INTRODUCTION — Iron deficiency is the most common nutritional deficiency in children. The World Health Organization (WHO) estimates that anemia affects one-quarter of the world's population and is concentrated within preschool-aged children and women; anemia in the majority of individuals is due to iron deficiency. Iron deficiency is a particularly challenging problem for resource-limited nations in Asia and Africa [1,2]. In the United States and other resource-rich countries, rates of iron deficiency are substantially lower and are gradually improving. Nonetheless, iron deficiency remains common and has important consequences for health and neurodevelopment. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis", section on 'Prevalence'.)

The treatment of iron deficiency in infants and young children will be reviewed here. Related material can be found in the following topic reviews:

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

●(See "Iron requirements and iron deficiency in adolescents".)

●(See "Approach to the child with anemia".)

DIAGNOSIS — A presumptive diagnosis of iron deficiency anemia (IDA) is made by the combination of risk assessment and laboratory findings of a microcytic anemia, which may be mild. The diagnosis is confirmed if a trial of oral iron supplementation (3 mg/kg elemental iron per day) produces a hemoglobin (Hgb) rise of >1 g/dL within four weeks for children with mild anemia [3], or within two weeks for those with severe anemia. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Prior to embarking on the empiric trial of iron supplementation, every child should have a careful dietary history and review of risk factors for lead exposure; we also suggest blood screening for concomitant lead poisoning if risk factors are identified. In some cases, including children between three years of age and adolescence, and/or children with severe anemia (<7 g/dL), additional laboratory testing is appropriate before the therapeutic trial. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis".)

ORAL IRON THERAPY — Three steps are essential for successful treatment of iron deficiency anemia (IDA) in infants and young children:

●Appropriate dose and scheduling of oral iron therapy

●Dietary modifications to address the underlying etiology of the iron deficiency

●Follow-up assessment for response

Dose and scheduling — For infants and children with proven or suspected IDA, we suggest initiating treatment with oral ferrous sulfate, 3 mg/kg elemental iron, administered once daily. For optimal absorption, the supplement should be given between meals and with water or juice, and milk products should be avoided. Iron absorption is more effective when given with juice rather than milk (13.7 versus 5.7 percent absorbed in one report) [4].

Standard recommended dosing is 3 to 6 mg/kg elemental iron per day. We choose to use ferrous sulfate and the 3 mg/kg dose because it was effective in a randomized clinical trial of 80 young children (ages 9 to 48 months) with nutritional IDA (NCT01904864) [5]. In this trial, treatment with ferrous sulfate 3 mg/kg once daily for 12 weeks resulted in a 1 g/dL greater increase in hemoglobin concentration than an equivalent dose of an iron polysaccharide complex formulation, based on a linear mixed model. Similarly, 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 [6,7].

Side effects — Side effects commonly attributed to oral iron therapy include abdominal pain, constipation, and diarrhea. However, placebo-controlled trials have demonstrated that low-dose iron supplementation (eg, 3 mg/kg) and iron-fortified formulas rarely cause gastrointestinal symptoms [8-13]. Larger doses rarely are necessary and may produce some degree of intolerance.

Oral iron is best absorbed on an empty stomach when taken with water or juice. It should not be taken with milk or other dairy and calcium-containing products as this will lessen its absorption. There are limited data on whether taking oral iron with meals lessens gastrointestinal side effects.

Liquid preparations of iron occasionally cause gray staining of the teeth or gums. These effects are temporary and can be avoided or minimized by brushing the child's teeth and/or rinsing the mouth with water after administration of the drops. Liquid iron may also stain fingernails if the child places his or hand in their mouth after iron administration.

Iron therapy appears to have mixed effects on immune function and susceptibility to infection. There is no evidence that iron supplementation increases the risk for infection, with the possible exception of special populations in which malaria is endemic if initiated during high-transmission seasons. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis", section on 'Immunity and infection'.)

Dietary changes — For children with proven or suspected IDA, in addition to therapeutic iron supplementation, we suggest the following dietary changes, which are also used to prevent iron deficiency (table 1). (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis", section on 'Dietary recommendations'.)

●All infants younger than 12 months of age should either be breastfed or receive iron-fortified formula. Infants should not be given low-iron formula or unmodified cow's milk. Feeding of infants with unmodified cow's milk (rather than formula or breastfeeding) may increase the risk for cow's milk protein-induced colitis with resultant intestinal blood loss. The resulting iron deficiency is exacerbated by lack of iron fortification in unmodified cow's milk. A cow's milk-based formula is acceptable if there is no evidence of cow's milk protein-induced colitis. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis", section on 'Dietary factors'.)

●For infants six months and older, especially breastfed infants, ensure adequate consumption of iron in complementary foods including iron-fortified infant cereals, foods rich in vitamin C, and pureed meats.

●For all children 12 months of age and older, intake of cow's milk should be limited to less than 20 oz per day. Higher intake of cow's milk in toddlers has been associated with increased risk for iron deficiency [14,15]. When iron deficiency is first detected or suspected, the toddler's diet should be promptly evaluated and steps taken to reduce cow's milk intake to below this threshold. If the child is still bottle fed, discontinuation of the bottle will help to limit milk intake and encourage intake of other foods [16]. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis" and "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis", section on 'Dietary factors'.)

For those with persistent or refractory IDA, the stools should be checked for blood (guaiac) and, if blood is present, all milk products should be stopped.

Follow-up assessment for response — All children should have follow-up laboratory testing to determine their response to therapeutic iron. This is important to monitor for adherence to therapy, and also to identify children who fail to respond to therapy and warrant consideration of parenteral therapy and further evaluation to determine the cause of the anemia [17]. The testing should be performed when the child is healthy, without signs of an acute or recent illness, because a viral infection may cause a transient decrease in hemoglobin (Hgb).

The timing of follow-up testing depends on the severity of the IDA: Children with mild anemia (Hgb ≥9 g/dL) should be reevaluated by checking Hgb or complete blood count (CBC) about four weeks after treatment initiation. Children with moderate or severe anemia (Hgb <9 g/dL) should be retested one or two weeks after treatment initiation.

Responders — An adequate initial response to therapeutic iron is reflected by the following results:

●Mild anemia (Hgb ≥9 g/dL) – The Hgb should rise at least 1 g/dL within four weeks of treatment initiation [3].

●Moderate or severe anemia (Hgb <9 g/dL) – The Hgb should rise at least 1 g/dL within the first two weeks of treatment initiation. If testing is performed earlier, a reticulocyte response may be seen as soon as 72 hours after treatment initiation.

For patients who respond to treatment as described above, therapeutic iron should be continued. Additional testing should be performed about three months after initiation of iron therapy, including a CBC, Hgb, mean corpuscular volume (MCV), and red blood cell distribution width (RDW). Measurement of serum ferritin concentration also may be helpful to determine the need for further iron therapy to replenish iron stores.

In general, we suggest continuing iron therapy for about one month after all CBC parameters have normalized (Hgb, MCV, and RDW), to permit replenishment of iron stores. Early discontinuation of iron therapy frequently leads to recurrent IDA. Total duration of therapy is typically at least three months.

Nonresponders — Patients who do not demonstrate an adequate rise in Hgb as described above should be reevaluated. Potential causes of recurrent or refractory IDA include ineffective treatment (nonadherence or incorrect dosing), an incorrect diagnosis, or blood loss or malabsorption (table 2) [17]. The clinician should interview the parent to determine whether the supplement has been given at the appropriate dose and timing, whether the appropriate diet modifications have been made, and if there has been any significant intercurrent illness (which might cause a transient decrease in Hgb).

If the patient has indeed been taking an appropriate dose of iron and has not had an intercurrent illness, we suggest the following additional evaluation:

●Evaluation of anemia – The three most common causes of microcytic anemia in children are IDA, alpha or beta thalassemia trait, and anemia of chronic inflammation (also known as anemia of chronic disease) (table 3). These conditions can be assessed by measuring serum ferritin, Hgb electrophoresis (to assess for beta thalassemia trait), and C-reactive protein (CRP), respectively. Newborn screening results should be reviewed to determine whether any abnormal Hgb were present. Elevated levels of Hgb Barts or Hgb H suggest the possibility of a form of alpha thalassemia. Alpha thalassemia trait (also known as alpha thalassemia minima) cannot be detected by hemoglobin electrophoresis after the newborn period. (See "Clinical manifestations and diagnosis of the thalassemias".)

In children with both thalassemia trait (alpha or beta) and iron deficiency, sufficient treatment of the iron deficiency is necessary to ensure accurate Hgb electrophoresis results. Rare genetic mutations that interfere with iron transport result in a moderate to severe anemia that has hematologic parameters identical to IDA but is refractory to iron supplementation; this condition is termed iron refractory iron deficiency anemia (IRIDA) [18] (see "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Inherited disorders/IRIDA'). After other more common causes of anemia are excluded, the possibility of IRIDA can be explored by genetic testing or, for less cost, by an oral iron absorption test [19]. (See "Approach to the child with anemia".)

●Evaluate for gastrointestinal blood loss – Test three stool samples for occult blood. If the results are positive, additional screening for common causes of gastrointestinal blood loss is appropriate, as outlined below. Of note, oral iron supplements do not cause false positive results of the more current generation of tests for occult blood in stool (Hemoccult II, Hemocullt Sensa, and HemoQuant) [20-22] and, therefore, iron supplementation should not be stopped prior to such testing. This can be done before or after referral to a pediatric gastroenterologist. The following disorders should be considered, depending on the patient's age and characteristics (see "Lower gastrointestinal bleeding in children: Causes and diagnostic approach"):

•Cow's milk protein-induced colitis – This is a common cause of occult or overt fecal blood loss in infants and should be considered for any infant whose diet includes cow's milk protein (through breast milk, cow's milk-based formula, or solid foods). It is most likely to be induced by feeding of unmodified cow's milk but can also occur in breastfed infants whose mother's diet includes cow's milk, or in infants fed cow's milk-based formulas. The colitis generally responds to elimination of all milk protein from the diet of the infant and from the mother's diet if the infant is breastfed. (See "Food protein-induced proctocolitis of infancy".)

•Celiac disease – Celiac disease is a common cause of refractory IDA in children and should be considered in any infant or child whose diet includes wheat or other sources of gluten. Screening for celiac disease is performed using tissue transglutaminase antibodies (tTG), although testing of additional antibodies may be useful in children younger than two years. Other steps in the diagnosis of celiac disease, including upper endoscopy, are discussed separately. (See "Diagnosis of celiac disease in children", section on 'Antibody testing'.)

•Inflammatory bowel disease – Inflammatory bowel disease (IBD) occasionally presents with IDA, usually in association with other symptoms such as loose stools (with or without gross blood) and/or growth failure. Most children with IBD are diagnosed in late childhood or adolescence but a few present in early childhood or even infancy. Measurement of a CBC, erythrocyte sedimentation rate (ESR), CRP, and serum albumin serve as an initial screen. However, a more detailed evaluation including endoscopy is warranted in children with clinical features suggesting IBD. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)

INTRAVENOUS IRON THERAPY — During the past two decades, several new forms of intravenous (IV) iron therapy with good safety profiles have become available. Nonetheless, IV iron is generally considered second-line therapy for the majority of patients with iron deficiency anemia (IDA) due to its high cost, as well as potential for adverse effects, though rare [23]. Indications for IV iron therapy include 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 (IBD), may have particular difficulty tolerating oral iron and require early initiation of IV iron therapy. (See "Nutrient deficiencies in inflammatory bowel disease", section on 'Iron'.)

Each of the following IV iron preparations is a reasonable choice for treatment of children. Selection among these options may depend on relative costs and availability, time required for administration, and maximum permissible dose per infusion.

●Iron sucrose – Iron sucrose (Venofer) is the most common form of IV iron utilized in children [24]. Rates of adverse events including anaphylaxis are very low in this formulation when given in low doses. No test dose or routine premedications are indicated. Dosing is typically limited to 200 mg elemental iron per infusion for adolescents and 100 mg per infusion for children. As a result, most patients require multiple infusions to complete replacement of their calculated iron deficit.

●Iron dextran – Low molecular weight (LMW) iron dextran (INFeD) is commonly given as a single replacement dose (eg, up to 1000 mg elemental iron in adults) [25]. Minor self-limiting infusion reactions occur in less than 1 percent of patients. Serious adverse events such as anaphylaxis are extremely rare [25]. A protocol for a test dose and replacement dose in pediatric patients are outlined in the related drug monograph (see "Iron dextran: Pediatric drug information"). (See "Treatment of iron deficiency anemia in adults", section on 'LMW iron dextran'.)

High molecular weight (HMW) iron dextran (Dexferrum) should not be used because of higher rates of adverse events such as anaphylaxis; it is no longer available in the United States.

●Ferric carboxymaltose – Ferric carboxymaltose (Injectafer) is increasingly used for adults who are intolerant to oral iron therapy and also permits administration of the full replacement dose in a single infusion in the majority of patients. There is limited experience with its use in children. In a study of 72 children with IDA who failed oral iron therapy, administration of ferric carboxymaltose resulted in a good hematologic response and low rates of adverse effects [26]; the subjects had a variety of causes for IDA and included some young children with nutritional IDA. Another report demonstrated its safe and effective use in children with IBD and other gastrointestinal conditions [27].

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

BLOOD TRANSFUSION — Transfusion therapy is appropriate for selected children with severe iron deficiency anemia (IDA; hemoglobin [Hgb] concentration is <5 g/dL), if there is clinical evidence of distress (heart rate greater than 160/min, respiratory rate greater than 30/min, lethargy, and/or not feeding well). These symptomatic patients are presumed to be at risk for serious short-term morbidity and mortality, such as cardiac failure or stroke, which could be prevented by judicious transfusion. In this setting, transfusions should be administered with caution to avoid fluid overload and heart failure, giving transfusion volumes of 5 mL/kg over three to four hours. (See "Red blood cell transfusion in infants and children: Indications" and "Red blood cell transfusion in infants and children: Administration and complications".)

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

Initial approach — Our therapeutic approach for a child with suspected or proven iron deficiency anemia (IDA) is as follows:

●Oral iron therapy is started at a dose of 3 mg/kg of elemental iron once daily, typically with ferrous sulfate. For maximum absorption, the iron should be given 30 to 45 minutes before meals or two hours after meals, and only with juice or water. Administration with food or milk should be avoided. (See 'Dose and scheduling' above.)

●Meanwhile, the following dietary goals should be implemented to prevent recurrence (table 1) (see 'Dietary changes' above):

•Infants younger than 12 months of age should be fed with breast milk or iron-fortified formula. A cow's milk-based formula is acceptable if there is no evidence of cow's milk protein-induced colitis. Infants should not be given low-iron formula or unmodified cow's milk.

•For patients six months and older, especially breastfed infants, ensure adequate consumption of iron in complementary foods. These include infant cereals, which are fortified with iron, foods rich in vitamin C, and pureed meats.

•For children older than 12 months of age, intake of cow's milk should be limited to less than 20 oz per day and bottle feeding should be discontinued to limit milk intake. Excessive intake of cow's milk is the primary reason for the development of IDA in this age group and can be associated with occult intestinal blood loss.

●After beginning therapeutic iron, all children should have follow-up testing of a complete blood count (CBC) or hemoglobin (Hgb) to determine their response. The testing should be performed when the child is healthy, about four weeks after beginning iron therapy for children with mild anemia, or one to two weeks after beginning iron therapy in those with moderate to severe anemia. Follow-up is essential to confirm that the anemia was due to iron deficiency and to ensure that it is adequately treated. This is particularly important because of the effects of iron deficiency on neurodevelopment. (See 'Follow-up assessment for response' above.)

If the Hgb has increased by 1 g/dL, therapy is continued, and the CBC is retested at three months to ensure that the Hgb and other parameters reach the age-adjusted normal range. Oral iron therapy should be continued for at least one month after the Hgb reaches the normal range for age, to ensure that iron stores are replenished. A serum ferritin concentration can also be measured to check iron stores prior to discontinuation of iron therapy. (See 'Responders' above.)

Further evaluation — Patients who do not demonstrate an adequate response within four weeks of initiating iron therapy should be reevaluated. Potential causes of recurrent or refractory IDA include ineffective treatment (nonadherence or incorrect dosing), an incorrect diagnosis, or ongoing blood loss or malabsorption (table 2). Our approach is as follows:

●Interview the parent to determine whether the supplement has been given at the appropriate dose and timing, whether the appropriate diet modifications have been made, and if there has been any significant intercurrent illness (which might cause a transient decrease in Hgb). The most common reason for failure is that the treatment plan was not correctly followed. (See 'Nonresponders' above.)

●If the patient has indeed been taking an appropriate dose of iron and has not had an intercurrent illness, perform additional laboratory tests to rule out conditions that might simulate or complicate IDA such as thalassemia trait or anemia of chronic disease (table 3). In addition, several stool samples should be tested for occult blood. If the results are positive, additional screening should be performed for common causes of gastrointestinal blood loss, including cow's milk protein-induced colitis in infants, and celiac disease and inflammatory bowel disease (IBD) in older children. (See 'Nonresponders' above.)

●Intravenous (IV) iron is considered second-line therapy for patients who have failed oral iron therapy. It is generally reserved for patients with severe or persistent anemia who have proven oral iron intolerance, malabsorption, or nonadherence despite family education and support to optimize oral therapy. (See 'Intravenous iron therapy' above.)