Effectiveness of low-dose iron treatment in non-anaemic iron-deficient women: a prospective open-label single-arm trial
BACKGROUND: Iron deficiency without anaemia is highly prevalent and is particularly associated with fatigue, cognitive impairment, or poor physical endurance. Standard oral iron therapy often results in intestinal irritation with associated side effects and premature discontinuation of therapy, therefore, optimal oral iron therapy with sufficient iron absorption and minimal side effects is desirable.
METHODS: Thirty-six iron-deficient non-anaemic premenopausal women (serum ferritin ≤30 ng/ml, haemoglobin ≥117 g/l) with normal body mass index (BMI) and no hypermenorrhea received 6 mg of elemental oral iron (corresponding to 18.6 mg ferrous sulphate) twice daily for 8 weeks.
RESULTS: Participants treated with low-dose iron had an average age of 28 years and a BMI of 21 kg/m2. Their serum ferritin and haemoglobin increased significantly from 18 ng/ml to 33 ng/ml (p <0.001) and from 135 g/l to 138 g/l (p = 0.014), respectively. Systolic blood pressure increased from 114 mmHg to 120 mmHg (p = 0.003). Self-reported health status improved after 8 weeks (p <0.001) and only one woman reported gastrointestinal side effects (3%).
CONCLUSION: This prospective open-label single-arm trial shows that oral iron treatment of 6 mg of elemental iron twice daily over 8 weeks is effective in iron-deficient non-anaemic women. Due to the negligible side effects, low-dose iron treatment is a valuable therapeutic option for iron-deficient non-anaemic women with normal BMI and menstruation. Further placebo-controlled studies with a larger number of participants are needed to confirm these results.
- Kassebaum NJ, Collaborators GA; GBD 2013 Anemia Collaborators. The Global Burden of Anemia. Hematol Oncol Clin North Am. 2016 Apr;():247–308. 10.1016/j.hoc.2015.11.002
- Cogswell ME, Looker AC, Pfeiffer CM, Cook JD, Lacher DA, Beard JL, et al. Assessment of iron deficiency in US preschool children and nonpregnant females of childbearing age: National Health and Nutrition Examination Survey 2003-2006. Am J Clin Nutr. 2009 May;():1334–42. 10.3945/ajcn.2008.27151
- Galan P, Yoon HC, Preziosi P, Viteri F, Valeix P, Fieux B, et al. Determining factors in the iron status of adult women in the SU.VI.MAX study. SUpplementation en VItamines et Minéraux AntioXydants. Eur J Clin Nutr. 1998 Jun;():383–8. 10.1038/sj.ejcn.1600561
- Abuaisha M, Itani H, El Masri R, Antoun J. Prevalence of Iron Deficiency (ID) without anemia in the general population presenting to primary care clinics: a cross-sectional study. Postgrad Med. 2020 Apr;():282–7. 10.1080/00325481.2020.1715701
- Krayenbuehl PA, Battegay E, Breymann C, Furrer J, Schulthess G. Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration. Blood. 2011 Sep;():3222–7. 10.1182/blood-2011-04-346304
- Favrat B, Balck K, Breymann C, Hedenus M, Keller T, Mezzacasa A, et al. Evaluation of a single dose of ferric carboxymaltose in fatigued, iron-deficient women—PREFER a randomized, placebo-controlled study. PLoS One. 2014 Apr;():e94217. 10.1371/journal.pone.0094217
- Verdon F, Burnand B, Stubi CL, Bonard C, Graff M, Michaud A, et al. Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial. BMJ. 2003 May;():1124. 10.1136/bmj.326.7399.1124
- Scott SP, Murray-Kolb LE. Iron Status Is Associated with Performance on Executive Functioning Tasks in Nonanemic Young Women. J Nutr. 2016 Jan;():30–7. 10.3945/jn.115.223586
- Bruner AB, Joffe A, Duggan AK, Casella JF, Brandt J. Randomised study of cognitive effects of iron supplementation in non-anaemic iron-deficient adolescent girls. Lancet. 1996 Oct;():992–6. 10.1016/S0140-6736(96)02341-0
- Hinton PS, Giordano C, Brownlie T, Haas JD. Iron supplementation improves endurance after training in iron-depleted, nonanemic women. J Appl Physiol (1985). 2000;88(3):1103-1111.
- Rubeor A, Goojha C, Manning J, White J. Does Iron Supplementation Improve Performance in Iron-Deficient Nonanemic Athletes? Sports Health. 2018;():400–5. 10.1177/1941738118777488
- Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, et al. Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016 Dec;():2585–93. 10.1212/WNL.0000000000003388
- McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. Corrigendum to: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2021 Dec;():4901. 10.1093/eurheartj/ehab670
- Milman NT. Dietary Iron Intake in Women of Reproductive Age in Europe: A Review of 49 Studies from 29 Countries in the Period 1993-2015. J Nutr Metab. 2019 Jun;:7631306. 10.1155/2019/7631306
- Richards T, Breymann C, Brookes MJ, Lindgren S, Macdougall IC, McMahon LP, et al. Questions and answers on iron deficiency treatment selection and the use of intravenous iron in routine clinical practice. Ann Med. 2021 Dec;():274–85. 10.1080/07853890.2020.1867323
- Snook J, Bhala N, Beales IL, Cannings D, Kightley C, Logan RP, et al. British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults. Gut. 2021 Nov;():2030–51. 10.1136/gutjnl-2021-325210
- Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One. 2015 Feb;():e0117383. 10.1371/journal.pone.0117383
- Cancelo-Hidalgo MJ, Castelo-Branco C, Palacios S, Haya-Palazuelos J, Ciria-Recasens M, Manasanch J, et al. Tolerability of different oral iron supplements: a systematic review. Curr Med Res Opin. 2013 Apr;():291–303. 10.1185/03007995.2012.761599
- Ribeiro M, Fonseca L, Anjos JS, Capo-Chichi JC, Borges NA, Burrowes J, et al. Oral iron supplementation in patients with chronic kidney disease: can it be harmful to the gut microbiota? Nutr Clin Pract. 2022 Feb;():81–93. 10.1002/ncp.10662
- Cook JD, Reddy MB. Efficacy of weekly compared with daily iron supplementation. Am J Clin Nutr. 1995 Jul;():117–20. 10.1093/ajcn/62.1.117
- Moretti D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015 Oct;():1981–9. 10.1182/blood-2015-05-642223
- Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al.; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009 Dec;():2436–48. 10.1056/NEJMoa0908355
- Rosado JL, González KE, Caamaño MC, García OP, Preciado R, Odio M. Efficacy of different strategies to treat anemia in children: a randomized clinical trial. Nutr J. 2010 Sep;():40. 10.1186/1475-2891-9-40
- Mozaffari-Khosravi H, Noori-Shadkam M, Fatehi F, Naghiaee Y. Once weekly low-dose iron supplementation effectively improved iron status in adolescent girls. Biol Trace Elem Res. 2010 Jun;():22–30. 10.1007/s12011-009-8480-0
- Rimon E, Kagansky N, Kagansky M, Mechnick L, Mashiah T, Namir M, et al. Are we giving too much iron? Low-dose iron therapy is effective in octogenarians. Am J Med. 2005 Oct;():1142–7. 10.1016/j.amjmed.2005.01.065
- Andersson M, Hurrell R, Zimmermann MB. Impact evaluation of food fortification with iron in school children and women of reproductive age. Laboratory of Human Nutrition, Institute of Food, Nutrition and Health. Vol. Doctor of Sciences. Zürich: ETH; 2010. p. 241.
- Kortman GA, Raffatellu M, Swinkels DW, Tjalsma H. Nutritional iron turned inside out: intestinal stress from a gut microbial perspective. FEMS Microbiol Rev. 2014 Nov;():1202–34. 10.1111/1574-6976.12086
- Paganini D, Zimmermann MB. The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review. Am J Clin Nutr. 2017 Dec; Suppl 6:1688S–93S. 10.3945/ajcn.117.156067
- Stoffel NU, El-Mallah C, Herter-Aeberli I, Bissani N, Wehbe N, Obeid O, et al. The effect of central obesity on inflammation, hepcidin, and iron metabolism in young women. Int J Obes. 2020 Jun;():1291–300. 10.1038/s41366-020-0522-x