INTRODUCTION — The approach to anemia in the pediatric patient is reviewed here. Included are pertinent issues related to the history and physical examination, the initial laboratory workup, methods for classifying anemia, and algorithms designed to help guide diagnosis.

A systematic approach to the examination of the peripheral blood smear and bone marrow is discussed separately. (See "Evaluation of the peripheral blood smear" and "Evaluation of bone marrow aspirate smears".)

DEFINITION OF ANEMIA — Anemia may be defined as a reduction in red blood cell (RBC) mass or blood hemoglobin concentration. In practice, anemia most commonly is defined by reductions in one or both of the following:

●Hematocrit (HCT) − The hematocrit is the fractional volume of a whole blood sample occupied by RBCs, expressed as a percentage. As an example, the normal HCT in a child age 6 to 12 years is approximately 40 percent.

●Hemoglobin (HGB) − This is a measure of the concentration of the RBC pigment hemoglobin in whole blood, expressed as grams per 100 mL (dL) of whole blood. The normal value for HGB in a child age 6 to 12 years is approximately 13.5 g/dL (135 g/L).

Normal ranges for HGB and HCT vary substantially with age, race, and sex (table 1). The threshold for defining anemia is a HCT or HGB at or below the 2.5^th percentile for age, race, and sex.

PATIENT CHARACTERISTICS — Causes of anemia in children vary based upon age at presentation, sex, race, and ethnicity.

Age of patient — The age of the patient is important to consider because normal values of hematocrit (HCT) and hemoglobin (HGB) vary greatly with age, and because different causes of anemia present at different ages (table 1):

●Birth to three months − The most common cause of anemia in young infants is "physiologic anemia", which occurs at approximately six to nine weeks of age. Erythropoiesis decreases dramatically after birth as a result of increased tissue oxygenation and a reduced production of erythropoietin [1,2]. In healthy term infants, hemoglobin levels are high (>14 g/dL) at birth and then rapidly decline, reaching a nadir of approximately 11 g/dL at six to nine weeks of age, which is called "physiologic anemia of infancy" (also called the "physiologic nadir") (figure 1) [3,4].

Pathologic anemia in newborns and young infants is distinguished from physiologic anemia by any of the following [1]:

•Anemia (HGB <13.5 g/dL) within the first month of life

•Anemia with lower HGB level than is typically seen with physiologic anemia (ie, <9 g/dL)

•Signs of hemolysis (eg, jaundice, scleral icterus, or dark urine) or symptoms of anemia (eg, irritability or poor feeding)

Common causes of pathologic anemia in newborns include blood loss, immune hemolytic disease (ie, Rh or ABO incompatibility), congenital infection, twin-twin transfusion, and congenital hemolytic anemia (eg, hereditary spherocytosis, glucose-6-phosphate dehydrogenase [G6PD] deficiency) (algorithm 1).

Hyperbilirubinemia in the newborn period suggests a hemolytic etiology; microcytosis at birth suggests chronic intrauterine blood loss or thalassemia.

Compared with term infants, preterm infants are born with lower HCT and HGB, have shorter red blood cell (RBC) life span, and have impaired erythropoietin production due to immature liver function [1]. Hence the decline in RBC production occurs earlier after birth and is more severe than the anemia seen in term infants. This is referred to as "anemia of prematurity" and is discussed in detail separately. (See "Anemia of prematurity".)

●Infants three to six months − Anemia detected at three to six months of age suggests a hemoglobinopathy. Nutritional iron deficiency is an unlikely cause of anemia before the age of six months in term infants. (See "Diagnosis of sickle cell disorders" and "Clinical manifestations and diagnosis of the thalassemias".)

●Toddlers, children, and adolescents − In toddlers, older children, and adolescents, acquired causes of anemia are more likely, particularly iron deficiency anemia. Screening for iron deficiency anemia is recommended in all children at 9 to 12 months of age. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis", section on 'Screening recommendations'.)

Sex — Some inherited causes of anemia are X-linked (eg, G6PD deficiency and X-linked sideroblastic anemia), and occur most commonly in males. In postmenarchal girls, excessive menstrual bleeding is an important cause of anemia. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase deficiency", section on 'Epidemiology' and "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Excessive menstrual bleeding' and "Causes and pathophysiology of the sideroblastic anemias", section on 'X-linked sideroblastic anemia (ALAS2 mutation)'.)

Race and ethnicity — Race and ethnic background are helpful in guiding the workup for hemoglobinopathies and enzymopathies (eg, G6PD deficiency). Hemoglobin S and C are most commonly seen in black and Hispanic populations; thalassemia syndromes are more common in individuals of Mediterranean and Southeast Asian descent; G6PD deficiency is more common among Sephardic Jews, Filipinos, Greeks, Sardinians, Kurds, and black populations [1]. (See "Clinical manifestations and diagnosis of the thalassemias" and "Diagnosis of sickle cell disorders".)

EVALUATION

History — The evaluation of a child with anemia begins with a thorough history. The degree of symptoms, past medical history, family history, dietary history, and developmental history may provide important clues to the cause of anemia (table 2):

●Symptoms — Characterizing the symptoms helps elucidate the severity and chronicity of anemia and may identify patients with blood loss or hemolytic etiologies:

•Onset and severity of symptoms − Common symptoms of anemia include lethargy, tachycardia, and pallor. Infants may present with irritability and poor oral intake. Because of the body's compensatory abilities, patients with chronic anemia may have few or no symptoms compared with those with acute anemia at comparable hemoglobin (HGB) levels.

•Symptoms of hemolysis − Changes in urine color, scleral icterus, or jaundice may indicate the presence of a hemolytic disorder. Hemolytic episodes that occur only in male family members may indicate the presence of a sex-linked disorder, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency. (See "Overview of hemolytic anemias in children" and "Diagnosis and management of glucose-6-phosphate dehydrogenase deficiency", section on 'Clinical manifestations'.)

•Bleeding symptoms − Specific questions related to bleeding from the gastrointestinal tract, including changes in stool color, the identification of blood in stools, and history of bowel symptoms, should be reviewed. Severe or chronic epistaxis also may result in anemia from blood loss and iron deficiency. In adolescent girls, menstrual history should be obtained, including duration and amount of bleeding. Severe epistaxis and/or menorrhagia should raise suspicion for an underlying bleeding disorder [5]. In patients who have symptoms of gastrointestinal bleeding, it is important to determine whether there is a family history of inflammatory bowel disease, intestinal polyps, colorectal cancer, hereditary hemorrhagic telangiectasia, von Willebrand disease, platelet disorders, or hemophilia. (See "Approach to upper gastrointestinal bleeding in children" and "Evaluation of epistaxis in children" and "Approach to the child with bleeding symptoms" and "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'History'.)

●Past medical history — The past medical history should focus on characterizing past episodes of anemia and identifying underlying medical conditions:

•Birth history − The birth and neonatal history should include gestational age, duration of birth hospitalization, and history of jaundice and/or anemia in the newborn period. Results of newborn screening (which typically includes screening for sickle cell disease) should be reviewed. (See "Postnatal diagnosis and management of hemolytic disease of the fetus and newborn" and "Anemia of prematurity" and "Diagnosis of sickle cell disorders", section on 'Newborn screening' and "Diagnosis and management of glucose-6-phosphate dehydrogenase deficiency", section on 'Neonatal jaundice'.)

•History of anemia − Previous complete blood counts (CBCs) should be reviewed, and if prior anemic episodes occurred, they should be characterized (including duration, etiology, therapy, and resolution). Prior episodes of anemia suggest an inherited disorder, whereas anemia in a patient with previously documented normal CBC suggests an acquired etiology. Patients with certain hemoglobinopathies (such as hemoglobin E or the various thalassemias) may have a history of treatment on multiple occasions for an erroneous diagnosis of iron deficiency anemia. (See "Clinical manifestations and diagnosis of the thalassemias".)

•Underlying medical conditions − Past medical history and review of symptoms should be obtained to elucidate chronic underlying infectious or inflammatory conditions that may result in anemia. Travel to/from areas of endemic infection (eg, malaria, hepatitis, tuberculosis) should be noted (the Centers for Disease Control and Prevention website provides updated information on malaria and tuberculosis). Recent illnesses should be reviewed to investigate for possible infectious etiologies of anemia.

●Drug and toxin exposure — Current and past medications (including homeopathic or herbal supplements) should be reviewed with particular attention to oxidant drugs that can cause hemolysis, particularly in patients with underlying G6PD deficiency (table 3). Possible environmental toxin exposure should be explored, including lead exposure and nitrates in well water. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase deficiency", section on 'Inciting drugs, foods, illnesses' and "Childhood lead poisoning: Exposure and prevention" and "Hemolytic anemia due to drugs and toxins", section on 'Nitrites'.)

●Family history — Family history of anemia should be reviewed in depth. Family members with jaundice, gallstones, or splenomegaly should be identified. Asking if family members have undergone cholecystectomy or splenectomy may aid in the identification of additional individuals with inherited hemolytic anemias. (See "Overview of hemolytic anemias in children", section on 'Intrinsic hemolytic anemias'.)

●Dietary history— The dietary history is focused on assessing iron intake and, to a lesser degree, folate and B12 content. The type of diet, type of formula (if iron fortified), and age of infant at the time of discontinuation of formula or breast milk should be documented. In addition, the amount and type of milk the patient is drinking should be determined. Infants and children who are exclusively fed goat's milk can develop anemia due to folate deficiency [6-8]. Pica (particularly pagophagia, the eating of ice) may suggest lead poisoning and/or iron deficiency. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis" and "Causes and pathophysiology of vitamin B12 and folate deficiencies" and "Childhood lead poisoning: Clinical manifestations and diagnosis".)

●Developmental history — Parents should be asked questions to determine if the child has reached age-appropriate developmental milestones. Developmental delay can be associated with iron deficiency, vitamin B12/folic acid deficiency, and Fanconi anemia [9]. (See "Developmental-behavioral surveillance and screening in primary care", section on 'Monitoring milestones'.)

Physical examination — The physical examination also may provide important clues to the cause of anemia. Particular focus should be directed to examination of the skin, eyes, mouth, facies, chest, hands, and abdomen (table 4).

Pallor is assessed by examining sites where capillary beds are visible (eg, conjunctiva, palm, and nail beds). However, the sensitivity of clinical assessment of pallor in these locations in detecting severe anemia (ie, HGB <7 g/dL) is only approximately 50 to 60 percent [10-12].

Patients with hemolytic processes resulting in anemia may present with signs of scleral icterus, jaundice, and hepatosplenomegaly resulting from increased red cell destruction. However, as with the clinical detection of anemia through evaluation of pallor, clinical detection of jaundice often is poor. As an example, in an emergency department setting, the clinical detection of jaundice was found to have sensitivity and specificity of only approximately 70 percent [13].

Laboratory evaluation — Initial laboratory studies include a CBC with red blood cell (RBC) indices and review of the peripheral blood smear. A reticulocyte count should be obtained, although this is not necessary for the diagnosis of iron deficiency anemia in children <2 years old who present with a mild microcytic anemia and a suggestive dietary history. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

The CBC, RBC indices, blood smear, and reticulocyte count are used to focus the diagnostic considerations and guide further testing to confirm the etiology of anemia (algorithm 2 and algorithm 3). (See 'Diagnostic approach' below.)

Complete blood count — The complete blood count (CBC) provides information about the RBCs and other cell lines (ie, white blood cells and platelets). All three cell lines should be evaluated for abnormalities.

Hemoglobin and hematocrit — Normal ranges for HGB and hematocrit (HCT) vary substantially with age, so it is important to use age- and sex- adjusted norms (figure 1 and table 1).

Falsely elevated results may be obtained when HGB and HCT values are measured using capillary samples (eg, finger or heel "sticks"), particularly when using microhematocrit measurements, although the likelihood of masking significant anemia is low [14-16]. Spurious results may also occur with automated counters in the presence of lipemia, hemolysis, leukocytosis (with white blood cell counts >50 x 10⁹/L), or high immunoglobulin levels [17].

RBC indices — The red blood cell indices are an integral part of the evaluation of the anemic child. These include:

●Mean corpuscular volume (MCV) − MCV is measured directly by automated blood cell counters and represents the mean value (in femtoliters [fL]) of the volume of individual RBCs in the blood sample. Normal values for MCV vary based upon age (infants have increased MCV compared with older children) (table 1). In preterm infants, MCV values increase with decreasing gestational age [18].

MCV is the most useful RBC parameter when evaluating a patient with anemia and is used to classify the anemia as follows:

•Microcytic anemia is defined as anemia with a low MCV value (ie, ≤2.5^th percentile for age, race, and sex).

•Normocytic anemia is defined as anemia with a normal MCV value (ie, between the 2.5^th and 97.5^th percentile for age, race, and sex).

•Macrocytic anemia is defined as anemia with a high MCV value (ie, ≥97.5^th percentile for age, race, and sex).

Because reticulocytes have a greater MCV than do mature cells (picture 1), patients with significant degrees of reticulocytosis may have elevated MCV values in the face of otherwise normocytic RBCs [19]. (See 'Macrocytic anemia' below and "Macrocytosis/Macrocytic anemia".)

●Red cell distribution width (RDW) − The red cell distribution width (RDW) is a quantitative measure of the variability of RBC sizes in the sample (anisocytosis). Normal values vary little with age and are generally between 12 and 14 percent [14].

●Mean corpuscular hemoglobin concentration (MCHC) − The mean corpuscular hemoglobin concentration (MCHC) is a calculated index (MCHC = HGB/HCT), yielding a value of grams of HGB per 100 mL of RBC. MCHC values vary depending upon the age (infants have higher values than older children) and sex (males have slightly higher values than females) of the child. MCHC also increases with decreasing gestational age [18]. MCHC measurements may vary slightly based upon the technology used and should be interpreted using the normal range for the specific laboratory.

Anemia can also be classified on the basis of MCHC:

•Hypochromic anemia is defined as anemia with low MCHC (≤32 g/dL).

•Normochromic anemia is defined as anemia with MCHC values in the normal range (33 to 34 g/dL).

•Hyperchromic anemia is defined as anemia with high MCHC (≥35 g/dL).

Hypochromia and hyperchromia usually can be appreciated on the peripheral smear (picture 2 and picture 3) [20].

White blood count and platelet count — The other cell lines may provide clues to the underlying cause of anemia (algorithm 3). Leukocytosis (high total white blood cell count) suggests an infectious etiology or an acute leukemia. Thrombocytosis (high platelet count) is a common finding in iron deficiency [21]. Thrombocytosis commonly occurs as part of the acute phase reaction in response to infection and other inflammatory conditions, particularly Kawasaki disease. (See "Approach to the patient with neutrophilia" and "Kawasaki disease: Clinical features and diagnosis".)

Leukopenia, neutropenia, and/or thrombocytopenia may signify abnormal bone marrow function or increased peripheral destruction of blood cells:

●Causes of bone marrow suppression/failure include drugs or toxins, nutritional deficiency (eg, folic acid or vitamin B12 deficiency, and rarely iron deficiency), acute leukemia, or aplastic anemia.

●Increased peripheral destruction of blood cells may be due to splenic hyperfunction ("hypersplenism"), microangiopathic hemolytic anemia (eg, hemolytic uremic syndrome), or Evans syndrome (a variant of autoimmune hemolytic anemia).

Blood smear — A review of the peripheral smear is an essential part of any anemia evaluation. Even if the patient's RBC indices are normal, review of the blood smear may reveal abnormal cells that can help identify the cause of anemia. (See "Evaluation of the peripheral blood smear".)

The following features should be noted:

●RBC size – A normal RBC should have the same diameter as the nucleus of a small lymphocyte (picture 4). This comparison will help the investigator identify the patient with microcytosis (picture 2) or macrocytosis (picture 5).

●Central pallor – The normal mature RBC is a biconcave disc (picture 6). As a result, RBCs on the peripheral smear demonstrate an area of central pallor, which, in normochromic RBCs, is approximately one-third the diameter of the cell (picture 4). Increased central pallor indicates hypochromic cells, which most often are seen in iron deficiency (picture 2) and thalassemia (picture 7). On the other hand, spherocytes (picture 3) and reticulocytes (picture 1) do not display central pallor, because they are not biconcave discs.

●Fragmented cells – Although the patient's overall RBC indices may be normal, review of the blood smear may reveal the presence of small numbers of fragmented cells, indicating a microangiopathic process (picture 8). (See "Extracorpuscular non-immune hemolytic anemia: Fragmentation hemolysis and hypersplenism" and "Overview of hemolytic anemias in children".)

●Other features – Other anemias may be characterized by typical morphologic abnormalities, which may go undetected without inspection of the peripheral smear; these include:

•Sickle cells, as seen in sickle cell disease (picture 9). (See "Diagnosis of sickle cell disorders".)

•Elliptocytes, as seen in congenital elliptocytosis (picture 10). (See "Hereditary elliptocytosis and related disorders".)

•Stomatocytes, as seen in hereditary or acquired stomatocytosis (picture 11). (See "Stomatocytosis and xerocytosis".)

•Pencil poikilocytes, which can be seen in iron deficiency anemia or thalassemia (picture 2).

•Target cells, as seen in the various hemoglobinopathies, including thalassemia, as well as in liver disease, and post-splenectomy (picture 12 and picture 7). (See "Causes of spiculated cells (echinocytes and acanthocytes) and target cells".)

•Bite cells and Heinz bodies (picture 13) are seen in hemolytic anemia due to oxidant sensitivity, such as G6PD deficiency. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase deficiency".)

•The presence of numerous nucleated RBCs indicates rapid bone marrow turnover and is seen with hemolytic processes (picture 9 and picture 14).

•Red blood cell agglutination (picture 15) is seen in cold agglutinin hemolytic anemia. (See "Autoimmune hemolytic anemia in children: Classification, clinical features, and diagnosis", section on 'Cold AIHA'.)

•Howell-Jolly bodies (picture 16) are associated with absence or hypofunction of the spleen. (See "Approach to the adult with splenomegaly and other splenic disorders", section on 'Hyposplenism and asplenia'.)

•Basophilic stippling (picture 17) is classically seen in lead poisoning and may also be present in thalassemia, sickle cell anemia, and sideroblastic anemia. (See "Childhood lead poisoning: Clinical manifestations and diagnosis".)

The appearance of the patient's leukocytes should also be noted:

●Increases in circulating neutrophils, especially increased numbers of band forms or toxic changes (picture 18), or the presence of atypical lymphocytes (picture 19) suggests the possibility of infectious or inflammatory conditions. (See "Approach to the patient with neutrophilia" and "Approach to the child with lymphocytosis or lymphocytopenia".)

●Hypersegmented neutrophils (picture 20) suggest vitamin B12 or folate deficiency.

●The presence of early white blood cell forms (eg, blasts) (picture 21) along with anemia should raise the suspicion of leukemia or lymphoma. (See "Overview of the presentation and diagnosis of acute lymphoblastic leukemia in children and adolescents".)

Reticulocyte count — Reticulocytes are the youngest red cells in the circulation, and are identified by the presence of residual RNA (picture 1 and picture 22). The reticulocyte is reported as a percentage of the RBC population. After the first few months of life, the normal reticulocyte percentage is the same as that of the adult, approximately 1.5 percent [1].

In patients with anemia, the reticulocyte percentage must be interpreted in relation to the reduced number of red blood cells. The simplest approach is to calculate the absolute reticulocyte count (ARC) as follows:

Absolute reticulocyte count = percent reticulocytes x red blood cell count/L

The ARC is calculated and reported by many automated cell counters. ARC is expected to increase in the presence of anemia, although laboratories do not provide normal ranges adjusted for the level of anemia. In a patient with anemia, ARC values within the normal range (<100 x 10⁹/L) generally indicate an inappropriately low erythropoietic response [22]. The ARC is an indication of bone marrow erythropoietic activity and is used to classify the bone marrow response to anemia (see 'Classification of anemia' below):

●Anemia with a high ARC reflects an increased erythropoietic response to hemolysis or blood loss.

●Anemia with a low or normal ARC reflects deficient production of RBCs (ie, a reduced marrow response to the anemia).

These two categories are not mutually exclusive, however. Hemolysis or blood loss can be associated with a low reticulocyte count if there is a concurrent disorder that impairs RBC production (eg, infection).

In some cases, the reticulocyte count depends on the phase of the illness. As an example, the reticulocyte count is low in a child during the acute phase of transient erythroblastopenia of childhood or transient bone marrow suppression caused by a viral illness. However, during the recovery phase from these disorders, children may have elevated reticulocyte counts, as the bone marrow recovers and responds to the anemia. The absence of scleral icterus, jaundice, and hepatosplenomegaly distinguishes this recovery process from a hemolytic process. (See "Anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood (TEC)'.)

DIAGNOSTIC APPROACH — The history, physical examination, and initial laboratory tests are used to narrow the diagnostic possibilities and guide further testing.

Abnormalities in other cell lines — The first step in narrowing the diagnostic possibilities is determining whether the patient has an isolated anemia or if other cell lines (ie, white blood cells [WBC] and platelets [PLT]) are also abnormal (algorithm 3):

●Pancytopenia − Causes of pancytopenia in children include leukemia, infection, myelosuppressive medications, aplastic anemia, and hypersplenism. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis" and "Overview of the presentation and diagnosis of acute lymphoblastic leukemia in children and adolescents" and "Approach to the child with an enlarged spleen".)

●Anemia with thrombocytopenia − Causes of anemia associated with low PLT count include hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and Evans syndrome. (See "Overview of hemolytic uremic syndrome in children" and "Pathophysiology of acquired TTP and other primary thrombotic microangiopathies (TMAs)" and "Warm autoimmune hemolytic anemia: Clinical features and diagnosis", section on 'Evans syndrome'.)

●Anemia with thrombocytosis − Iron deficiency anemia is commonly associated with thrombocytosis [21].Other causes of anemia associated with elevated PLT count include post-splenectomy anemia and infection or inflammation. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis" and "Approach to the patient with thrombocytosis".)

●Anemia with leukocytosis − Causes of anemia associated with elevated WBC count include leukemia and infection. (See "Overview of the presentation and diagnosis of acute lymphoblastic leukemia in children and adolescents".)

Classification of anemia — Anemias are classified based upon red blood cell (RBC) size and the physiologic response of the bone marrow (ie, the reticulocyte response). Approaching the evaluation of an anemic patient using these classification schemes helps to further narrow the diagnostic possibilities (algorithm 2).

Microcytic anemia — Microcytic anemia (picture 2) is defined as anemia with a low mean corpuscular volume (MCV) (ie, ≤2.5^th percentile for age, race, and sex) (table 1). (See 'RBC indices' above.)

The most common causes of microcytic anemia in children are iron deficiency and thalassemia (algorithm 2) [17,23].

The red cell distribution width (RDW) can be helpful in differentiating iron deficiency from thalassemia. Anisocytosis (high RDW) is typical of iron deficiency whereas the RDW is usually normal in patients with thalassemia (though elevated RDW can occur). (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of the thalassemias".)

Normocytic anemia — Normocytic anemia is defined as anemia with a normal MCV (ie, between the 2.5^th and 97.5^th percentile for age, race, and sex (table 1)). Common causes of normocytic anemia include hemolytic anemias, blood loss, infection, medication, and anemia of chronic disease. (See 'RBC indices' above.)

Macrocytic anemia — Macrocytic anemia (picture 5) is defined as anemia with a high MCV (ie, ≥97.5^th percentile for age, race and sex (table 1)). (See 'RBC indices' above.)

The most common cause of macrocytosis in children is exposure to certain medications (eg, anticonvulsants, zidovudine, and immunosuppressive agents) [23,24]. Other causes include vitamin B12 or folate deficiency, liver disease, Diamond-Blackfan anemia, hypothyroidism, and aplastic anemia (algorithm 2).

Reticulocyte response — The reticulocyte count is especially helpful in evaluating children with normocytic anemia (algorithm 2 and algorithm 3) (see 'Reticulocyte count' above):

●High reticulocyte count − A high reticulocyte count (>3 percent) reflects an increased erythropoietic response to blood loss or hemolysis (table 5). Common causes include: hemorrhage; autoimmune hemolytic anemia; membranopathies (eg, hereditary spherocytosis); enzymopathies (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency); hemoglobinopathies (eg, sickle cell disease); and microangiopathic hemolytic anemia (eg, hemolytic uremic syndrome) (algorithm 2 and algorithm 3). (See "Overview of hemolytic anemias in children".)

●Low or normal reticulocyte count − A low or normal reticulocyte count reflects deficient production of RBCs (ie, a reduced marrow response to the anemia).

Causes of inadequate marrow response include infections, lead poisoning, hypoplastic anemias, transient erythroblastopenia of childhood (TEC), Diamond-Blackfan anemia (which typically presents with macrocytic anemia), drugs (most drugs that decrease erythropoiesis affect other cell lines as well; cisplatin is an example of a medication that can cause isolated suppression of erythropoiesis), and kidney disease (algorithm 2 and algorithm 3).

In addition, anemia due to acute blood loss can be associated with low absolute reticulocyte count (ARC) if there has not been time for the bone marrow to mount an appropriate reticulocyte response, which typically takes approximately one week.

Confirmatory testing — Once the diagnostic possibilities have been narrowed based upon the MCV and reticulocyte count, confirmatory testing is performed (algorithm 2 and algorithm 3).

If hemolytic anemia is suspected, testing should include serum indirect bilirubin, lactate dehydrogenase, and haptoglobin levels. Testing for specific etiologies may include direct antiglobulin test, G6PD deficiency screening test, osmotic fragility, and/or hemoglobin electrophoresis. (See "Overview of hemolytic anemias in children".)

If iron deficiency is suspected, additional studies may include serum ferritin, iron, and total iron binding capacity (TIBC). Iron studies are not necessary in children <2 years old who present with a mild microcytic anemia and a suggestive dietary history. A therapeutic trial of iron may be used to confirm the diagnosis in these children. (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis".)

Testing for other nutritional deficiencies and/or lead poisoning may include serum folate, B12, and lead levels. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Childhood lead poisoning: Clinical manifestations and diagnosis".)

Bone marrow aspirate and/or biopsy may be necessary to evaluate for leukemia or other diseases of bone marrow failure (eg, aplastic anemia, Diamond-Blackfan anemia).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric iron deficiency".)

SUMMARY

●The threshold for defining anemia is a hemoglobin (HGB) or hematocrit (HCT) that is ≤2.5^th percentile for age, race, and sex (table 1). Hemoglobin levels are high (>14 g/dL) at birth and then rapidly decline, reaching a nadir of approximately 11 g/dL at six to nine weeks of age, which is called "physiologic anemia of infancy" (figure 1). (See 'Definition of anemia' above.)

●The causes of anemia vary based upon the age at presentation. In neonates and young infants, immune hemolytic disease, infection, and hereditary disorders are most common (algorithm 1). In older children, acquired causes of anemia are more likely, particularly iron deficiency anemia (dietary or due to blood loss). (See 'Age of patient' above and "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis" and "Overview of hemolytic anemias in children" and "Introduction to hemoglobin mutations".)

●Key historical factors in the assessment of a child with anemia include the severity and onset of symptoms, evidence of jaundice or blood loss (gastrointestinal symptoms and menstrual history), drug and toxin exposure, chronic disease, and family history of anemias or hemoglobinopathy (table 2). (See 'History' above.)

●The physical examination should include a careful assessment for pallor, scleral icterus, jaundice, hepatomegaly, and splenomegaly (table 4). (See 'Physical examination' above.)

●The laboratory examination should begin with a complete blood count, including red blood cell (RBC) indices, reticulocyte count, and review of the peripheral blood smear. (See 'Laboratory evaluation' above.)

●Examination of the peripheral blood smear may reveal features that suggest a specific cause of anemia, and helps to evaluate the possibility of a hematologic malignancy. (See 'Blood smear' above.)

●The mean corpuscular volume (MCV) provides a preliminary categorization of the anemia, which guides additional testing (algorithm 2 and algorithm 3). Common causes of microcytic (ie, low MCV) anemia include iron deficiency and thalassemia. Common causes of normocytic (ie, normal MCV) anemia include hemolytic anemias, blood loss, infection, medication, and anemia of chronic disease. Common causes of macrocytic (ie, high MCV) anemia include medications (eg, anticonvulsant drugs) and deficiency of vitamin B12 or folate. (See 'Classification of anemia' above.)

●The reticulocyte count distinguishes disorders resulting from rapid destruction or loss of RBCs (hemolysis or bleeding) from disorders resulting in an inability to adequately produce RBCs (ie, bone marrow depression). Hemolysis and bleeding are usually associated with a high reticulocyte count (>3 percent), whereas bone marrow depression is associated with a low reticulocyte count (algorithm 2). (See 'Reticulocyte count' above.)

●Once the diagnostic possibilities have been narrowed based upon RBC indices and reticulocyte response, further confirmatory testing is performed (algorithm 2 and algorithm 3). (See 'Confirmatory testing' above.)