Approach to the child with anemia

INTRODUCTION — 

The diagnostic approach to anemia in pediatric patients includes taking a careful clinical history, performing a physical examination, and a targeted initial laboratory evaluation.

This topic will outline the general approach to evaluating anemia in children, including approaches for classifying anemia and algorithms to narrow the differential diagnosis.

Related topics include:

●(See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Evaluation for suspected iron deficiency anemia'.)

●(See "Overview of causes of anemia in children due to decreased red blood cell production".)

●(See "Overview of hemolytic anemias in children".)

●(See "Evaluation of pallor in children".)

●(See "Evaluation of the peripheral blood smear".)

DEFINITION OF ANEMIA — 

Anemia is defined as reduced blood hemoglobin (HGB) concentration or red blood cell (RBC) mass:

●Hemoglobin (HGB) – A measure of the RBC pigment HGB concentration, expressed as grams per 100 mL (dL) of whole blood. The reference range for HGB in children ages 6 to 12 years old is approximately 11.2 to 14.5 g/dL (112 to 145 g/L).

●Hematocrit (HCT) – The fractional volume of whole blood occupied by RBCs, expressed as a percentage. The reference range for HCT in children ages 6 to 12 years old is 35 to 44 percent.

Reference ranges for HGB and HCT vary with age and sex (table 1). The threshold for defining anemia is HGB or HCT at or below the 2.5^th percentile for age and sex based upon reference data from healthy individuals. We recommend using the same HGB and HCT thresholds for evaluating anemia in all racial and ethnic groups (ie, we do not assume that a slightly lower value in a Black individual is "normal"). Historic reports have described lower values for HGB in some ethnic and racial minority populations, but those differences likely reflect health disparities due to social determinants or nonmedical drivers of health. (See "Use of race and ethnicity in medicine", section on 'Race as a proxy for other risk factors'.)

PATIENT CHARACTERISTICS — 

Causes of anemia in children vary based upon age at presentation and sex (table 2).

Age of patient — The patient's age is important to consider because reference values of hemoglobin (HGB) and hematocrit (HCT) vary 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, which reduces erythropoietin production [1,2]. In healthy term infants, HGB levels are high (>14 g/dL) at birth and then rapidly decline, reaching a nadir of approximately 10 to 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 (AOP)".)

●Infants three to six months – Anemia detected at three to six months of age suggests a hemoglobinopathy or other inherited hemolytic anemia. 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 "Diagnosis of thalassemia (adults and children)".)

●Toddlers – In toddlers, acquired causes of anemia are more likely, particularly iron deficiency anemia. Screening for iron deficiency anemia is recommended in all young children at 9 to 12 months of age. At that age, children who are exclusively breastfed or breastfed without sufficient iron supplementation are at highest risk for iron deficiency. In contrast, infants who primarily receive iron-fortified formula during the first year of life are at risk for iron deficiency after transition to cow milk. Therefore, additional laboratory screening should be considered in children with additional risk factors (eg, excessive cow milk intake in toddlers 12 to 36 months of age). Recommendations for screening for iron deficiency are discussed in detail separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Screening recommendations'.)

●School aged children – The prevalence of iron deficiency anemia in school aged children is low, so further investigation for other cause of anemia is generally warranted.

●Adolescents – Onset of menarche and increased growth are risk factors for iron deficiency in the adolescent age group. Athlete's anemia and other causes of anemia should also be assessed based on clinical history. (See "Iron requirements and iron deficiency in adolescents".)

Sex — Some inherited causes of anemia are X-linked (eg, G6PD deficiency and X-linked sideroblastic anemia) and occur most commonly in males. (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'X-linked inheritance' and "Causes and pathophysiology of the sideroblastic anemias", section on 'X-linked sideroblastic anemia (XLSA; ALAS2 gene)'.)

In postmenarchal adolescent females, excessive menstrual bleeding is an important cause of anemia and iron deficiency. In some cases, evaluation for an underlying bleeding disorder may be warranted. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis" and "Approach to the child with bleeding symptoms".)

Ethnicity/ancestry — Ethnic background and ancestry can increase the pretest probability of specific hemoglobinopathies and enzymopathies (eg, G6PD deficiency). As examples:

●HGB S and C are most commonly seen in individuals of African or Hispanic descent, and Middle Eastern populations. (See "Diagnosis of sickle cell disorders" and "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis", section on 'Epidemiology of carrier state and disease'.)

●Thalassemia syndromes are more common in individuals of Mediterranean and Southeast Asian descent. (See "Diagnosis of thalassemia (adults and children)", section on 'Epidemiology'.)

●G6PD deficiency is more common among Sephardic Jewish individuals; Black individuals from sub-Saharan Africa or Brazil; African Americans; and people from Thailand, Sardinia, Greece, South China, and India (areas where malaria was once endemic) (figure 2). (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Epidemiology'.)

EVALUATION

History — The evaluation of a child with anemia begins with a thorough history. Symptoms of anemia, bleeding, jaundice, infection, 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:

•Symptoms attributable to anemia – Common symptoms of anemia can include easy fatiguability, lethargy, tachycardia, and pallor. Infants may present with irritability and poor oral intake. However, 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 (tea- or cola-colored urine), 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 "Glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Clinical manifestations'.)

•Bleeding symptoms – Severe or recurrent epistaxis, heavy menstrual bleeding, gastrointestinal bleeding, or other bleeding symptoms should raise suspicion for an underlying bleeding disorder. Bleeding questionnaires such as the International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH BAT) (table 3) are useful screening tools to help identify patients who are more likely to have an underlying bleeding disorder (ie, those for whom laboratory evaluation may be appropriate). (See "Approach to the child with bleeding symptoms", section on 'Bleeding questionnaires'.)

Severe or recurrent epistaxis may result in anemia from blood loss and iron deficiency, particularly in children with an underlying bleeding disorder. (See "Evaluation of epistaxis in children".)

In postmenarchal adolescent females, menstrual history should be obtained, including duration and amount of bleeding. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'History'.)

It is also important to determine whether there is a family history of bleeding problems (eg, von Willebrand disease, platelet disorders), inflammatory bowel disease, celiac disease, intestinal polyps, colorectal cancer, hereditary hemorrhagic telangiectasia [5]. (See "Approach to the child with bleeding symptoms", section on 'Family history'.)

•Pica – The presence of pica, the intense craving for nonfood items, should be assessed given its strong association with iron deficiency. In young children, pica may manifest as craving dirt, rocks, and/or paper. In adolescents, craving for ice, or pagophagia, may be more common.

●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 (including timing of onset and need for phototherapy) and/or anemia in the newborn period. Results of newborn screening (which typically includes screening for sickle cell disease and thalassemia) should be reviewed. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management" and "Diagnosis of sickle cell disorders", section on 'Newborn screening'.)

•History of anemia – Previous complete blood counts (CBCs), if available, should be reviewed. If the child had previously documented anemia, additional details should be solicited (including duration, etiology, therapy, and resolution). The presence of anemia on prior CBCs suggest an inherited disorder, whereas anemia in a patient with previously documented normal CBC suggests an acquired etiology. Patients with certain hemoglobinopathies (such as HGB E or the various thalassemias) may have a history of treatment on multiple occasions for an erroneous diagnosis of iron deficiency anemia. (See "Diagnosis of thalassemia (adults and children)".)

•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 provides updated information on malaria and tuberculosis). Recent illnesses should be reviewed to investigate for possible infectious etiologies of anemia. Surgical history is important since intestinal resection can result in micronutrient deficiencies [6].

●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 (eg, drugs such as fluoroquinolones, dapsone, nitrofurantoin, and sulfonylureas; foods such as fava beans; and others, as summarized in the table (table 4)). Possible environmental toxin exposure should be explored, including lead exposure and nitrates in well water. (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Inciting drugs, chemicals, foods, illnesses' and "Childhood lead exposures: Exposure and prevention".)

●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 such as hereditary spherocytosis. (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 vitamin B12 content.

For infants and toddlers, 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 milk can develop anemia due to folate deficiency [7-9]. Exclusively breastfed infants who do not receive sufficient iron supplementation may be anemic at the time of the initial screening at age 9 to 12 months, whereas infants receiving iron-fortified formula until age 12 months are unlikely to be anemic at this time, though they may be at risk for iron deficiency during the second year of life after transitioning to cow milk. Pica (particularly pagophagia, the eating of ice) may suggest lead poisoning and/or iron deficiency. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Causes and pathophysiology of vitamin B12 and folate deficiencies" and "Childhood lead poisoning: Clinical manifestations and diagnosis".)

In older children and adolescents, it is important to ask about special dietary practices (eg, vegetarian or vegan diet), junk food intake, and picky or restrictive eating habits. Children with certain neurodevelopmental disorders (eg, autism spectrum disorder) may present with a restricted range of food choices, which may result in nutritional deficiencies [10,11]. Additional details of dietary screening for iron deficiency are provided separately. (See "Iron requirements and iron deficiency in adolescents".)

●Developmental history – Parents/caregivers should be asked questions to determine if the child has reached age-appropriate developmental milestones. Developmental delay can be associated with iron deficiency, lead toxicity, vitamin B12/folic acid deficiency, and Fanconi anemia [12]. (See "Developmental-behavioral surveillance and screening in primary care", section on 'Approach to surveillance'.)

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 5).

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 [13-15].

Patients with hemolytic processes resulting in anemia may present with signs of scleral icterus, jaundice, and splenomegaly 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 [16]. Splenomegaly may be present in individuals with an inherited hemolytic anemia such as hereditary spherocytosis.

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 children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Evaluation for suspected iron deficiency anemia'.)

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 CBC provides information about the RBCs and other cell lines (ie, white blood cells [WBCs] and platelets). All three cell lines should be evaluated for abnormalities.

Hemoglobin and hematocrit — Reference ranges for HGB and hematocrit (HCT) vary with age, so it is important to use age- and sex-adjusted ranges (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 [17-19]. Spurious results may also occur with automated counters in the presence of lipemia, hemolysis, leukocytosis (with WBC counts >50 × 10⁹/L), or high immunoglobulin levels [20].

Red blood cell indices — The RBC 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. Reference values for MCV vary based upon age (infants have increased MCV compared with older children) (table 1). A useful rule of thumb to remember approximate age-appropriate lower reference limits for MCV values is 70 + age in years.

MCV is the most useful RBC parameter when evaluating a patient with anemia and is used to classify the anemia as microcytic (ie, ≤2.5^th percentile), normocytic, or macrocytic (ie, ≥97.5^th percentile), as discussed below. (See 'Microcytic anemia' below and 'Normocytic anemia' below and 'Macrocytic anemia' below.)

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 [21]. (See 'Macrocytic anemia' below and "Macrocytosis/Macrocytic anemia".)

●Red cell distribution width (RDW) – The RDW is a quantitative measure of the variability of RBC sizes in the sample (anisocytosis). Reference values vary little with age and are generally between 12 and 14 percent [17]. The RDW is usually elevated in patients with iron deficiency anemia, and it is the final hematologic parameter to normalize with iron therapy.

●Mean corpuscular hemoglobin concentration (MCHC) – The 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 [22]. MCHC measurements may vary slightly based upon the technology used and should be interpreted using the reference range for the specific laboratory.

The MCHC provides a quantitative assessment of the degree of hypo- or hyperchromia (MCHC ≤32 and ≥35 g/dL, respectively). Hypochromia and hyperchromia usually can be appreciated on the peripheral smear (picture 2 and picture 3) [23].

White blood count and platelet count — The other cell lines may provide clues to the underlying cause of anemia (algorithm 3). Leukocytosis (high total WBC count) most commonly suggests an infectious etiology or, less commonly, an acute leukemia. Hypersegmented neutrophils suggest vitamin B12 deficiency. Thrombocytosis (high platelet count) is a common finding in iron deficiency [24], and it also frequently 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 transient suppression due to viral infection, 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 an autoimmune process (eg, systemic lupus erythematosus, Evans syndrome, autoimmune lymphoproliferative disease)

Reticulocyte count — Reticulocytes are the youngest red cells in the circulation and are identified by the presence of residual RNA (picture 1 and picture 4). When interpreting the reticulocyte count, attention must be paid to the particular reticulocyte parameter reported (percentage versus absolute count). It is often helpful to estimate the corrected reticulocyte count (ie, the reticulocyte count corrected for the degree of anemia).

●Reticulocyte percentage – The reticulocyte is reported as a percentage of the RBC population. After the first few months of life, the reference reticulocyte percentage is the same as that of the adult: approximately 1.5 percent [1].

●Absolute reticulocyte count (ARC) – The ARC is the product of the total RBC count multiplied by the reticulocyte count percentage:

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 reference ranges adjusted for the level of anemia. In a patient with anemia, ARC values within the reference range (<100 × 10⁹/L) generally indicate an inappropriately low erythropoietic response [25].

●Corrected reticulocyte count – Estimating the corrected reticulocyte count can be a useful method to determine whether the bone marrow response to anemia is appropriate. The calculation is based on the measured reticulocyte count, measured hematocrit, and normal hematocrit for the patient's age and sex (normal values for hematocrit are summarized in the table (table 1)):

Corrected reticulocyte count = Measured reticulocyte count [percent] × (measured hematocrit ÷ normal hematocrit for age)

A corrected reticulocyte count <2 percent is inappropriately low in the setting of anemia (excluding acute blood loss anemia).

●Interpretation – The reticulocyte count is an indication of bone marrow erythropoietic activity and is used to classify the bone marrow response to anemia (see 'Reticulocyte response' below):

•Anemia with a high reticulocyte count reflects an appropriate erythropoietic response to hemolysis or blood loss

•Anemia with a low or normal reticulocyte count reflects deficient production of RBCs

Blood smear — A review of the peripheral smear is an essential part of any anemia evaluation. Even if the patient's RBC indices are within reference range, 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 5). This comparison will help the investigator identify the patient with microcytosis (picture 2) or macrocytosis (picture 6).

●Central pallor – The normal mature RBC is a biconcave disc (picture 7). As a result, RBCs on the peripheral smear demonstrate an area of central pallor, which, in normochromic RBCs, is approximately one-third of the diameter of the cell (picture 5). Increased central pallor indicates hypochromic cells, which most often are seen in iron deficiency (picture 2) and thalassemia (picture 8). 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 within reference range, review of the blood smear may reveal the presence of small numbers of fragmented cells, indicating a microangiopathic process (picture 9). (See "Overview of hemolytic anemias in children" and "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Fragmentation'.)

●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 10) (see "Diagnosis of sickle cell disorders")

•Spherocytes (picture 3), as seen in hereditary spherocytosis and acute hemolysis, or elliptocytes, as seen in congenital elliptocytosis (picture 11) (see "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders")

•Stomatocytes, as seen in hereditary or acquired stomatocytosis (picture 12) (see "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)")

•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 postsplenectomy (picture 13 and picture 8) (see "Burr cells, acanthocytes, and target cells: Disorders of red blood cell membrane")

•Bite cells, blister cells (picture 14), and Heinz bodies (picture 15) are seen in hemolytic anemia due to oxidant sensitivity, such as G6PD deficiency (see "Glucose-6-phosphate dehydrogenase (G6PD) deficiency")

•The presence of numerous nucleated RBCs indicates rapid bone marrow turnover and is seen with hemolytic processes (picture 10 and picture 16)

•RBC agglutination (picture 17) is seen in cold agglutinin hemolytic anemia (see "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Cold AIHA')

•Howell-Jolly bodies (picture 18) are associated with absence or hypofunction of the spleen (see "Splenomegaly and other splenic disorders in adults", section on 'Asplenia or hyposplenia')

•Basophilic stippling (picture 19) 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 20), or the presence of atypical lymphocytes (picture 21) suggest 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 22) suggest vitamin B12 or folate deficiency

●The presence of early WBC forms (eg, blasts) (picture 23) along with anemia should raise the suspicion of leukemia or lymphoma (see "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children")

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 isolated anemia or if other cell lines (ie, white blood cells [WBCs] and platelets) are also abnormal (algorithm 3):

●Pancytopenia – Causes of pancytopenia in children include infection, myelosuppressive medications, leukemia, aplastic anemia, and hypersplenism. Severe pancytopenias should prompt urgent hematologic evaluation. (See "Acquired aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Approach to the child with an enlarged spleen".)

●Anemia with thrombocytopenia – Causes of anemia associated with low platelet count include hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and Evans syndrome. Rarely, children with severe iron deficiency anemia may also have thrombocytopenia. (See "Overview of hemolytic uremic syndrome in children" and "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)" and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Evans syndrome'.)

●Anemia with thrombocytosis – Iron deficiency anemia is commonly associated with thrombocytosis but can also be associated with thrombocytopenia [24]. Other causes of anemia associated with elevated platelet count include postsplenectomy anemia and infection or inflammation. (See "Iron deficiency in infants and children <12 years: 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 clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

Classification of anemia — There are various approaches to classifying anemia. The approach described in the following sections is based upon red blood cell (RBC) size (ie, mean corpuscular volume [MCV]) and the reticulocyte response. This approach is useful for narrowing the diagnostic possibilities (algorithm 2).

An alternative approach is to classify the causes of anemia according to the mechanism (decreased RBC production, increased RBC breakdown [hemolysis], or acute blood loss). (See "Overview of causes of anemia in children due to decreased red blood cell production" and "Overview of hemolytic anemias in children".)

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

The most common causes of microcytic anemia in children are iron deficiency and thalassemia (algorithm 2) [20,26]. Long-standing inflammation can also result in a microcytic anemia due to iron-restricted erythropoiesis.

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 within reference range in patients with thalassemia (though elevated RDW can occur). (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Diagnosis of thalassemia (adults and children)".)

Normocytic anemia — Normocytic anemia is defined as anemia with an MCV within reference range (ie, between the 2.5^th and 97.5^th percentile for age and sex (table 1)). (See 'Red blood cell indices' above.)

Common causes of normocytic anemia include hemolytic anemias, blood loss, infection, medication, and anemia of chronic disease. Other causes of normocytic anemia include hypothyroidism and chronic kidney disease. Transient erythroblastopenia of childhood is an acquired red cell aplasia that typically presents with a progressive normocytic anemia in otherwise healthy children and is a diagnosis of exclusion. (See "Overview of hemolytic anemias in children" and "Anemia of chronic disease/anemia of inflammation" and "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood'.)

Macrocytic anemia — Macrocytic anemia (picture 6) is defined as anemia with a high MCV (ie, ≥97.5^th percentile for age and sex (table 1)). (See 'Red blood cell indices' above.)

The most common cause of macrocytosis in children is exposure to certain medications (eg, anticonvulsants, zidovudine, and immunosuppressive agents) [26,27]. Other causes include vitamin B12 or folate deficiency, liver disease, Diamond-Blackfan anemia, hypothyroidism, and aplastic anemia (algorithm 2). Isolated macrocytosis is also commonly seen in children with Down syndrome [28].

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 6). 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). (See "Overview of causes of anemia in children due to decreased red blood cell production".)

These two categories are not mutually exclusive, however. Hemolysis can be associated with a low reticulocyte count if there is a concurrent disorder that impairs RBC production (eg, infection). Similarly, anemia due to acute blood loss can be associated with low reticulocyte count if there has not been time for the bone marrow to mount an appropriate reticulocyte response, which typically takes approximately one week.

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 TEC 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 "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood'.)

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 direct antiglobulin test, 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 (HGB) analysis/electrophoresis. The diagnostic approach is discussed separately. (See "Overview of hemolytic anemias in children", section on 'Diagnostic approach'.)

If iron deficiency is suspected, additional studies may include iron parameters (eg, serum ferritin). 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 children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Empiric trial of iron therapy'.)

Testing for other nutritional deficiencies and/or lead poisoning may include serum folate, vitamin 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 AND RECOMMENDATIONS

●Definition of anemia – The threshold for defining anemia is a hemoglobin (HGB) or hematocrit (HCT) that is ≤2.5^th percentile for age and sex (table 1). HGB levels are high (>14 g/dL) at birth and then rapidly decline, reaching a nadir of approximately 10 to 11 g/dL at six to nine weeks of age, which is called "physiologic anemia of infancy" (figure 1). (See 'Definition of anemia' above.)

●Common causes by age – The causes of anemia vary based upon the age at presentation (see 'Age of patient' above):

•In neonates and young infants, alloimmune hemolytic disease, infection, and hereditary disorders are most common (algorithm 1). (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management" and "Overview of hemolytic anemias in children", section on 'Intrinsic hemolytic anemias'.)

•In toddlers and postmenarchal adolescents, acquired causes of anemia are more likely, particularly iron deficiency anemia (dietary or due to blood loss). (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron requirements and iron deficiency in adolescents".)

●History and physical examination

•Key historical factors in the assessment of a child with anemia include the severity and onset of symptoms, diet, evidence of jaundice, bleeding symptoms (eg, epistaxis, gastrointestinal bleeding, heavy menstrual bleeding), 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 5). (See 'Physical examination' above.)

●Laboratory evaluation

•The laboratory evaluation begins with a complete blood count (CBC), 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. (See 'Blood smear' above.)

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

●Classification by red cell volume – 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, MCV within reference range) anemia include hemolytic anemias, blood loss, infection, medication, and anemia of chronic disease

•Common causes of macrocytic (ie, high MCV) anemia include medications (eg, antiseizure medications) and deficiency of vitamin B12 or folate (see 'Classification of anemia' above)

●Reticulocyte response – 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.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Claudio Sandoval, MD, who contributed to earlier versions of this topic review.