Iron requirements and iron deficiency in adolescents

INTRODUCTION — Adolescence is a time of increased iron needs because of the expansion of blood volume and increase in muscle mass. Adolescent girls are at particular risk for the development of iron deficiency due to menstrual blood loss. In addition, adolescent athletes and adolescents who limit their intake of meat products are at risk for iron imbalance, specifically low iron.

Iron deficiency affects both physical endurance and cognitive performance in adolescents. The risk factors, evaluation, and management of iron deficiency in adolescents will be addressed here. Iron deficiency in infants and young children and in adults is discussed in separate topic reviews:

●(See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

●(See "Iron deficiency in infants and children <12 years: Treatment".)

●(See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

●(See "Treatment of iron deficiency anemia in adults".)

DEFINITIONS

●Iron deficiency refers to a state in which there is insufficient total body iron to maintain normal physiologic functions, sometimes defined by serum ferritin <15 micrograms/L (or ng/mL) in individuals five years and older [1,2].

●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 (WHO) has used the following hemoglobin thresholds to define anemia in adolescents [3]:

•Females:

-12 years and older, nonpregnant – Hemoglobin <12 g/dL

-Pregnant adolescents and women – Hemoglobin <11 g/dL

•Males:

-12 to 15 years – Hemoglobin <12 g/dL

-15 years and older – Hemoglobin <13 g/dL

●Iron deficiency anemia (IDA) in adolescents can thus be defined as:

•Females:

-12 years and older, nonpregnant – Ferritin <15 micrograms/L, and hemoglobin <12 g/dL

-Pregnant adolescents and adults – Ferritin <15 micrograms/L and hemoglobin <11 g/dL

•Males:

-12 to 15 years – Ferritin <15 micrograms/L, and hemoglobin <12 g/dL

-15 years and older – Ferritin <15 micrograms/L, and hemoglobin <13 g/dL

These thresholds are common but not universally used; some experts use higher ferritin cutoffs for defining IDA. As an example, a large cross-sectional study in the United States suggested that a serum ferritin level closer to 20 micrograms/L would be a physiologically appropriate threshold for defining iron deficiency in adolescent females [4]. The extent of the evaluation needed to determine that anemia is due to iron deficiency depends on the likelihood of IDA in the population and on the clinical characteristics of the individual patient.

EPIDEMIOLOGY

●Prevalence – Globally, iron deficiency anemia (IDA) is a leading cause of years lived with disability for children and adolescents, affecting over 600 million in 2013 [5]. In the United States, approximately 17 percent of adolescent females (12 to 21 years) have iron deficiency (determined by ferritin <15 micrograms/L) and 6 percent have IDA [6]. The risk for IDA increases 10-fold after menarche. Less than 1 percent of adolescent males have iron deficiency [7]. Studies in other countries have found higher rates of iron deficiency in male and female adolescents [8,9]. Some of the variation in incidence noted among different studies is related to the controversy regarding the appropriate laboratory cutoffs to make the diagnosis. (See 'Evaluation and presumptive diagnosis' below.)

●Risk factors – Risk factors for iron deficiency in adolescents include abnormal uterine bleeding, most commonly in the form of heavy menstrual blood loss (>80 mL/month) in females; any history of gastrointestinal or other blood loss; vegetarian or vegan diet; low body weight or malnutrition; previous diagnosis of IDA; diagnosis of an underlying bleeding disorder; presence of a chronic illness; or history of blood donation (table 1). Adolescents with any of these risk factors should have laboratory screening for anemia with a complete blood count (CBC) during health supervision or specialty clinic visits [10,11]. To assess for the presence of iron deficiency without anemia, a serum ferritin should be obtained in addition to a CBC. (See 'Whom to screen' below.)

Children with excess body weight also appear to be at increased risk for iron deficiency and should undergo screening [12,13]. In one study, the prevalence of iron deficiency was 2.1 percent among children with healthy weight and 5.5 percent among children with obesity [13]. Obesity was a risk factor for IDA in both males and females, but rates were approximately three times higher in females. The etiology of anemia in individuals with obesity is uncertain but may be related to low-quality diets, inflammation, or increased needs relative to body weight [12,13].

In addition, adolescent athletes, particularly those participating in endurance training, following alternative diets (vegetarian), or post-menarchal females, appear to be at higher risk for iron deficiency and should be screened as part of the pre-sport physical examination [14-16]. These individuals may present with a change in exercise tolerance or may be asymptomatic. (See "Sports participation in children and adolescents: The preparticipation physical evaluation" and "Exercise-related gastrointestinal disorders", section on 'Gastrointestinal bleeding'.)

IRON REQUIREMENTS — The recommended dietary allowances (RDAs) for elemental iron are based on requirements for absorbed iron, proportion of dietary iron that is absorbed, and estimated iron losses (eg, due to menstruation) (figure 1). In adolescents, a substantial proportion of the requirement is attributable to increases in hemoglobin mass and tissue iron due to growth. The RDAs for iron during adolescence are [17]:

●Children 9 to 13 years – 8 mg daily

●Adolescents 14 to 18 years – 11 mg daily for males; 15 mg daily for females

Iron requirements are substantially higher for pregnant adolescents and women. (See "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Iron'.)

Data from a food survey conducted among adolescents across Europe found that average consumption of iron was 13.8 mg/day among males and 11 mg/day among females [18]. A majority of males met the estimated average requirement for bioavailable iron intake (72.4 percent), whereas only 13.7 percent of females did so.

STAGES OF IRON DEFICIENCY — The laboratory manifestations of iron deficiency occur in several stages (table 2) [19-22]. These stages are defined by the extent of depletion, first of iron stores, and then of iron available for hemoglobin synthesis [23]. Eventually, the iron and hemoglobin deficiency is so severe that iron-deficient red cell production occurs (ie, iron deficiency anemia [IDA]) [19,21].

●Iron deficiency without anemia – In the first stage, iron stores are depleted without affecting erythropoiesis. In an iron-sufficient individual, the storage pool can be utilized when the need for hemoglobin synthesis is increased (such as following acute blood loss or a growth spurt in adolescents). Once these stores are depleted, however, the patient becomes vulnerable to development of anemia if further iron losses occur without sufficient replacement (figure 2).

●Iron deficiency with mild anemia – Additional iron loss results in the second stage of iron-restricted erythropoiesis, resulting in a decrease in both the mean corpuscular volume (MCV) and reticulocyte hemoglobin equivalent (CHr or Retic-he).

●Iron deficiency with severe anemia – Finally, ongoing deficiency results in the classical hypochromic and microcytic anemia, with a decrease in hemoglobin concentration as the final stage of IDA (picture 1).

The erythropoietin concentration is appropriately elevated in IDA, but the absolute reticulocyte count is usually low because iron deficiency (specifically, a reduction in transferrin-bound plasma iron) becomes rate-limiting for erythropoiesis, thereby impairing the erythropoietic response.

CLINICAL FEATURES — Many adolescents with iron deficiency are asymptomatic or have unrecognized, nonspecific symptoms. They are identified only by the findings of anemia or low ferritin on laboratory testing. When symptoms arise, they are caused primarily by anemia and include weakness, headache, irritability, syncope, and varying degrees of fatigue and exercise intolerance. Patients may also experience symptoms of pica without recognizing its association with iron deficiency.

In general, symptoms are not a reliable predictor of the severity of iron deficiency within a population, as iron deficiency anemia (IDA) may develop gradually over time, and symptoms tend to vary significantly among patients. In very severe anemia, symptoms and signs are more likely to be present (eg, tachycardia, weakness, headache or syncope).

Iron deficiency without anemia is also associated with clinical symptoms in some patients and may include fatigue, decreased cognitive function, restless legs syndrome, and pica [10]. Placebo-controlled trials in adults have demonstrated improvement in both symptoms and laboratory measures of iron deficiency with oral or intravenous (IV) iron supplementation. (See "Treatment of iron deficiency anemia in adults", section on 'Iron deficiency without anemia'.)

Cognitive function — Iron deficiency can impair cognitive function in adolescents. This impairment was illustrated in a study in which 81 adolescent females with nonanemic iron deficiency (serum ferritin ≤12 micrograms/L with normal hemoglobin concentration) were randomly assigned to receive oral ferrous sulfate (130 mg elemental iron twice daily) or placebo for eight weeks [24]. Participants who received iron showed an elevation in serum ferritin (27.3 versus 12.1 micrograms/L in the placebo group) and performed significantly better on a test of verbal learning and memory.

Similar benefits of iron sufficiency were shown in a blinded placebo-controlled intervention trial in young adult women with varied iron status [25] At baseline, subjects who were iron sufficient performed better on a series of cognitive tasks than those with IDA; those with nonanemic iron deficiency had intermediate cognitive performance. After iron supplementation, subjects who had a significant increase in serum ferritin experienced a five- to sevenfold improvement in cognitive performance.

In another randomized trial of adolescent females, improvements in lassitude, the ability to concentrate in school, and mood were reported by the participants who ingested iron compared with the controls [26]. In the majority of those who improved, serum ferritin concentrations were low at baseline and normalized by the end of the study.

Cross-sectional data regarding iron status from National Health and Nutrition Examination Survey (NHANES) III (1988-1994) were compared with standardized test scores for 5398 children aged 6 to 16 years old [27]. Three percent of the children in this sample were iron deficient. Compared with children with normal iron status, children with iron deficiency, with and without anemia, had lower average mathematics scores (93.7 versus 86.4 and 87.4 percent, respectively). Reading, verbal, and performance scores did not differ between the groups.

Physical performance and fatigue — IDA impairs exercise capacity in adolescents; a similar effect may be seen with nonanemic iron deficiency [28,29]. In one study, 14 iron-deficient, nonanemic adolescent runners were randomly assigned to receive ferrous sulfate (195 mg/day of elemental iron) or placebo [28]. The mean ferritin concentration rose from 8.7 to 26.6 micrograms/L in patients taking iron and fell from 10.6 to 8.6 micrograms/L in the placebo group. Treadmill endurance times improved significantly in the iron-treated runners (increase of 0.03 to 1.92 minutes), while declining in all seven controls (decrease of 0.07 to 1.30 minutes). No significant differences in gas exchange or cardiac measures occurred between the two groups. Of note, iron supplementation in the absence of iron deficiency has not demonstrated a benefit in exercise capacity or performance.

An observational study in nonanemic, iron-deficient adolescent females reported improvement in self-reported fatigue after IV iron supplementation [30]. Placebo-controlled trials will be needed to determine the utility of such an approach for patients with subjective symptoms. Thus, evidence is limited regarding whether iron supplementation is beneficial for this group of patients and the appropriate targets for serum ferritin. A shared decision-making approach is recommended between patients and providers when selecting iron therapies.

Pica and pagophagia — 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 [31]. Pagophagia, or pica for ice, is particularly common and quite specific for the iron deficiency state [32,33]. It may be present in children with nonanemic iron deficiency and responds rapidly to treatment with iron, often before any increase is noted in the hemoglobin concentration.

Children with sickle cell disease or neurodevelopmental disorders such as autism may also develop pica, which is not consistently associated with iron deficiency in these groups [34].

The association of pica with severity of iron deficiency has not been well studied. However, for patients who report having pica with IDA, such symptoms can be utilized as an "early warning sign" of recurrent ID and warrant evaluation and therapy.

Beeturia — An occasional manifestation of iron deficiency is beeturia, in which the ingestion of beets leads to the excretion of red urine [35]. This finding is caused by increased intestinal absorption and subsequent excretion of the reddish pigment betalain (betanin). Betalain, a redox indicator, is decolorized by ferric ions, which presumably explains the predisposition to beeturia in iron deficiency. (See "Urinalysis in the diagnosis of kidney disease", section on 'Red to brown urine'.)

Restless legs syndrome — Restless legs syndrome is a common sleep-related movement disorder characterized by an often unpleasant or uncomfortable urge to move the legs that occurs during periods of inactivity, particularly in the evenings, and is transiently relieved by movement. The syndrome has been associated with low iron stores, and a subset of patients may have symptomatic improvement with iron replacement. (See "Restless legs syndrome and periodic limb movement disorder in children".)

SCREENING

Whom to screen — We suggest the following screening procedures for adolescents:

●Risk factor-based screening [11,36]:

•Review of risk factors for iron deficiency anemia (IDA) at least annually during adolescence, especially for dietary iron intake, heavy menstrual blood loss, or history or symptoms of iron deficiency or IDA (table 1)

•Laboratory screening for any adolescent if any major risk factors are identified

and

●Universal laboratory screening for females – In adolescent females, we suggest laboratory screening (regardless of risk factors) on at least one occasion during adolescence. The screening should be performed at least one year postmenarche and ideally by age 14 [36]. Repeat screening is appropriate for those with risk factors, as noted above.

We suggest universal laboratory screening for female adolescents because of the high frequency of iron deficiency in this population (up to 15 percent in the United States) and because most adolescent females have at least one risk factor (eg, low dietary iron intake, heavy menstrual blood loss, or underweight). In addition, the sensitivity and specificity of risk factor-based screening in this group is poor [37].

How to screen — To screen for iron deficiency, we suggest measuring a complete blood count (CBC) at a minimum. We also suggest simultaneous measurement of serum ferritin, if possible, especially for patients with a high risk for iron deficiency. (See 'Evaluation and presumptive diagnosis' below.)

●Screening with a CBC (rather than hemoglobin alone) is preferred because it includes red blood cell indices such as mean corpuscular volume and red blood cell distribution width (a measure of variability in red cell size), which help to evaluate for iron deficiency. Although measurement of hemoglobin alone is sufficient to diagnose anemia (defined as a hemoglobin level of <12 g/dL for females, or <13 g/dL for males) [36], anemia is neither a sensitive nor a specific screen for iron deficiency [38].

●We also measure serum ferritin at the time of the initial screen because this facilitates the diagnosis of IDA and also identifies children who are iron deficient but not yet anemic [39].

EVALUATION AND PRESUMPTIVE DIAGNOSIS — Iron deficiency or iron deficiency anemia (IDA) is suspected based on the results of the screening tests, performed either because of risk factors or suggestive symptoms. A presumptive diagnosis of IDA can be made after further laboratory testing, consisting of a complete blood count (CBC) with red blood cell indices, ideally with serum ferritin. For adolescent females, we suggest including serum ferritin if possible because nonanemic iron deficiency is common in this population.

A definitive diagnosis of iron deficiency or IDA can be made if the CBC and ferritin normalize after iron therapy.

Iron deficiency — Iron deficiency is generally identified by a serum ferritin concentration below 15 micrograms/L. In some patients, higher ferritin thresholds are targeted to mitigate symptoms such as fatigue and restless legs (serum ferritin >30 micrograms/L or >50 micrograms/L). In adolescent athletes, higher ferritin thresholds may also be targeted, though evidence regarding effects on performance is mixed. Iron deficiency is associated with adverse effects, with or without overt symptoms, and should be treated (see 'Management' below). A low serum ferritin is always consistent with iron deficiency, but normal or elevated ferritin does not exclude iron deficiency. This is because ferritin is an acute phase reactant, and serum levels increase in liver disease, inflammation, and malignancy (table 3). Thus, an adolescent with iron deficiency and an acute infection or a chronic inflammatory disease may have a "falsely" normal ferritin concentration.

Data are sparse regarding the duration of ferritin elevation after acute phase elevation. However, we generally wait two to four weeks after resolution of the underlying inflammation or infection before measuring serum ferritin. A C-reactive protein may be checked concurrently to assess for ongoing inflammation, which may assist with interpretation of the ferritin value. (See "Acute phase reactants".)

More minor reductions in iron stores (eg, ferritin <50 micrograms/L) also may be associated with adverse effects, including exercise intolerance, fatigue, restless legs, and other neurologic and/or sleep disorders. Patients with these characteristics may benefit from iron supplementation even if they are not anemic, although data in this population are not conclusive [40-46]. (See "Restless legs syndrome and periodic limb movement disorder in children".)

Iron deficiency anemia — In an otherwise healthy adolescent, a presumptive diagnosis of IDA can be made based upon the following:

●Risk factors for iron deficiency identified on clinical history (eg, low-iron diet, heavy menstrual bleeding), and

●Low hemoglobin concentration (typically <12 g/dL for nonpregnant adolescent females and males <15 years; or <13 g/dL for males >15 years), and

●Microcytosis (mean corpuscular volume [MCV] <80) and variable cell size (picture 1) (red blood cell distribution width >17), and/or

●Low serum ferritin – Measuring ferritin is valuable to support the diagnosis of IDA but is not always necessary

If a cause of anemia other than IDA is known or suspected, such as an underlying chronic illness, or a family history of thalassemia, further workup is appropriate before making the presumptive diagnosis of IDA. The possibility of thalassemia should also be raised by microcytic anemia with normal ferritin and/or elevated red blood cell count on the CBC, particularly if typical iron deficiency risk factors are not present. Patients with these characteristics warrant more detailed evaluation. (See 'Further evaluation for causes' below.)

The diagnosis of IDA is confirmed by performing a trial of iron supplementation and demonstrating a rise in serum hemoglobin of >1 g/dL in follow-up, as described below. (See 'Oral iron therapy' below and 'Follow-up' below.)

Further evaluation for causes

●Evaluation for causes of iron deficiency – Diseases that often cause or contribute to iron deficiency include:

•Bleeding diathesis (eg, von Willebrand disease, which can present with heavy menstrual bleeding). (See "Clinical presentation and diagnosis of von Willebrand disease".)

•Gastrointestinal diseases:

-Celiac disease – May cause iron deficiency due to iron malabsorption, as well as gastrointestinal symptoms and/or growth failure. Screening is with tissue transglutaminase antibodies. (See "Diagnosis of celiac disease in children".)

-Inflammatory bowel disease – May cause iron deficiency due to gastrointestinal blood loss, iron malabsorption, and/or anemia of chronic disease/inflammation. Screening stools for occult blood and stool calprotectin are a reasonable initial screen, with or without an index of inflammation such as C-reactive protein or erythrocyte sedimentation rate. Further workup depends on the level of suspicion. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)

●Differential diagnosis of anemia – Other conditions can produce a mild hypochromic, microcytic anemia and be confused with IDA. These include mild hereditary anemias (including alpha or beta thalassemia trait, hemoglobin C or E trait), anemia of chronic disease, and more rare anemias such as sideroblastic anemia. The table shows characteristics that help to distinguish between the most common of these disorders (table 4). (See "Diagnosis of thalassemia (adults and children)".)

Combined nutritional anemias (eg, vitamin B12 or folate deficiency with malabsorption states) also may make it difficult to categorize the anemia using red blood cell indices, though these are relatively uncommon in children. All iron tests must be interpreted with the full clinical context and patient history as most measures can be affected by factors other than iron status (table 3). (See "Approach to the child with anemia".)

MANAGEMENT — For patients with a presumptive diagnosis of iron deficiency anemia (IDA), we suggest each of the following steps:

●A trial of treatment with oral iron supplementation (see 'Oral iron therapy' below)

●Dietary counseling to improve iron intake (see 'Dietary counseling' below)

●Measures to evaluate and treat any underlying cause of the blood loss (see 'Address etiology of the iron deficiency' below)

●Follow-up monitoring to ensure response to the supplementation, which also helps to confirm the diagnosis of iron deficiency (see 'Follow-up' below)

These steps are also appropriate for adolescents with iron deficiency but without anemia. Although dietary changes may gradually improve iron status in this population, use of oral iron supplements generally results in more rapid and reliable resolution of the iron deficiency.

Initial treatment — For most patients, the first step in management is oral iron therapy, in conjunction with dietary counseling and other measures to prevent recurrence (minimization of blood loss), as discussed in the following sections.

Oral iron therapy

Dose and form — For adolescents with iron deficiency, with or without anemia, we suggest treatment with ferrous sulfate, providing 65 to 130 mg elemental iron (typically, one to two tablets) once daily for at least three months. As an alternative, for adolescents with mild iron deficiency who report poor tolerance of daily iron therapy, it is reasonable to adjust the dosing regimen to every other day or three times per week (eg, Monday, Wednesday, and Friday). This strategy is based upon studies in adults with mild iron deficiency in which alternate-day dosing (eg, 60 mg every other day for 28 days) compared with daily dosing (eg, 60 mg daily for 14 consecutive days) improved total iron absorption and reduced side effects such as nausea [47]. The efficacy of this strategy in individuals with more severe iron deficiency or in younger age groups is unclear and needs further study. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)

Standard recommended dosing in adolescents and adults varies widely, ranging from 60 to 300 mg elemental iron per day [23]. We use ferrous sulfate because it was effective and generally well tolerated in a randomized clinical trial in young children with nutritional IDA [48]. We recommend dosing at the lower end of the recommended range (65 to 130 mg elemental iron) because studies in adults have demonstrated efficacy, improved tolerance, and higher fractional absorption of oral iron in persons treated with relatively low doses of oral iron therapy [47,49,50]. If other forms of iron therapy are used, the dose should be calculated to provide a similar amount of elemental iron (table 5). Larger doses rarely are necessary and may produce some degree of intolerance. Additional considerations of absorption and side effects govern the choice of a supplementation regimen [51], as outlined below. (See 'Absorption' below and 'Intolerance' below.)

In resource-limited countries, simpler approaches such as the use of iron pots for cooking, might be a useful alternative [52]. Iron ingots shaped like fish (Lucky Iron Fish) used in cooking water have been studied in low-resource settings and have been safe and effective as well [53,54]. Another alternative is the use of weekly rather than daily supplements. In one study of Indonesian adolescents, supplementation with 60 mg of elemental iron (and retinol and vitamin C to increase iron absorption) once weekly was equally efficacious as daily supplementation with the same dose, but better tolerated [55]. Similar results were demonstrated in a population of adolescent Nepalese females [56], Indian adolescent females [57], and Jordanian children [58]. Reasons that the weekly approach was successful may include improve tolerance, adherence, and higher fractional absorption of iron in persons treated with relatively low doses of iron therapy, based on studies in adults and children [48-50]. However, these strategies are based upon relatively low doses of iron (eg, 70 to 100 mg elemental iron once weekly for adolescents [56,57]), which may not be sufficient to treat patients with clinically significant anemia. Therefore, we favor once daily dosing where this is possible, using relatively low doses of elemental iron, as outlined above.

Absorption

●Iron is absorbed best from the duodenum and proximal jejunum. Thus, enteric-coated or sustained-release capsules, which release iron further down in the gastrointestinal tract, are counterproductive as well as expensive and should be avoided if possible.

●Iron is absorbed as heme iron (from hemoglobin and myoglobin in meat) and nonheme iron (iron salts extracted from plant and dairy foods) [59]. Heme iron is highly bioavailable but comprises a small portion of dietary iron in most diets. Because of lack of heme iron, individuals consuming vegetarian diets may have increased iron requirements.

●The bioavailability of nonheme iron is affected by several intraluminal factors:

•Calcium, phytates (present in legumes, rice, and grains), and tannates in food impair iron absorption to a variable degree. A study comparing iron administration with water, with a small meal, or with vitamin C demonstrated higher fractional absorption with vitamin C and decreased absorption with food [60]. Thus, optimally, iron supplements are given separately from a meal. Concomitant administration of ascorbic acid can improve iron absorption [61,62].

•Iron should be given two hours before, or four hours after, ingestion of antacids.

•Calcium inhibits the absorption of iron by as much as 60 percent. Thus, for individuals with iron deficiency, it is best to optimize absorption by trying to give iron supplements separately from calcium supplements. For individuals without iron deficiency, calcium and iron may be combined in one pill for convenience, as it is likely that there is some adaptation to absorption when supplements are taken regularly.

●The iron preparation used should be based upon cost and effectiveness with minimal side effects. The least expensive preparation is iron sulfate tablets, which are usually provided in tablets containing 325 mg of iron salts, of which 65 mg is elemental iron [63].

Intolerance — Iron therapy can cause unpleasant gastrointestinal symptoms such as nausea and constipation, likely related directly to the amount of elemental iron ingested. Placebo-controlled trials have demonstrated that low-dose iron supplementation (eg, 3 mg/kg) rarely causes gastrointestinal symptoms [64]. Larger doses rarely are necessary and may produce some degree of intolerance.

Gastrointestinal intolerance often can be reduced by altering the supplementation regimen:

●Use doses on the lower end of the recommended range, such as the dose of 65 to 130 mg elemental iron once daily recommended above. (See 'Oral iron therapy' above.)

●Try alternate-day dosing (eg, 60 mg every other day). Studies in adults suggest improved tolerance and absorption with alternate-day dosing, although the efficacy of this strategy in individuals with more severe iron deficiency or in younger age groups has not been established. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)

●Patients with persistent gastric intolerance may tolerate ferrous sulfate elixir, which provides approximately 45 mg of elemental iron per 5 mL (table 5). Using the liquid form, patients can titrate the dose down to the level at which the gastrointestinal symptoms become acceptable.

Adverse effects and toxicity — Gastrointestinal symptoms such as nausea and constipation are the most common side effects of iron supplementation. These are dose-related and often can be minimized by altering the supplementation regimen as described above.

The risk of iron overload during treatment with standard doses of iron supplements is very low in children and adolescents. Patients with juvenile hemochromatosis are at risk for iron overload, but this is a very rare disorder and is effectively ruled out by the presence of a low or normal serum ferritin value [65]. Acute iron intoxication may occur in small children after an accidental overdose, and can be life-threatening [65]. (See "HFE and other hemochromatosis genes", section on 'Hemojuvelin (HJV)' and "Acute iron poisoning".)

Dietary counseling — For patients with iron deficiency with or without anemia, we recommend review of the diet and counseling to improve dietary intake if possible. Dietary sources of iron are found in meat, grains, fruits, and vegetables. Ready-to-eat, iron-fortified cereal is a major contributor to iron intake among all children and typically provides two to three times more iron per serving than meats (table 6). To meet their recommended intake for iron (11 mg for males and 15 mg for females), adolescents typically require two to four servings of iron-rich foods daily, depending on the source. Adolescents who do not meet this requirement through their diet should take a supplement such as a multivitamin with iron. (See 'Iron requirements' above.)

Heme dietary sources (fish, poultry, and meat) have a higher bioavailability than do nonheme (vegetable) sources (30 versus 10 percent). Thus, iron deficiency may be a particular problem in vegetarian children. In addition, intraluminal factors can affect absorption (table 7). Ascorbic acid enhances the absorption of non-animal sources of iron such as cereal, breads, fruits, and vegetables, whereas tannates (teas), bran foods rich in phosphates, and phytates (found in seeds and grains) inhibit iron absorption [66-71]. (See "Vegetarian diets for children", section on 'Iron'.)

A relatively high calcium concentration also inhibits iron absorption. However, adaptation of iron absorption to high calcium intakes has been demonstrated, suggesting that this should not pose a significant clinical problem [72-74].

Address etiology of the iron deficiency — Many adolescents with IDA or iron deficiency without anemia have additional risk factors other than a low-iron diet. Any adolescent with IDA should be assessed for causes of blood loss; any underlying cause should be treated to ensure appropriate response to iron therapy and prevent recurrence.

Adolescent females are particularly at risk for IDA due to menstrual blood loss. Many young women may have abnormal uterine bleeding during the years immediately postmenarche, which may be worse in individuals with underlying bleeding disorders. This excessive blood loss coupled with rapid growth during adolescence and potentially low or poor-iron diet results in an inability to maintain normal iron stores. Those with heavy menstrual bleeding should have guidance on options available to control bleeding. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis" and "Abnormal uterine bleeding in adolescents: Management".)

Adolescent males and females with IDA should be assessed for gastrointestinal blood loss and referred for additional evaluation if any concerning symptoms are present (eg, poor growth, gastrointestinal blood loss, or malabsorption).

Follow-up — The complete blood count (CBC), with hemoglobin, hematocrit, and red blood cell indices, should be checked four weeks after initiation of iron therapy to assess clinical improvement and therapeutic efficacy. This testing should be done when the child is healthy (without signs of a recent illness because a viral illness may cause a transient decrease in hemoglobin). If the hemoglobin has increased by 1 g/dL (or 2 g/dL if the hemoglobin is <10 g/dL at diagnosis), therapy is continued. Another CBC and ferritin may be retested at three months to reassess for resolution of anemia, as well as normalization of other hematologic parameters and iron stores (table 8). If the underlying etiology has not been fully addressed (ie, ongoing excessive menstrual blood loss), patients may need to continue on iron supplementation to prevent recurrence.

After stopping iron supplementation, repeat testing of the CBC and serum ferritin after 6 to 12 months may be performed to ensure that iron deficiency has not recurred.

Nonresponders — If the microcytic anemia fails to improve after four weeks, the first step is to interview the patient and family to determine whether the supplement has been given appropriately, if there is ongoing or additional blood loss, or if there has been a significant intercurrent illness (which might cause a transient decrease in hemoglobin).

Additional testing — For nonresponders in whom there is not a clear explanation (ie, appropriately taking iron supplement, no additional risk factors), we suggest additional evaluation, including serum ferritin if not previously obtained, hemoglobin electrophoresis, and stool testing for calprotectin and occult blood. These results will help to rule out conditions that might mimic or complicate the IDA (table 4). Hemoglobin electrophoresis results may be falsely negative in a patient with concomitant beta thalassemia trait and iron deficiency. Therefore, iron deficiency, if present, must be corrected to ensure accurate interpretation of electrophoresis results. (See 'Further evaluation for causes' above.)

Indications for parenteral iron therapy — Intravenous (IV) iron is generally considered second-line therapy for patients with IDA due to the efficacy of oral iron supplementation, cost of IV iron preparations, preference to avoid IV placement in adolescents, as well as potential for adverse effects, although these are rare [75].

Indications for IV iron therapy include severe anemia, persistent anemia with oral iron intolerance, malabsorption, or nonadherence to oral iron therapy despite attempts at family education and support. Children with underlying gastrointestinal disease, such as short bowel syndrome or inflammatory bowel disease, may have particular difficulty tolerating oral iron and require early initiation of IV iron therapy.

Six forms of IV iron therapy are now US Food and Drug Administration approved for adults; four have labeled approvals in children. The IV iron preparations that are most commonly used for treatment of children are iron sucrose (Venofer) [76], low molecular weight iron dextran (INFeD) [77], and ferric carboxymaltose (Injectafer) [78,79]. Selection among these options may depend on relative costs and availability, time required for administration, and maximum permissible dose per infusion. (See "Iron deficiency in infants and children <12 years: Treatment", section on 'Intravenous iron therapy' and "Treatment of iron deficiency anemia in adults", section on 'Intravenous iron'.)

Response to treatment with IV iron may be assessed in the same manner as that of oral iron therapy. (See 'Follow-up' above.)

Blood transfusion for severe anemia — Transfusion therapy is reserved for severe, symptomatic IDA. Adolescents may have more difficulty tolerating anemia compared with younger children and may benefit from transfusion at hemoglobin concentrations of less than 7 g/dL, particularly in the setting of active blood loss. Transfusions should be administered with caution (transfusion volumes of 5 mL/kg over three to four hours) to avoid inducing heart failure. In adults, transfusion is not recommended in hemodynamically stable patients without end-organ ischemia unless the hemoglobin level is less than 7 g/dL. (See "Treatment of iron deficiency anemia in adults", section on 'Severe/life-threatening anemia'.)

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".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Anemia caused by low iron in adults (Beyond the Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Iron deficiency anemia".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Among adolescent females in the United States, approximately up to 16 percent are iron deficient. Among adolescent males, less than 1 percent are iron deficient. Risk factors for iron deficiency include heavy menstrual blood loss (>80 mL/month), vegetarian or vegan diet, underweight or undernutrition, endurance training, blood donation, or chronic illness (table 1). (See 'Epidemiology' above.)

●Recommended iron intake – The recommended dietary allowance (RDA) for elemental iron is (see 'Iron requirements' above):

•Children 9 to 13 years – 8 mg daily

•Adolescents 14 to 18 years – 11 mg daily for males and 15 mg daily for females

•Pregnant adolescents – 27 mg daily

●Clinical features

•Laboratory findings – The laboratory manifestations of iron deficiency occur in several stages (table 2), characterized by progressive degrees of anemia. (See 'Stages of iron deficiency' above.)

•Clinical symptoms – Many adolescents with iron deficiency are asymptomatic or have unrecognized, nonspecific symptoms such as weakness, headache, irritability, and varying degrees of fatigue and exercise intolerance. In addition, iron deficiency can impair cognitive function, concentration, and exercise capacity. Occasionally, iron deficiency may cause pica (particularly of ice). (See 'Clinical features' above.)

●Screening – Screening for iron deficiency is an important component of health maintenance during adolescence and includes (see 'Whom to screen' above):

•Screening for risk factors – All adolescents should be evaluated annually for risk factors for or symptoms of iron deficiency, including low dietary iron intake, heavy menstrual blood loss, and/or pica (table 1). Laboratory screening should be performed if any risk factors are identified.

•Laboratory screening for all females – For all females, we suggest universal laboratory screening on at least one occasion during adolescence, at least one year postmenarche and ideally by age 14 (Grade 2C).

•Laboratory tests – Ideal screening includes both a complete blood count (CBC) and serum ferritin to identify those patients with iron deficiency anemia (IDA) or nonanemic iron deficiency. In most clinical settings, the simplest and most cost-effective screen for iron deficiency is to perform a CBC, which includes measurements of hemoglobin, hematocrit, mean corpuscular volume (MCV), and red blood cell distribution width. (See 'How to screen' above.)

●Diagnosis and initial management

•Presumptive diagnosis – In otherwise healthy adolescents, a presumptive diagnosis of IDA can be made based upon clinical risk factors in the presence of a low hemoglobin concentration (typically <12 g/dL for nonpregnant adolescent females and males <15 years; or <13 g/dL for males >15 years) and microcytosis (MCV <80). A low serum ferritin (usually defined as less than 15 micrograms/L) further supports the diagnosis.

Interpretation of iron measures must account for full clinical context as most of these measures can be affected by factors other than iron status (table 3) and to distinguish between IDA and other causes of microcytic anemia (table 4). Serum ferritin is an acute phase reactant, so levels may increase in states of acute or chronic inflammation or in liver disease. A low serum ferritin value is always consistent with iron deficiency. (See 'Evaluation and presumptive diagnosis' above.)

•Therapeutic trial – For patients with a presumptive diagnosis of IDA, we suggest a trial of treatment with oral iron supplements, rather than dietary treatment alone (Grade 2C). We suggest a dose of 65 to 130 mg elemental iron once daily (Grade 2C). Doses in this range are generally effective, improve adherence, and tend to be better tolerated (decreased side effects) than higher doses of oral iron or more frequent dosing. Iron supplementation is also appropriate for patients with iron deficiency (low serum ferritin) without anemia. (See 'Oral iron therapy' above.)

Follow-up monitoring should be performed to ensure response to the supplementation, which also helps to confirm the diagnosis of iron deficiency. (See 'Follow-up' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Steven A Abrams, MD, who contributed to earlier versions of this topic review.