INTRODUCTION — Iron deficiency is the most common nutritional deficiency in children. The global prevalence of anemia in 2010 was 32.9 percent, with the highest burden in children less than five years of age [1]. Iron deficiency is a particularly challenging problem for resource-limited nations in Asia and Africa [2,3]. In the United States and other resource-abundant settings, rates of iron deficiency are substantially lower, yet iron deficiency is still common and can have important consequences to health and development.
This topic review focuses on evaluation for anemia that is likely due to iron deficiency in infants and young children, including screening, clinical manifestations, and diagnosis. Related material can be found in the following topic reviews:
●(See "Iron deficiency in infants and children <12 years: Treatment".)
●(See "Iron requirements and iron deficiency in adolescents".)
●(See "Approach to the child with anemia".)
DEFINITIONS
●Iron deficiency – Iron deficiency refers to a state in which there is insufficient total body iron to maintain normal physiologic functions. We define this with a serum ferritin <15 micrograms/L for all pediatric age groups. There is some disagreement about the most appropriate ferritin threshold for infants and young children, in whom either lower [4,5] or higher thresholds have been suggested [6,7]. Of note, these are thresholds to guide clinical decision-making and may differ from the reference range used by individual clinical laboratories.
●Anemia – Anemia is typically defined as a hemoglobin concentration that is 2 standard deviations (SD) or more below the mean for a healthy population of the same sex and age. The World Health Organization uses the following hemoglobin thresholds to define anemia [3]:
•Children:
-6 months to <5 years – 11 g/dL
-5 to <12 years – 11.5 g/dL
-12 to <15 years – 12 g/dL
•Females ≥15 years:
-Nonpregnant – 12 g/dL
-Pregnant – 11 g/dL
•Males ≥15 years – 13 g/dL
The same hemoglobin thresholds should be utilized regardless of the patient's race or ethnicity. For individuals living at altitude, use of these thresholds may lead to underdiagnosis of anemia [8].
●Iron deficiency anemia (IDA) – IDA in children can thus be defined as:
•Children 6 months to <5 years:
-Ferritin <15 micrograms/L, and
-Hemoglobin <11 g/dL (for children 0.5 to 5 years)
•Children 5 to <12 years:
-Ferritin <15 micrograms/L, and
-Hemoglobin <11.5 g/dL (for children 5 to 12 years)
These definitions are common but not universally used; some experts use slightly higher hemoglobin and ferritin cutoffs as thresholds for initiating an evaluation and defining IDA, respectively [6,9]. The extent of the evaluation needed depends on the likelihood of IDA in the population and on the clinical history of the individual patient.
PREVALENCE — In the United States, up to 15 percent of toddlers (one to three years old) are iron deficient and up to 5 percent have iron deficiency anemia (IDA) (figure 1) [10,11]. The overall rate of iron deficiency in young children has declined only slightly during the past four decades but improved markedly in some subgroups. As an example, rates of iron deficiency among children 12 to 24 months old declined from 23 to 11 percent between two study periods (1976 to 1980 and 1999 to 2002) [12]. Rates decrease with advancing age until adolescence, when up to 16 percent of girls develop iron deficiency and 3 percent have IDA.
In the United States, the prevalence of iron deficiency is higher among children living at or below the poverty level and in certain racial and ethnic groups due to nonmedical drivers of health [12-15]. Young Hispanic/Latin American children have approximately double the rates of iron deficiency compared with White children [13]. Asian American children and children from families recently immigrating to the United States also have higher rates of iron deficiency. Other risk factors include low birth weight, prematurity, and childhood obesity [12,15-17]. These findings demonstrate the need for ongoing surveillance and early intervention to prevent iron deficiency during infancy and early childhood, particularly among high-risk groups.
In resource-limited countries, anemia is a common public health problem. In most of Africa, Latin America, and Southeast Asia, prevalence of anemia ranges from 45 to 65 percent in children (figure 2), 35 to 40 percent in women, and 10 to 35 percent in men [18,19]. From one-third to one-half of the anemia is thought to be attributable to iron deficiency, depending on the region [1,2].
PATHOPHYSIOLOGY AND RISK FACTORS
Iron balance — Iron is an essential nutrient. Approximately 75 percent is bound in the heme proteins hemoglobin and myoglobin. The remainder is bound in storage proteins such as ferritin and hemosiderin, and a small portion (3 percent) is bound in critical enzyme systems, such as catalase and cytochromes [20]. In healthy adults, only 1 to 2 mg of daily iron is required from dietary sources to maintain balance with the iron loss that occurs from the gastrointestinal tract. The majority of iron needs are met by efficient iron recycling, which occurs via the breakdown of older red blood cells by macrophages within the reticuloendothelial system. However, in infants and children, 30 percent of daily iron needs must come from diet because of the rapid growth and increase in body (muscle) mass that occurs during this age range.
Iron homeostasis is primarily regulated at the site of intestinal absorption and transport. Absorption is regulated by the peptide hormone hepcidin, which acts primarily on ferroportin, the transmembrane protein that is found on the basolateral surface of enterocytes and is responsible for iron uptake into the plasma from the intestine [21]. Serum hepcidin expression, and therefore intestinal iron absorption, is influenced by body iron stores, erythropoietic rate, and states of inflammation. Low iron stores result in hepcidin suppression, allowing for enhanced iron absorption and transport. Conversely, normal iron status results in higher levels of hepcidin and decreased iron absorption. There is no mechanism for active iron excretion from the body. The steps involved in the regulation of iron metabolism are discussed in detail separately. (See "Regulation of iron balance".)
Perinatal risk factors — At birth, healthy term infants have iron stores of approximately 75 mg/kg (two-thirds of which is bound in hemoglobin) and mean hemoglobin concentrations of 15 to 17 g/dL. These infants generally have sufficient iron to support growth and development for the first four to six months of life [22,23].
Several conditions in the perinatal period can increase the risk for iron deficiency anemia (IDA) during the first three to six months of life by reducing the iron stores at birth or through other mechanisms (table 1):
●Maternal iron deficiency
●Fetal-maternal hemorrhage (FMH)
●Twin-twin transfusion syndrome (TTTS)
●Other perinatal hemorrhagic events
●Prematurity
●Administration of erythropoietin (EPO) for anemia of prematurity
●Insufficient dietary intake of iron during early infancy
The majority of maternal-fetal iron transfer occurs during the third trimester of pregnancy. For this reason, both maternal iron deficiency during pregnancy and premature birth increase the risk of iron deficiency in the infant [24]. In populations in which maternal iron deficiency is common, iron supplementation during pregnancy is beneficial [25]. The efficacy of food fortification strategies for pregnant women has not been established [26,27].
Premature infants are at increased risk of IDA due to less maternal-fetal iron transfer, smaller total blood volume at birth, blood loss through phlebotomy, and poor gastrointestinal absorption [28]. The more premature the infant, the lower his or her iron stores at birth. The use of erythropoietin to prevent and treat the anemia of prematurity further increases the risk for iron deficiency [23]. Therefore, some form of iron supplementation is recommended for all preterm infants. Perinatal hemorrhage (FMH or TTTS) in any infant further increases the risk for developing IDA early in infancy because the hemorrhage further reduces iron stores at birth. (See "Anemia of prematurity (AOP)", section on 'Preemptive Management'.)
Dietary factors
●Common dietary factors – Dietary issues are the primary cause of IDA in infancy and early childhood (table 1). Common factors leading to an imbalance in iron status include [29]:
•Insufficient iron intake
•Inefficient absorption due to dietary sources of iron with low bioavailability
•Introduction of unmodified cow's milk (nonformula cow's milk) before 12 months of age [30-33]
•Occult blood loss secondary to cow's milk protein-induced colitis
•Obesity
●Insufficient iron intake in infants – Insufficient iron intake in infants less than 12 months of age is typically due to either breastfeeding without initiation of adequate iron supplementation by six months of age, formula with insufficient iron fortification, or early transition to cow's milk [32-34]. Human milk has low iron content but high bioavailability (50 percent), so it provides sufficient iron until approximately four months of age. Standard infant formulas have much higher concentrations of iron (at least 6.7 mg/L of iron, most with 12 mg/L), with lower bioavailability (5 percent) [35]. Most formulas with iron content below 6.7 mg/L have been removed from the market in the United States.
Insufficient iron intake is common in breastfed infants 6 to 12 months of age, despite contributions from complementary foods such as iron-fortified cereal. In the United States, the mean estimated absorbed iron for these infants was 0.3 mg/day, below the recommended intake of 0.69 mg/day [36]. These findings support the recommendation for iron supplementation for breastfed infants beginning between four and six months of age, in addition to iron-rich complementary foods beginning at approximately six months of age. (See 'Recommendations for iron supplementation' below.)
●Insufficient iron absorption – Intestinal iron absorption is dependent on the form of iron ingested (heme versus nonheme iron) and the other foods consumed at the same time. Heme dietary sources (fish, poultry, and meat) have a higher bioavailability of iron than do nonheme (vegetable) sources (30 versus 10 percent) (table 2). Other dietary components can affect iron absorption (table 3). Ascorbic acid (vitamin C) enhances absorption of nonheme iron from cereal, breads, fruits, and vegetables. Conversely, absorption is inhibited by tannates (teas), bran foods rich in phosphates, and phytates (plant fiber, especially in seeds and grains) [20,37-41]. Therefore, children with vegan or vegetarian diets are at higher risk for iron deficiency compared with those with less restrictive diets. (See "Vegetarian diets for children", section on 'Iron'.)
●Unmodified cow's milk in infancy – Early introduction of unmodified (nonformula) cow's milk during infancy is an important risk factor for IDA. Unmodified cow's milk increases intestinal blood loss in infants compared with formula or breastfeeding [30-34]. One study of infants five to six months of age found that those who switched to cow's milk had an increase in guaiac-positive stools (3 to 30 percent) during the first 28 days, while it remained low (5 percent) in those receiving a cow's milk-based infant formula [31]. (See "Food protein-induced allergic proctocolitis of infancy".)
Excessive ingestion of cow's milk (drinking more than 24 oz [720 mL] of milk daily) in young children is also an important risk factor for iron deficiency due to the low concentration and low bioavailability of iron in cow's milk, in contrast with the high bioavailability (50 percent) of iron in breast milk. Children with excessive milk intake are also at increased risk for occult intestinal blood loss [42,43]. Patients with a severe form of this syndrome can develop a protein-losing enteropathy in which albumin and total protein are low, resulting in edema and anasarca, in addition to IDA [44]. Children with prolonged bottle-feeding have higher milk consumption and increased risk of IDA compared with those who switch to a cup. As an example, one study found that children who bottle-fed during the second and third years of life had an adjusted relative risk (RR) for iron deficiency of 2.5 (95% CI 2.46-2.53), compared with those who transitioned to cups [45]. Bottle-feeding appears to be a particularly important contributor to iron deficiency among Mexican American toddlers [13,46].
●Obesity – Data from the National Health and Nutrition Examination Survey III (NHANES III) and other studies have demonstrated an increased prevalence of iron deficiency in children with obesity [16,17,47]. The etiology of iron deficiency in these children may be multifactorial and include increased iron requirements as well as the effects of obesity on hepcidin levels, resulting in either an inflammation-mediated functional iron deficiency and/or a diminished response to oral iron therapy and impaired iron absorption [48-50].
Gastrointestinal disease — Dietary iron is absorbed primarily within the duodenum. Malabsorption of iron may occur in diseases affecting the duodenum, including celiac disease; Crohn disease, giardiasis; or any surgical resection of the proximal small intestine, such as in infants and children with intestinal failure, including short bowel syndrome [51]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children" and "Chronic complications of short bowel syndrome in children", section on 'Nutritional complications'.)
Conditions that cause gastrointestinal blood loss, such as cow's milk protein-induced colitis, inflammatory bowel disease (IBD), or chronic use of aspirin or nonsteroidal antiinflammatory drugs, are also associated with iron deficiency. (See "Lower gastrointestinal bleeding in children: Causes and diagnostic approach" and "Approach to upper gastrointestinal bleeding in children", section on 'Etiology'.)
PREVENTION OF IRON DEFICIENCY
Recommended intake — Recommended dietary allowances (RDA) for iron are based on requirements for absorbed iron, the proportion of dietary iron that is absorbed, and estimated iron losses (eg, due to menstruation). In infants and children, a substantial portion of this requirement is attributable to increases in hemoglobin mass and tissue iron due to growth. The RDA for iron in children under 12 years of age are [29,52,53]:
●Infants:
•Full term – 1 mg/kg daily (maximum 15 mg)
•Premature – 2 to 4 mg/kg daily (maximum 15 mg)
●Children:
•1 to 3 years old – 7 mg daily
•4 to 8 years old – 10 mg daily
•9 to 13 years old – 8 mg daily
Because only a fraction of dietary iron is absorbed, the dietary requirement is considerably higher than the net absorbed iron requirement, which is dependent on the bioavailability of the iron in the food. For example, breast milk contains only 0.3 to 1.0 mg/L iron but has high bioavailability (50 percent). By contrast, proprietary iron-containing formulas typically have 12 mg/L iron but low bioavailability (4 to 6 percent) [54].
Iron requirements in adolescents are discussed separately. (See "Iron requirements and iron deficiency in adolescents", section on 'Iron requirements'.)
Recommendations for iron supplementation — Iron requirements for infants listed above are met when infants are fed an appropriate iron-fortified infant formula.
●For breastfed infants, an additional iron source (complementary foods or iron supplement) should be added at the following ages and doses [29,52]:
•Full-term infants – Start an iron supplement between four and six months of age (elemental iron 1 mg/kg daily, maximum 15 mg). Continue the supplement until the infant is taking sufficient quantities of iron-rich complementary foods (eg, two or more servings of iron-fortified infant cereal daily).
•Premature infants – Start an iron supplement by two weeks of age (elemental iron 2 mg/kg daily, maximum 15 mg). Continue to provide iron at a dose of at least 2 mg/kg per day, via supplements or fortified formula, through the first year of life. (See "Breastfeeding the preterm infant", section on 'Vitamin D and iron supplements'.)
●In populations with a high prevalence of iron deficiency (typically resource-limited countries), universal iron supplementation is recommended for infants and children 6 months to 12 years. The recommended dose and schedule is outlined in guidelines from the World Health Organization:
•For infants and children in high-risk populations (prevalence of anemia >40 percent) – Daily iron supplementation [55]. Supplements should not be given to children who lack access to malaria-prevention strategies, because they may increase susceptibility to malaria. (See 'Associated disorders and effects of treatment' below.)
•For preschool- and school-aged children in moderate-risk populations (prevalence of anemia 20 to 40 percent) – Intermittent iron supplementation (one supplement/week, in three-month cycles) [56].
The evidence supporting the above recommendations for iron supplementation in populations with high rates of iron deficiency is mixed. Although universal iron supplementation to infants reduces the prevalence of anemia, studies reached conflicting conclusions about whether it improves growth or neurodevelopmental outcomes, as discussed below. (See 'Associated disorders and effects of treatment' below.)
Other strategies to prevent iron deficiency vary by region; these include food fortification (eg, iron fortification of whole maize flour, milk, noodles, or rice or as part of a multiple micronutrient powder [57,58]) and control of hookworm (helminth) infection and malaria [59].
Dietary recommendations — In populations with relatively low rates of iron deficiency, such as the United States, there is little evidence that routine iron supplementation is beneficial in healthy children six months and older [60,61]. Instead, the following general dietary measures are recommended to help meet the estimated iron requirements (table 4):
●Infants:
•Encourage exclusive breastfeeding for the first six months. Infants who receive greater than one-half of their nutrition from breast milk should initiate iron supplements between four and six months of age for term infants and at two weeks of age for preterm infants; the supplements should be continued until the infant is receiving sufficient iron from complementary foods or formula. (See 'Recommended intake' above.)
•For infants less than 12 months of age who are formula fed or take less than one-half of their nutrition from breast milk, iron-fortified formulas (6 to 12 mg of iron per liter) should be provided [62]. Low-iron infant formulas (ie, those containing less than 6 mg/L of iron) should not be used [35]. Iron fortification of formula is necessary to prevent deficiency [29].
No adverse effects of this level of iron supplementation have been demonstrated. A possibility of adverse effects on cognitive outcomes was raised by a large randomized trial performed in Chile, in which infants fed an iron-fortified formula (12 mg/L) had slightly worse long-term cognitive outcomes compared with those fed a low-iron formula (2 mg/L) [63,64]. However, the opposite effect was seen for the subset of infants with low baseline hemoglobin concentrations (<10.5 g/dL). Moreover, it is important to note that this trial enrolled infants at six months of age, when most infants consume significant iron from complementary foods. Thus, the trial is not informative about the optimal concentration of iron in formula in younger infants (<6 months).
•At age six months, encourage one feeding per day of foods rich in vitamin C (eg, citrus fruits, cantaloupe, strawberries, tomatoes, and dark green vegetables) to enhance iron absorption [62]. (See "Introducing solid foods and vitamin and mineral supplementation during infancy", section on 'What to feed and how to advance'.)
•After age six months, or when developmentally ready, consider introduction of pureed meats. The heme iron in meats is more bioavailable than nonheme iron and also enhances absorption of nonheme iron [65,66].
•For all infants (<12 months), avoid feeding unmodified (nonformula) cow's milk or goat's milk [62].
●Children aged one to five years:
•Limit cow's milk consumption to no more than 20 oz (600 mL) per day. We suggest this limit because the risk of iron deficiency increases in young children drinking more than 24 oz of milk per day [42].
•Encourage at least three servings per day of iron-containing foods (eg, fortified breakfast cereal, 3 oz of meat, or 4 oz of tofu); children who eat less than this target usually have suboptimal iron intake and may benefit from an iron supplement [67].
●Children aged five to 12 years: Older children can consume a variety of iron-rich foods (table 2) to meet their iron requirement (10 mg daily for children 4 to 8 years; 8 mg daily for those 9 to 13 years). For all age groups common iron-rich foods are fortified cereals and meats.
CLINICAL MANIFESTATIONS OF IRON DEFICIENCY ANEMIA
●Stages of iron deficiency – Iron deficiency anemia (IDA) is a microcytic, hypochromic, and hypoproductive state. The progression from normal iron status to iron deficiency, followed by iron-limited erythropoiesis and finally to IDA, is shown in the table (table 5). With iron deficiency, storage sites are depleted, but there is sufficient iron in the "labile" iron pool from the daily turnover of red cells for normal hemoglobin synthesis, unless further iron losses occur. Anemia develops only in the final stage of iron deficiency. Conversely, when iron repletion is initiated, the anemia is the first to recover and normalization of iron stores is the final thing to fully correct.
●Clinical findings – The most common presentation of IDA is an otherwise asymptomatic, well-nourished infant or child who has a mild to moderate microcytic, hypochromic anemia (picture 1). Some children are diagnosed in the setting of an acute illness, at which time, pallor and fatigue may be more notable. Much less frequent are infants with severe anemia, who present with lethargy, pallor, irritability, cardiomegaly, poor feeding, and tachypnea. However, some of these symptoms (decreased energy, mild pallor or yellow skin [not jaundice], and pica) may not be appreciated until the improvement is seen once a child begins iron therapy.
Pica is the intense craving for nonfood items. Various forms of pica have been associated with iron deficiency, including clay or dirt, rocks, starch, chalk, soap, paper, cardboard, or raw rice [68]. Pagophagia, or craving for ice, is particularly common and specific for the iron-deficient state. It may be present in children who are not anemic and responds rapidly to treatment with iron, often before any increase is noted in the hemoglobin concentration [69,70]. The mechanism for the association of iron deficiency and pica is unknown.
Pica may also occur in children between the ages of two and three with developmental disabilities, including autism and intellectual disability, as well as children with brain injuries that affect their development and is not consistently associated with iron deficiency in these populations [71]. It is also reported in children with sickle cell disease, though the mechanism in this condition is unknown as well. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis" and "Autism spectrum disorder in children and adolescents: Surveillance and screening in primary care", section on 'Approach to ASD surveillance and screening' and "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Terminology'.)
ASSOCIATED DISORDERS AND EFFECTS OF TREATMENT — Iron deficiency anemia (IDA) is associated with multiple deficits, including impaired neurodevelopment, growth, and immunity. However, it is uncertain whether iron supplementation can prevent or reverse these effects, based on evidence from clinical trials.
●Neurodevelopment – In young children, IDA has been associated with impaired neurocognitive development, including slower visual and auditory processing [72-80]. The observed associations provide the rationale for routine supplementation to breastfed infants and subsequent screening of all infants and young children in the United States and universal iron supplementation for children in populations with high rates of IDA. (See 'Recommendations for iron supplementation' above.)
Most clinical evidence comes from longitudinal cohort studies in low- and middle-income countries with high rates of IDA that showed associations between IDA and neurodevelopmental deficits, especially for children with more severe and chronic IDA [81-87].
Despite the observed association, clinical trials of iron supplementation have generally failed to demonstrate benefits on neurodevelopmental outcomes or growth parameters. As an example, a large randomized trial in 3300 infants in rural Bangladesh evaluated the effects of a universal iron supplementation approach (12.5 mg elemental iron per day either alone or with multiple micronutrients, compared with placebo) given for three months starting in late infancy [88]. Approximately one-third of the infants were iron deficient and one-fifth had IDA at the onset of the study. Iron supplementation effectively reduced the prevalence of IDA. However, there were no significant differences between the three groups on neurocognitive tests, when measured after completion of the regimen (at three months) or nine months later, including in the subgroup with IDA. These findings are consistent with prior meta-analyses of randomized trials, which found inconclusive evidence for effects of iron supplementation on neurodevelopment and other functional outcomes for children <24 months [57,89] or for older children [55,56,89,90].
Possible explanations for these negative results are that the iron supplementation in late infancy was insufficient to compensate for chronic exposure to iron deficiency in utero and early infancy, that it was too low of a dose or for an insufficient period of time, or that the observed association between IDA and neurodevelopmental outcomes is not causal. Moreover, although the study was large, its power to detect a treatment effect was limited because only a minority of subjects had iron deficiency or IDA at enrollment.
Limited data suggest that iron therapy has some benefit on other neurologic conditions in young children, including breath-holding spells, restless legs syndrome, and periodic limb movement disorder [91-93]. (See "Restless legs syndrome and periodic limb movement disorder in children", section on 'Iron deficiency'.)
●Febrile seizures – Several studies have demonstrated an association between febrile seizures and iron deficiency or IDA. No causal relationship between iron deficiency and development of febrile seizures has been demonstrated [94-98]. However, serum ferritin levels are significantly lower in children with febrile seizures compared with those with fever alone. Therefore, screening for iron deficiency in young children with a history of febrile seizures may be warranted.
●Immunity and infection – Data on the impact of iron supplementation on immune function and susceptibility to infection are mixed. On one hand, iron deficiency appears to be associated with mild to moderate defects in leukocyte and lymphocyte function, including defective interleukin-2 and -6 production [99-103]. On the other hand, iron supplementation may paradoxically increase the risk for certain types of infection. In particular, iron supplementation may increase the risk for bacterial infection because the iron-binding proteins transferrin and lactoferrin have bacteriostatic effects, which are lost when they are saturated with iron [102]. Similarly, there is some evidence that iron supplementation results in increased susceptibility to or reactivation of dormant infections, such as malaria or tuberculosis [104].
The clinical relevance of these observations is unclear. Some studies suggest the susceptibility to malaria is only relevant in endemic areas and high-transmission seasons; other than in this group, standard doses of iron supplements do not appear to significantly increase the risk for malaria [103,105]. In confirmation of this finding, a large meta-analysis found that iron supplementation does not increase the risk of clinical malaria or death when regular malaria surveillance and treatment services are provided [106]. Furthermore, in a systematic review of randomized trials (most of which were in populations at risk for malaria and diarrheal disease), iron supplementation was associated with a higher risk of diarrhea but had no apparent harmful effect on the incidence of malaria or other infectious illnesses in children [107].
A study in Kenyan infants demonstrated that those who were iron deficient at the time of vaccination had a decreased humoral response to vaccines [108]. Iron supplementation at the time of vaccination resulted in an improved humoral response to vaccines. These findings further support the role of iron in optimal immune response.
●Exercise capacity – Moderately severe IDA is associated with decreased work capacity, in part because iron is an essential cofactor for enzyme-driven aerobic metabolism. Decreased iron stores, in the absence of anemia, is associated with decreased exercise performance in laboratory animals. Similar findings have been noted in children, particularly adolescent athletes. (See "Iron requirements and iron deficiency in adolescents", section on 'Physical performance and fatigue'.)
●Thrombosis/stroke – IDA has been associated with cerebral vein thrombosis [109]. In a large case-control study from a comprehensive Stroke Registry in Canada, previously healthy children with stroke (arterial or venous) were 10 times more likely to have IDA than healthy children without stroke [110]. The mechanisms for this complication are not clear but may be related to thrombocytosis (platelet counts approaching 1 million/uL) that is sometimes present in IDA or as a result of abnormal rheologic properties in children with severe IDA. One case report describes a fatal stroke in a young child with severe IDA and no other thrombophilia risk factors [111].
SCREENING RECOMMENDATIONS
Indications and timing — We suggest routine screening for iron deficiency anemia (IDA) in all infants 4 to 36 months of age, consisting of regular clinical risk assessment at well-child visits and laboratory testing at times of highest risk, as outlined below. (See 'Risk assessment' below and 'Laboratory screening' below.)
Guidelines differ in their recommendations about the utility of routine universal laboratory screening in resource-abundant settings:
●Our suggestion for routine universal laboratory screening is consistent with recommendations from the American Academy of Pediatrics (AAP) [29,52]. The rationale is that indirect evidence from populations with moderate or high rates of IDA (including historical studies in the United States) suggest important health benefits, such as prevention of neurocognitive deficits. Moreover, symptoms and risk factors are not reliable factors for selective screening strategies in young children.
●Other societies, including the United States Preventive Services Task Force and guidelines in Canada and the United Kingdom, do not recommend universal laboratory screening for IDA in young children, citing lack of direct evidence of the benefits or the harms of this approach [112-114]. No studies adequately assess the impact of routine screening and iron supplementation in the United States and other similar countries. Furthermore, available screening tests (such as point-of-care measurements of hemoglobin) have only fair accuracy in identifying IDA (positive predictive value 10 to 40 percent at 12 months of age) [112].
Of note, all of the above societies recommend targeted laboratory screening for IDA in infants and children with risk factors, including those with malnutrition, prematurity, low birth weight, dietary risk factors, obesity, or symptoms of IDA (table 1).
In resource-limited settings with a high population frequency of iron deficiency (40 percent or higher), universal daily iron supplementation is recommended (except in children with high risks for malaria), as outlined in a guideline from the World Health Organization [55]; intermittent iron supplementation is recommended for populations at moderate risk [56]. (See 'Recommendations for iron supplementation' above.)
Risk assessment — The AAP suggests performing a brief review of IDA risk factors for all infants at all well-child evaluations from 4 to 36 months of age and annually thereafter [29,52].
The assessment should review the primary risk factors for iron deficiency (table 1), which are [52] (see 'Dietary recommendations' above):
●Young infants – A history of prematurity or low birth weight, or administration of erythropoietin for anemia of prematurity (see 'Perinatal risk factors' above)
●Under 12 months – Use of "low-iron" formula, nonformula cow's milk, goat's milk, or soy milk before 12 months of age; fewer than two servings/day of iron-rich foods (meats or fortified infant cereal) after six months of age
●12 months and older – Milk intake greater than 24 oz daily; fewer than three servings daily of iron-rich foods (eg, iron-fortified breakfast cereal or meats) (see 'Dietary factors' above)
A focused dietary history is an important screening tool and is more accurate than an isolated measurement of hemoglobin level for identifying children with iron deficiency and IDA. As an example, a study in 305 healthy African American children age one to five years found that a brief dietary history was an effective screening test for microcytic anemia [115]. Specifically, a normal dietary history had a negative predictive value of 97 percent. In this study, dietary risk for iron deficiency was defined as one or more of the following: more than 480 mL (16 oz) of milk per day; less than five servings each of meat, grains, vegetables, and fruit per week; or daily intake of fatty snacks, sweets, or more than 480 mL (16 oz) of soft drink.
Laboratory screening — The AAP suggests universal laboratory screening for IDA at approximately 9 to 12 months of age and repeated screens for children with risk factors (or a few months later for formula-fed infants) [29,52].
Screening at one year of age is particularly important in children who are primarily breastfed and in populations with increased risks of iron deficiency, including communities with low income levels (eg, those who receive support from the Women, Infants, and Children [WIC] program). Children receiving iron-fortified formula during the first year of life are at low risk for iron deficiency at one year of age. Such children may have higher risk beyond 12 months of age after transition from iron-fortified formula to cow's milk.
●Timing – The screening protocol depends on the child's risk factors:
•For all children, perform laboratory screening at 9 to 12 months of age. For those who are fed an iron-fortified formula, it may be appropriate to delay the screen until approximately 15 to 18 months of age. This timing will better capture the child's iron status after transitioning from formula to cow's milk.
•For children with risk factors for iron deficiency (eg, history of prematurity or dietary risk factors such as excessive milk intake (table 1)) – Test again, eg, at 15 to 18 months of age or when risk is identified.
•For children with special health needs (chronic infection, inflammatory disorders, chronic gastrointestinal dysfunction, history of intestinal surgery, or restricted diets) – Repeat laboratory screening at 15 to 18 months of age, and again in early childhood, eg, between two to five years of age.
●Method
•Complete blood count (CBC) – In most clinical settings, the simplest and most cost-effective measurement is a CBC, which will include measurements of hemoglobin, mean corpuscular volume (MCV), and red blood cell distribution width (RDW; a measure of variability in red cell size). In IDA, MCV usually is decreased and RDW increased (table 6).
•Hemoglobin concentration – In settings in which a full CBC cannot be performed, the minimum laboratory screen for IDA is measurement of hemoglobin. Common definitions of low hemoglobin are <11 g/dL in children 0.5 to <5 years of age and <11.5 g/dL in children 5 to <12 years. Note that children with a normal hemoglobin may have iron deficiency that is not revealed by measurement of hemoglobin alone. (See 'Definitions' above.)
•Serum ferritin – If feasible within the clinical setting in which the child is being seen, we suggest measuring serum ferritin at the time of the initial screen to assess for iron deficiency in addition to anemia. This facilitates the diagnosis and will identify children who are iron deficient but not yet anemic [4,29]. In the majority of otherwise healthy children, serum ferritin is a reliable measure of iron status. However, because ferritin is an acute phase reactant, it can be falsely normal or elevated in children with a concurrent acute infection or chronic comorbid condition, even if the child is iron deficient. Importantly, a low ferritin level is always consistent with iron deficiency. (See 'Laboratory testing' below.)
In resource-limited settings with a high population frequency of anemia, universal iron supplementation is recommended rather than laboratory screening. (See 'Recommendations for iron supplementation' above.)
Screening recommendations for adolescents are presented separately. (See "Iron requirements and iron deficiency in adolescents", section on 'Screening'.)
EVALUATION FOR SUSPECTED IRON DEFICIENCY ANEMIA — Children with a laboratory finding of anemia (hemoglobin <11 g/dL for 0.5 to <5 years of age; <11.5 g/dL for 5 to 12 years) should be further evaluated to determine the underlying etiology, whether iron deficiency or another cause.
To confirm the diagnosis of iron deficiency anemia (IDA), particularly when a hemoglobin alone or complete blood count (CBC) demonstrating a microcytic anemia is identified but without a confirmatory serum ferritin, we suggest the following additional steps (algorithm 1):
●Review history (see 'Focused history' below)
•For risk factors for IDA (dietary, blood loss, obesity, or malabsorptive disease) (table 1)
•For evidence of other causes of anemia (acute infection, chronic diseases, or family history of anemia or hemoglobinopathy)
●Initial laboratory testing – If the history is consistent with likely or possible IDA, performing a limited laboratory evaluation can confirm the diagnosis. If the presentation is typical for IDA (age <3 years, with any dietary risk factors for IDA), a CBC demonstrating a microcytic anemia is sufficient to make the diagnosis. If the presentation is atypical, more extensive laboratory testing may be appropriate. (See 'Laboratory testing' below.)
●Trial of iron therapy – If the history and laboratory testing is consistent with IDA, perform an empiric trial of iron therapy. (See 'Empiric trial of iron therapy' below.)
●Reevaluate within four weeks to confirm a response to the iron therapy.
These additional steps are important because an isolated low hemoglobin concentration is neither a sensitive nor a specific screen for iron deficiency [29,116]. The proportion of anemia that is caused by iron deficiency is considerably higher in populations with risk factors for iron deficiency in the United States and elsewhere.
Focused history — A focused history is a critical step to fully assess risk factors and etiology for IDA, as well as exclude other causes of anemia. The key elements depend on the child's age (table 1). The history can be used to categorize patients by their likelihood for having nutritional IDA:
●Typical presentation of nutritional IDA (all of the following):
•Age nine months to three years
•One or more risk factors for nutritional IDA
-Lack of iron supplementation in breastfed infants (starting by four to six months in term infants or by two weeks of age for preterm infants), feeding of low-iron formula or unmodified (nonformula) cow's milk, and insufficient iron-rich complementary foods after four to six months of age
-In toddlers and young children (12 months or older), dietary risk factors include excessive intake of cow's milk (>20 oz [600 mL] daily) and insufficient consumption of iron-rich foods
•Otherwise healthy
●Atypical presentation of nutritional IDA (any of the following):
•Age 3 to 12 years
•No dietary risk factors for iron deficiency
•Features suggesting non-nutritional cause of IDA (due to blood loss or malabsorption):
-Marked blood loss – eg, frequent nose bleeds, grossly bloody stools, or menorrhagia in girls who are menstruating
-Disorders associated with iron malabsorption – eg, celiac disease or inflammatory bowel disease (IBD)
•Features suggesting other causes of anemia, including:
-Other systemic disorders associated with anemia – eg, systemic inflammatory disorders or cancer
-Acute or recurrent infections consistent with anemia of inflammation
-Family history of anemia or hemoglobinopathy, such as thalassemia trait
If the history suggests a specific cause of anemia other than IDA (eg, systemic disease or hemoglobinopathy) or if there is evidence of marked blood loss, a targeted evaluation or referral may be appropriate (see "Approach to the child with anemia"). Otherwise, the next step is focused laboratory testing, as described in the next section. (See 'Laboratory testing' below.)
Laboratory testing — If the history is consistent with IDA, perform a limited laboratory evaluation to confirm the presence of a microcytic anemia (algorithm 1).
Selection of tests — The extent of the laboratory testing depends on patient characteristics and the history:
●Typical presentation of IDA – If the presentation is typical for nutritional IDA (age <3 years, with any dietary risk factors for IDA), a CBC is sufficient, although measuring serum ferritin provides additional valuable information.
●Atypical presentation for IDA – If the presentation is atypical (age 3 to 12 years or no dietary risk factors or other possible risk factors present), somewhat more extensive laboratory testing is appropriate because nutritional IDA is less common in these patients. In our program, we perform a CBC with indices, reticulocyte count, serum ferritin, and peripheral blood smear. Providers may also consider testing stools for occult blood.
In addition, a blood lead level should be measured if there are any risk factors for lead exposure or symptoms of pica [29,117,118]. (See "Screening tests in children and adolescents", section on 'Lead poisoning'.)
If the results of these tests are consistent with IDA, the next step is a therapeutic trial of iron and further evaluation is performed only if the response is inadequate. Patients with nutritional IDA should have dietary counseling to address the underlying etiology (table 4). Patients with any evidence of gastrointestinal blood loss or malabsorption should be started on iron supplements and referred to a gastroenterologist for further evaluation. (See 'Empiric trial of iron therapy' below.)
Interpretation
●Diagnosis of IDA – The following findings support a diagnosis of IDA (table 6) [119,120] (see 'Definitions' above):
•Microcytic anemia on CBC (low hemoglobin, low mean corpuscular volume [MCV], and elevated red cell distribution width [RDW])
•Low serum ferritin (<15 micrograms/L)
●Role for other laboratory tests – Several additional iron measures are available to evaluate for IDA. However, all iron tests must be interpreted with the full clinical context and patient history since most measures can be affected by factors other than iron status (table 7). A low serum ferritin is always consistent with iron deficiency, but normal or elevated ferritin does not exclude iron deficiency. Ferritin is an acute phase reactant and may be increased in states of liver disease, inflammation (acute or chronic), obesity, and malignancy. Thus, a patient with iron deficiency and a concomitant inflammatory disease, or even an acute infection such as acute otitis media, may have a "falsely" normal ferritin concentration. In patients with a concurrent infection at the time of testing, a measure of inflammation, such as C-reactive protein (CRP), may be assessed to validate the results of serum ferritin [52,121]. However, this test is not routinely indicated in patients who are healthy (see "Acute phase reactants"). Of note, the reticulocyte hemoglobin content (CHr) or equivalent (Ret-He) reflect the hemoglobin content in reticulocytes and low values reliably indicate early iron deficient erythropoiesis, prior to onset of anemia [122,123]. However, the CHr/Ret-He is also low in patients with thalassemia trait.
●Differential diagnosis – Other conditions can produce a mild hypochromic, microcytic anemia and may be misinterpreted as IDA or coexist with IDA, including [124,125]:
•Anemia of inflammation – Mild anemia (decline of 0.5 to 2.0 g/dL) following a recent infection or immunization.
•Hemoglobinopathies, including alpha or beta thalassemia traits, hemoglobin C or E trait – Children with thalassemia trait may have a microcytic anemia. In children with both thalassemia trait and IDA, appropriate iron therapy will improve measures of iron stores and may modestly improve the hemoglobin concentration, but microcytosis with or without a mild anemia may persist.
•Anemia of chronic disease – Longstanding chronic inflammatory diseases can result in iron-restricted erythropoiesis, which is similar but distinct from classic IDA. Both conditions may have microcytic anemia on complete blood count (CBC), but chronic inflammation will result in a different pattern on laboratory tests in the iron panel and often improves as inflammation decreases.
•Combined nutritional anemias – In patients with iron deficiency and concomitant vitamin B12 or folate deficiency it may be difficult to categorize the anemia using red blood cell indices. These combined nutritional anemias are rare in otherwise healthy children.
A method to distinguish among the more common conditions is noted in the table (table 6). These conditions should be considered in patients with predisposing factors and in children who fail to respond to a therapeutic trial of iron. Children with known thalassemia trait should always have iron measures (ie, serum ferritin) assessed prior to initiation of iron therapy. (See "Iron deficiency in infants and children <12 years: Treatment", section on 'Nonresponders' and "Approach to the child with anemia".)
●Contributing factors – Although IDA is typically caused by insufficient dietary iron, it is sometimes caused by an underlying medical problem resulting in gastrointestinal blood loss, malabsorption syndrome, or menstrual blood loss in a postmenarchal girl, each of which should be assessed on history. As an example, refractory IDA can be the presenting symptom of celiac disease [126], Helicobacter pylori infection [127], or inflammatory bowel disease (refer to appropriate UpToDate topic reviews).
Empiric trial of iron therapy — For infants and children with a presumptive diagnosis of IDA based on the history and initial laboratory testing, the next step is a therapeutic trial of iron, consisting of the following steps (algorithm 1):
●Initiate ferrous sulfate, 3 mg/kg of elemental iron, once daily in the morning or between meals. Iron may be given alone or with water or orange juice, with care to ensure that the entire dose is taken. Milk and/or dairy products should be avoided for approximately one hour before and two hours after each dose. We choose to use ferrous sulfate and the 3 mg/kg dose because it was effective in a clinical trial and may be better tolerated than higher doses that are sometimes used [128]. (See "Iron deficiency in infants and children <12 years: Treatment", section on 'Dose and scheduling'.)
●In addition to iron therapy, provide dietary counseling to ensure adequate intake of iron and avoid dietary risk factors such as excessive milk intake (table 4). (See 'Dietary recommendations' above.)
●Confirm the response to iron therapy by a repeat CBC within four weeks from initiation of iron treatment.
•An appropriate response is indicated by a rise in hemoglobin of >1 g/dL within four weeks for children with mild anemia (hemoglobin 9 to 11 g/dL) [29] or within two weeks for those with moderate or severe anemia (hemoglobin <9 g/dL).
•Children who do not display an adequate rise in hemoglobin as described above should be reevaluated. Potential causes of recurrent or refractory IDA include ineffective treatment (nonadherence or incorrect dosing), incorrect diagnosis, or blood loss or malabsorption. (See "Iron deficiency in infants and children <12 years: Treatment", section on 'Follow-up assessment for response'.)
●Once the response is confirmed, iron therapy and monitoring should be continued and the CBC is retested at three months. Iron therapy should be given for at least three months, and many children require longer treatment courses to replenish iron stores. In general, iron therapy should be continued for at least one month after the hemoglobin reaches the age-adjusted normal range. (See "Iron deficiency in infants and children <12 years: Treatment", section on 'Follow-up assessment for response'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric iron deficiency".)
SUMMARY AND RECOMMENDATIONS
●Overview – Iron deficiency is the most common nutritional deficiency in children. If iron deficiency is unrecognized, it can result in iron deficiency anemia (IDA). Children with IDA have poorer neurocognitive outcomes compared with those without IDA, but a causal effect has not been established. (See 'Clinical manifestations of iron deficiency anemia' above.)
●Prevention – Measures to prevent iron deficiency and IDA include (table 4):
•For breastfed infants, iron supplementation between four to six months of age for term infants and two weeks of age for premature infants. The iron supplements should be continued until the infant is taking sufficient quantities of iron-rich complementary foods, such as infant cereal.
•In populations with a high prevalence of iron deficiency (age-specific prevalence of anemia >40 percent), universal iron supplementation for infants and children 6 months to 12 years. Supplements should not be given to children who lack access to malaria-prevention strategies, because the iron supplements may increase susceptibility to malaria.
•For all children, dietary measures include:
-Introduce iron-rich complementary foods at four to six months of age
-Avoid unmodified (nonformula) cow's milk until age 12 months; after 12 months of age, limit milk intake to no more than 20 oz (600 mL) daily
(See 'Recommendations for iron supplementation' above and 'Dietary recommendations' above.)
●Screening for risk factors – A focused dietary history is the most important screening test for detecting iron deficiency. In the United States, risk assessment for iron deficiency through a brief review of dietary risk factors (table 1) is recommended at all well-child checks from four months to three years of age and annually thereafter. (See 'Risk assessment' above.)
●Laboratory screening – In addition, we suggest universal laboratory screening for IDA for children in the United States and similar populations, rather than selective screening for those with risk factors (Grade 2C). The frequency of screening depends on patient characteristics (see 'Laboratory screening' above):
•All children – Screen once at 9 to 12 months of age. For those who are fed an iron-fortified formula, it may be appropriate to delay the screen until approximately 15 to 18 months of age. This timing will better capture the child's iron status after transitioning from formula to cow's milk.
•High-risk children – For children at high risk for IDA by dietary history (excessive cow's milk intake) or prematurity, screen a second time several months later (eg, at 15 to 18 months or when risk is identified).
•Children with special health needs – For children at risk for IDA because of underlying medical conditions such as chronic infection, inflammatory disorders, chronic gastrointestinal dysfunction, restricted diets, or other significant dietary risk factors for IDA, repeat screening at 15 to 18 months of age and again in early childhood (eg, at two to five years of age).
In most clinical settings, the simplest and most cost-effective measurement is a complete blood count (CBC). For children with substantial risk factors for iron deficiency, measuring serum ferritin at the time of the initial screen facilitates the diagnosis. (See 'Laboratory screening' above.)
●Diagnostic evaluation – IDA should be suspected in children with laboratory findings of anemia (hemoglobin <11 g/dL in children 0.5 to 5 years of age and <11.5 g/dL in children 5 to 12 years) (see 'Definitions' above). The diagnosis can be confirmed through the following additional steps (algorithm 1):
•Review the history for risk factors for IDA and for other causes of anemia (table 1). (See 'Focused history' above.)
•If the history is consistent with likely or possible IDA, perform a limited laboratory evaluation:
-Typical presentation (age <3 years, with any dietary risk factors for IDA) – CBC, with or without serum ferritin
-Atypical features – CBC, reticulocyte count, serum ferritin, peripheral blood smear, and stools for occult blood (see 'Selection of tests' above)
•The combination of a hemoglobin concentration below 11 g/dL with low serum ferritin makes the diagnosis of IDA (table 6). MCV is typically low and RDW elevated [119,120]. Most of these measures can be affected by factors other than iron status (table 7). (See 'Interpretation' above.)
●Treatment trial – For children with presumed IDA (on the basis of history and initial laboratory testing), we suggest an empiric trial of oral iron therapy and dietary changes rather than either intervention alone (Grade 2C):
•We suggest using a dose of 3 mg/kg of elemental iron, once daily between meals, rather than higher doses (Grade 2C). A 3 mg/kg dose of ferrous sulfate is generally effective and is tolerated by most children. (See 'Empiric trial of iron therapy' above and "Iron deficiency in infants and children <12 years: Treatment".)
•Dietary counseling should be provided to ensure adequate intake of iron and avoid dietary risk factors such as excessive milk intake (table 4).
•The diagnosis of iron deficiency is confirmed if there is an appropriate response to empiric iron therapy. (See 'Empiric trial of iron therapy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Donald H Mahoney, Jr, MD, who contributed to earlier versions of this topic review.
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