Pediatric anemia

Article written and reviewed by Dr Luca Moretti

Pediatric anemia is one of the major hematologic conditions of childhood and adolescence. According to the 2024 WHO guideline, at sea level the cutoffs are <10.5 g/dL between 6 and 23 months, <11 g/dL between 24 and 59 months, <11.5 g/dL between 5 and 11 years, and <12 g/dL between 12 and 14 years; between 15 and 65 years, the cutoff is <12 g/dL in nonpregnant females and <13 g/dL in males. These values are diagnostic and epidemiologic tools and must be interpreted in the clinical context.

During childhood, anemia not only reduces the oxygen-carrying capacity of blood but is also associated with a significantly increased risk of impaired linear growth and weight gain, neurocognitive developmental impairment, worsening outcomes of chronic diseases and increased mortality in the most vulnerable settings. Longitudinal studies show that iron deficiency, especially when severe or prolonged during the first years of life, is associated with poorer neurocognitive and behavioral outcomes that may persist after hematologic correction; however, the causal relationship and degree of reversibility are not uniformly established.

The global prevalence of pediatric anemia reflects social and economic disparities: in low-income countries, it is estimated that more than 40 to 60% of children under 5 years of age are anemic, with rates exceeding 70% in regions affected by food insecurity, malaria or chronic parasitic infections. In high-income countries prevalence is substantially lower, about 5 to 15%, but remains elevated in disadvantaged groups, children with special needs, those born preterm, those with chronic diseases or selective diets.

Pediatric anemia is therefore a multidimensional problem: its causes range from nutritional deficiencies to hemoglobinopathies, chronic diseases and rare conditions such as bone marrow aplasias, as well as infections, occult bleeding and enzyme deficiencies. The pediatrician should therefore not merely correct the hemoglobin value, but should assess the child within the biological, social and family context, identify risk factors early and intervene both diagnostically and preventively.

Finally, it is essential to emphasize that the child's adaptive response to anemia differs substantially from that of adults: iron stores, maturation of the hematopoietic system, hemodynamic compensatory capacity and vulnerability to vitamin deficiencies are closely related to age and growth rate, making each pediatric age group distinctive from a pathophysiologic and therapeutic standpoint.

Physiology of hematopoiesis and blood requirements in children

Understanding the pathophysiology of pediatric anemia requires detailed analysis of the distinctive features of hematopoiesis at different developmental stages, from the neonatal period through adolescence. Neonatal hematopoiesis is strongly influenced by intrauterine conditions, with predominance of fetal hemoglobin (HbF), which has high oxygen affinity and allows effective gas transport across the placenta. After birth, the transition to adult hemoglobin (HbA) and rapid adaptation to the extrauterine environment produce the physiologic anemia of infancy: between 8 and 12 weeks, erythrocyte production temporarily declines because of erythropoietin suppression and improved oxygenation, lowering hemoglobin to about 11 g/dL in term infants, with values below 10 g/dL being uncommon in the absence of other pathologic findings.

During the first year of life, iron requirements become extremely high, both to support rapid expansion of blood volume and to promote brain myelination, muscle growth and immune development. Iron stores accumulated during fetal life, mainly in the third trimester, are rapidly depleted during the first 4 to 6 months, especially in exclusively breastfed infants without supplementation, preterm infants and newborns with low birth weight. At this stage, iron deficiency is the dominant cause of anemia, although folate deficiency, infections, occult bleeding or genetic conditions may also play a significant role.

During the preschool and school years, periods of growth spurt create new challenges for hematopoietic balance: requirements for iron, folate and vitamin B12 increase in proportion to linear and weight growth and expansion of muscle mass and blood volume. The rapid growth of adolescence is particularly relevant, when physiologic requirements are compounded by menstrual blood loss after menarche, restrictive diets, eating disorders, intensive sports or secondary malabsorption.

Iron homeostasis in children is regulated by a dynamic balance among intestinal absorption, bone marrow utilization for erythropoiesis, hepatic storage and blood loss, which is minimal during the first years of life but can become significant with chronic infections, parasitic infestations, occult bleeding, for example from cow's milk protein intolerance, inflammatory bowel disease or hemoglobinopathies. Hepcidin, the key hormone produced by the liver, finely regulates iron absorption according to the child's needs, but its production may be altered by inflammation, chronic infection or nutritional imbalance.

A distinctive feature of childhood is the close dependence of erythrocyte metabolism on overall nutritional balance: not only iron, but also protein, vitamin A, zinc and other micronutrients play essential roles in erythropoiesis. Deficiency of one or more of these nutrients may trigger a vicious cycle of anemia, malnutrition, immune dysfunction and impaired growth, aggravated by environmental factors such as poverty, inadequate access to preventive care and repeated infections.

Compared with adults, children also have a greater vulnerability to anemia-related effects on the central nervous system: iron depletion during the first two years of life has been associated with persistent alterations in neurocognitive development, attention, memory and executive functions, even after correction of the hematologic deficit. The association between early iron deficiency and neurocognitive development is one of the clinically relevant distinctive features of childhood compared with adulthood.

Etiology and risk factors

Pediatric anemia is clinically distinct from anemia in adults because of the central role of nutritional deficiencies and genetic conditions and the lesser contribution of chronic diseases, which instead become dominant in adult populations. Understanding its etiology requires integrating growth stages, hematologic requirements and the specific dynamics of childhood and adolescence.

In children, iron deficiency is by far the most common cause of anemia. This reflects rapid body growth, the physiologic depletion of neonatal stores and the frequent monotony of childhood diets, which may lack foods rich in bioavailable iron. Vulnerability is greatest during the first two years of life, when blood volume expansion and neurocognitive development are greatest, and recurs during adolescence, particularly in females after menarche.

Folate deficiency and vitamin B12 deficiency, although less common, are important causes of anemia in exclusively breastfed infants whose mothers follow unsupplemented restrictive diets, in children with malabsorption or chronic intestinal disease, and in the presence of severe nutritional imbalance.

Inherited hemoglobinopathies, including thalassemias and sickle cell disease, and red blood cell membrane defects such as hereditary spherocytosis play a major role in some geographic areas and population groups. They may present during childhood with highly variable severity, from asymptomatic or mild forms to severe disease, depending on the specific disorder and genotype.

Less commonly, but with severe clinical impact, anemias due to defective bone marrow production are found, including Fanconi anemia, Diamond-Blackfan anemia and congenital dyserythropoietic anemias, as well as hemolytic anemias of genetic origin, such as G6PD or pyruvate kinase deficiency, or autoimmune origin, and anemias secondary to chronic blood loss, including gastrointestinal bleeding, parasitic infestations in high-risk settings and heavy menstrual bleeding in adolescents.

Anemia of chronic disease, associated with chronic inflammation, kidney failure, autoimmune disease, cancer or chronic infections, accounts for a substantially smaller proportion in children than in adults. In these settings, anemia usually develops in children with known diseases requiring multidisciplinary follow-up and often presents as normocytic, normochromic anemia that may be poorly responsive to iron supplementation.

Finally, even rarer forms include anemia secondary to myelotoxic drugs, chemotherapy, or bone marrow infiltration by solid tumors or leukemias. Although exceptional in the general pediatric population, these causes must always be considered in the presence of warning signs or failure to respond to conventional therapy.

The factors that increase the likelihood of anemia in children reflect the complexity of development and variability in living conditions. Risk is greatest during periods of fastest growth, namely the first two years of life and adolescence. During these phases, blood volume expansion and iron and vitamin requirements are so substantial that even modest deviations from optimal nutritional balance can lead to anemia.

The main risk factors include:

• Prematurity and low birth weight, because of lower iron stores and greater susceptibility to iatrogenic blood loss
• Exclusive breastfeeding beyond 6 months without iron supplementation, delayed complementary feeding, and monotonous diets poor in iron-rich or vitamin-rich foods
• Restrictive diets, selective eating, eating disorders and social disadvantage
• Chronic gastrointestinal diseases, including celiac disease, inflammatory bowel disease and food allergies, which can impair absorption of essential micronutrients
• Chronic infections and parasitic infestations, particularly in endemic areas where chronic blood loss or increased red blood cell consumption is relevant
• Adolescence, especially in females after menarche, because pubertal growth, inadequate diets and menstrual blood loss may coexist
• Poverty, food insecurity, low parental educational attainment and reduced access to preventive and screening services

These factors, often coexisting, increase a child's vulnerability both directly and indirectly and may predispose to clinically significant anemia even without an underlying disease.

During childhood, deficiencies of nutrients directly involved in erythropoiesis, particularly iron, vitamin B12 and folate, can promote anemia when sufficiently severe or prolonged, with greater risk during rapid growth. Chronic conditions, although less common than in adults, should be suspected particularly in persistent normocytic anemia that is refractory to conventional therapy or in children with known disease, and require a more detailed diagnostic assessment.

Pathogenesis and Pathophysiology

The pathogenesis of pediatric anemia reflects the complex interaction among deficiency, destruction and ineffective red blood cell production and the distinctive requirements of growth. Compared with adulthood, rapid weight gain, tissue plasticity and the immaturity of compensatory systems can make anemia more insidious in children but also potentially more consequential for physical, neurocognitive and immune development.

In infants and young children, the pathogenesis of the most common form, iron deficiency anemia, is rooted in early depletion of neonatal iron stores. After birth, especially after early umbilical cord clamping or in preterm infants, hepatic stores may be limited and are rapidly consumed by hematopoietic requirements and neurologic development. A diet poor in bioavailable iron, typical of monotonous diets or inadequate iron intake from appropriate complementary foods after the recommended period of exclusive breastfeeding, leads to progressively reduced hemoglobin synthesis. In parallel, iron deficiency affects mitochondrial function, neurotransmitter synthesis and myelination, with effects extending beyond the hematologic deficit itself.

In school-age children and adolescents, pubertal growth produces a new increase in erythropoietic requirements that is not always matched by adequate dietary intake or supplementation. In females, menstrual blood loss after menarche and eating disorders may further worsen iron balance, making the pathogenesis of anemia particularly multifactorial at this stage.

In megaloblastic anemias, folate or vitamin B12 deficiency impairs DNA synthesis and maturation of erythroid precursors, producing ineffective erythropoiesis and accumulation of marrow megaloblasts. The deficiency impairs proliferation in high-turnover tissues; vitamin B12 deficiency may also cause abnormalities of myelination and neurologic manifestations, which should not be attributed to a generic defect in neuronal cell division.

Inherited anemias, including thalassemias, hereditary spherocytosis and sickle cell disease, have distinct pathogenic mechanisms: production of abnormal hemoglobin or structurally fragile red blood cells causes chronic hemolysis, stimulates erythroid marrow hyperplasia and produces chronic anemia, hypercatabolism and, over time, multiorgan damage (splenomegaly, hepatomegaly, bone disease and impaired growth).

In anemia of chronic disease, much less common in childhood but important in children with known underlying disorders, inflammatory cytokines, particularly IL-6, increase production of hepcidin, the key hormone that inhibits intestinal iron absorption and iron mobilization from stores. The result is typically normocytic anemia, often poorly responsive to iron supplementation, reflecting the interaction between functional iron restriction and reduced erythropoietin responsiveness.

Overall, the impact of pediatric anemia depends on cause, severity, rate of onset and age. Severe forms can compromise oxygen delivery; prolonged iron deficiency during the first years of life and vitamin B12 deficiency may be associated with specific neurocognitive consequences. Recurrent infections and the prognosis of intercurrent illnesses depend mainly on the underlying disease, associated deficiencies and treatments, rather than universally on anemia itself.

Clinical Manifestations

The clinical presentation of pediatric anemia is highly variable and depends closely on age, rate of onset, severity of the deficit and underlying mechanism. In children, symptoms are often insidious and may be masked by natural adaptive capacity, but the consequences, especially if anemia persists, may be profound and long-lasting and affect physical, neurologic and psychosocial development.

In infants and younger children, anemia may begin subtly, with signs that are difficult to distinguish from normal age-related behavioral variation. Early findings include irritability, pallor of the skin and mucous membranes, lethargy, feeding difficulties, sleepiness and poor weight gain and linear growth. Tachycardia and dyspnea may appear only in more severe forms when physiologic compensation is exceeded. A characteristic but often overlooked feature is delayed motor and cognitive development: children with prolonged iron deficiency or specific chronic disorders may have difficulties with learning, memory and attention; any vulnerability to infections depends mainly on the cause of anemia, associated deficiencies and comorbidities.

In preschool and school-age children, signs and symptoms may be more subtle, including early fatigue during play, reduced exercise tolerance, headache, difficulty concentrating and declining school performance. Pallor remains a common but nonpathognomonic sign, often associated with brittle nails, atrophic glossitis, cheilosis and, in advanced cases, pica, a craving to ingest nonfood substances such as soil or ice.

The adolescent tends to underestimate or not report symptoms, often attributing them to fatigue, school stress or mood changes. In this age group, the presentation may be dominated by asthenia, palpitations, exertional dyspnea, dizziness and, in more severe cases, syncope, as well as worsening of any eating disorder. In girls, heavy menstrual bleeding may exacerbate anemia, while in athletes it may present as a sudden decline in sports performance.

Some specific forms of pediatric anemia have characteristic findings:

• Chronic iron deficiency anemia: in addition to pallor and asthenia, hair fragility, spoon nails (koilonychia), glossitis, angular stomatitis and taste disturbances may occur.
• Megaloblastic anemia: hyperemic glossitis; in vitamin B12 deficiency, especially when prolonged, neurocognitive abnormalities, motor and sensory deficits, ataxia, muscular hypotonia and developmental delay may occur. These neurologic signs are not typical of isolated folate deficiency.
• Inherited hemolytic anemias, including thalassemia, hereditary spherocytosis and sickle cell disease: jaundice, splenomegaly, pain crises in sickle cell disease, growth delay, bone deformities from chronic marrow hyperplasia and early gallstones.
• Anemia of chronic disease: the presentation may be subtle and associated with manifestations of the underlying disorder, such as arthralgia, skin lesions, recurrent infections, or signs of kidney failure or chronic inflammation.

The physical examination should always be careful and systematic: pallor of the skin and mucous membranes, assessed at the conjunctivae, palms and nail beds, is common but has limited sensitivity, and its absence does not exclude significant anemia. Advanced cases may show tachycardia, functional cardiac murmurs, dyspnea at rest, hepatosplenomegaly and signs of heart failure.

It is important to remember that cardiovascular adaptation in children may mask anemia until hemoglobin values are very low. Consequently, prolonged or severe forms, and particularly some early deficiencies such as iron or vitamin B12 deficiency, may have harmful and sometimes persistent effects on psychophysical development.

Investigations and Diagnosis

Diagnosis of pediatric anemia requires a systematic and reasoned approach that takes into account both age-related physiologic characteristics and the many potential causes. The goal is not only to recognize anemia, but above all to determine its nature, origin and degree of risk to the child's development and general health.

Clinical suspicion often arises from subtle symptoms or findings noted during routine visits, screening or assessment for growth delay, recurrent infections or cognitive difficulties. A careful history is essential, including diet, growth milestones, intercurrent illnesses, family history of anemia, ethnicity, travel and medication use, because it directs selection of the most appropriate laboratory tests.

The complete blood count is the starting point: it identifies reduced hemoglobin relative to age- and sex-specific reference values and provides red blood cell indices, including MCV, MCH and RDW, that help classify anemia as microcytic, normocytic or macrocytic. Cutoffs vary considerably during the first years of life, so updated pediatric reference values are essential to avoid underdiagnosis or overdiagnosis.

The peripheral blood smear provides information on red blood cell morphology: microcytosis and hypochromia suggest iron deficiency anemia or thalassemia; schistocytes, spherocytes or elliptocytes suggest hemolytic forms; macro-ovalocytes and neutrophil hypersegmentation raise suspicion for megaloblastic anemia. Erythroblasts, anisopoikilocytosis, increased reticulocytes or atypical cells provide essential clues for differential diagnosis.

Iron studies, including serum iron, ferritin, transferrin and transferrin saturation, are fundamental for identifying iron deficiency: in apparently healthy children under 5 years of age, a ferritin <12 ng/mL indicates iron deficiency; in the presence of infection or inflammation, a threshold <30 ng/mL may be used in children under 5 years. In older children, the threshold should be interpreted according to age and clinical context. Combining ferritin with other markers, such as soluble transferrin receptor, can help in uncertain cases.

Folate and vitamin B12 measurement is indicated in macrocytic anemia, in infants breastfed by mothers with restrictive diets, in children with neurologic signs or when anemia does not respond to iron therapy. In selected cases, homocysteine and methylmalonic acid measurement may be useful.

Other targeted investigations are guided by clinical suspicion:

• Reticulocytes: assess the erythropoietic response and help distinguish hyporegenerative from regenerative anemias.
• Testing for hemoglobinopathies: electrophoresis, HPLC and genetic testing in unexplained microcytosis after iron deficiency has been excluded or in the presence of a relevant family history and/or ancestry associated with increased risk.
• Inflammatory markers, ESR and CRP: useful for documenting an inflammatory context and interpreting iron indices; diagnosis of anemia of inflammation requires integration with the complete blood count, iron studies, reticulocytes, kidney function and clinical picture.
• Tests for malabsorption: evaluation for celiac disease, stool testing for parasites and investigations for enteropathies.
• Bone marrow examination: reserved for pancytopenia, suspected bone marrow failure, aplastic disorders or infiltrative disease.

The differential diagnosis must always consider coexistence of multiple causes. Nutritional deficiencies, chronic infections, parasitic disease and genetic conditions frequently overlap, especially in high-risk settings. The sequence of investigations should be guided by clinical suspicion and history, avoiding unnecessary second-level tests in typical cases and reserving them for resistant or atypical presentations.

Severe anemia, symptoms of heart failure or altered consciousness require urgent assessment, including cardiac evaluation, blood gas analysis when indicated, and consideration of transfusion pathways or protected hospital admission.

In summary, diagnosis of pediatric anemia requires a comprehensive interpretation that integrates clinical, historical and laboratory data in a sequential and rational pathway, so that correctable causes can be identified promptly, complications prevented and management genuinely individualized.

Treatment and Prognosis

Management of pediatric anemia is based on a child-centered approach that considers age, severity, underlying cause and comorbidities. The aim is to correct the hemoglobin deficit promptly to limit effects on somatic and neurocognitive development and improve quality of life.

Primary prevention is the most effective strategy: iron supplementation in at-risk infants, including preterm infants, those with low birth weight and those with prolonged exclusive breastfeeding, nutritional education, timely introduction of foods rich in heme and nonheme iron, and food fortification in settings at risk of deficiency. Guidelines recommend:

• Elemental iron: in term infants who are exclusively or predominantly breastfed, the 2026 AAP recommends 1 mg/kg/day beginning by 4 months of age until an adequate dietary iron intake is established; preterm infants and other risk groups require specific regimens.
• Screening for iron deficiency: complete blood count and ferritin between 9 and 12 months if feeding is predominantly human milk and between 15 and 18 months in children transitioned to formula or cow's milk according to the risk profile; in adolescent girls, screening should be performed at least one year after menarche and in any case no later than 14 years of age.
• Folic acid and vitamin B12 supplementation in children with documented deficiency or at risk, including infants breastfed by vegan or vegetarian mothers, children with restrictive diets and those with malabsorption disorders.

Treatment of iron deficiency anemia preferably uses ferrous sulfate: in young children, an initial dose of about 3 mg/kg/day of elemental iron as a single daily dose, and in adolescents about 65 mg of elemental iron once daily, with adjustment to the clinical picture. Severe cases require close follow-up of hematologic and clinical response; treatment generally continues beyond normalization of hemoglobin to replenish iron stores. Taking iron away from meals improves absorption when tolerated; administration with food may improve tolerability but reduces absorption. Intravenous iron is reserved for selected indications such as intolerance, malabsorption, inadequate response or the need for rapid correction, under specialist supervision.

Megaloblastic anemias require targeted correction of the vitamin deficiency. Dose, route and duration of folic acid and vitamin B12 depend on age, cause, severity, available formulation and applicable guidelines; any underlying cause of malabsorption should also be identified and treated.

Inherited anemias, including thalassemias, hereditary spherocytosis and sickle cell disease, require multidisciplinary specialist management: regular transfusions in severe cases, iron chelation to prevent iron overload, selective splenectomy, infection prophylaxis when indicated and, for specific hemoglobinopathies and age groups, gene therapies that are already authorized or remain investigational. For sickle cell disease, hydroxyurea and hematopoietic stem cell transplantation are options in selected cases.

Anemias secondary to chronic disease require management of the underlying condition, including inflammatory diseases, kidney failure and cancer, and in selected cases recombinant erythropoietin or transfusions.

Blood transfusions are indicated in emergencies and also in chronic programs for specific disorders according to specialist protocols, including severe anemia associated with clinical instability or cardiovascular failure, clinically significant acute or persistent bleeding, and specific oncohematologic indications or indications related to chronic anemias.

Regular follow-up is essential to monitor response to therapy, prevent recurrence and identify late complications. Family education, treatment adherence, and nutritional and psychological support are key elements of long-term success.

The prognosis of pediatric anemia depends on timely diagnosis and appropriate intervention: in deficiency forms, early correction promotes recovery; persistent neurocognitive outcomes are described mainly after prolonged iron deficiency during the first years of life or vitamin B12 deficiency, not uniformly across all deficiencies; infection risk in chronic cases depends mainly on the underlying disease, associated deficiencies or treatments.

In children with genetic or chronic diseases, prognosis is more variable and depends on severity of the underlying condition, response to treatment and access to integrated specialist treatment programs.

Complications

The complications of pediatric anemia are numerous and often underestimated, with consequences that extend beyond the hematologic parameter itself and can affect a child's overall development and long-term quality of life.

The main complications are:

• Impaired linear growth and weight gain: iron deficiency and disorders causing anemia may be associated with reduced growth; recovery may be incomplete particularly after prolonged or severe deficiencies, but it is not invariably only partial.
• Neurocognitive deficits: iron is essential for myelination, neurotransmitter synthesis and synaptic development; prolonged deficiency is associated with learning, memory and attention difficulties, with effects that may persist into adulthood.
• Delayed pubertal maturation: chronic or severe anemia may be associated with delayed appearance of secondary sexual characteristics and pubertal milestones.
• Heart failure: in severe and persistent forms, increased cardiac workload may lead to tachycardia, cardiomegaly and overt heart failure.
• Complications specific to inherited anemias: these vary according to the disorder and treatment. Chronic hemolytic anemias may cause splenomegaly and pigment gallstones; severe or transfusion-dependent thalassemias are also associated with iron overload and bone abnormalities, while infectious and thrombotic risk depends on the specific disease, splenectomy and treatment.

Psychosocial complications are often overlooked but clinically relevant: children and adolescents with chronic anemia experience greater social isolation, relationship difficulties, insecurity and psychological distress, with negative effects on school performance and quality of life.

Prevention, early diagnosis and targeted treatment are fundamental tools for reducing the burden of complications and improving long-term outcomes for these children.

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