Anemia in children can be identified through universal screening or based on signs and symptoms. The American Academy of Pediatrics recommends universal screening with a hemoglobin or hematocrit measurement for all infants at 12 months of age [6]. In addition, newborn screening is mandated and can identify patients with hemoglobinopathies (sickle cell disease, beta thalassemia). The signs and symptoms of anemia that may be present largely depend upon how abrupt the onset of anemia is. The onset can be very rapid (e.g., acute blood loss, hemolysis) or insidious (iron deficiency, anemia of chronic disease, lead poisoning). Family and medical history often provide valuable information in the diagnostic evaluation of an anemic patient. The majority of children with mild anemia of insidious onset are clinically asymptomatic. Infants and young children often present with non-specific symptoms such as poor feeding, irritability, excessive sleepiness, or tiredness. Older children and adolescents may have shortness of breath, palpitations, syncope, or exercise intolerance. Parents also often report pallor as a presenting symptom, which has poor sensitivity for predicting mild anemia, but correlates well with severe anemia [7, 8]. Physical examination may show pallor, jaundice, lymphadenopathy, hepatosplenomegaly, frontal bossing and congenital anomalies, and reflect a variety of causes of anemia. Vital signs (heart rate, respiratory rate, blood pressure, and oxygen saturation) should be evaluated in all anemic patients to ensure hemodynamic stability. In addition, patients may have signs and symptoms associated with a chronic condition such as systemic lupus erythematosus, rheumatoid arthritis, chronic kidney disease, or hepatic disease. Clinical clues for some causes of anemia are enumerated in Table 12.3.

The initial laboratory evaluation of anemia includes a complete blood count, reticulocyte count, and a peripheral smear. Most physicians use the morphological classification of anemia based on MCV (microcytic, macrocytic, or normocytic) to help guide the diagnostic process (Table 12.2). An elevated reticulocyte count (or percentage) suggests hemolysis or chronic blood loss as the cause of anemia, whereas a decreased count (or percentage) suggests decreased RBC production. A reticulocyte index (reticulocyte count x patient’s hematocrit/normal hematocrit) is a more accurate marker of erythropoietic activity. In general, a reticulocyte index ≥3 indicates chronic blood loss or a hemolytic process, while an index of <3 (often <1.5) is seen in patients with impaired RBC production [9]. Evaluation of a peripheral blood smear of a child may provide particularly valuable clues toward a particular etiology of anemia. For example, the presence of a large number of spherocytes strongly suggests the diagnosis of hereditary spherocytosis. Table 12.4 lists some of the important blood smear findings and their associated clinical significance. The use of special RBC stains is necessary to identify inclusion bodies such as Heinz bodies (RBC enzymopathies, chronic liver disease, asplenia), siderocytes (aplastic anemia, chronic infection), and intraerythrocytic parasites (malaria, babesiosis).

After the initial laboratory evaluation has been conducted, additional studies may be helpful to identify the physiological process resulting in anemia (Table 12.2). Reduced serum ferritin (<12 ng/mL) levels with an elevated total iron binding capacity (TIBC > 450 μg/mL) suggests iron deficiency anemia. An elevated lactate dehydrogenase level, a low haptoglobin level, and indirect hyperbilirubinemia point toward a hemolytic process. Other tests required for diagnostic confirmation include the osmotic fragility test (hereditary spherocytosis), hemoglobin electrophoresis (sickle cell disease, thalassemia, and other hemoglobin variants), RBC enzyme panel (G6PD and pyruvate kinase deficiency), direct and indirect antiglobulin test (autoimmune hemolytic anemia), and CD55/59 flow cytometric assay (Paroxysmal nocturnal hemoglobinuria).

Anemia in the neonate can be classified into three major categories: anemia due to blood loss, hemolysis, or decreased RBC production. Anemia as a result of blood loss can occur due to twin-to-twin transfusion, internal hemorrhage that occurs with a cephalohematoma or splenic rupture from a traumatic birth, an intraventricular hemorrhage that occurs in premature, low birth weight babies, or fetomaternal hemorrhage. Fetomaternal hemorrhage is diagnosed by the Kleihauer-Betke acid elution test which is based on the resistance of fetal hemoglobin to elution from the intact cell in an acid medium [10]. Fetal–maternal transfusion occurs in approximately 50% of pregnancies, but does not usually result in significant blood loss [11]. Additional risk factors for substantial blood loss in the neonate include rupture of the umbilical cord, placental abruption, placenta previa, placental tumors, and amniocentesis during the third trimester of pregnancy.

Immune hemolytic anemia occurs as a result of blood group incompatibility [Rh (D antigen), ABO, and minor blood group incompatibilities] between the mother and the fetus. Newborns with immune hemolytic anemia usually present with anemia, jaundice, and a positive Coomb’s test within the first 24 h of life. These infants need to be monitored closely with appropriate interventions (phototherapy, exchange transfusion) as indirect bilirubin levels can rise rapidly and lead to kernicterus. Although hemolytic anemia due to Rh incompatibility is usually severe, its incidence has decreased dramatically thanks to antenatal screening and the use of Rh immunoglobulin (RhoGam) in Rh-negative mothers. In contrast, hemolytic anemia secondary to ABO incompatibility is usually milder and occurs in the setting of a mother with blood Group O and an infant who has either Group A or B blood type. Other conditions that may manifest as hemolytic anemia in the newborn period include G6PD deficiency, hereditary spherocytosis, and thalassemia syndromes.

Anemia as a result of decreased RBC production in the neonate can occur due to physiological anemia of infancy or anemia of prematurity (AOP), Diamond-Blackfan anemia (discussed later in the chapter), and congenital infections. After birth, there is initially a decrease in RBC mass due to transition from a hypoxic state in utero to a hyperoxic state with increased tissue oxygenation. This process continues until oxygen delivery is inadequate which in turn stimulates erythropoiesis again. Due to this physiological adaptation to postnatal life, all term infants develop a normocytic and asymptomatic anemia (hemoglobin 9–11 g/dL) at 8–12 weeks of age. AOP, on the other hand, is an exaggerated physiological response, characterized by a normocytic, normochromic anemia with a decreased reticulocyte count and decreased serum erythropoietin (EPO) levels. The low hemoglobin concentration in these premature infants is due to a lack of third-trimester hematopoiesis and iron transport, suboptimal EPO level and response, shorter RBC life span and iatrogenic blood loss in relation to their body weight. The nadir of hemoglobin (7–9 g/dL) typically occurs by 4–8 weeks after birth and usually improves by 3–6 months of age [12]. The management of AOP includes optimal nutrition with iron supplementation and judicious use of blood sampling and blood transfusion. Routine use of recombinant EPO for the treatment of AOP is not recommended due to its limited benefit in reducing blood transfusions and exposure to blood donors, and because its early use (first 8 days after birth) can increase the risk of retinopathy of prematurity [13].