 10.1586/ern.12.116. Review

24. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials.
Litton E, Xiao J, Ho KM.
BMJ. 2013 Aug 15;347:f4822. doi: 10.1136/bmj.f4822. Review

Summary
Do Iron Supplements Work? Conclusions From 24 Research Papers
Article Name
Do Iron Supplements Work? Conclusions From 24 Research Papers
Author
Healthy But Smart

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