Anemia is a global health issue, with up to 43% of children being diagnosed with anemia worldwide.1 In the United States, the rate of anemia in children age 1 to 4 years is 3.6%; however, this increases to 13.4% in children who are under resourced economically and 18.2% in children age 12 to 17 months.2
Iron deficiency anemia (IDA) remains the most common cause of anemia in the US, and accounts for nearly 50% of cases worldwide.1,2 It is important to remember that although we use the practical definition in most clinical situations, there are patients who are functionally anemic with hemoglobin levels in the normal range (ie, cyanotic congenital heart disease, chronic respiratory insufficiency, arteriovenous pulmonary shunts).
Anemia can be classified in various ways; the two most common based on pathophysiology or red blood cell (RBC) morphology. The ability to appropriately classify the type of anemia is crucial to narrow your differential diagnosis and tailor your history, physical examination, and laboratory evaluation.
Anemia can be due to three inherent problems: decreased RBC production, hemolysis, or blood loss (Figure 1). A useful test to help differentiate these three groups is a reticulocyte count. A reticulocyte count is an RBC precursor that measures bone marrow function, which in normal, healthy children, ranges from 0.5% to 1%. When a child is anemic, the bone marrow should respond by releasing more reticulocytes. If the reticulocyte count remains inappropriately low, this suggests a problem with bone marrow RBC production, possibly due to nutritional deficiency, marrow infiltration, or marrow suppression from infection. If the reticulocyte count is appropriately elevated, it suggests the problem is external to the bone marrow such as hemolysis or blood loss. In this setting, obtaining a bilirubin level can be helpful to differentiate those two processes.
A pathophysiologic approach to anemia.
Another common method to classify anemia is based on RBC size, which is determined by the mean corpuscular volume (MCV) (Table 1). It is important to remember that the lower limit of MCV is based on age and does not reach the adult lower limit of 80 fL until age 10 years. Based on MCV, anemia can be classified as microcytic, normocytic, or macrocytic. Common causes of microcytic anemia include iron deficiency, lead poisoning, or thalassemia. Normocytic anemia is seen with chronic disease, hemolytic anemia, or acute blood loss. Causes of macrocytic anemia include B12 or folate deficiencies, hypothyroidism, liver disease, and bone marrow failure syndromes. Ideally, both approaches can be used to narrow the differential diagnosis further (Figure 2).
Morphologic Approach to Anemia
A combined approach to anemia. ACD, anemia of chronic disease; BMFS, bone marrow failure syndrome; MCV, mean corpuscular volume; MDS, myelodysplastic syndrome; TEC, transient erythroblastopenia of childhood.
Principles of Clinical and Diagnostic Evaluation
A good history is the first crucial step to determining the cause of anemia. As the most common cause of childhood anemia is iron deficiency,3 it is important to ask for dietary history including duration of breast-feeding, age when solid foods were introduced, and amount of cow milk consumption. Birth history, past medical history, medications, and family history are also essential to document and can help narrow the differential diagnosis. Lastly, patients should be evaluated for symptomatic anemia, which can manifest as pallor, fatigue, headaches, dizziness, or shortness of breath. Patients with symptomatic anemia require prompt evaluation and treatment, which may include a blood transfusion.
A complete blood count (CBC) and reticulocyte count should be the first line of laboratory tests ordered. These tests, along with history and physical examination, will help guide additional testing. Other laboratory tests that can be obtained include iron studies, hemoglobin electrophoresis, hemolysis labs (direct antiglobulin test [DAT], lactic acid dehydrogenase (LDH), haptoglobin, bilirubin), thyroid function, assessment for blood loss with a stool hemoccult, and urinalysis.
Iron Deficiency Anemia
Iron deficiency is the most common nutrient deficiency worldwide.4 There are various risk factors for the development of iron deficiency, which include inadequate iron endowment at birth due to prematurity or low maternal ironstores during pregnancy, increased iron requirements during rapid phases of growth (infants and adolescents), insufficient dietary iron, inadequate iron absorption, or excessive blood loss. In pediatrics, the two populations at highest risk for IDA are toddlers, due to excessive cow milk intake, and adolescent girls, due to heavy menstrual bleeding.
In infants who do not receive any dietary iron, stores will be fully depleted by age 5 to 6 months in term infants and by age 3 months in low birth weight and/or premature infants (due to less iron endowment at birth and faster rates of growth). IDA can lead to neurodevelopmental delays, poor cognitive function, behavioral disturbances, concentration difficulties, irritability, pica, and mood lability.4,6–9 Iron can be found in breast milk as well as fortified formula and cereals. The American Academy of Pediatrics (AAP) currently recommends iron supplementation in exclusively breast-fed infants after age 4 months until iron-containing foods are introduced to the diet.10 Standard infant formula contains the appropriate amount of iron, and complementary foods, including iron-fortified cereal, should be introduced around age 4 to 6 months.10 Additionally, cow milk should not be introduced until age 12 months and should be limited to 18 to 24 ounces daily.9 Cow milk predisposes to iron deficiency during infancy due to low iron content, poor iron absorption, and reduced intake of other iron-enriched foods. Additionally, there are some data to suggest that cow milk may cause gastrointestinal (GI) bleeding.11
Unfortunately, there is no consensus on whom is best to screen for IDA.3 The AAP recommends universal screening at age 9 to 12 months and selective screening at any age for patients with risk factors.10 The Centers for Disease Control and Prevention only recommends screening in infants with high-risk factors and preschool age children.12 The US Preventive Services Task Force Guidelines did not find sufficient evidence to make a recommendation on the role of screening.13 Another important consideration is the method of screening. The AAP recommends screening with a routine hemoglobin test, which is only abnormal in late stages of iron deficiency. Ferritin is a useful test to determine total body iron stores; however, because it is an acute-phase reactant, it will be falsely normalized or elevated in any inflammatory state. There is no one best test to measure iron deficiency and obtaining hemoglobin along with full iron studies may not be a cost-effective strategy for screening.
Treatment of IDA is with iron supplementation to replenish the body's stores. Oral iron is typically given in the form of ferrous sulfate, and dosing is 4 to 6 mg/kg/day of elemental iron divided twice daily. In mild cases, 3 mg/kg/day as a single dose may be sufficient. Laboratory changes should be evident within the first week of iron therapy, with the hemoglobin rising to approximately 1 g/dL per week until reaching the normal range. Additionally, a marked reticulocytosis is seen during the first 6 to 8 weeks. Iron should continue for at least 2 months after the anemia has resolved to ensure iron stores have been fully replenished. Side effects of iron therapy include constipation, dark stools, stained teeth, and bad taste, which often leads to poor adherence.There are liquid alternatives, known as iron polysaccharide complexes, which can be substituted for ferrous sulfate if bad taste is a factor. It is important to note, however, that ferrous sulfate has a more significant effect on hemoglobin concentration than iron polysaccharide complexes.14
To prevent patients from becoming iron deficient again in the future, it is essential to determine and treat the underlying cause of IDA. For toddlers with IDA due to poor dietary iron, counseling families on reducing milk intake and increasing iron-enriched foods is imperative. Products containing heme iron, such as meats and shellfish, have much better absorption than non-heme iron foods, including fruits and vegetables. In adolescents with IDA due to menorrhagia, menstrual regulation may be needed, and in children with evidence of GI bleeding, a gastroenterology evaluation is warranted.
Lead poisoning is predominantly caused by ingestion of lead in the environment, including lead paint, dust, water, ceramics, and folk medications.15 Lead poisoning leads to anemia due to impaired heme synthesis leading to reduced RBC lifespan.16 Symptoms of lead toxicity include nausea, vomiting, abdominal pain, behavioral changes, lethargy, and loss of developmental milestones. The microcytic anemia seen in young children with lead poisoning is usually due to concomitant iron deficiency.17 Specifically, iron deficiency in young children often manifests as pica, which promotes lead ingestion. Additionally, iron deficiency increases lead absorption from the intestines, which will amplify the problem. The AAP recommends lead screening at age 1 and 2 years in children with high risk factors.15 Treatment of lead toxicity includes removing the offending source, correction of iron deficiency (if present), and chelation therapy in serious cases.
Thalassemia is an inherited hemoglobinopathy due to a qualitative defect in hemoglobin (Table 2). Hemoglobin is made up of two alpha-globin chains and two beta-globin chains. Alpha globins are encoded on four genes, and beta globins on two genes. Defects in one of these two globins produce alpha or beta thalassemia. Specifically, alpha thalassemia is a defect in alpha globins, typically due to deletion of alpha globin genes. Beta thalassemia represents a defect in beta globins due to point mutations that lead to either reduced or no expression of this chain. Both types of thalassemia have varying clinical severity: minor, intermedia, and major. Patients with thalassemia minor have mild anemia and are asymptomatic. Thalassemia intermedia will present as moderate anemia with need for periodic transfusions. Patients with thalassemia major present early in life with severe anemia and transfusion dependence.
Overview of Thalassemia
Thalassemia will often present as a microcytic anemia, however, the red blood cell distribution width is typically normal and the microcytosis will not resolve with iron therapy. Diagnosis can often be made by hemoglobin electrophoresis, with some important caveats. First, IDA will impair the results of hemoglobin electrophoresis, so it is always imperative to test for and treat iron deficiency before performing this test. Secondly, alpha thalassemia trait will often have a normal electrophoresis, so if your clinical suspicion is high, alpha globin gene testing is often needed to make the diagnosis. Another helpful way to distinguish thalassemia from iron deficiency is the Metzger index, which is the quotient of the MCV (in femto-liters) divided by the RBC count (in millions/microliter). If this is less than 13, thalassemia is thought to be more likely, whereas iron deficiency is more probable in patients with a score greater than 13. Patients with thalassemia have increased iron absorption and are at risk for iron overload. As such, iron replacement should only be given for patients with documented iron deficiency.
Sickle Cell Disease
Sickle cell disease is a major global health problem, with nearly 300,000 infants being born with this condition annually.18 Sickle cell disease is defined as homozygosity for the sickle hemoglobin (HbS) gene, which leads to abnormal sickling of RBCs that have a shortened life span and can lead to vaso-occlusion and organ damage over time. Acute complications of sickle cell disease include pain crises, acute chest syndrome, splenic sequestration, stroke, aplastic crises, and bacterial infections due to encapsulated organisms. Chronic complications include end organ damage of every major system, such as cardiac, pulmonary, central nervous system, renal, skeletal, and ocular. Hydroxyurea has revolutionized the rate of acute and chronic complications of sickle cell disease. This drug works by increasing the amount of fetal hemoglobin in the blood, which reverses the sickling of RBCs. In patients with severe, poorly controlled disease, allogenic bone marrow transplantation can be used. Although this is currently the only curative option for sickle cell disease, the use of gene therapy is promising.19
Hereditary spherocytosis is a RBC membranopathy due to mutations in the RBC cytoskeleton that lead to a change in shape. These spherical-shaped, hyperdense, RBCs have a shortened life span and can present in infancy with profound anemia and hyperbilirubinemia.20 Classical CBC findings also include an elevated mean corpuscular hemoglobin concentration, reticulocytosis, and spherocytes on peripheral blood smear. A thorough family history is essential. Aside from standard laboratory tests and review of the peripheral smear and family history, diagnosis can be made with an incubated osmotic fragility test or by the eosin-5-maleimide binding test. It is also important to obtain a family history; a hereditary spherocytosis include hemolytic crises during infection, aplastic crises, and gallstones. Splenectomy (total or partial) can be considered in patients with severe disease; however, this must be weighed with the risk for infections due to encapsulated bacteria.21
Glucose-6-Phosphatase Dehydrogenase Deficiency
Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is the most common RBC enzymopathy in the world.22 This enzyme is part of the pentose phosphatase pathway of glucose metabolism, and loss of activity leads to shortened RBC survival and hemolysis. There are different variants of G6PD deficiency based on residual enzyme activity. Patients with <10% activity often have a chronic hemolytic anemia, whereas patients with >10% activity will have episodic hemolysis with oxidative triggers.23 The most common oxidative triggers are drugs, so it is important to counsel families on compounds and foods to avoid (Table 3).
Agents Capable of Inducing Hemolysis in Patients with G6PD Deficiency
Autoimmune Hemolytic Anemia
Hemolytic anemia can be intrinsic to the RBC or extrinsic (external) to the RBC (Figure 3). Intrinsic causes include membranopathies, enzymopathies, and hemoglobinopathies, such as those described above. The most common extrinsic cause of RBC hemolysis is autoimmune-mediated hemolytic anemia. This often presents with a positive DAT; however, a negative result should not remove this from the differential diagnosis as some rarer forms will not be DAT positive. Patients will have other evidence of hemolysis, such as an elevated LDH, indirect bilirubin, and low haptoglobin. Additionally, they will have reticulocytosis, demonstrating that their marrow is responding to acute anemia. Causes of autoimmune hemolytic anemia are vast and include viral infections (Epstein-Barr virus, cytomegalovirus, mycoplasma), immunodeficiency, and malignancy. Often, an inciting trigger is not identified, and the patient is deemed to have idiopathic autoimmune hemolytic anemia. Typical treatment includes blood transfusions and a prolonged course of steroids with a slow taper. Relapse is common with tapering of steroids, in which case B cell-depleting agents such as rituximab can be used.
A pathophysiologic approach to hemolytic anemia. aHUS, atypical hemolytic uremic syndrome; DIC, disseminated intravascular coagulation; G6PD, glucose 6 phosphatase dehydrogenase deficiency; HUS, hemolytic uremic syndrome; PNH, paroxysmal nocturnal hemoglobuinuria; RBC, red blood cells; TTP, thrombotic thrombocytopenic purpura.
Megaloblastic anemias are characterized by macrocytic RBCs and hypersegmented neutrophils in the peripheral blood, as well as megalo-blasts in the bone marrow. The most common cause of megaloblastic anemia is B12 or folate deficiency. B12 is present in all meat and dairy products and absorbed in the terminal ileum when bound to intrinsic factor. Folate can be found in fresh fruits, leafy vegetables, meat, milk, and cereals and is absorbed in the duodenum and jejunum. Aside from malnutrition, B12 deficiency can occur due intestinal infection, inflammatory bowel disease, ileal resection, or gastric issues that lead to impaired intrinsic factor production. Folate deficiency can similarly be seen with malnutrition, inflammatory bowel disease, or use of anti-folate drugs, such as methotrexate. The most sensitive laboratory tests for these deficiencies are serum methylmalonic acid, which will be elevated in vitamin B12 deficiency, and RBC folate, which will be low in folate deficiency. Treatment includes determining and, when possible, treating the underlying cause, as well as vitamin replacement.
Inherited Bone Marrow Failure Syndromes
Inherited bone marrow failure syndromes are a heterogeneous group of genetic disorders characterized by the inability of the bone marrow to produce normal, healthy blood cells. Patients will often present with cytopenias along with abnormal physical features. A common hematologic finding in patients with a bone marrow failure syndrome is anemia and reticulocytopenia in the setting of an elevated MCV and no other clear etiology. The most common inherited bone marrow failure syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Schwachman Diamond syndrome.26 Diagnosis is made by genetic testing. Due to an increased risk for developing leukemia and solid tumors, these patients require close surveillance and annual bone marrow evaluation.
As a pediatrician, it is important to know how to recognize and evaluate anemia in childhood. A good history, including birth history, dietary history, past medical history, family history, social history, and a full review of systems are essential to help guide examination and laboratory testing. Aside from hemoglobin, other RBC indices and the reticulocyte count will help narrow your differential diagnosis. Both a pathophysiologic and morphologic approach to anemia can be used to make the diagnosis (Figure 2).
IDA remains the most common cause of anemia and should be confirmed and monitored with iron studies. Recognizing and treating the underlying cause of iron deficiency is essential to prevent recurrence. Many children do not tolerate ferrous sulfate due to poor taste, in which case iron polysaccharide complexes can be considered. Lead toxicity is common in children with IDA and should be included in routine screening.
Anemia can also be found in the setting of hemolysis, which is due to problems either intrinsic or extrinsic to the RBC (Figure 3). Patients with macrocytic anemia may have a nutritional deficiency, especially in the setting of GI issues. However, cytopenias in the setting of an elevated MCV can be a marker of a bone marrow failure syndrome and require additional testing.
Education remains a pivotal part of our job as pediatricians, both for prevention and treatment of anemia. For example, iron deficiency may be prevented by reviewing common causes of iron deficiency and good dietary sources of iron. In patients with intrinsic RBC defects, counseling families on triggers and symptoms of hemolysis may reduce hemolytic crises and allow families to seek care more promptly. It is through good history taking, screening, and education that we can strive to reduce the burden of childhood anemia in the US.