Pediatric Algorithms

* Initial hemoglobin and red blood cell indices may be normal despite severe hemorrhage.

¶ Examples of possible conditions are provided within appropriate categories.

HGB: hemoglobin; MCV: mean corpuscular volume; TIBC: total iron-binding capacity; TEC: transient erythroblastopenia of childhood; G6PD: glucose-6-phosphate dehydrogenase; HUS: hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; DIC: disseminated intravascular coagulation; HU: hydroxyurea; PMNs: polymorphonuclear cells; LDH: lactate dehydrogenase; DAT: direct antiglobulin test; RDW: red cell distribution width.

*  HGB levels vary considerably by age, race, and sex; when diagnosing anemia, HGB values should be compared with age-, race-, and sex-adjusted norms. Mild anemia occurring at 6 to 9 weeks of life is consistent with “physiologic anemia” and is not pathologic. Falsely elevated HGB values may occur when measured using capillary samples (eg, finger or heel “sticks”), particularly when using microhematocrit measurements. Spurious results may also occur with automated counters in the presence of lipemia, hemolysis, leukocytosis, or high immunoglobulin levels.

¶  The RDW can be helpful in differentiating thalassemia from iron deficiency. High RDW is typical of iron deficiency, whereas the RDW is usually normal in patients with thalassemia (though elevated RDW can occur).

Δ  Anemia of chronic disease typically presents as a normocytic anemia but can have low MCV.

◊  Selected testing is based upon review of the patient’s history and examination of the peripheral blood smear.

  • In children with mild microcytic anemia and dietary history that is suggestive of iron deficiency, serum iron studies (ie, ferritin, iron, and TIBC levels) are generally not necessary. In these children, a therapeutic trial of iron can be used to confirm the diagnosis.

¥  Evidence of hemolysis includes jaundice, indirect hyperbilirubinemia, elevated lactate dehydrogenase, and/or decreased haptoglobin.

‡  Findings on blood smear may suggest an underlying etiology of anemia, but they are generally not diagnostic. Further confirmatory testing should be carried out to confirm the diagnosis.

HGB: hemoglobin; MCV: mean corpuscular volume; PLT: platelets; HUS: hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; DIC: disseminated intravascular coagulation; WBC: white blood cell; PMNs: polymorphonuclear cells; TIBC: total iron-binding capacity; LDH: lactate dehydrogenase; DAT: direct antiglobulin test.

*  HGB levels in children vary considerably by age. During adolescence, HGB values also differ according to sex. When diagnosing anemia in pediatric patients, HGB values should be compared with age- and sex-adjusted norms. Mild anemia occurring at 6 to 9 weeks of life is consistent with “physiologic anemia” and is not pathologic. Falsely elevated HGB values may occur when measured using capillary samples (eg, finger or heel sticks), particularly when using microhematocrit measurements. Spurious results may also occur with automated counters in the presence of lipemia, hemolysis, leukocytosis, or high immunoglobulin levels.

¶  Findings on blood smear may suggest an underlying etiology of anemia, but they are generally not diagnostic. Further confirmatory testing should be performed to confirm the diagnosis.

Δ  Selected testing is based upon review of the patient’s history and examination of the peripheral blood smear.

◊  In children with mild microcytic anemia with thrombocytosis and a dietary history that is suggestive of iron deficiency, serum iron studies (ie, ferritin, iron, and TIBC levels) are generally not necessary. In these children, a therapeutic trial of iron can be used to confirm the diagnosis.

  1. Neonatal pallor is a sign of asphyxia, shock, hypothermia and hypoglycemia as well as anemia. Pallor is usually apparent when the Hb is <7–8 g/dl (1.09–1.24 mmol/l). Neonatal anemia requires immediate investigation. Anemia at birth is usually due to hemorrhage or severe alloimmunization. Anemia manifesting in the first 2 days of life is often due to internal or external hemorrhage, while anemia after the first 48 h is usually hemolytic and associated with jaundice. When assessing whether a neonate is anemic, consider that capillary samples can average 3.5 g/dl (0.54 mmol/l) higher than venous samples. Hb also varies with age and with gestational age.
  2. Reticulocyte counts vary from 3 to 7% of RBCs in the first 2 days of life, decreasing to 0–1% by 7 days. Most neonates with hemolysis have reticulocyte counts of 5–8% or higher. In the first few days of life, nucleated erythrocytes are normally seen in peripheral blood as are small numbers of spherocytes. As an indicator of hemolysis, indirect hyperbilirubinemia is limited by the frequency of hyperbilirubinemia in infants without hemolysis; however, hemolytic anemia in the neonate is almost always associated with a bilirubin level >10–12 mg/dl (171–180 μmol/l).
  3. Anemia unaccompanied by jaundice is usually due to hemorrhage in the first 24–72 hours of life. Ensure that the infant is not dangerously hypovolemic and that blood loss is not continuing. With acute blood loss, the Hb may not fall immediately, the MCV will be normal and a reticulocytosis is usually delayed for 3–7 days. Obstetrical complications cause anemia in approximately 1% of newborns; common etiologies include abruptio placentae, placenta previa, twin-twin transfusion, ruptured cord, emergency Caesarian section, cephalohematomas, and feto-maternal hemorrhage. The latter is very common and is most easily diagnosed using a Kleihauer-Betke test to identify fetal cells in maternal blood. Common etiologies of serious internal hemorrhage include intracranial or subgaleal, intra-abdominal (particularly hepatic or splenic rupture or hematomas), and pulmonary hemorrhage. Iatrogenic blood loss (phlebotomy, accidents with catheters) should be considered. The Apt test differentiates neonatal gastrointestinal hemorrhage from swallowed maternal blood. Bleeding disorders, such as vitamin K deficiency, DIC, neonatal alloimmune thrombocytopenia and hemophilia may be responsible for hemorrhage.
  4. Iatrogenic blood loss is a routine component of anemia in sick neonates.
  5. Viral and bacterial infections are often associated with hemolysis as well as impaired erythroid production. The hemolysis is usually a direct result of infection, but in very ill infants may also be a consequence of DIC. Infection is often associated with hepatosplenomegaly. One-half of the newborns with toxoplasmosis have anemia, which may be severe. CMV, rubella and herpes simplex are usually associated with mild anemia. Bacterial infection, whether complicated by DIC or not, is often associated with anemia. Malaria must be considered in endemic areas.
  6. Hemolytic anemia often accompanies neonatal asphyxia, regardless of etiology, and is often due to DIC. Shock, regardless of etiology, can trigger DIC.
  7. Anisocytosis, poikilocytosis, polychromasia, occasional spherocytes or fragmented erythrocytes, are findings which suggest hemolysis but are not specific.
  8. G6PD screening tests are useful, but false-negative results are common in mild variants during a reticulocytosis. Perform the more accurate G6PD assay or alternatively repeat the screen once the reticulocyte is normal. Note that 3% of the world population is G6PD deficient, with neonates most often affected in Mediterranean and Chinese populations.
  9. Rare etiologies of hemolytic anemia include other enzyme deficiencies (pyruvate kinase and glucose phosphate isomerase deficiencies most frequently), vitamin E deficiency, oxidizing agents, and metabolic disorders (e.g. galactosemia, amino acid disorders and lysosomal storage diseases).
  • Specific smear abnormalities can establish a diagnosis. Frequent spherocytes suggest hereditary spherocytosis or ABO incompatibility. Hereditary elliptocytosis and hereditary stomatocytosis are easily recognized by a large number of these cells in peripheral blood. Hereditary pyropoikilocytosis presents with microcytosis and bizarrely shaped, fragmented or budded red cells as well as elliptocytes and spherocytes. Microangiopathic hemolytic anemias are identified by the predominant pattern of red cell fragmentation usually accompanied by thrombocytopenia. Malarial parasites may be seen on routine smears, but thick smears may be necessary when the intensity of parasitemia is low.
  • The direct Coombs test may be negative in ABO incompatibility, but this diagnosis may be confirmed by eluting and identifying anti-A or anti-B antibodies from neonatal erythrocytes.
  • Half of the newborns with hereditary spherocytosis are icteric and some may require exchange transfusion. Anemia is frequent in the neonate but does not predict disease severity later in life. The family history will be negative in 1/4–1/3 of families.
  • There is a strong relationship between hereditary elliptocytosis and hereditary pyropoikilocytosis; 1/3 of pyropoikilocytosis patients have family members with typical hereditary elliptocytosis and many patients with pyropoikilocytosis proceed to develop typical HE
  • Malaria must be considered in endemic areas since transplacental infection rates are as high as 9%. Most neonates are asymptomatic, developing manifestations at 3–12 weeks of age. Progressive hemolytic anemia is common and severe disease can resemble erythroblastosis fetalis.
  • Hemolysis due to blood group incompatibility is very common in the first day of life. Maternal blood type should be determined if the baby is Rh+ or type A or B. The antigen specificity of anti-RBC antibodies in the neonate’s sera or on RBCs should be determined when incompatibility is present or when the direct Coombs test is positive.
  • Clinically apparent minor blood group incompatibility is usually due to Kell, E or c antigen incompatibility. Elution of the specific antibody from the neonate’s red cells allows identification of the specific antigen involved. Maternal autoimmune hemolytic anemia can cause transient neonatal hemolysis but this is rarely seen.