Anemia can lead to many detrimental outcomes for pediatric patients. Children can become acutely symptomatic with fatigue, headaches, pica, and bruising but they can also be afflicted with neurocognitive detriments that are much longer lasting. The most common cause of anemia in the pediatric population is iron deficiency. Because this is a condition that clinicians see routinely, it can be easy to jump to the obvious diagnosis and treatment without putting much more thought into it. Although this leads to appropriate care in many cases, keeping the broad differential in mind when faced with anemia is important. Good screening and treatment options for many types of anemia are also lacking so continued investigation will improve patient quality of care and enhance outcomes. This article focuses on the most common cause of anemia—iron deficiency—as well as briefly reviews other causes that are important to consider.
Classification of Anemia
The different types of anemia can be classified in many ways. These classifications can be helpful in determining the cause of the anemia and help to guide treatment.
One common way to look at anemia is based on the size of the red blood cells. This divides anemia into three categories: microcytic, normocytic, and macrocytic (Figure 1). In general, microcytic anemia includes iron deficiency,1,2 lead toxicity,1 and thalassemia.2 Normocytic anemia includes chronic disease, hemolytic anemia, and acute blood loss.2 Macrocytic anemia includes B12 and folate deficiencies, hypothyroidism, and liver disease.2
Classification of anemia by cell size.
Another way to categorize anemia is to consider common causes by age group. From birth to age 3 months, physiologic anemia, immune hemolytic disease, infection, and congenital hemolytic anemia are the most common causes.2 From age 3 to 6 months, the most common cause is hemoglobinopathies2 and after age 6 months, iron deficiency is the leading cause of anemia.2
Finally, anemia can be considered in relation to the lifecycle of the red blood cell. Anemia can be caused by decreased bone marrow production of cells, increased destruction of red blood cells peripherally, or loss of cell volume acutely through hemorrhage.1
Types of Anemia
Iron Deficiency Anemia
Iron deficiency is the most common mineral deficiency in the US and worldwide4,5,8,9 and is also the leading cause of anemia.1 Lack of sufficient iron stores leads to a failure of hemoglobin production and anemia.1 Incidence peaks in the early toddler years and again in teenage girls after the onset of menstruation.1
There are several risk factors for developing iron deficiency anemia in children. Among these are prematurity, exclusive breast-feeding without regular intake of iron-fortified foods after age 6 months,8,10 introduction of cow's milk prior to age 1 year, low socioeconomic status, bottle-feeding older than age 1 year, weight/height greater than the 95th percentile, and dietary restrictions (ie, vegetarian).8 These factors become important when deciding who and when to screen.
It is essential to identify and to treat iron deficiency because of the number of potential side effects. Even if the iron deficiency is not enough to cause anemia, the affects can still be detrimental. Symptoms may include neurodevelopmental and behavioral delays, poor performance on cognitive tests,7 irritability, malaise, pica,6,11 poor school performance, mood lability, and concentration difficulties.7 Concentration and some physical affects have been shown to improve with iron supplementation,7 although neurocognitive delays and exercise intolerance can persist even after restoration of iron stores.10
Currently, there is no consensus on screening recommendations and many groups have weighed in with different approaches. The American Academy of Pediatrics (AAP) recommends screening at age 12 months for everyone and selective screening after that for those in high-risk groups.4,5,8 The Centers for Disease Control and Prevention recommends screening at age 9 to 12 months and again 6 months later for all children and yearly from age 2 to 5 years in those who are high-risk.8 The Institute of Medicine recommends screening at age 9 months for babies who are breast-fed or babies who are not drinking iron-fortified formula, and at age 3 months in premature babies not drinking iron-fortified formula.8 Finally, the US Preventative Service Task Force and the American Academy of Family Physicians concluded that studies are lacking to make a recommendation.5,8 So, as we can see, there is a wide range of recommendations, making it difficult to standardize practices. The lack of consensus emphasizes the need for more studies to determine the best screening tools and timing of the screen to minimize poor outcomes.
There are pros and cons to screening that must also be considered when choosing which recommendation to follow. By screening, we diagnose many children who are iron deficient, allowing for early treatment and minimizing symptoms and harmful outcomes. However, our screening tool of hemoglobin is nonspecific for iron deficiency8 and is a late-stage indicator of deficiency, meaning the damage may already be done.1,3
The treatment of iron deficiency is supplementation with iron to replete the body's stores. Patients who present with mild iron deficiency anemia (or iron deficiency without anemia) should try to increase their dietary intake of iron. It is important to note that non-heme iron from vegetables, fruits, and fortified foods is not as well absorbed as heme iron from meat.7 For more significant iron depletion, medication is often needed in addition to dietary changes. Studies have shown that oral ferrous sulfate, despite its poor taste and subsequent poor adherence, results in greater increases in hemoglobin concentrations than its popular counterpart, iron polysaccharide complexes, which have a better taste and thus better adherence.11,12 Oral iron should be continued for 2 months after normalization of hemoglobin to build up the body's stores.1
Food and medication can affect iron absorption, which is important to consider when counseling patients. For instance, antacids, proton pump inhibitors, and H2 blockers inhibit the uptake of iron, and citrus can increase absorption.6 Finally, intravenous (IV) iron is an option for those with severe iron deficiency.
Prevention is also important and there are several tactics that can help improve iron stores in children. Studies have shown that delayed cord clamping can improve iron status from age 2 to 6 months, setting infants up for better outcomes as they age.5,13 Introducing iron-fortified supplements in the form of cereal, formula, or oral iron can also help. The AAP recommends that exclusively breast-fed babies be supplemented beginning at age 4 months. This same recommendation is made for babies receiving greater than one-half of their feeding as breast milk and who are not receiving iron-fortified foods.4 Encouraging iron-rich diets and screening for risk factors will help identify those children at higher risk and promote early intervention with the hopes of preventing iron deficiency anemia.
Lead toxicity causes anemia by destroying red blood cells by blocking the uptake of iron and interfering with heme synthesis.14 Anemia caused by lead toxicity is diagnosed by elevated lead levels and the presence of basophilic stippling on microscopy.1 It is caused primarily by ingestion of lead from the environment. The most common culprits are lead paint in older homes and buildings, as well as some toys and contaminated water.1,14 The most common physical complaints from lead toxicity are abdominal pain and vomiting, malaise, constipation, and encephalopathy,1 depending on the severity of the intoxication. Lead toxicity is treated by removal of the offending source and perhaps chelation if needed.
Sickle Cell Disease
Sickle cell disease is an inherited autosomal recessive condition caused by an amino acid substitution of valine for glutamic acid in the hemoglobin molecule, leading to instability that causes sickling of the red blood cells.1 These cells then lose function, lyse, and subsequently cause anemia. Sickle cell disease is found primarily in the African American population in the US with about 8% being carriers and 0.2% with the disease.3,15
The profile of symptoms is quite diverse for those afflicted. Carriers are largely asymptomatic.1 Some people have a mild form of the disease and do not require much intervention, whereas others suffer greatly. The most common symptoms include splenic dysfunction and eventual auto-infarction of the spleen, infection, pain crises due to tissue infarction, ischemic injury (stroke is seen in up to 10%), dactylitis, priapism, and acute chest syndrome.1,3,15
Patients with sickle cell disease should be immunized fully to protect them from infection, including a 23-valent-pneumococcal vaccine.1 In addition, for patients presenting with fever, providers should obtain a blood culture and empirically treat with intramuscular or IV antibiotics.15 Infants up to age 1 year should also be given prophylactic antibiotics to prevent serious infection.15 Preventive care is also important and teaching patients to stay well hydrated, get sufficient sleep, control stress, and minimize exposure to infection can improve outcomes. Some patients require chronic blood transfusions to maintain enough normal cells in their body to prevent ischemic events.15 Frequent hospitalization is not rare. More recently, the use of stem cell transplant to help and even cure these patients is being studied.16
Thalassemia is another inherited disease that disrupts the structure of hemoglobin, leading to anemia. Hemoglobin is made of 2-alpha and 2-beta chains. The alpha chains rely on four genes and the beta chains rely on two genes. Mutations of these genes lead to the different types of thalassemia.3 Thalassemia is one of the most common genetic disorders worldwide,17 with about 5% of the global population carrying at least one gene mutation.17 It is seen most commonly in people of Mediterranean and Southeast Asian descent.2
Alpha-thalassemia has four different types. A 1-gene mutation presents as a silent carrier and mutation of two genes tends to result in a mild microcytic anemia.5,17 These two types do not require intervention. Mutation of three genes is known as hemoglobin H disease or Bart syndrome and results in chronic hemolysis and often the need for transfusion.5,17 Mutations of all 4-alpha chain genes is not compatible with life.5,17
Beta-thalassemia has three different types. Mutation of one gene leads to mild anemia. Mutation of two genes can be minor with a milder anemia and slightly increased risk for heart failure or major with irritability, failure to thrive, hepatosplenomegaly, and the need for chronic transfusions17 (Table 1).
Hereditary spherocytosis (HS) is an autosomal dominant disease, although about 25% of cases are sporadic mutations.17 It is seen primarily in the white population and should be considered in infants with early onset of jaundice.1 It is a membrane defect due to a spectrin deficiency.1 Without spectrin, the red blood cells take on a spherical shape and do not function properly. Patients with HS often present with anemia, reticulocytosis, jaundice, and splenomegaly.17 It is diagnosed by doing an osmotic fragility test or an eosin-5-maleimide flow cytometry test.1,17 Patients are often asymptomatic but more severe disease does exist and may require folate supplementation, cholecystectomy, or even chronic transfusions.17 Infections and sometimes medication can trigger a hemolytic crisis.
G6PD is an X-linked disorder that is prevalent in about 400 million people globally,17 making it the most common enzymopathy in the world.17 Deficiency of this enzyme leads to lysis of cells and a subsequent anemia. G6PD is found in 10% to 14% of African American males in the US,3 and is the leading cause of jaundice in all newborn males.17 Beyond the period of infancy, however, it is a largely asymptomatic disease.17 There are a few things that are known to send people into acute hemolysis, including certain medications, fava beans, and sometimes illness.17 Testing for G6PD can be difficult because enzyme levels may be normal right after a hemolytic episode. During hemolysis, many of the deficient cells are lysed and the normal cells remain, leading to a false negative test.3 This is an important consideration when timing the testing for G6PD.
Megaloblastic anemia is caused by a deficiency in vitamin B12 or folate and leads to a macrocytic anemia. It is uncommon in children but can occur. Low vitamin B12 and folate can be related to nutrition or absorption abnormalities and can lead to neurologic problems such as seizures.5 Both can be diagnosed by observing neutrophils with hypersegmented nuclei under the microscope.1 Treatment is through supplementation via diet or medication.
There are many other causes of anemia in childhood that may be considered as well. Some of these include infections such as parvovirus, Epstein-Barr virus, cytomegalovirus, human herpesvirus-6, and HIV and transient erythroblastopenia of childhood, which is a self-limited red cell aplasia that occurs after an illness in young children.1,3 Chronic illness, kidney disease, and many other genetic conditions may also present with anemia. If diagnostic tests and treatment do not yield the expected results, these should be kept in mind.
Anemia is a widespread problem in the pediatric population, both in the US and globally. Although iron deficiency anemia is the most common cause of anemia in pediatric practice, it is important not to forget the other causes. This is particularly important in patients who do not respond appropriately to empiric iron repletion or who possess risk factors for other types of anemia.
Screening for anemia in the pediatric population is important, as the consequences of anemia can be significant and long lasting. Unfortunately, the current screening tools are problematic so recommendations for screening are variable. Because anemia is such a problem in the pediatric patient population, continued efforts to improve its diagnosis and management and work toward a more cohesive message are necessary.
It is also important to note that although “common things are common” and it is reasonable to assume a diagnosis of iron deficiency with a positive screen and associated risk factors, it is equally important that appropriate follow up is in place to evaluate treatment response and determine if further investigation into the cause of anemia is warranted. In one study, of 14% of children who had a positive anemia screen, only 18.3% had follow-up testing done and only 11% had documented correction of their hemoglobin.4 Without follow up, we are likely to miss the nonresponders and the opportunity to investigate and treat the true cause of their anemia.
In patients who do not fit into the category of iron deficiency, other causes of anemia should be evaluated. These causes could include mineral toxicities, hemoglobinopathies, membrane defects, enzyme deficiencies, and vitamin deficiencies. By pushing ourselves to investigate further, we will improve care and outcomes for our patients.
Finally, as important as the diagnosis and treatment of anemia is, we must also educate our patients on prevention. Ensuring that caregivers of young children are aware of iron needs and sources could have a large effect on preventing iron deficiency. For those patients with hemoglobinopathies or enzyme deficits, knowing common triggers and supportive measures they can take may prevent hemolytic crises. By empowering our patients with knowledge, we can avoid poor outcomes and improve the overall health of children in the US (Table 2).