Oral iron supplementation dosed every 48 hours is preferred over a daily regimen for at least 2 reasons: higher absorption and better tolerability. Improved absorption is due to an increase in hepcidin after oral intake of iron that lasts up to 48 hours which, paradoxically, also results in blocking further iron absorption during that period. In fact, a study comparing consecutive-day versus alternate-day dosing of oral iron supplementation found the fractional iron absorption to be 40-50% higher in alternate-day dosing.¹

As for tolerability, the most frequent side effect of oral iron is gastrointestinal in nature, including nausea, vomiting, diarrhea, and constipation which are related to: 1. Excess amounts of unabsorbed iron leading to inflammation in the gut; and 2. An increase in the production of free radicals and peroxidation in the gut.² Not surprisingly, alternate-day dosing has been shown to result in less side effects due to higher fractional iron absorption – leading to reduced levels of unabsorbed iron in the gut.³

Understanding the importance of optimal dosing regimen for oral iron supplementation is more than an academic exercise. Iron deficiency is the number one nutritional deficiency globally, affecting 30% of the world’s population.⁴ The most common causes are gastrointestinal blood loss and menstrual cycle blood loss, followed by a decrease in dietary fiber intake and decreased iron absorption. Undoubtedly, many providers will encounter patients with iron deficiency in need of oral supplementation. To increase both efficacy and compliance of oral iron supplementation, providers should consider every other day (every 48 h) dosing of oral iron in preference to daily dosing. 

Bonus Pearl:  Did you know that heme sources of iron from animals (eg, red meat, liver or kidney) are usually more bioavailable than their non-heme counterparts (eg, from green leafy vegetables) except for blackstrap molasses which has high iron content as well as exceptionally high bioavailability?^5,6 

Contributed by Morgan Walters, DO, Internal Medicine Resident, Mercy Hospital-St. Louis, St. Louis, Missouri 

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References: 

1. Stoffel N, Zeder C, Brittenham G, et al. Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anemic women. Haematologica. 2020 May;105(5):1232-1239. doi: 10.3324/haematol.2019.220830.  Epub 2019 Aug 14. https://pubmed.ncbi.nlm.nih.gov/32650997/
2. DeLoughery T, Jackson C, Ko C, et al. AGA Clinical Practice Update on management of Iron Deficiency Anemia: Expert Review. Clinical Gastroenterology and Hepatology 2024;22:1575–1583. Doi:0.1016/j.cgh.2024.03.046.  https://pubmed.ncbi.nlm.nih.gov/38864796/
3. Stoffel N, Zeder C, Brittenham G, et al. Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anemic women Haematologica. 2020 May;105(5):1232-1239. doi: 10.3324/haematol.2019.220830.  Epub 2019 Aug 14. https://pubmed.ncbi.nlm.nih.gov/32650997/
4. Kumar A, Sharma E, Marley A, et al. Iron deficiency anaemia: pathophysiology, assessment, practical management. BMJ Open Gastro 2022;9:e000759. doi:10.1136/bmjgast-2021-000759. https://pubmed.ncbi.nlm.nih.gov/34996762/
5. Brittany Lubeck, MS. “Is Molasses Healthy? What to Know about This Sweetener.” Verywell Health, May 10, 2024. https://www.verywellhealth.com/molasses-8640108.
6. Hamlett, C. (2024, March 22). Meet Blackstrap Molasses: The “best source” of plant-based Iron. Plant Based News. https://plantbasednews.org/lifestyle/health/blackstrap-molasses-is-an-iron-rich-nutritional-powerhouse/ 

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!