Practice Essentials
Pediatric anemia refers to a hemoglobin or hematocrit level lower than the age-adjusted reference range for healthy children. Physiologically, anemia is a condition in which reduced hematocrit or hemoglobin levels lead to diminished oxygen-carrying capacity that does not optimally meet the metabolic demands of the body.
Anemia is not a specific disease entity but is a condition caused by various underlying pathologic processes. It may be acute or chronic. [1] This article provides a general overview of anemia, with an emphasis on the acute form. In addition, conditions are emphasized in which anemia is the only hematologic abnormality. The combination of anemia with leukopenia, neutropenia, or thrombocytopenia may suggest a more global failure of hematopoiesis, caused by conditions such as aplastic anemia, Fanconi anemia, myelofibrosis, or leukemia, or may suggest a rapid destruction or trapping of all blood elements, such as hypersplenism, autoimmune disease, localized coagulopathy in a large hemangioma, or hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). (See Etiology.)
The main physiologic role of red blood cells (RBCs) is to deliver oxygen to the tissues. Certain physiologic adjustments can occur in an individual with anemia to compensate for the lack of oxygen delivery. These include (1) increased cardiac output; (2) shunting of blood to vital organs; (3) increased 2,3-diphosphoglycerate (DPG) in the RBCs, which causes reduced oxygen affinity, shifting the oxygen dissociation curve to the right and thereby enhancing oxygen release to the tissues; and (4) increased erythropoietin to stimulate RBC production.
The clinical effects of anemia depend on its duration and severity. When anemia is acute, the body does not have enough time to make the necessary physiologic adjustments, and the symptoms are more likely to be pronounced and dramatic. In contrast, when anemia develops gradually, the body is able to adjust, using all 4 mechanisms mentioned above (1, 3, and 4 in most cases), ameliorating the symptoms relative to the degree of the anemia. (See History and Physical Examination.)
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Complications in pediatric acute anemia
Acute and severe anemia can result in cardiovascular compromise. Moreover, if individuals with acute anemia are not treated immediately and appropriately, the resulting hypoxemia and hypovolemia can lead to brain damage, multiorgan failure, and death. Long-standing anemia can result in failure to thrive in children. (See Prognosis.)
Many studies have shown the deleterious effects of iron deficiency anemia or iron deficiency without anemia on the neurocognitive and behavioral development in children. Other complications can include congestive heart failure, hypoxia, hypovolemia, shock, seizure, and acute silent cerebral ischemic event (ASCIE; see Magnetic resonance imaging in research settings in Workup). [2]
Workup in pediatric acute anemia
To evaluate anemia, obtain initial laboratory tests, including the complete blood count (CBC), reticulocyte count, and review of the peripheral smear.
Chest radiography is performed in patients who may have congestive heart failure (CHF) and to rule out mediastinal mass (associated with acute leukemia and lymphoma).
Abdominal ultrasonography is used to assess for gallstones or splenomegaly in hemolytic anemia, while computed tomography (CT) scanning is used to evaluate occult bleeding in blunt trauma (eg, splenic rupture, subcapsular hemorrhage of the liver) or a bleeding disorder. Abdominal Doppler study is used to detect portal vein thrombosis.
Management of pediatric acute anemia
Transfusion with packed red blood cells (PRBCs) is the universal treatment for most individuals with severe acute anemia. The indication to transfuse should not be based solely on the hemoglobin or hematocrit levels; more importantly, one must consider the clinical effects or the signs and symptoms of the individual with anemia. [3]
Patient education
Girls with heavy and/or prolonged menstrual periods should seek medical attention (should tell parents to obtain CBC). One of the most common reasons for fainting spell or syncope in adolescent girls is rapidly developing anemia due to menstrual blood loss.
Toddlers who drink more than 24 oz of milk a day most likely have iron deficiency. Primary care physicians should inquire about the amount of milk intake. [4]
Children diagnosed with anemia should be taught to look at their stool color and to report to their parents if it is tarry or bloody.
Educate the patient and/or the family about the specific disease that causes the anemia. For example, provide a list of drugs, food, and other agents to avoid because of their effect of triggering acute hemolysis in glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.
In pediatrics, beyond the immediate neonatal period, acute anemia is rare in otherwise healthy children. In most instances, it is due to blood loss, usually through the GI tract or via a heavy menstrual period, occurs as a result of an acute hemolytic episode in a child with undiagnosed G-6-PD deficiency, or is due to autoimmune hemolytic anemia. The most common reason for hospitalization because of acute anemia is so-called aplastic crisis in children with chronic hemolytic anemia who otherwise had been stable. The most common varieties are hereditary spherocytosis and sickle cell disease. Therefore, it would be prudent to educate parents regarding this complication, at the time when the diagnosis is established.
Etiology
Causes of anemia are either inherent in the RBCs or related to an external factor. The underlying pathologic processes that cause anemia can be broadly categorized as (1) decreased or ineffective red cell production, (2) increased red cell destruction (hemolysis), and (3) blood loss, although more than 1 mechanism may be involved in some anemias.
Anemia caused by decreased red cell production
This generally develops gradually and causes chronic anemia. Marrow failure may result from the following:
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Diamond-Blackfan anemia (congenital pure red cell aplasia) [5]
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Transient erythroblastopenia of childhood (TEC)
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Aplastic crisis caused by parvovirus B19 infection (in patients with an underlying chronic hemolytic anemia) (though termed "aplastic crisis," only RBC lineage is affected)
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Marrow replacement (eg, leukemia, neuroblastoma, medulloblastoma, retinoblastoma, Ewing sarcoma, soft tissue sarcoma, myelofibrosis, osteopetrosis)
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Aplastic anemia
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Paroxysmal nocturnal hemoglobinuria (PNH)
Impaired erythropoietin production may result from the following:
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Renal failure
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Chronic inflammatory diseases
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Hypothyroidism
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Severe protein malnutrition
Defect in red cell maturation and ineffective erythropoiesis may result from the following:
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Nutritional anemia secondary to iron, folate, or vitamin B-12 deficiency
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Congenital dyserythropoietic anemia
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Erythropoietic protoporphyria
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Myelodysplastic syndromes [6]
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Myeloproliferative neoplasia
Anemia caused by increased red cell destruction
Extracellular causes may include the following:
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Mechanical injury (hemolytic-uremic syndrome, [7] thrombotic thrombocytopenic purpura [TTP], cardiac valvular defects, Kasabach-Merritt phenomenon [also called hemangioma with thrombocytopenia])
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Antibodies (autoimmune hemolytic anemia)
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Infections, drugs, toxins
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Thermal injury to RBCs (with severe burns)
Intracellular causes may include the following:
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Red cell membrane defects (eg, hereditary spherocytosis, elliptocytosis)
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Enzyme defects (eg, G-6-PD deficiency, pyruvate kinase deficiency, glutathione synthetase deficiency)
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Hemoglobinopathies (sickle cell disease, thalassemia, unstable hemoglobinopathies)
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PNH
Anemia caused by blood loss
Obvious or occult sites of blood loss may include the GI tract or intra-abdominal, pulmonary, or intracranial (in neonates) sites. Patients with bleeding disorders are at particular risk for massive hemorrhage (internal or external).
Acute anemia caused by multiple mechanisms
Anemia associated with acute infection is common. This may be mediated by increased destruction by erythrophagocytosis [8] and suppression of erythropoiesis by the infection.
Epidemiology
In adolescents and adults, normal values for the hemoglobin and hematocrit levels vary according to gender. Racial differences are also apparent, with black children having lower normal values than white and Asian children of the same age and socioeconomic background.
Occurrence
Among all races, ages, and socioeconomic groups studied, an overall steady decline (from 7.8% in 1975 to 2.9% in 1985) in prevalence of anemia in the US pediatric population (aged 6 mo to 6 y) has been observed. Data showed continued decline in the prevalence of anemia from the mid-1980s to the mid-1990s. [9] Iron deficiency was the most common etiology.
A prevalence study of anemia on selected groups using the National Health and Nutrition Examination Surveys covering 1988-1994 and 1999-2002 showed a decrease in the prevalence of anemia from 8% to 3.6% in children aged 12-59 months and from 10.8% to 6.9% in women aged 20-49 years. However, no significant change in the prevalence of iron deficiency anemia was seen in either group. [10] . Another report, by Brotanek et al, still showed the prevalence of iron deficiency and iron deficiency anemia among US toddlers to be 9% and 3%, respectively. [11]
In developing nations, the prevalence of anemia is extremely high. This is particularly true in preschool-aged children, in whom the prevalence reached as high as 90% of the sample population studied. Although iron deficiency is identified as the major factor, the etiology is often multifactorial, including recurrent or chronic infections (bacteria, malaria, parasites), malnutrition, and reduced immunity.
In addition, the prevalence of certain hereditary forms of anemia (eg, thalassemia, sickle cell disease) varies with ethnicity and, thus, with geography. For instance, α thalassemia, which may be the most common single gene disorder in the world, has a frequency of as much as 68% in the southwest Pacific, 20-30% in western Africa, and 5-10% in the Mediterranean region. Beta thalassemia mutations have high frequencies in the Mediterranean, northern Africa, Southeast Asia, and India, but they have low frequencies in Great Britain, Iceland, and Japan.
A study by Mujica-Coopman et al of anemia rates in children under age 6 years in Latin America and the Caribbean found the lowest rates in Chile (4.0%), Costa Rica (4.0%), Argentina (7.6%), and Mexico (19.9%). Anemia was found to pose a severe public health threat in Guatemala, Haiti, and Bolivia. [12]
A study by Aladjidi et al estimated that in the Aquitaine region of France, the incidence of the rare disease autoimmune hemolytic anemia in persons under age 18 years is 0.81 per 100,000 per year. [13]
Racial-related demographics
Acute anemia is universal, but the likely underlying etiologies are influenced by race. Inherited red cell disorders are predominant in certain racial populations, such as sickle cell disease in black persons, β thalassemia in persons of Mediterranean ethnicity, and α thalassemia in Asians, African Americans, and others. [14]
Sex-related demographics
Sex predisposition to anemia varies according to the underlying etiology. For instance, certain hereditary X-linked red cell disorders (eg, G-6-PD deficiency) are observed in males. Anemia caused by blood loss can be observed in males with an X-linked bleeding disorder (eg, hemophilia).
Females with the autosomally inherited von Willebrand disease may be anemic because of heavy blood loss during menstruation. Even without this disorder, they have a high risk of developing iron deficiency and iron deficiency anemia, quite often worsened by acute blood loss. Acquired hemolytic anemia related to autoimmune disorders such as systemic lupus erythematosus is more common in females because of their relative predisposition to autoimmune disease.
Age-related differences in incidence
Acute anemia most commonly occurs among newborns. Significant blood loss can occur from birth trauma or blood exchange from the baby's mother (fetomaternal transfusion) or the placenta (placenta previa, abruption, velamentous cord insertion, or coagulopathy). Isoimmune anemia can result from maternal antibodies crossing the placenta. Neonates have a shorter red cell life span and limited erythropoiesis that can aggravate any hemolytic process. Abnormalities of fetal hemoglobin may cause anemia that resolves with the normal shift to adult-type hemoglobins. Deletion of α globin gene, unlike β globin gene mutation, causes anemia in neonates. Hemoglobin H disease is a good example (in neonates Hb Barts is the abnormal hemoglobin rather than Hb H).
Nutritional anemia is common in infancy because of the associated rapid growth (necessitating an increase in red blood cell mass) and dietary adjustments.
With exposure to new infections in early childhood, the anemia of acute infection is common. Rarely, severe autoimmune hemolytic anemia can be triggered by certain infections. Adolescence is characterized by rapid growth and vulnerability to nutritional anemia. In addition, blood loss with heavy menstruation can be observed in adolescent girls.
Prognosis
The prognosis depends on the severity and acuteness with which the anemia develops and the underlying cause of the anemia.
Mortality and morbidity rates vary according to the underlying pathologic process causing the anemia, the degree of severity, and the acuteness of the process. When a precipitous drop in the hemoglobin or hematocrit level occurs (eg, due to massive bleeding or acute hemolysis), the clinical presentation is typically dramatic and can be fatal if the person is not immediately treated. A good example is so-called splenic sequestration crisis in infants and young children with sickle cell anemia (equivalent to massive blood loss). In this instance, the patients may develop a state of shock due to pooling of the blood in the spleen. In addition to the signs and symptoms of anemia, patients can present with congestive heart failure (CHF) or hypovolemia. Cerebral injury has been reported in perioperative patients with anemia. [15]
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Algorithm for diagnostic approach and workup of anemia in children. Hb=hemoglobin; Hct=hematocrit; HS=hereditary spherocytosis; HE=hereditary elliptocytosis; G-6-PD=glucose-6-phosphate dehydrogenase; PK=pyruvate kinase; HUS=hemolytic uremic syndrome; TTP=thrombotic thrombocytopenic purpura; DIC=disseminated intravascular coagulation; DBA=Diamond-Blackfan anemia.
