Iron Deficiency Anemia

Introduction

Iron is a mineral that is naturally present in many foods, added to some food products, and available as a dietary supplement. Iron is an essential component of hemoglobin, an erythrocyte (red blood cell) protein that transfers oxygen from the lungs to the tissues [1]. As a component of myoglobin, another protein that provides oxygen, iron supports muscle metabolism and healthy connective tissue [2]. Iron is also necessary for physical growth, neurological development, cellular functioning, and synthesis of some hormones [2,3].

Dietary iron has two main forms: heme and nonheme [1]. Plants and iron-fortified foods contain nonheme iron only, whereas meat, seafood, and poultry contain both heme and nonheme iron [2]. Heme iron, which is formed when iron combines with protoporphyrin IX, contributes about 10% to 15% of total iron intakes in western populations [3-5].

Most of the 3 to 4 grams of elemental iron in adults is in hemoglobin [2]. Much of the remaining iron is stored in the form of ferritin or hemosiderin (a degradation product of ferritin) in the liver, spleen, and bone marrow or is located in myoglobin in muscle tissue [1,5]. Transferrin is the main protein in blood that binds to iron and transports it throughout the body. Humans typically lose only small amounts of iron in urine, feces, the gastrointestinal tract, and skin. Losses are greater in menstruating women because of blood loss. Hepcidin, a circulating peptide hormone, is the key regulator of both iron absorption and the distribution of iron throughout the body, including in plasma [1,2,6].

The assessment of iron status depends almost entirely on hematological indicators [7]. However, these indicators are not sensitive or specific enough to adequately describe the full spectrum of iron status, and this can complicate the diagnosis of iron deficiency. A complementary approach is to consider how iron intakes from the diet and dietary supplements compare with recommended intakes.

Iron deficiency progresses from depletion of iron stores (mild iron deficiency), to iron-deficiency erythropoiesis (erythrocyte production), and finally to iron deficiency anemia (IDA) [8,9]. With iron-deficiency erythropoiesis (also known as marginal iron deficiency), iron stores are depleted and transferrin saturation declines, but hemoglobin levels are usually within the normal range. IDA is characterized by low hemoglobin concentrations, and decreases in hematocrit (the proportion of red blood cells in blood by volume) and mean corpuscular volume (a measure of erythrocyte size) [2,10].

Serum ferritin concentration, a measure of the body’s iron stores, is currently the most efficient and cost-effective test for diagnosing iron deficiency [11-13]. Because serum ferritin decreases during the first stage of iron depletion, it can identify low iron status before the onset of IDA [7,9,14]. A serum ferritin concentration lower than 30 mcg/L suggests iron deficiency, and a value lower than 10 mcg/L suggests IDA [15]. However, serum ferritin is subject to influence by inflammation (due, for example, to infectious disease), which elevates serum ferritin concentrations [16].

Hemoglobin and hematocrit tests are the most commonly used measures to screen patients for iron deficiency, even though they are neither sensitive nor specific [5,7,17]. Often, hemoglobin concentrations are combined with serum ferritin measurements to identify IDA [7]. Hemoglobin concentrations lower than 11 g/dL in children under 10 years of age, or lower than 12 g/dL in individuals aged 10 years or older, suggest IDA [8]. Normal hematocrit values are approximately 41% to 50% in males and 36% to 44% in females [18].

Recommended Intakes

Intake recommendations for iron and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine (IOM) of the National Academies (formerly National Academy of Sciences) [5]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:

• Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
• Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.
• Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.
• Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects.

Table 1 lists the current iron RDAs for nonvegetarians. The RDAs for vegetarians are 1.8 times higher than for people who eat meat. This is because heme iron from meat is more bioavailable than nonheme iron from plant-based foods, and meat, poultry, and seafood increase the absorption of nonheme iron [5].

For infants from birth to 6 months, the FNB established an AI for iron that is equivalent to the mean intake of iron in healthy, breastfed infants.

* Adequate Intake (AI)

Sources of Iron

Food

The richest sources of heme iron in the diet include lean meat and seafood [19]. Dietary sources of nonheme iron include nuts, beans, vegetables, and fortified grain products. In the United States, about half of dietary iron comes from bread, cereal, and other grain products [2,3,5]. Breast milk contains highly bioavailable iron but in amounts that are not sufficient to meet the needs of infants older than 4 to 6 months [2,20].

In the United States, Canada, and many other countries, wheat and other flours are fortified with iron [21,22]. Infant formulas are fortified with 12 mg iron per liter [20].

Heme iron has higher bioavailability than nonheme iron, and other dietary components have less effect on the bioavailability of heme than nonheme iron [3,4]. The bioavailability of iron is approximately 14% to 18% from mixed diets that include substantial amounts of meat, seafood, and vitamin C (ascorbic acid, which enhances the bioavailability of nonheme iron) and 5% to 12% from vegetarian diets [2,4]. In addition to ascorbic acid, meat, poultry, and seafood can enhance nonheme iron absorption, whereas phytate (present in grains and beans) and certain polyphenols in some non-animal foods (such as cereals and legumes) have the opposite effect [4]. Unlike other inhibitors of iron absorption, calcium might reduce the bioavailability of both nonheme and heme iron. However, the effects of enhancers and inhibitors of iron absorption are attenuated by a typical mixed western diet, so they have little effect on most people’s iron status.

Several food sources of iron are listed in Table 2. Some plant-based foods that are good sources of iron, such as spinach, have low iron bioavailability because they contain iron-absorption inhibitors, such as polyphenols [23,24].

* DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for iron is 18 mg for adults and children age 4 years and older [26]. FDA requires food labels to list iron content. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

The U.S. Department of Agriculture’s (USDA’s) FoodData Central [25] lists the nutrient content of many foods and provides a comprehensive list of foods containing iron arranged by nutrient content and by food name.

Dietary supplements

Iron is available in many dietary supplements. Multivitamin/multimineral supplements with iron, especially those designed for women, typically provide 18 mg iron (100% of the DV). Multivitamin/multimineral supplements for men or seniors frequently contain less or no iron. Iron-only supplements usually deliver more than the DV, with many providing 65 mg iron (360% of the DV).

Frequently used forms of iron in supplements include ferrous and ferric iron salts, such as ferrous sulfate, ferrous gluconate, ferric citrate, and ferric sulfate [3,27]. Because of its higher solubility, ferrous iron in dietary supplements is more bioavailable than ferric iron [3]. High doses of supplemental iron (45 mg/day or more) may cause gastrointestinal side effects, such as nausea and constipation [5]. Other forms of supplemental iron, such as heme iron polypeptides, carbonyl iron, iron amino-acid chelates, and polysaccharide-iron complexes, might have fewer gastrointestinal side effects than ferrous or ferric salts [27].

The different forms of iron in supplements contain varying amounts of elemental iron. For example, ferrous fumarate is 33% elemental iron by weight, whereas ferrous sulfate is 20% and ferrous gluconate is 12% elemental iron [27]. Fortunately, elemental iron is listed in the Supplement Facts panel, so consumers do not need to calculate the amount of iron supplied by various forms of iron supplements.

Approximately 14% to 18% of Americans use a supplement containing iron [28,29]. Rates of use of supplements containing iron vary by age and gender, ranging from 6% of children aged 12 to 19 years to 60% of women who are lactating and 72% of pregnant women [28,30].

Calcium might interfere with the absorption of iron, although this effect has not been definitively established [4,31]. For this reason, some experts suggest that people take individual calcium and iron supplements at different times of the day [32].

Iron Intakes and Status

People in the United States usually obtain adequate amounts of iron from their diets, but infants, young children, teenaged girls, pregnant women, and premenopausal women are at risk of obtaining insufficient amounts [28,33-35]. The average daily iron intake from foods is 11.5–13.7 mg/day in children aged 2–11 years, 15.1 mg/day in children and teens aged 12–19 years, and 16.3–18.2 mg/day in men and 12.6–13.5 mg/day in women older than 19 [28]. The average daily iron intake from foods and supplements is 13.7–15.1 mg/day in children aged 2–11 years, 16.3 mg/day in children and teens aged 12–19 years, and 19.3–20.5 mg/day in men and 17.0–18.9 mg/day in women older than 19. The median dietary iron intake in pregnant women is 14.7 mg/day [5].

Rates of iron deficiency vary by race and other sociodemographic factors. Six percent of white and black toddlers aged 1 to 3 years in the United States are iron deficient (defined as at least two abnormal results for the child’s age and gender on transferrin saturation, free erythrocyte protoporphyrin, and/or serum ferritin tests), compared with 12% of Hispanic toddlers [36]. Deficiency (including IDA) is more common among children and adolescents in food-insecure households than in food-secure households [36,37]. Among pregnant women, deficiency based on depleted iron stores is more common in Mexican American (23.6%) and non-Hispanic black women (29.6%) than in non-Hispanic white women (13.9%) [38].

Some groups are at risk of obtaining excess iron. Individuals with hereditary hemochromatosis, which predisposes them to absorb excessive amounts of dietary iron, have an increased risk of iron overload [39]. One study suggests that elderly people are more likely to have chronic positive iron balance and elevated total body iron than iron deficiency. Among 1,106 elderly white adults aged 67 to 96 years in the Framingham Heart Study, 13% had high iron stores (serum ferritin levels higher than 300 mcg/L in men and 200 mcg/L in women), of which only 1% was due to chronic disease [40]. The authors did not assess genotypes, so they could not determine whether these results were due to hemochromatosis [40].

Iron Deficiency

Iron deficiency is not uncommon in the United States, especially among young children, women of reproductive age, and pregnant women. Because iron deficiency is associated with poor diet, malabsorptive disorders, and blood loss, people with iron deficiency usually have other nutrient deficiencies [2]. The World Health Organization (WHO) estimates that approximately half of the 1.62 billion cases of anemia worldwide are due to iron deficiency [41]. In developing countries, iron deficiency often results from enteropathies and blood loss associated with gastrointestinal parasites [2].

Iron depletion and deficiency progresses through several stages [8-10]:

1. Mild deficiency or storage iron depletion: Serum ferritin concentrations and levels of iron in bone marrow decrease.
2. Marginal deficiency, mild functional deficiency, or iron-deficient erythropoiesis (erythrocyte production): Iron stores are depleted, iron supply to erythropoietic cells and transferrin saturation decline, but hemoglobin levels are usually within the normal range.
3. IDA: Iron stores are exhausted; hematocrit and levels of hemoglobin decline; and the resulting microcytic, hypochromic anemia is characterized by small red blood cells with low hemoglobin concentrations.

In 2002, the WHO characterized IDA as one of the 10 leading risk factors for disease around the world [42]. Although iron deficiency is the most common cause of anemia, deficiencies of other micronutrients (such as folate and vitamin B12) and other factors (such as chronic infection and inflammation) can cause different forms of anemia or contribute to their severity.

The functional deficits associated with IDA include gastrointestinal disturbances; weakness; fatigue; difficulty concentrating; and impaired cognitive function, immune function, exercise or work performance, and body temperature regulation [15,43]. In infants and children, IDA can result in psychomotor and cognitive abnormalities that, without treatment, can lead to learning difficulties [2,43]. Some evidence indicates that the effects of deficiencies early in life persist through adulthood [2]. Because iron deficiency is often accompanied by deficiencies of other nutrients, the signs and symptoms of iron deficiency can be difficult to isolate [2].

Groups at Risk of Iron Inadequacy

The following groups are among those most likely to have inadequate intakes of iron.

Pregnant women

During pregnancy, plasma volume and red cell mass expand due to dramatic increases in maternal red blood cell production [2]. As a result of this expansion and to meet the needs of the fetus and placenta, the amount of iron that women need increases during pregnancy. Iron deficiency during pregnancy increases the risk of maternal and infant mortality, premature birth, and low birthweight [44].

Infants and young children

Infants—especially those born preterm or with low birthweight or whose mothers have iron deficiency—are at risk of iron deficiency because of their high iron requirements due to their rapid growth [34,45]. Full-term infants usually have sufficient iron stores and need little if any iron from external sources until they are 4 to 6 months old [2]. However, full-term infants have a risk of becoming iron deficient at 6 to 9 months unless they obtain adequate amounts of solid foods that are rich in bioavailable iron or iron-fortified formula.

Women with heavy menstrual bleeding

Women of reproductive age who have menorrhagia, or abnormally heavy bleeding during menstruation, are at increased risk of iron deficiency. At least 10% of menstruating women are believed to have menorrhagia, but the percentage varies widely depending on the diagnostic criteria used [46-48]. Women with menorrhagia lose significantly more iron per menstrual cycle on average than women with normal menstrual bleeding [49]. Limited evidence suggests that menorrhagia might be responsible for about 33% to 41% of cases of IDA in women of reproductive age [50,51].

Frequent blood donors

Frequent blood donors have an increased risk of iron deficiency [5]. In the United States, adults may donate blood as often as every 8 weeks, which can deplete iron stores. About 25%–35% of regular blood donors develop iron deficiency [52]. In a study of 2,425 blood donors, men who had given at least three and women who had given at least two whole-blood donations in the previous year were more than five times as likely to have depleted iron stores as first-time donors [53]. A clinical trial of iron supplementation found that of 215 adults who had donated a unit of blood within the past 3–8 days, those randomized to take an iron supplement (37.5 mg/day elemental iron from ferrous gluconate) for 24 weeks recovered their lost hemoglobin and iron in less than half the time of those not given the supplement [52]. Without iron supplementation, two-thirds of the donors had not recovered the iron they lost, even after 24 weeks.

People with cancer

Up to 60% of patients with colon cancer have iron deficiency at diagnosis, probably due to chronic blood loss [54]. The prevalence of iron deficiency in patients with other types of cancer ranges from 29% to 46%. The main causes of iron deficiency in people with cancer are anemia of chronic disease (discussed in the Iron and Health section below) and chemotherapy-induced anemia. However, chronic blood loss and deficiencies of other nutrients (due, for example, to cancer-induced anorexia) can exacerbate iron deficiency in this population.

People who have gastrointestinal disorders or have had gastrointestinal surgery

People with certain gastrointestinal disorders (such as celiac disease, ulcerative colitis, and Crohn’s disease) or who have undergone certain gastrointestinal surgical procedures (such as gastrectomy or intestinal resection) have an increased risk of iron deficiency because their disorder or surgery requires dietary restrictions or results in iron malabsorption or blood loss in the gastrointestinal tract [55-57]. The combination of low iron intake and high iron loss can lead to a negative iron balance; reduced production of hemoglobin; or microcytic, hypochromic anemia [58].

People with heart failure

Approximately 60% of patients with chronic heart failure have iron deficiency and 17% have IDA, which might be associated with a higher risk of death in this population [59,60]. Potential causes of iron deficiency in people with heart failure include poor nutrition, malabsorption, defective mobilization of iron stores, cardiac cachexia, and use of aspirin and oral anticoagulants, which might result in the loss of some blood in the gastrointestinal tract [61].

Iron and Health

This section focuses on the role of iron in IDA in pregnant women, infants, and toddlers, as well as in anemia of chronic disease.

IDA in pregnant women

Insufficient iron intakes during pregnancy increase a woman’s risk of IDA [62-65]. Low intakes also increase her infant’s risk of low birthweight, premature birth, low iron stores, and impaired cognitive and behavioral development.

An analysis of 1999–2006 data from the National Health and Nutrition Examination Survey (NHANES) found that 18% of pregnant women in the United States had iron deficiency [38]. Rates of deficiency were 6.9% among women in the first trimester,14.3% in the second trimester, and 29.7% in the third trimester.

Randomized controlled trials have shown that iron supplementation can prevent IDA in pregnant women and related adverse consequences in their infants [66,67]. A Cochrane review showed that daily supplementation with 9–90 mg iron reduced the risk of anemia in pregnant women at term by 70% and of iron deficiency at term by 57% [64]. In the same review, use of daily iron supplements was associated with an 8.4% risk of having a low-birthweight newborn compared to 10.2% with no supplementation. In addition, mean birthweight was 31 g higher for infants whose mothers took daily iron supplements during pregnancy compared with the infants of mothers who did not take iron.

Guidelines on iron supplementation during pregnancy vary, but many recommend some form of iron supplementation to prevent IDA:

• The American College of Obstetricians and Gynecologists (ACOG) states that good and consistent evidence shows that iron supplementation decreases the prevalence of maternal anemia at delivery [68]. However, it acknowledges that only limited or inconsistent evidence shows that IDA during pregnancy is associated with a higher risk of low birthweight, preterm birth, or perinatal mortality. ACOG recommends screening all pregnant women for anemia and treating those with IDA (which it defines as hematocrit levels less than 33% in the first and third trimesters and less than 32% in the second trimester) with supplemental iron in addition to prenatal vitamins [68].
• The Centers for Disease Control and Prevention (CDC) recommends that all pregnant women, at their first prenatal visit, begin taking an oral, low dose (30 mg/day) supplement of iron and be screened for IDA [17]. Women with IDA (which it defines as a hemoglobin concentration less than 9 g/dL or a hematocrit level less than 27%) should be treated with an oral dose of 60-120 mg/day of iron.
• In contrast, the U.S. Preventive Services Task Force (USPSTF) has concluded that the current evidence is insufficient to recommend for or against both screening for IDA in pregnant women and routinely supplementing them with iron to prevent adverse maternal health and birth outcomes [69]. They note, however, that their recommendation does not apply to pregnant women who are malnourished, have symptoms of iron deficiency anemia, or those with special hematologic conditions or nutritional needs that increase iron requirements.

The IOM notes that because the median intake of dietary iron by pregnant women is well below the EAR, pregnant women need iron supplementation [5]. The Dietary Guidelines for Americans advises that women who are pregnant take an iron supplement when recommended by an obstetrician or other health-care provider [19]. It adds that low intakes of iron are a public health concern for pregnant women.

IDA in infants and toddlers

Approximately 12% of infants aged 6 to 11 months in the United States have inadequate iron intakes, and 8% of toddlers have iron deficiency [36,70]. The prevalence of IDA in U.S. toddlers aged 12 to 35 months ranges from 0.9% to 4.4% depending on race or ethnicity and socioeconomic status [20]. Full-term infants typically have adequate iron stores for approximately the first 4 to 6 months, but the risk of iron deficiency in low-birthweight and preterm infants begins at birth because of their low iron stores.

IDA in infancy can lead to adverse cognitive and psychological effects, including delayed attention and social withdrawal; some of these effects might be irreversible [2,20]. In addition, IDA is associated with higher lead concentrations in the blood (although the cause of this is not fully understood), which can increase the risk of neurotoxicity [20].

A Cochrane review of 26 studies in 2,726 preterm and low-birthweight infants found that enteral iron supplementation (at least 1 mg/kg/day) reduces the risk of iron deficiency, but the long-term effects of supplementation on neurodevelopmental outcomes and growth is not clear [71]. Another Cochrane review of 8 trials in 3,748 children younger than 2 in low-income countries showed that home fortification of semi-solid foods with micronutrient powders containing 12.5 mg to 30 mg elemental iron as ferrous fumarate and 4 to 14 other micronutrients for 2 to 12 months reduced rates of anemia by 31% and of iron deficiency by 51% compared with no intervention or placebo but had no effect on any growth measurements [72].

Guidelines vary on dietary iron intakes and possible supplementation to ensure adequate iron status and to prevent or treat IDA in infants and young children:

• The CDC recommends that infants less than 12 months of age who are not exclusively or primarily breastfed drink iron-fortified infant formula [17]. Breastfed infants who were born preterm or with a low birthweight should receive 2-4 mg/kg/day of iron drops (to a maximum of 15 mg/day) from ages 1-12 months. Breastfed infants who receive insufficient iron (less than 1 mg/kg/day) from supplementary foods by age 6 months should receive 1 mg/kg/day of iron drops. The CDC also recommends that infants and preschool children at high risk for IDA (e.g., children from low-income families and migrant children) be screened between ages 9-12 months, 6 months later, and annually from ages 2-5 years. Treatment for IDA begins with 3 mg/kg/day of iron drops given between meals. (See reference 17 for additional advice from the CDC.)
• The American Academy of Pediatrics recommends 1 mg/kg daily iron supplementation for exclusively or primarily breastfed full-term infants from age 4 months until the infants begin eating iron-containing complementary foods, such as iron-fortified cereals [20]. Standard infant formulas containing 10 to 12 mg/L iron can meet the iron needs of infants for the first year of life. The Academy recommends 2 mg/kg/day iron supplementation for preterm infants aged 1 to 12 months who are fed breast milk.
• The WHO recommends universal supplementation with 2 mg/kg/day of iron in children aged 6 to 23 months whose diet does not include foods fortified with iron or who live in regions (such as developing countries) where anemia prevalence is higher than 40% [44].
• In a recommendation statement issued in 2015, the USPSTF concluded that the available evidence is insufficient to recommend for or against routine screening for IDA in children ages 6 to 24 months who live in the United States and who are asymptomatic for IDA [73]. It added that this recommendation does not apply to severely malnourished children or children who were born prematurely or with low birthweight. Earlier, in 2006, the USPSTF stated that while it found insufficient evidence to recommend routine iron supplementation in asymptomatic infants at average risk of IDA, it did recommend routine iron supplements for children aged 6 to 12 months who are at increased risk of IDA (e.g., those who were premature or low birthweight) [74]. The USPSTF’s 2015 statement notes that its current recommendation is limited to screening because the widespread use of iron-fortified foods in the United States (including infant formulas and cereals) would likely limit the impact of iron supplementation prescribed by physicians [73].

Some studies have suggested that iron supplementation in young children living in areas where malaria is endemic could increase their risk of malaria [75,76]. However, a Cochrane review of 33 trials in 13,114 children showed that intermittent supplementation does not appear to have this effect [77]. The WHO therefore recommends 6-month supplementation cycles as follows: children aged 24 to 59 months should receive 25 mg iron and those aged 5 to 12 years should receive 45 mg every week for 3 months, followed by 3 months of no supplementation [75]. The WHO recommends providing these supplements in malaria-endemic areas in conjunction with measures to prevent, diagnose, and treat malaria.

Anemia of chronic disease

Certain inflammatory, infectious, and neoplastic diseases (such as rheumatoid arthritis, inflammatory bowel disease, and hematologic malignancies) can cause anemia of chronic disease, also known as anemia of inflammation [2,78]. Anemia of chronic disease is the second most common type of anemia after IDA [79]. In people with anemia of chronic disease, inflammatory cytokines upregulate the hormone hepcidin. As a result, iron homeostasis is disrupted and iron is diverted from the circulation to storage sites, limiting the amount of iron available for erythropoiesis.

Anemia of chronic disease is usually mild to moderate (hemoglobin levels 8 to 9.5 g/dL) and is associated with low counts of erythrocytes and decreased erythropoiesis [78]. The condition can be difficult to diagnose because, although low serum ferritin levels indicate iron deficiency, these levels tend to be higher in patients with infection or inflammation [80].

The clinical implications of iron deficiency in people with chronic diseases are not clear. Even mild anemia of chronic disease is associated with an increased risk of hospitalization and mortality in elderly people [81]. Two prospective observational studies found that iron deficiency in patients with objectively measured heart failure was associated with an increased risk of heart transplantation and death, and this association was independent of other well-established prognostic factors for poor outcomes, including anemia [82,83]. However, an analysis of NHANES data on 574 adults with self-reported heart failure found no association between iron deficiency and all-cause or cardiovascular mortality [60].

The main therapy for anemia of chronic disease is treatment of the underlying disease [79]. But when such treatment is not possible, iron supplementation and/or erythropoiesis-stimulating agents (ESAs) are sometimes used. The use of iron supplements—whether oral, intravenous, or parenteral—in this setting is controversial because they might increase the risk of infection and cardiovascular events and could cause tissue damage [79].

Only a few small studies have evaluated the benefits of oral iron supplementation alone or in combination with ESAs to treat anemia of chronic disease. For example, a prospective observational study in 132 patients with anemia and chronic kidney disease who were not on dialysis or ESAs found that oral supplements (130 mg/day elemental iron from ferrous sulfate twice daily) for 1 year resulted in a decline in hemoglobin of only 0.13 g/dL compared with 0.46 g/dL in the placebo group [76,84]. A randomized trial of oral iron supplements (equivalent to 200 mg/day elemental iron, form of iron not specified) taken with an ESA once weekly in 100 patients with cancer-related anemia resulted in a mean increase of 2.4 g/dL hemoglobin after 24 weeks compared with oral supplements only [85]. Iron administered parentally increases hemoglobin levels to a greater extent and is associated with fewer side effects than oral iron supplementation in patients with anemia of chronic disease [86].

Health Risks from Excessive Iron

Adults with normal intestinal function have very little risk of iron overload from dietary sources of iron [2]. However, acute intakes of more than 20 mg/kg iron from supplements or medicines can lead to gastric upset, constipation, nausea, abdominal pain, vomiting, and faintness, especially if food is not taken at the same time [2,5]. Taking supplements containing 25 mg elemental iron or more can also reduce zinc absorption and plasma zinc concentrations [3,87,88]. In severe cases (e.g., one-time ingestions of 60 mg/kg), overdoses of iron can lead to multisystem organ failure, coma, convulsions, and even death [27,89].

Between 1983 and 2000, at least 43 U.S. children died from ingesting supplements containing high doses of iron (36–443 mg iron/kg body weight) [27]. Accidental ingestion of iron supplements caused about a third of poisoning deaths among children reported in the United States between 1983 and 1991.

In 1997, the FDA began requiring oral supplements containing more than 30 mg elemental iron per dose to be sold in single-dose packaging with strong warning labels. At the same time, many manufacturers voluntarily replaced the sugar coating on iron tablets with film coatings. Between 1998 and 2002, only one child death due to ingesting an iron-containing tablet was reported [27]. As a result of a court decision, the FDA removed its single-dose packaging requirement for iron supplements in 2003 [90]. FDA currently requires that iron-containing dietary supplements sold in solid form (e.g., tablets or capsules but not powders) carry the following label statement: “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” [91]. In addition, since 1978, the Consumer Product Safety Commission has required manufacturers to package dietary supplements containing 250 mg or more elemental iron per container in child-resistant bottles or packaging to prevent accidental poisoning [92,93].

Hemochromatosis, a disease caused by a mutation in the hemochromatosis (HFE) gene, is associated with an excessive buildup of iron in the body [3,39,94]. About 1 in 10 whites carry the most common HFE mutation (C282Y), but only 4.4 whites per 1,000 are homozygous for the mutation and have hemochromatosis [95]. The condition is much less common in other ethnic groups. Without treatment by periodic chelation or phlebotomy, people with hereditary hemochromatosis typically develop signs of iron toxicity by their 30s [3]. These effects can include liver cirrhosis, hepatocellular carcinoma, heart disease, and impaired pancreatic function. The American Association for the Study of Liver Diseases recommends that treatment of hemochromatosis include the avoidance of iron and vitamin C supplements [39].

The FNB has established ULs for iron from food and supplements based on the amounts of iron that are associated with gastrointestinal effects following supplemental intakes of iron salts (see Table 3). The ULs apply to healthy infants, children, and adults. Physicians sometimes prescribe intakes higher than the UL, such as when people with IDA need higher doses to replenish their iron stores [5].

Interactions with Medications

Iron can interact with certain medications, and some medications can have an adverse effect on iron levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their iron status with their healthcare providers.

Levodopa

Some evidence indicates that in healthy people, iron supplements reduce the absorption of levodopa (found in Sinemet® and Stalevo®), used to treat Parkinson’s disease and restless leg syndrome, possibly through chelation [96-98]. In the United States, the labels for levodopa warn that iron-containing dietary supplements might reduce the amount of levodopa available to the body and, thus, diminish its clinical effectiveness [99,100].

Levothyroxine

Levothyroxine (Levothroid®, Levoxyl®, Synthroid®, Tirosint®, and Unithroid®) is used to treat hypothyroidism, goiter, and thyroid cancer. The simultaneous ingestion of iron and levothyroxine can result in clinically significant reductions in levothyroxine efficacy in some patients [101]. The labels for some of these products [102,103] warn that iron supplements can reduce the absorption of levothyroxine tablets and advise against administering levothyroxine within 4 hours of iron supplements.

Proton pump inhibitors

Gastric acid plays an important role in the absorption of nonheme iron from the diet. Because proton pump inhibitors, such as lansoprazole (Prevacid®) and omeprazole (Prilosec®), reduce the acidity of stomach contents, they can reduce iron absorption [3]. Treatment with proton pump inhibitors for up to 10 years is not associated with iron depletion or anemia in people with normal iron stores [104]. But patients with iron deficiency taking proton pump inhibitors can have suboptimal responses to iron supplementation [105].

Iron and Healthful Diets

The federal government’s 2020–2025 Dietary Guidelines for Americans notes that “Because foods provide an array of nutrients and other components that have benefits for health, nutritional needs should be met primarily through foods. … In some cases, fortified foods and dietary supplements are useful when it is not possible otherwise to meet needs for one or more nutrients (e.g., during specific life stages such as pregnancy).”

For more information about building a healthy dietary pattern, refer to the Dietary Guidelines for Americans and the U.S. Department of Agriculture’s MyPlate.

The Dietary Guidelines for Americans describes a healthy dietary pattern as one that:

• Includes a variety of vegetables; fruits; grains (at least half whole grains); fat-free and low-fat milk, yogurt, and cheese; and oils.Many ready-to-eat breakfast cereals are fortified with iron, and some fruits and vegetables contain iron.
• Includes a variety of protein foods such as lean meats; poultry; eggs; seafood; beans, peas, and lentils; nuts and seeds; and soy products.Oysters and beef liver have high amounts of iron. Beef, cashews, chickpeas, and sardines are good sources of iron. Chicken, tuna, and eggs contain iron.
• Limits foods and beverages higher in added sugars, saturated fat, and sodium.
• Limits alcoholic beverages.
• Stays within your daily calorie needs.

References

1. Wessling-Resnick M. Iron. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler RG, eds. Modern Nutrition in Health and Disease. 11th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2014:176-88.
2. Aggett PJ. Iron. In: Erdman JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Washington, DC: Wiley-Blackwell; 2012:506-20.
3. Murray-Kolbe LE, Beard J. Iron. In: Coates PM, Betz JM, Blackman MR, et al., eds. Encyclopedia of Dietary Supplements. 2nd ed. London and New York: Informa Healthcare; 2010:432-8.
4. Hurrell R, Egli I. Iron bioavailability and dietary reference values. Am J Clin Nutr 2010;91:1461S-7S. [PubMed abstract]
5. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc : a Report of the Panel on Micronutrients. Washington, DC: National Academy Press; 2001.
6. Drakesmith H, Prentice AM. Hepcidin and the Iron-Infection Axis. Science 2012;338:768-72. [PubMed abstract]
7. Taylor CL, Brannon PM. Introduction to workshop on iron screening and supplementation in iron-replete pregnant women and young children. Am J Clin Nutr. 2017 Dec;106(Suppl 6):1547S-54S. [PubMed abstract]
8. Powers JM, Buchanan GR. Disorders of iron metabolism: New diagnostic and treatment approaches to iron deficiency. Hematol Oncol Clin North Am. 2019 Jun;33(3):393-408. [PubMed abstract]
9. Lynch S, Pfeiffer CM, Georgieff MK, Brittenham G, Fairweather-Tait S, Hurrell RF, et al. Biomarkers of Nutrition for Development (BOND)-Iron Review. J Nutr. 2018 Jun 1;148(suppl 1):1001S-67S. [PubMed abstract]
10. World Health Organization. Report: Priorities in the Assessment of Vitamin A and Iron Status in Populations, Panama City, Panama, 15-17 September 2010. Geneva; 2012.
11. DeLoughery TG. Microcytic anemia. N Engl J Med. 2014 Oct 2;371(14):1324-31. [PubMed abstract]
12. DeLoughery TG. Iron deficiency anemia. Med Clin North Am. 2017 Mar;101(2):319-32. doi: 10.1016/j.mcna.2016.09.004. [PubMed abstract]
13. Short MW, Domagalski JE. Iron deficiency anemia: evaluation and management. Am Fam Physician. 2013 Jan 15;87(2):98-104. [PubMed abstract]
14. Gibson RS. Assessment of Iron Status. In: Principles of Nutritional Assessment. 2nd ed. New York: Oxford University Press; 2005:443-76.
15. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015 May 7;372(19):1832-43. [PubMed abstract]
16. Suchdev PS, Williams AM, Mei Z, Flores-Ayala R, Pasricha SR, Rogers LM, Namaste SM. Assessment of iron status in settings of inflammation: challenges and potential approaches. Am J Clin Nutr. 2017 Dec;106(Suppl 6):1626S-33S. [PubMed abstract]
17. Centers for Disease Control and Prevention (CDC). Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep 1998;47:1-29. [PubMed abstract]
18. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US). Hematocrit.
19. 2015–2020 Dietary Guidelines for Americans. 8th Edition. December 2015.
20. Baker RD, Greer FR. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age). Pediatrics 2010;126:1040-50. [PubMed abstract]
21. Whittaker P, Tufaro PR, Rader JI. Iron and folate in fortified cereals. J Am Coll Nutr 2001;20:247-54. [PubMed abstract]
22. Flour Fortification Initiative. Country Profiles.
23. Rutzke CJ, Glahn RP, Rutzke MA, Welch RM, Langhans RW, Albright LD, et al. Bioavailability of iron from spinach using an in vitro/human Caco-2 cell bioassay model. Habitation 2004;10:7-14. [PubMed abstract]
24. Gillooly M, Bothwell TH, Torrance JD, MacPhail AP, Derman DP, Bezwoda WR, et al. The effects of organic acids, phytates and polyphenols on the absorption of iron from vegetables. Br J Nutr 1983;49:331-42. [PubMed abstract]
25. U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019.
26. U.S. Food and Drug Administration. Food Labeling: Revision of the Nutrition and Supplement Facts Labels. 2016.
27. Manoguerra AS, Erdman AR, Booze LL, Christianson G, Wax PM, Scharman EJ, et al. Iron ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2005;43:553-70. [PubMed abstract]
28. U.S. Department of Agriculture, Agricultural Research Service. What We Eat in America, 2009-2010. 2012.
29. Bailey RL, Gahche JJ, Lentino CV, Dwyer JT, Engel JS, Thomas PR, et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011;141:261-6. [PubMed abstract]
30. Cogswell ME, Kettel-Khan L, Ramakrishnan U. Iron supplement use among women in the United States: science, policy and practice. J Nutr 2003;133:1974S-7S. [PubMed abstract]
31. Lonnerdal B. Calcium and iron absorption–mechanisms and public health relevance. Int J Vitam Nutr Res 2010;80:293-9. [PubMed abstract]
32. Lynch SR. The effect of calcium on iron absorption. Nutr Res Rev 2000;13:141-58. [PubMed abstract]
33. Blanck HM, Cogswell ME, Gillespie C, Reyes M. Iron supplement use and iron status among US adults: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr 2005;82:1024-31. [PubMed abstract]
34. Black MM, Quigg AM, Hurley KM, Pepper MR. Iron deficiency and iron-deficiency anemia in the first two years of life: strategies to prevent loss of developmental potential. Nutr Rev 2011;69 Suppl 1:S64-70. [PubMed abstract]
35. Halterman JS, Kaczorowski JM, Aligne CA, Auinger P, Szilagyi PG. Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States. Pediatrics 2001;107:1381-6. [PubMed abstract]
36. Brotanek JM, Gosz J, Weitzman M, Flores G. Iron deficiency in early childhood in the United States: risk factors and racial/ethnic disparities. Pediatrics 2007;120:568-75. [PubMed abstract]
37. Eicher-Miller HA, Mason AC, Weaver CM, McCabe GP, Boushey CJ. Food insecurity is associated with iron deficiency anemia in US adolescents. Am J Clin Nutr 2009;90:1358-71. [PubMed abstract]
38. Mei Z, Cogswell ME, Looker AC, Pfeiffer CM, Cusick SE, Lacher DA, et al. Assessment of iron status in US pregnant women from the National Health and Nutrition Examination Survey (NHANES), 1999-2006. Am J Clin Nutr 2011;93:1312-20. [PubMed abstract]
39. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54:328-43. [PubMed abstract]
40. Fleming DJ, Jacques PF, Tucker KL, Massaro JM, D’Agostino RB, Sr., Wilson PW, et al. Iron status of the free-living, elderly Framingham Heart Study cohort: an iron-replete population with a high prevalence of elevated iron stores. Am J Clin Nutr 2001;73:638-46. [PubMed abstract]
41. World Health Organization. Worldwide Prevalence of Anaemia 1993–2005: WHO Global Database on Anaemia. World Health Organization, 2008.
42. World Health Organization. The World Health Report. Geneva: World Health Organization; 2002.
43. Clark SF. Iron Deficiency Anemia. Nutr Clin Pract 2008;23:128-41. [PubMed abstract]
44. World Health Organization. Iron Deficiency Anaemia: Assessment, Prevention, and Control. World Health Organization, 2001.
45. Domellöf M. Iron requirements in infancy. Ann Nutr Metab 2011;59:59-63. [PubMed abstract]
46. Matthews ML. Abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol Clin North Am 2015;42:103-15. 
      [PubMed abstract]
47. Bitzer J, Heikinheimo O, Nelson AL, Calaf-Alsina J, Fraser IS. Medical management of heavy menstrual bleeding: a comprehensive review of the literature. Obstet Gynecol Surv 2015;70:115-30. [PubMed abstract]
48. El-Hemaidi I, Gharaibeh A, Shehata H. Menorrhagia and bleeding disorders. Curr Opin Obstet Gynecol 2007;19:513-20. [PubMed abstract]
49. Napolitano M, Dolce A, Celenza G, Grandone E, Perilli MG, Siragusa S, et al. Iron-dependent erythropoiesis in women with excessive menstrual blood losses and women with normal menses. Ann Hematol 2014;93:557-63. [PubMed abstract]
50. Vannella L, Aloe Spiriti MA, Cozza G, Tardella L, Monarca B, Cuteri A, et al. Benefit of concomitant gastrointestinal and gynaecological evaluation in premenopausal women with iron deficiency anaemia. Aliment Pharmacol Ther 2008;28:422-30. [PubMed abstract]
51. Philipp CS, Faiz A, Dowling N, Dilley A, Michaels LA, Ayers C, et al. Age and the prevalence of bleeding disorders in women with menorrhagia. Obstet Gynecol 2005;105:61-6. [PubMed abstract]
52. Kiss JE, Brambilla D, Glynn SA, Mast AE, Spencer BR, Stone M, et al. Oral iron supplementation after blood donation: a randomized clinical trial. JAMA 2015;313:575-83. [PubMed abstract]
53. Cable RG, Glynn SA, Kiss JE, Mast AE, Steele WR, Murphy EL, et al. Iron deficiency in blood donors: analysis of enrollment data from the REDS-II Donor Iron Status Evaluation (RISE) study. Transfusion 2011;51:511-22. [PubMed abstract]
54. Aapro M, Osterborg A, Gascon P, Ludwig H, Beguin Y. Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of i.v. iron. Ann Oncol 2012;23:1954-62. [PubMed abstract]
55. Bayraktar UD, Bayraktar S. Treatment of iron deficiency anemia associated with gastrointestinal tract diseases. World J Gastroenterol 2010;16:2720-5. [PubMed abstract]
56. Gasche C, Berstad A, Befrits R, Beglinger C, Dignass A, Erichsen K, et al. Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. Inflamm Bowel Dis 2007;13:1545-53. [PubMed abstract]
57. Bermejo F, Garcia-Lopez S. A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World J Gastroenterol 2009;15:4638-43. [PubMed abstract]
58. Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn’s disease. Aliment Pharmacol Ther 2006;24:1507-23. [PubMed abstract]
59. Groenveld HF, Januzzi JL, Damman K, van Wijngaarden J, Hillege HL, van Veldhuisen DJ, et al. Anemia and mortality in heart failure patients a systematic review and meta-analysis. J Am Coll Cardiol 2008;52:818-27. [PubMed abstract]
60. Parikh A, Natarajan S, Lipsitz SR, Katz SD. Iron deficiency in community-dwelling US adults with self-reported heart failure in the National Health and Nutrition Examination Survey III: prevalence and associations with anemia and inflammation. Circ Heart Fail 2011;4:599-606. [PubMed abstract]
61. Lipsic E, van der Meer P. Erythropoietin, iron, or both in heart failure: FAIR-HF in perspective. Eur J Heart Fail 2010;12:104-5. [PubMed abstract]
62. Milman N. Iron in pregnancy: How do we secure an appropriate iron status in the mother and child? Ann Nutr Metab 2011;59:50-4. [PubMed abstract]
63. Pavord S, Myers B, Robinson S, Allard S, Strong J, Oppenheimer C. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2012;156:588-600. [PubMed abstract]
64. Pena-Rosas JP, De-Regil LM, Dowswell T, Viteri FE. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev 2012;12:CD004736. [PubMed abstract]
65. Scholl TO. Maternal iron status: relation to fetal growth, length of gestation, and iron endowment of the neonate. Nutr Rev 2011;69 Suppl 1:S23-9. [PubMed abstract]
66. Makrides M, Crowther CA, Gibson RA, Gibson RS, Skeaff CM. Efficacy and tolerability of low-dose iron supplements during pregnancy: a randomized controlled trial. Am J Clin Nutr 2003;78:145-53. [PubMed abstract]
67. Cogswell ME, Parvanta I, Ickes L, Yip R, Brittenham GM. Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial. Am J Clin Nutr 2003;78:773-81. [PubMed abstract]
68. American Congress of Obstetrics and Gynecology. ACOG Practice Bulletin No. 95: anemia in pregnancy. Obstet Gynecol 2008;112:201-7. [PubMed abstract]
69. Siu AL, on behalf of the U.S. Preventive Services Task Force. Screening for iron deficiency anemia and iron supplementation in pregnant women to improve maternal health and birth outcomes: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. doi:10.7326/M15-1707. [PubMed abstract]
70. Butte NF, Fox MK, Briefel RR, Siega-Riz AM, Dwyer JT, Deming DM, et al. Nutrient intakes of US infants, toddlers, and preschoolers meet or exceed dietary reference intakes. J Am Diet Assoc 2010;110:S27-37. [PubMed abstract]
71. Mills RJ, Davies MW. Enteral iron supplementation in preterm and low birth weight infants. Cochrane Database Syst Rev 2012;3:CD005095. [PubMed abstract]
72. De-Regil LM, Suchdev PS, Vist GE, Walleser S, Pena-Rosas JP. Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age (review). Cochrane Database Syst Rev 2011:CD008959. [PubMed abstract]
73. Siu AL, on behalf of the US Preventive Services Task Force. Screening for iron deficiency anemia in young children: USPSTF recommendation statement. Pediatrics 2015;136:746-52. [PubMed abstract]
74. U.S. Preventive Services Task Force. Screening for Iron Deficiency Anemia—Including Iron Supplementation for Children and Pregnant Women: Recommendation Statementexternal. Publication No. AHRQ 06-058., 2006.
75. World Health Organization. Guideline: Intermittent Iron Supplementation in Preschool and School-age Children. Geneva; 2011. [PubMed abstract]
76. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 2006;367:133-43. [PubMed abstract]
77. De-Regil LM, Jefferds ME, Sylvetsky AC, Dowswell T. Intermittent iron supplementation for improving nutrition and development in children under 12 years of age. Cochrane Database Syst Rev 2011:CD009085. [PubMed abstract]
78. Cullis JO. Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol 2011;154:289-300. [PubMed abstract]
79. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352:1011-23. [PubMed abstract]
80. Thurnham DI, McCabe LD, Haldar S, Wieringa FT, Northrop-Clewes CA, McCabe GP. Adjusting plasma ferritin concentrations to remove the effects of subclinical inflammation in the assessment of iron deficiency: a meta-analysis. Am J Clin Nutr 2010;92:546-55. [PubMed abstract]
81. Riva E, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, et al. Association of mild anemia with hospitalization and mortality in the elderly: the Health and Anemia population-based study. Haematologica 2009;94:22-8. [PubMed abstract]
82. Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J 2010;31:1872-80. [PubMed abstract]
83. Klip IT, Comin-Colet J, Voors AA, Ponikowski P, Enjuanes C, Banasiak W, et al. Iron deficiency in chronic heart failure: An international pooled analysis. Am Heart J 2013;165:575-82 e3. [PubMed abstract]
84. Kim SM, Lee CH, Oh YK, Joo KW, Kim YS, Kim S, et al. The effects of oral iron supplementation on the progression of anemia and renal dysfunction in patients with chronic kidney disease. Clin Nephrol 2011;75:472-9. [PubMed abstract]
85. Mystakidou K, Kalaidopoulou O, Katsouda E, Parpa E, Kouskouni E, Chondros C, et al. Evaluation of epoetin supplemented with oral iron in patients with solid malignancies and chronic anemia not receiving anticancer treatment. Anticancer Res 2005;25:3495-500. [PubMed abstract]
86. Cavill I, Auerbach M, Bailie GR, Barrett-Lee P, Beguin Y, Kaltwasser P, et al. Iron and the anaemia of chronic disease: a review and strategic recommendations. Curr Med Res Opin 2006;22:731-7. [PubMed abstract]
87. Solomons NW. Competitive interaction of iron and zinc in the diet: consequences for human nutrition. J Nutr 1986;116:927-35. [PubMed abstract]
88. Whittaker P. Iron and zinc interactions in humans. Am J Clin Nutr 1998;68:442S-6S. [PubMed abstract]
89. Chang TP, Rangan C. Iron poisoning: a literature-based review of epidemiology, diagnosis, and management. Pediatr Emerg Care 2011;27:978-85. [PubMed abstract]
90. Food and Drug Administration. Iron-Containing Supplements and Drugs; Label Warning Statements and Unit-Dose Packaging Requirements; Removal of Regulations for Unit-Dose Packaging Requirements for Dietary Supplements and Drugs. 2003.
91. Code of Federal Regulations. Title 21 (Food and Drugs), Section 101.17 (Food labeling warning, notice, and safe handling statements).
92. Consumer Product Safety Commission. Poison Prevention Packaging: A Guide For Healthcare Professionals. 2005.
93. Substances Requiring Special Packaging. 16 CFR 1700.4. 1973.
94. Fleming RE, Ponka P. Iron Overload in human disease. N Engl J Med 2012;366:348-59. [PubMed abstract]
95. Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006;145:209-23. [PubMed abstract]
96. Campbell NR, Hasinoff B. Ferrous sulfate reduces levodopa bioavailability: chelation as a possible mechanism. Clin Pharmacol Ther 1989;45:220-5. [PubMed abstract]
97. Campbell RR, Hasinoff B, Chernenko G, Barrowman J, Campbell NR. The effect of ferrous sulfate and pH on L-dopa absorption. Can J Physiol Pharmacol 1990;68:603-7. [PubMed abstract]
98. Greene RJ, Hall AD, Hider RC. The interaction of orally administered iron with levodopa and methyldopa therapy. J Pharm Pharmacol 1990;42:502-4. [PubMed abstract]
99. Novartis. Stalevo Package Insert. 2010.
100. Merck & Co. I. Sinemet Package Insert. 2011.
101. Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med 1992;117:1010-3. [PubMed abstract]
102. Forest Laboratories I. Levothroid Package Insert. 2011.
103. Abbvie Inc. Synthroid Package Insert. 2012.
104. Stewart CA, Termanini B, Sutliff VE, Serrano J, Yu F, Gibril F, et al. Iron absorption in patients with Zollinger-Ellison syndrome treated with long-term gastric acid antisecretory therapy. Aliment Pharmacol Ther 1998;12:83-98. [PubMed abstract]
105. Ajmera AV, Shastri GS, Gajera MJ, Judge TA. Suboptimal response to ferrous sulfate in iron-deficient patients taking omeprazole. Am J Ther 2012;19:185-9. [PubMed abstract]

Source:

https://ods.od.nih.gov/factsheets/Iron-HealthProfessional/