Iron
Iron stores in infants are directly proportional to birth weight; iron stores in healthy, full-term infants are typically not enough to last more than 4 to 6 months after birth, and breast milk is low in iron. Thus, premature, low-birth-weight, and exclusively breastfed infants are at a higher risk for iron deficiency.
Essential for growth and development,[1] especially during fetal brain and nervous system development (myelination, neurotransmitters) [2]
Part of hemoglobin in red blood cells and myoglobin in muscle cells [1,3,4]
Essential for cellular energy production [1,3,4] Part of numerous enzymes, including some that make proteins, collagen, hormones, and neurotransmitters [1] and those that create and repair DNA [2]
Aids in removing toxins, is part of enzymes that act as antioxidants, and supports the immune system [2,4]
How it works
Recommended daily amount
*Menstruating people under 14 years, over 51 years, and breastfeeding women have an increased requirement of about 2.5 mg per day. [3].
Daily upper limits
Lentils, beans, soybeans, chickpeas
Nuts and seeds
Dark chocolate
Dark leafy vegetables
Whole and fortified grains and cereals
Using cast iron pans can increase iron intake.
Sources of nutrient
Examples of nutrient-rich foods
Heme iron is found in meats, poultry, fish, and the organs of animals. Non-heme iron is in many foods, including plant-based and iron-fortified foods, dairy, and meats. [2]
Most of the iron consumed by humans is in the non-heme form. [3] Heme iron is more bioavailable than non-heme iron because it has an independent transport system and is less influenced by other dietary factors (e.g., tannins).
On average, about 25% of heme iron is absorbed. [4] A separate pathway transports non-heme iron, and on average, about 17% of non-heme iron is absorbed. [4]
Many factors can influence non-heme iron absorption. However, enhancers or inhibitors may have little effect on non-heme iron absorption with a mixed diet.[1]
Bioavailability
The effects of diet on iron absorption Iron bioavailability has been reported to be about 18% in omnivorous mixed diets, 10% in vegetarian diets, and can be as low as 5% in strict vegan diets or in food insecure situations where food variety is limited. [3] However, a vegetarian diet does not appear to be associated with an increased risk of iron deficiency when it includes whole grains, legumes, nuts and seeds, iron-fortified cereals, and green leafy vegetables. [2]
Because non-heme iron has a lower bioavailability than heme iron, persons on a plant-based diet may benefit from iron supplementation. Caution iron supplements can become toxic with high doses, and accidental overdose of iron-containing supplements is a leading cause of fatal poisoning in children under 6 years of age. [6]
Supplements containing ferrous iron (Fe2+), such as ferrous glutamate, sulfate, or fumarate, are more soluble and better absorbed than ferric iron supplements (Fe3+).[1,4,7] (Ferric supplement bioavailability is typically 3 to 4 times lower than ferrous supplements. Note that chelated polysaccharide supplements are often in the ferric form. [7])
Supplements containing ferrous iron salts (ferrous sulfate, fumarate, or gluconate) and amino acid chelates (e.g., ferrous bisglycinate) are similar in absorption and efficacy when the same amount of elemental iron is given. [7]
Iron Supplements
Amount of elemental iron in select iron supplements [8]
Iron supplements are generally best when taken on an empty stomach a least an hour before meals because many foods and drinks contain inhibitors that can reduce absorption. [7] However, if iron supplements are taken with food, including vitamin C-rich foods helps to reduce inhibitory effects. [7]
Side effects from iron supplements may include constipation, nausea, and vomiting. [1,3] However, chelated complexes (with polysaccharides or amino acids, such as ferrous bisglycinate) may have fewer side effects than other supplement forms. [1]
More iron is absorbed with lower-dose supplements than higher doses and may result in fewer side effects. [7] For example, taking lower dose supplements (20 to 50 mg of elemental iron a day, see table above for equivalents of various supplements) may generate fewer side effects than higher daily regimens. [7] Alternatively, taking a higher dose (e.g., 120 mg of elemental iron) every other day may have lower side effects than a lower-dose daily supplement. [7] Studies suggest oral iron doses of more than 60 mg of elemental iron should be spaced by 48 hours to maximize absorption. [7]
Multivitamin/mineral supplements typically contain low doses of iron and may have other minerals that interfere with iron absorption. [7] Slow-release iron and carbonyl iron supplements are poorly absorbed and are generally not recommended. [7]
Iron is stored as ferritin or as a metabolite called hemosiderin, primarily in the liver, spleen, and bone marrow. [3]
Iron is transported in the blood by the protein transferrin, and virtually all iron in plasma is bound to it. [3] When all of transferrin’s binding sites are full, iron mobilization from storage or from intestinal cells is inhibited. However, when iron is low, transferrin receptors increase for more iron to bind.[12] Transferrin can be measured indirectly by measuring total iron binding capacity (TIBC). [3]
Transferrin receptors (TfR) are on all cells in direct proportion to their needs, and soluble serum transferrin receptors (sTfR) are the proteolytic cleaved domains of these receptors. [3] A rise in blood sTfR occurs in response to low iron.[3]
Acute-phase response to injury and infection suppresses iron transport; this is thought to be a protective response to the host by reducing available iron to pathogens.[3,12] Thus, inflammation and infection can cause iron to shift from circulation (blood) into storage (liver), limiting the amount of iron available to other tissues (e.g., bone for blood cell formation).[1] Clinically, serum iron levels are depressed, while serum ferritin may increase. [1]
Iron homeostasis is largely achieved by enterocytes controlling dietary iron absorption via the hormone hepcidin. [4] However, the body cannot excrete excess iron. [2]
Nutrient Metabolism
Serum ferritin concentrations reflect iron stores in healthy individuals and those with early iron deficiency. [3] Serum ferritin is a good marker of iron stores and should be used to diagnose iron deficiency in otherwise apparently healthy individuals. [1,13]
Note that inflammation, infection, cancer, liver disease, high ethanol consumption, and high blood glucose can affect serum ferritin values; as an acute-phase protein, serum ferritin often increases [1,2] while serum iron decreases. [2]
Hemoglobin and hematocrit are neither specific nor sensitive to iron deficiency but are commonly used. Combining these values with serum ferritin may help diagnose iron deficiency anemia. [1,3]
Hemoglobin values that suggest anemia:
-
< 110 g/L in children under 10 years [1]
-
< 120 g/L in those older than 10 years [1]
-
< 130 g/L adult men [3]
-
< 120 g/L adult women[3]; 105-110 g/L pregnancy [20]
Mean cell volume < 80fL suggests anemia [3]
Normal hematocrit ranges are 41% – 50% in males and 36% - 44% in females [1]; <32-33% suggests anemia in pregnancy [1]
Measures of Status
a Markers of inflammation should be assessed with serum ferritin
b High ferritin levels, particularly > 500, may also be due to other diseases; further clinical and lab evaluation is needed to establish the diagnosis and underlying cause of elevated ferritin levels
c ACOG has proposed < 30mcg/L to suggest inadequate iron [11]
d Physiological changes during the second and third trimesters of pregnancy contribute to large variation in serum ferritin values
Other measures of iron include:
-
Serum transferrin receptor > 8.5 mg/L indicates early functional iron deficiency. sTfR is a specific and sensitive indicator of early iron deficiency and is unaffected by infection, inflammation, or neoplastic disorders. [3] Increases in sTfR occur with low iron. [3]
-
Total iron-binding capacity (TIBC) > 400 mcg/dL suggests depleted iron stores. TIBC is reduced with infection, inflammatory or neoplastic disorders. [3] TIBC is less precise than serum ferritin, and 30-40% of iron-deficient patients may have normal values. [3] Normal pregnancy TIBC values are 216-400 mcg/dL. [11]
-
Transferrin saturation < 16% suggests early functional iron deficiency but is not specific to iron as it can be affected by other conditions, including anemia of chronic disease. [3] In pregnancy, normal transferrin saturation is 16 – 60%. [11]
-
Free erythrocyte protoporphyrin > 70mcg/dL erythrocyte indicates early functional iron deficiency. [3] When iron is not incorporated into erythrocytes, free protoporphyrin remains for the duration of the cell’s lifespan. Conditions such as impaired heme synthesis and anemia, elevated lead, and chronic disease can affect erythrocyte protoporphyrin. [3] Normal free erythrocyte values in pregnancy are < 3 mcg/g. [11]
-
Zinc may be incorporated into erythrocyte protoporphyrin during iron deficiency. The ratio zinc protoporphyrin:heme could be used as an indicator of heme synthesis impairment and is sensitive to insufficient iron delivery to the erythrocyte. [3]
-
-
Serum/plasma iron measures iron attached to transferrin. [12,14] Serum iron reference ranges are: [14]
-
Male: 80-180 mcg/dL or 14-32 μmol/L
-
Female: 60-160 mcg/dL or 11-29 μmol/L
-
Newborn: 100-250 mcg/dL
-
Child: 50-120 mcg/dL
-
-
Normal values for plasma iron in pregnancy are 40 – 175 mcg/dL [11]
Increases in serum iron level are associated with the following: idiopathic hemochromatosis, liver necrosis (viral hepatitis), hemosiderosis caused by excessive iron intake (e.g., multiple transfusions, excess iron administration), acute iron poisoning (children), hemolytic anemia, pernicious anemia, aplastic or hypoplastic anemia, lead poisoning, thalassemia, vitamin B6 deficiency, estrogens, ethanol, and oral contraceptive use. [14]
Decreases in the serum iron level are associated with the following: iron deficiency anemia, nephrotic syndrome (loss of iron-binding proteins), iron deficiency, chronic renal failure, infections, active hematopoiesis, remission of pernicious anemia, hypothyroidism, malignancy (carcinoma), postoperative state, and kwashiorkor. [14]
-
Vitamin A deficiency often co-exists with iron deficiency and may exacerbate iron-deficiency anemia by potentially limiting iron transport from storage into red blood cells. [2]
-
Adequate copper status is necessary for normal iron metabolism [3]
-
High iron intake may interfere with copper absorption [2]
-
Zinc is required for red blood cell formation, and low zinc status may exacerbate anemia.[2] Taking zinc with high-dose iron supplements on an empty stomach may reduce zinc absorption; however, zinc and iron do not appear to interact when taken with food. [3]
-
Calcium may inhibit heme and non-heme iron absorption. [2]
-
Iron-deficiency anemia can impair thyroid metabolism, which may affect iodine levels. [2]
Nutrient Interactions
Infants born premature or with low birthweight [1]
Exclusively breastfed infants since breast milk iron is low, and iron stores in the full-term, healthy infant last only about four to six months [9]
Infants, children, and adolescents due to iron needs for growth and development [1,4] (the CDC estimates 14% of 1-2-year-olds in the US are iron deficient) [10]
Pregnant women (The CDC estimates 16% of US pregnant people are iron deficient,[10] and NHANES data estimates up to nearly a third of pregnant people in their third trimester in the US may be iron deficient (highest in non-white women, teenaged mothers, and people with parity > 2) [11]
People with heavy menstrual bleeding [1]
Frequent blood donors or with chronic blood loss [1-3]
Gastrointestinal conditions (e.g., Crohn’s, IBS, parasites), including those that inhibit gastric acidity (e.g., antacid use, atrophic gastritis) and surgeries (e.g., bypass) [1-3]
Patients with anemia of chronic disease [1]
Patients with chronic kidney disease, especially with dialysis [2]
Athletes and those with regular intense physical activity [3] (may have a 30% higher iron requirement [2] and some subpopulations of athletes may need up to 70% more iron [3])
Populations at risk for deficiency
Deficiency signs and symptoms
Brittle, spoon-shaped nails (koilonychia) [2,3]
Sores at the corner of the mouth (angular stomatitis) [2,3]
Taste bud atrophy [2]
Sore tongue (glossitis) [2,3]
Esophageal webs [3]
Chronic gastritis [3]
Microcytic hypochromic anemia [2,4]
Impaired muscle aerobic capacity and lower exercise performance [3]
Impaired work performance, slower nerve conduction, and impaired memory [3]
Slower nerve conduction and impaired memory [3]
In pregnancy, anemia (which may include IDA [2]) is associated higher risk of
low birth weight,[1,2]
premature birth,[1,2] and
perinatal mortality [1-3]
In infants and children, iron deficiency is related to a higher risk of
impaired cognitive and behavioral development, [1-4]
impaired psychomotor development, [3]
developmental delays, [1,3]
abnormal behavior patterns, [2]
poor school performance, [2] and
lower mental and motor test scores [3]
The content provided is for informational purposes only and may not be an exhaustive list of potential interactions.
Medications used to reduce stomach acidity may reduce iron absorption (e.g., antacids,2 H2 antagonists (e.g., Zantac), 2 proton pump inhibitors (e.g., Prilosec) [1,2]
Taking iron supplements with these medications can reduce the absorption and efficacy of the following: [2] (take 2-4 hours apart [1,2])
Carbidopa and levodopa (e.g., Sinemet) [1,2]
Methyldopa (e.g., Aldomet) [2]
Levothyroxine [1,2]
Penicillamine [2]
Quinolones [2]
Tetracyclines [2]
Bisphosphonates [2]
Cholestyramine (e.g., Questran) and colestipol (e.g., Colestid) should be taken 4 hours apart from iron supplements as they may interfere with iron absorption. [2]
Potential drug-nutrient interactions
Toxicity is most often due to genetic variants or conditions requiring multiple repeated blood transfusions. [4]
Patients that have the following conditions may be susceptible to adverse effects of excess iron intake: [3]
Hereditary hemochromatosis
Iron-loading abnormalities, particularly thalassemias
Congenital atransferrinemia
Aceruloplasminemia
Chronic Alcoholics
Liver diseases, including cirrhosis
Acute overdose of iron supplements can occur. Symptoms include: [4]
Vomiting
Diarrhea
Dizziness
Confusion
Death (in severe cases)
Toxicity signs and symptoms
Infants
Iron stores in infants are directly proportional to birth weight. [3] Iron stores in healthy, full-term infants are typically not enough to last more than 4 to 6 months after birth, and breast milk is low in iron. [9] Thus, premature, low-birth-weight, and exclusively breastfed infants are at a higher risk for iron deficiency. [9,15]
Iron supplementation of infants
Not all countries/organizations agree on the routine use of iron supplements in infants, and in general, most guidelines do not recommend routine use in infants. [16]
In 2010, the AAP recommended iron supplementation for exclusively and partially breastfed infants beginning at four months of age and older babies not consuming adequate iron (term infants 4 to 6 months of age 1mg/kg; pre-term infants 1-12 months of age 2 mg/kg). [17] However, the AAP recommendations were published before delayed umbilical cord clamping, shown to improve iron status, [2] was recommended in the US. [16]
A 2012 AAP publication states that iron supplements should only be used if needed before six months; premature babies should receive both multivitamin and iron supplements until they are completely consuming a mixed diet and have normal growth and hematological values. [15] The most recent AAP policy statement (2022) restates these findings without further guidance. [21]
Pregnancy
ACOG recommends low-dose iron supplements starting the first trimester to reduce the likelihood of iron deficiency at term. [11]
The WHO recommends that all pregnant women take 30 to 60 mg of elemental iron daily (in areas where anemia is 40% or higher; the 60 mg dose is preferred). If side effects reduce compliance, a 120 mg elemental iron supplement once a week is recommended in areas where anemia prevalence is less than 20%, such as in the US.[18]
The WHO recommends that pregnant women diagnosed with anemia receive 120 mg iron until hemoglobin concentrations rise to 110g/L or higher; thereafter, the standard daily iron regimen can resume. [18]
ACOG recommends screening for anemia and iron supplementation in cases of iron-deficient anemia during pregnancy in addition to prenatal vitamins. [11]
Adolescent girls and women
Globally, it is estimated that about 250 million non-pregnant females have iron-deficiency anemia. [8] In the US, current anemia prevalence (commonly caused by iron deficiency) in non-pregnant women and girls is estimated at about 10%. [19]
In areas where anemia is highly prevalent (40% or higher), the WHO recommends that menstruating women and adolescent girls take 30 – 60 mg of elemental iron daily for at least 3 consecutive months a year. [8]
In populations where anemia prevalence is 20% or higher, a 60 mg elemental iron per week for 3 months followed by 3 months of no supplements, after which supplementation should restart. [7, 8]
Intermittent regimens may also be an option in areas where anemia is 20 to 40%. [8]
Guidelines vary for oral iron supplementation for iron deficiency and iron deficiency anemia (IDA). Although traditionally 80 – 200 mg of daily elemental iron have been recommended, newer guidelines suggest lower doses may be as effective and produce less side effects. [7] For example, recent studies suggest optimal dosing to maximize fractional iron absorption in women with iron deficiency and mild IDA is ≤40 mg daily or ≥60 mg on alternate days. [7] (Note: 60 mg elemental iron is equal to 300 mg ferrous sulfate heptahydrate, 180 mg ferrous fumarate, 500 mg ferrous gluconate [7]).
Prevention of deficiency
1. Iron. Fact Sheet for Health Professionals. Office of Dietary Supplements. National Institutes of Health. Updated Feb 2020. Accessed Sept 2020. https://ods.od.nih.gov/factsheets/Iron-HealthProfessional/
2. Iron. Linus Pauling Institute Micronutrient Information Center, Oregon State University. Updated Apr 2016. Accessed Sept 2020. https://lpi.oregonstate.edu/mic/minerals/iron.
3. Institute of Medicine 2001. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: The National Academies Press. https://doi.org/10.17226/10026.
4. McDermid JM, Lonnerdal B. Adv. Nutr. 2012; 3: 532–533.
5. FoodData Central Database. United States Department of Agriculture. Accessed Oct 2021. https://fdc.nal.usda.gov.
6. Food and Drug Administration Code of Federal Regulations Title 21. Sec. 310.518 Drug products containing iron or iron salts. Current as of Oct 2021. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=310.518. Accessed Dec 2021.
7. Stoffel NU, von Sienbenthal HK, Moretti, D. Oral iron supplementation in iron-deficient women: How much and how often? Mol Asp Med. 2020;75,100865.
8. Daily iron supplementation in adult women and adolescent girls. World Health Organization e-Library of Evidence for Nutrition Actions (eLENA). Last Update Feb 2019. https://www.who.int/elena/titles/iron_women/en/. Accessed Dec 2021.
9. U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2020-2025. 9th Edition. December 2020. Available at DietaryGuidelines.gov.
10. Poor Nutrition. Chronic Disease Facts. US Centers for Disease Control. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/nutrition.htm. Updated Jan 2021. Accessed Dec 2021.
11. Anemia in pregnancy. AGOG Practice Bulletin No 233. The American College of Obstetricians and Gynecologists. Obst Gyne 2021;(138):2.
12. The ASPEN Adult Nutrition Support Core Curriculum 2nd Edition. The American Society of Parenteral and Enteral Nutrition. Silver Spring, MD. 2012.
13. WHO Guideline: Use of ferritin concentration to assess iron status in individuals and populations. Executive Summary. World Health Organization. Apr 2020. https://www.who.int/publications/i/item/9789240000124
14. Iron. Medscape. https://emedicine.medscape.com/article/2085704-overview Updated Dec 2019. Accessed Dec 2021.
15. American Academy of Pediatrics. Executive Summary: Breastfeeding and the Use of Human Milk. Pediatrics 2012; 129(3) 601.
16. National Academies of Sciences, Engineering, and Medicine. 2020. Feeding Infants and Children from Birth to 24 Months: Summarizing Existing Guidance. Washington, DC: The National Academies Press.https://doi.org/10.17226/25747. https://www.nap.edu/catalog/25747/feeding-infants-and-children-from-birth-to-24-months-summarizing.
17. Baker RD, Greer FR. The Committee on Nutrition; Diagnosis and Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children (0–3 Years of Age). Pediatrics November 2010; 126 (5): 1040–1050. 10.1542/peds.2010-2576. https://www.nap.edu/catalog/25747/feeding-infants-and-children-from-birth-to-24-months-summarizing.
18. Daily iron and folic acid supplementation during pregnancy. World Health Organization e-Library of Evidence for Nutrition Actions (eLENA). 2016. https://www.who.int/elena/titles/guidance_summaries/daily_iron_pregnancy/en/. Accessed Dec 2021.
19. Sun H, Weaver CM. Decreased Iron Intake Parallels Rising Iron Deficiency Anemia and Related Mortality Rates in the US Population. J Nutr. 2021; (151)7:1947–1955.
20. James, A. Iron Deficiency Anemia in Pregnancy. Obstet Gyn. 2021; 138(4):663-674, doi: 10.1097/AOG.0000000000004559.
21. Meek, J. Y., Noble, L., & Section on Breastfeeding. Policy Statement: Breastfeeding and the Use of Human Milk. Pediatrics 150, e2022057988 (2022).