Blood and endocrine system diseases in children . Lesson 6. Topic:
Anemias in children
Anemia refers to a reduction in the number of red blood cells in the body. Red blood cells are responsible for carrying oxygen to the brain and to all the other organs and tissues in the body. New blood cells are produced in the bone marrow (the soft, spongy tissue inside bones) and then migrate to the bloodstream where they survive for about 120 days.
What causes it?
Anemia occurs for different reasons:
· inadequate production of red blood cells by the bone marrow
· increased destruction of red blood cells (RBCs)
· increased blood loss from the body
·
Anemia Caused by Inadequate RBC Production
Infants are born with high levels of hemoglobin and RBCs in their blood. After birth, the baby’s hemoglobin level normally drops to a low point at about 2 months of age, a condition known as physiologic anemia of infancy. After this occurs, the infant’s body gets the signal to increase RBC production. This temporary and expected drop in the blood count (called physiological anemia of the newborn) is considered normal and no treatment is needed.
Anemia also occurs when the body isn’t able to produce enough healthy red blood cells. This can happen because of a deficiency of iron or certain other substances in the body or from inherited defects or diseases that interfere with the production of red blood cells.
Iron is essential for the production of hemoglobin in red blood cells. Poor dietary iron intake (or excessive loss of iron from the body) leads to iron-deficiency anemia, the most common cause of anemia in children. Iron-deficiency anemia can affect children at any age, but it is most commonly seen in children under 2 years of age, and in teens, particularly in adolescent girls who have started menstruating.
Anemia can also be caused by deficiency in the nutrients folic acid and vitamin B12, both of which are necessary for normal blood production. Children will develop megaloblastic anemia if one or both of these substances is deficient. People who eat little or no meat, vegetarians or vegans, may not have enough vitamin B12 in their diets. A folate deficiency can develop from eating too few folate-containing foods such as vegetables or infants drinking only goat’s milk. Some intestinal diseases such as celiac disease (gluten-sensitive enteropathy) can result in deficiencies of both Vitamin B12 and folate. These forms of anemia are rarely found in babies and young children.
Aplastic anemia occurs when the bone marrow is unable to produce sufficient numbers of blood cells because of a problem with the primitive cells in the bone marrow called stem cells. Some aplastic anemias affecting only red blood cells (red cell aplasia) may be inherited, such as Diamond-Blackfan and Fanconis anemia, and causes other physical abnormalities.
More often, aplastic anem ia is caused by a virus infection or exposure to certain toxic chemicals, radiation, or medications, such as antibiotics, antiseizure medications, or cancer medications. Some childhood cancers can cause anemia of this type, such as with certain types of leukemia in which abnormal cells crowd out the bone marrow cells needed to produce blood cells. In patients who have hemolytic disorders (e.g. sickle cell disease, thalassemia major), infections with a virus called Parvovirus B19 can cause severe anemia because virtually no production of erythrocytes occurs to compensate for hemolysis. This is known as an aplastic crisis. Healthy children can also develop a mild anemia for about one month following viral infections.
Another less common form of anemia resulting in absence of red cell precursors in the bone marrow is transient erythroblastopenia of childhood (TEC). This is a slowly developing anemia of early childhood (usually 18-26 months old) characterized by gradual onset of pallor. As the name suggests, all patients with TEC recover completely without any treatment and with no sequelae. The cause is unknown, although researchers have proposed a number of viral and immunologic mechanisms.
Chronic diseases of other organs can result in anemia. For example, in advanced kidney disease, hypothroidism, Addison’s disease (deficiency of the adrenal gland), and pituitary gland diseases, the body does not produce adequate hormones necessary for red blood cell production. Lead poisoning can also cause anemia by interfering with the production of heme, the iron containing portion of the hemoglobin molecule.
Anemia Caused by Destruction of Red Blood Cells (Hemolytic Anemia)
Hemolytic anemia occurs when red blood cells are being destroyed prematurely and the bone marrow can’t keep up with the body’s demand for new cells. This can happen for a variety of reasons. It may occur spontaneously or can be triggered by stressors such as infections, drugs, snake or spider venom, or certain foods. Toxins from advanced liver or kidney disease can also shorten the life of red blood cells. In a condition known as autoimmune hemolytic anemia, the immune system mistakes red blood cells for foreign invaders and begins destroying them. This can occur in the newborn period when a pregnant woman’s immune system targets her baby’s red blood cells, if those cells are different than the mother�s such as in Rh or ABO incompatibility. The baby develops a specific type of anemia called hemolytic disease of the newborn. Other children inherit defects in the red blood cells, which may involve the RBC’s structure or the production of hemoglobin. Common forms of inherited hemolytic anemia include sickle cell anemia, thalassemia, and glucose-6-phosphate dehydrogenase deficiency. Vascular grafts, prosthetic heart valves, tumors, severe burns, chemical exposure, severe hypertension (high blood pressure), and clotting disorders can all damage normal red blood cells and mark them for early destruction. In rare cases, an enlarged spleen can trap red blood cells and destroy them before their circulating time is up.
Anemia Caused by Blood Loss
Blood loss can also cause anemia, whether it’s because of excessive bleeding due to injury, surgery, intestinal bleeding, heavy menstrual periods or a problem with the blood’s clotting mechanism. Any of these factors will also increase the body’s need for iron because iron is needed to make new red blood cells.
Anemia is defined as a reduction of the red blood cell (RBC) volume or hemoglobin concentration below the range of values occurring in healthy persons. Table 453-1 lists the means and ranges for hemoglobin and hematocrit values by age groups of well-nourished children. There may be racial differences in hemoglobin levels. Black children have levels about 0.5 g/dL lower than those of white and Asian children of comparable age and socioeconomic status, possibly in part because of the high incidence of alpha thalassemia in blacks. Alternatively, higher levels of RBC 2,3-diphosphoglycerate (2,3-DPG) have been found in black children, which would permit better oxygen delivery and a lower hemoglobin.
Although a reduction in the amount of circulating hemoglobin deceases the oxygen-carrying capacity of the blood, few clinical disturbances occur until the hemoglobin level falls below 7-8 g/dL. Below this level, pallor becomes evident in the skin and mucous membranes. Physiologic adjustments to anemia include increased cardiac output, increased oxygen extraction (increased arteriovenous oxygen difference), and a shunting of blood flow toward vital organs and tissues. In addition, the concentration of 2,3-DPG increases within the RBC. The resultant “shift to the right” of the oxygen dissociation curve, reducing the affinity of hemoglobin for oxygen, results in more complete transfer of oxygen to the tissues. The same shift may also occur at high altitude. When moderately severe anemia develops slowly, surprisingly few symptoms or objective findings may be evident, but weakness, tachypnea, shortness of breath on exertion, tachycardia, cardiac dilatation, and congestive heart failure ultimately result from increasingly severe anemia, regardless of its cause.
Table 453-1. Hematologic values during infancy and childhood.
|
Age |
Hemoglobin (g/dL) |
Hematocrit (% ) |
Reticulocytes (% ) |
MCV (fL) |
Leukocytes (WBC/mm3 ) |
Neutrophils (% ) |
Lymphocytes (% ) |
Eosinophils (% ) |
Monocytes (% ) |
||||
|
|
Mean |
Range |
Mean |
Range |
Mean |
Lowest |
Mean |
Range |
Mean |
Range |
Mean* |
Mean |
Mean |
|
Cord blood |
16.8 |
13.7-20.1 |
55 |
45-65 |
5.0 |
110 |
18,000 |
(9,000-30,000) |
61 |
(40-80) |
31 |
2 |
6 |
|
2 wk |
16.5 |
13.0-20.0 |
50 |
42-66 |
1.0 |
|
12,000 |
(5,000-21,000) |
40 |
|
63 |
3 |
9 |
|
3mo |
16.5 |
9.5-14.5 |
36 |
31-41 |
1.0 |
|
12,000 |
(6,000-18,000) |
30 |
|
48 |
2 |
5 |
|
6 mo-6 yr |
12.0 |
10.5-14.0 |
37 |
33-42 |
1.0 |
70-74 |
10,000 |
(6,000-15,000) |
45 |
|
48 |
2 |
5 |
|
7-12 yr |
13.0 |
11.0-16.0 |
38 |
34-40 |
1.0 |
76-80 |
8,000 |
(4,500-13,500) |
55 |
|
38 |
2 |
5 |
|
Adult |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Female |
14 |
12.0-16.0 |
42 |
37-47 |
1.6 |
80 |
7,500 |
(5,000-10,000) |
55 |
(35-70) |
35 |
3 |
7 |
|
Male |
16 |
14.0-18.0 |
47 |
42-52 |
|
80 |
|
|
|
|
|
|
|
fL = femtoliters; MCV = mean corpuscular volume; WBC = white blood cells.
Anemia is not a specific entity but results from many underlying pathologic processes. A useful classification of the anemias of childhood divides them into three groups by the RBC mean corpuscular volume (MCV): microcytic, macrocytic, or normocytic. RBC size changes with age, and before an anemia can be specifically characterized with respect to RBC size, normal developmental changes in the MCV should be understood (see Table 453-1) . Table 453-2 classifies the important anemias of childhood by the MCV. Anemias in childhood may also be classified by variations in cell size, as reflected by alterations in the RBC distribution width (RDW). The RDW, as determined by the use of electronic cell counting, is the coefficient of variation of RBC size (standard deviation of the MCV ÷ mean MCV × 100). Knowledge of both the MCV and the RDW can be helpful in the initial classification of anemias of childhood (Table 453-3) . In every case of significant anemia, it is essential to review the appearance of RBCs on a peripheral blood smear (Fig. 453-1) . Specific morphologic features may point to the underlying diagnosis. In addition, the presence of polychromatophilia, which correlates roughly with the degree of reticulocytosis, indicates that the marrow is able to respond to RBC loss or destruction.
When oxygen delivery by red blood cells (RBCs) to tissues is decreased, various mechanisms, including expanded cardiac output, increased production of 2,3-diphosphoglycerate (2,3-DPG) in RBCs, and higher levels of erythropoietin (EPO) help the body to modify the deficiency. RBC production by the bone marrow in response to EPO may expand severalfold and may compensate for mild to moderate reductions in RBC life span. In various anemias, the bone marrow loses its usual capacity for sustained production and expansion of the RBC mass. In these instances, absolute reticulocyte numbers in the peripheral blood are decreased. If the normal reticulocyte percentage of total RBCs during most of childhood is about 1.0% and the expected RBC count is approximately 4.0×106 /mm3 , then the normal absolute reticulocyte number should be about 40,000/mm3 . In the presence of anemia, EPO production and the absolute number of reticulocytes should rise. A normal or low absolute number or percentage of reticulocytes in response to anemia indicates relative bone marrow failure or ineffective erythropoiesis (e.g., megaloblastic anemia, thalassemia). Measurement of the serum transferrin receptor (TfR) level or examination of the bone marrow distinguishes between these possibilities, because TfR is elevated in ineffective erythropoiesis (or in iron deficiency) and is decreased in marrow RBC hypoproliferation.
Table 453-2. Classification of Anemiax.
|
Microcytic |
|
Iron deficiency Thalassemias Lead poisoning Chronic disease Infection Cancer Inflammation Renal disease Vitamin B6 responsive Copper deficiency Sideroblastic (some) |
|
Normocytic |
|
Decreased production Aplastic anemia Congenital Acquired Pure RBC aplasia Congenital (Diamond-Blackfan) Acquired (transient erythroblastopenia) Bone marrow replacement Leukemia Tumors Storage diseases Osteopetrosis Myelofibrosis Blood loss Internal or external Sequestration |
|
Hemolysis: Intrinsic RBC abnormalities Hemoglobinopathies Enzymopathies Membrane disorders Hereditary spherocytosis Acquired: paroxysmal nocturnal hemoglobinuria |
|
Hemolysis: Extrinsic RBC abnormalities Immunologic Passive (hemolytic disease of the newborn) Active: Autoimmune Toxins Infections Microangiopathic Disseminated intravascular coagulation (DIC) |
|
Hemolytic uremic syndrome Hypertension Cardiac disease |
|
Macrocytic |
|
Normal newborn (spurious) Reticulocytosis (spurious) Vitamin B12 deficiency Folate deficiency Oroticaciduria Myelodysplasia Liver disease Hypothyroidism (some) Vitamin B6 deficiency (some) Thiamine deficiency |
|
RBC = red blood cell. |
|
Microcytic Homogeneous (MCV low, RDW normal) |
Microcytic Heterogeneous (MCV low, RDW high) |
Normocytic Homogeneous (MCV normal, RDW normal) |
Normocytic Heterogeneous (MCV normal, RDW high) |
Macrocytic Homogeneous (MCV high, RDW normal) |
Macrocytic Heterogeneous (MCV high, RDW high) |
|
Heterozygous thalassemia |
Iron deficiency |
|
Mixed deficiency |
Aplastic anemia |
Folate deficiency |
|
Chronic disease |
Hb S-beta-thalassemia; hemoglobin H; red cell fragmentation |
Chronic disease, chronic liver disease; nonanemic hemoglobinopathy (e.g., AS, AC); transfusion; chemotherapy; chronic myelocytic leukemia; hemorrhage; hereditary spherocytosis |
Early iron deficiency anemia; anemic hemoglobinopathy (e.g., SS, SC); myelofibrosis; sideroblastic |
Preleukemia |
Vitamin B12 deficiency; immune hemolytic anemia; cold agglutinin; high count |
MCV = mean corpuscular volume; RDW = red blood cell distribution width; AS = sickle cell trait, AC = hemoglobin C trait; SS = sickle cell anemia; SC = hemoglobin SC disease.
Iron-deficiency anemia
Anemia resulting from lack of sufficient iron for synthesis of hemoglobin is the most common hematologic disease of infancy and childhood. Its frequency is related to certain basic aspects of iron metabolism and nutrition. The body of a newborn infant contains about 0.5g of iron, whereas the adult content is estimated at 5g. To make up for this discrepancy, an average of 0.8mg of iron must be absorbed each day during the first 15yr of life. In addition to this growth requirement, a small amount is necessary to balance normal losses of iron by shedding of cells. Accordingly, to maintain positive iron balance in childhood, about 1mg of iron must be absorbed each day.
Iron is absorbed in the proximal small intestine, mediated in part by duodenal proteins (HFE, hephaestin, Nramp2 , and mobilferrin). Because absorption of dietary iron is assumed to be about 10%, a diet containing 8-10mg of iron daily is necessary for optimal nutrition. Iron is absorbed two to three times more efficiently from human milk than from cow’s milk, perhaps partly because of differences in calcium content. Breast-fed infants may, therefore, require less iron from other foods. During the first years of life, because relatively small quantities of iron-rich foods are eaten, it is often difficult to attain sufficient iron. For this reason, the diet should include such foods as infant cereals or formulas that have been fortified with iron; both of these are very effective in preventing iron deficiency. Formulas with 7-12mg Fe/L for full-term infants and premature infant formulas with 15mg/L for infants less than 1,800g at birth are effective. Infants breast-fed exclusively should receive iron supplementation from 4mo of age. At best, an infant is in a precarious situation with respect to iron. Should the diet become inadequate or external blood loss occur, anemia ensues rapidly.
Adolescents are also susceptible to iron deficiency because of high requirements due to the growth spurt, dietary deficiencies, and menstrual blood loss. In the
ETIOLOGY.
Low birthweight and unusual perinatal hemorrhage are associated with decreases ieonatal hemoglobin mass and stores of iron. As the high hemoglobin concentration of the newborn falls during the first 2-3mo of life, considerable iron is reclaimed and stored. These reclaimed stores are usually sufficient for blood formation in the first 6-9mo of life in term infants. In low birthweight infants or those with perinatal blood loss, stored iron may be depleted earlier, and dietary sources become of paramount importance. Anemia caused solely by inadequate dietary iron is unusual before 4-6mo but becomes common at 9-24mo of age. Thereafter, it is relatively infrequent. The usual dietary pattern observed in infants with iron deficiency anemia is consumption of large amounts of cow’s milk and of foods not supplemented with iron.
Blood loss must be considered a possible cause in every case of iron deficiency anemia, particularly in older children. Chronic iron deficiency anemia from occult bleeding may be caused by a lesion of the gastrointestinal (GI) tract, such as a peptic ulcer, Meckel’s diverticulum, a polyp, or hemangioma, or by inflammatory bowel disease. In some geographic areas, hookworm infestation is an important cause of iron deficiency. Pulmonary hemosiderosis may be associated with unrecognized bleeding in the lungs and recurrent iron deficiency after treatment with iron. Chronic diarrhea in early childhood may be associated with considerable unrecognized blood loss. Some infants with severe iron deficiency in the
Histologic abnormalities of the mucosa of the GI tract, such as blunting of the villi, are present in advanced iron deficiency anemia and may cause leakage of blood and decreased absorption of iron, further compounding the problem.
Intense exercise conditioning, as occurs in competitive athletics in high school, may result in iron depletion in girls; this occurs less commonly in boys.
CLINICAL MANIFESTATIONS.
Pallor is the most important clue to iron deficiency. Blue scleras are also common, although also found iormal infants. In mild to moderate iron deficiency (hemoglobin levels of 6-10g/dL), compensatory mechanisms, including increased levels of 2,3-diphosphoglycerate (2,3-DPG) and a shift of the oxygen dissociation curve, may be so effective that few symptoms of anemia are noted, although affected children may be irritable. Pagophagia, the desire to ingest unusual substances such as ice or dirt, may be present. In some children, ingestion of lead-containing substances may lead to concomitant plumbism. When the hemoglobin level falls below 5g/dL, irritability and anorexia are prominent. Tachycardia and cardiac dilation occur, and systolic murmurs are often present.
The spleen is enlarged to palpation in 10-15% of patients. In long-standing cases, widening of the diploe of the skull similar to that in congenital hemolytic anemias may occur. These changes resolve slowly with adequate replacement therapy. Children with iron deficiency anemia may be obese or may be underweight, with other evidence of poor nutrition. The irritability and anorexia characteristic of advanced cases may reflect deficiency in tissue iron, because with iron therapy striking improvement in behavior frequently occurs before significant hematologic improvement.
Iron deficiency may have effects oeurologic and intellectual function. A number of reports suggest that iron deficiency anemia, and even iron deficiency without significant anemia, affects attention span, alertness, and learning of both infants and adolescents. In a controlled trial, adolescent girls with serum ferritin levels of 12 ng/L or less but without anemia improved verbal learning and memory after taking iron for 8wk.
Monoamine oxidase (MAO), an iron-dependent enzyme, has a crucial role ieurochemical reactions in the central nervous system. Iron deficiency produces decreases in the activities of enzymes such as catalase and cytochromes. Catalase and peroxidase contain iron, but their biologic essentiality is not well established. Iron deficiency causes rigidity of red blood cells (RBCs) and may be associated with stroke in young children. Administration of iron may decrease the frequency of breath-holding spells, suggesting a role for iron deficiency or anemia.
LABORATORY FINDINGS.
In progressive iron deficiency, a sequence of biochemical and hematologic events occurs. First, the tissue iron stores represented by bone marrow hemosiderin disappear. The level of serum ferritin, an iron-storage protein, provides a relatively accurate estimate of body iron stores in the absence of inflammatory disease. Normal ranges are age dependent, and decreased levels accompany iron deficiency. Next, serum iron level decreases (also age dependent), the iron-binding capacity of the serum increases, and the percent saturation falls below normal (also varies with age). When the availability of iron becomes rate limiting for hemoglobin synthesis, a moderate accumulation of heme precursors, free erythrocyte protoporphyrins (FEP), results.
As the deficiency progresses, the RBCs become smaller thaormal and their hemoglobin content decreases. The morphologic characteristics of RBCs are best quantified by the determination of mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV). Developmental changes in MCV require the use of age-related standards for diagnosis of microcytosis (see Table 453-1) . With increasing deficiency, the RBCs become deformed and misshapen and present characteristic microcytosis, hypochromia, poikilocytosis, and increased RBC distribution width (RDW). The reticulocyte percentage may be normal or moderately elevated, but absolute reticulocyte counts indicate an insufficient response to anemia. Nucleated RBCs may occasionally be seen in the peripheral blood. White blood cell counts are normal. Thrombocytosis, sometimes of a striking degree (600,000-1,000,000/mm3 ), may occur or, in a few cases, thrombocytopenia. The mechanisms of these platelet abnormalities are not clear. They appear to be a direct consequence of iron deficiency, perhaps with associated GI blood loss or associated folate deficiency, and they return to normal with iron therapy and dietary change. The bone marrow is hypercellular, with erythroid hyperplasia. The normoblasts may have scanty, fragmented cytoplasm with poor hemoglobinization. Leukocytes and megakaryocytes are normal. Hemosiderin cannot be demonstrated in marrow specimens by Prussian blue staining. In about a third of cases, occult blood can be detected in the stools.
Iron deficiency must be differentiated from other hypochromic microcytic anemias. In lead poisoning associated with iron deficiency, the RBCs are morphologically similar, but coarse basophilic stippling of the RBCs, an artifact of drying the slide, is frequently prominent. Elevations of blood lead, FEP, and urinary coproporphyrin levels are seen. The blood changes of beta-thalassemia trait resemble those of iron deficiency, but RDW is usually normal or only slightly elevated. alpha-Thalassemia trait occurs in about 3% of blacks in the
TREATMENT.
The regular response of iron deficiency anemia to adequate amounts of iron is an important diagnostic and therapeutic feature. Oral administration of simple ferrous salts (sulfate, gluconate, fumarate) provides inexpensive and satisfactory therapy. No evidence shows that addition of any trace metal, vitamin, or other hematinic substance significantly increases the response to simple ferrous salts. For routine clinical use, physicians should be familiar with an inexpensive preparation of one of the simple ferrous compounds. The therapeutic dose should be calculated in terms of elemental iron; ferrous sulfate is 20% elemental iron by weight. A daily total of 6mg/kg of elemental iron in three divided doses provides an optimal amount of iron for the stimulated bone marrow to use. Intolerance to oral iron is uncommon in children. A parenteral iron preparation (iron dextran) is an effective form of iron and is usually safe when given in a properly calculated dose, but the response to parenteral iron is no more rapid or complete than that obtained with proper oral administration of iron, unless malabsorption is a factor.
While adequate iron medication is given, the family must be educated about the patient’s diet, and the consumption of milk should be limited to a reasonable quantity, preferably 500mL (
The expected clinical and hematologic responses to iron therapy are described in Table 461-1 . Within 72-96hr after administration of iron to an anemic child, peripheral reticulocytosis is noted. The height of this response is inversely proportional to the severity of the anemia. Reticulocytosis is followed by a rise in the hemoglobin level, which may increase as much as 0.5g/dL/24hr. Iron medication should be continued for 8wk after blood values are normal. Failures of iron therapy occur when a child does not receive the prescribed medication, when iron is given in a form that is poorly absorbed, or when there is continuing unrecognized blood loss, such as intestinal or pulmonary loss, or with menstrual periods. An incorrect original diagnosis of nutritional iron deficiency may be revealed by therapeutic failure of iron medication.
TABLE 461-1 — Responses to Iron Therapy in Iron Deficiency Anemia
|
Time After Iron Administration |
Response |
|
12-24 hr |
Replacement of intracellular iron enzymes; subjective improvement; decreased irritability; increased appetite |
|
36-48 hr |
Initial bone marrow response; erythroid hyperplasia |
|
48-72 hr |
Reticulocytosis, peaking at 5-7 days |
|
4-30 days |
Increase in hemoglobin level |
|
1-3 mo |
Repletion of stores |
Because a rapid hematologic response can be confidently predicted in typical iron deficiency, blood transfusion is indicated only when the anemia is very severe or when superimposed infection may interfere with the response. It is not necessary to attempt rapid correction of severe anemia by transfusion; the procedure may be dangerous because of associated hypervolemia and cardiac dilatation. Packed or sedimented RBCs should be administered slowly in an amount sufficient to raise the hemoglobin to a safe level at which the response to iron therapy can be awaited. In general, severely anemic children with hemoglobin values less than 4g/dL should be given only 2-3mL/kg of packed cells at any one time (furosemide may also be administered as a diuretic). If there is evidence of frank congestive heart failure, a modified exchange transfusion using fresh-packed RBCs should be considered, although diuretics followed by slow infusion of packed RBCs may suffice.
Anemias of newborns.
Anemia iewborns can be caused by hemorrhage, hemolysis or failure to produce red blood cells. In the premature infant, the hemoglobin races its nadir at approximately 8 – 12 weeks and is 2 – 3 g/dL lower than that in the term infant. The lower nadir in the premature appears to be the result of a decreased erythropoietin response to the low red cell mass. That’s why it is very important not only perform the diagnosis in time, but also prevent the development of anemia in premature newborns.
NORMAL BLOOD VALUES In the newborn the range of normal values is wider than at any other age:
Hb 14.5 – 21.5 g/dl
PCV 45-65%
MCV 110-128 fl
WBC 6-30 x 109/l
Differential count:
polymorphs predominate at birth
lymphocyte predominance develops after seven days
I/T ratio less than 12%
Platelets 100-300 x 109/l
Newborn term infants have approximately 75 mg/kg of body iron, 75% of which is in the form of hemoglobin. On average, infants almost triple their blood volume during the first year of life and will require the absorption of 0.4 to 0.6 mg daily of iron during that time to maintain adequate stores.
Premature infants have a lower level of body iron at birth, approximately 64 mg in infants weighing
Assuming that 10% of the iron in a mixed diet is absorbed, the recommended iron intake is approximately 7 mg/d for term infants aged 5 to 12 months, 6 mg/d for toddlers aged 1 to 3 years and 8 mg/d for children aged 4 to 12 years.
ANAEMIA
Background: Anemia frequently is observed in the infant who is hospitalized and premature. Although many causes are possible, anemia of prematurity (AOP) is the most common diagnosis. AOP is a normocytic, normochromic, hyporegenerative anemia that is characterized by the existence of a low serum erythropoietin (EPO) level in an infant who has what may be a remarkably reduced hemoglobin concentration.
Although common, AOP remains a controversial issue for clinicians. Few universally accepted signs or symptoms are attributable to AOP. Even less agreement exists regarding the timing, method, and effectiveness of current therapeutic interventions in individuals with AOP. With an increasing number of transfusion-related complications reported in the last 2 decades, caregivers and families of infants understandably are concerned about the use of blood products. This article reviews the pathophysiology of AOP, the means of reducing blood transfusions, and the current status of recombinant EPO.
Mortality/Morbidity: Although a premature infant is unlikely to be allowed to become so anemic as to die, complications from necessary blood transfusions ultimately can be responsible for the death of a patient. Anemia is blamed for a variety of signs and symptoms, including apnea, poor feeding, and inadequate weight gain.
Age:
· The more immature the infant, the more likely the development of AOP. AOP typically is not a significant issue for infants born beyond 32 weeks’ gestation.
· The nadir of the hemoglobin level typically is observed when the tiniest infants are aged 4-8 weeks.
· AOP spontaneously resolves by the time most patients are aged 3-6 months.
Inadequate red blood cell production The first mechanism of anemia is inadequate RBC production. The location of EPO and RBC production changes during gestation of the fetus. EPO synthesis initially occurs in cells of monocyte or macrophage origin that reside in the fetal liver, with production gradually shifting to the peritubular cells of the kidney. By the end of gestation, the liver remains a major source of EPO.
In the first few weeks of embryogenesis, fetal erythrocytes are produced in the yolk sac. This site is succeeded by the fetal liver, which, by the end of the first trimester, has become the primary site of erythropoiesis. Bone marrow then begins to take on a more active role in producing erythrocytes. By approximately 32 weeks’ gestation, the burden of erythrocyte production in the fetus is shared evenly by the liver and bone marrow. By 40 weeks’ gestation, the marrow is the sole erythroid organ. Premature delivery does not accelerate the ontogeny of these processes.
Although EPO is not the only erythropoietic growth factor in the fetus, it is the most important. EPO is synthesized in response to both anemia and hypoxia. The degree of anemia and hypoxia required to stimulate EPO production is far higher for the fetal liver than for the fetal kidney. As a result, new RBC production in the extremely premature infant (whose liver remains the major site of EPO production) is blunted despite what may be marked anemia.
In addition, EPO, whether endogenously produced or exogenously administered, has a larger volume of distribution and is eliminated more rapidly by neonates, resulting in a curtailed time for bone marrow stimulation. Erythroid progenitors of premature infants are quite responsive to EPO when that growth factor finally is produced or administered.
Shortened red blood cell life span or hemolysis Secondly, the average life span of a neonatal RBC is only one half to two thirds that of the RBC life span in an adult. Cells of the most immature infants may survive only 35-50 days. The shortened RBC life span of the neonate is a result of multiple factors, including diminished levels of intracellular ATP, carnitine, and enzyme activity; increased susceptibility to lipid peroxidation; and increased susceptibility of the cell membrane to fragmentation.
Blood loss Finally, blood loss may contribute to the development of AOP. If the neonate is held above the placenta for a time after delivery, a fetal-placental transfusion may occur. More commonly, because of the need to closely monitor the tiny infant, frequent samples of blood are removed for various tests. Because the smallest patients may be born with as little as 40 mL of blood in their circulation, withdrawing a significant percentage of an infant’s blood volume in a short period is relatively easy. In one study, mean blood loss in the first week of life was nearly 40 mL.
Taken together, the premature infant is at risk for the development of AOP because of limited synthesis, diminished RBC life span, and increased loss of RBCs.
Classification
І. Posthemorrhagic anemia (after hemorrhage):
А. Antenatal:
1. rupture of placenta
2. anomaly of the umbilical cord, and it’s vessels
3. feto-fetal transfusion
4. feto-maternal transfusion
B. Intranatal:
1. obstetric complications (Cesarean section, preterm placental separation, cord rupture, placental presentation)
2. cord compression during delivery
3. birth injury
4. placental transfusion
C. Postnatal:
1. internal hemorrhages (intraventricular, large cephalhematoma, rupture of the inner organs)
2. gastro-intestinal tract bleeding
3. cord vessels bleeding
4. iatrogenic blood loses
ІІ. Hemolytic (as a result of increased hemolysis)
А. Hereditary predisposed:
1. membranopathies (hereditary microspherocytosis)
2. enzymopathies (G-6-PD deficiency)
3. hemoglobinopathia
B. acquired:
1. immune (hemolytic disease by АВО and Rh–factors)
2. vitamin E deficiency
3. infectious (CMV–infection, toxoplasmosis, congenital syphilis, hepatitis C, В, sepsis)
ІІІ. Anemia due to hemopoesis depression
А. Hereditary: Fanconi anemia, Diamond-Blackfan anemia
B. Acquired: deficiency anemia (vit B 12, folic acid, Fe, protein, aminoacids, microelements).
CLINICAL Obstetric history:
1. maternal hemorrhages during pregnancy, delivery
2. maternal diseases during pregnancy (acute, chronic)
3. peculiarities of feeding during pregnancy
4. preterm birth
5. multiple pregnancy – feto–fetal transfusion (difference of hemoglobin concentration more than 50 g/l
6. perinatal or postnatal infections
7. family anamnesis (hematological diseases, jaundices)
Few symptoms are universally accepted as attributable to AOP; however, the following are among the symptoms that clinicians attribute to AOP:
· Poor weight gain
· Apnea
· Tachypnea
· Decreased activity
· Pallor
· Tachycardia
· Flow murmurs
Physical: Debate regarding the presence or absence of physical findings in the infant with AOP is ongoing. Clinical trials designed to determine the efficacy of blood transfusions in relieving these findings have produced conflicting results.
1. Poor growth Inadequate weight gain despite adequate caloric intake often is attributed to AOP.
2. Apnea If severe enough, anemia may result in respiratory depression manifested by increased periodic breathing and apnea.
3. Decreased activity: Lethargy frequently is attributed to anemia, with subjective improvement subsequent to transfusion.
4. Metabolic acidosis Significant anemia can result in decreased oxygen-carrying capacity less than the needs of the tissue, resulting in increased anaerobic metabolism with production of lactic acid.
5. Tachycardia Infants with AOP may respond by increasing cardiac output through increased heart rates, presumably in response to inadequate oxygen delivery to the tissues caused by anemia. Blood transfusions have been associated with a lowering of the heart rate in infants who are anemic.
6. Tachypnea
7. Flow murmurs
DIFFERENTIALS
|
Criterions |
Posthemorrhagic anemia |
Hemolytic anemia |
Early anemia of premature child |
Late anemia of premature child |
Hypo- and aplastic anemia |
|
History
Incidence
Clinical
Laborato-ry findings |
Feto–fetal, feto–maternal transfusion; Postnatal blood loses; Iatrogenic loses;
On the 2-3 day of life
Skin pallor, cardiorespira-tory syndrome, hypovolemia, unconsciousness
normochromic, later hypochromic anemia, decreasing of the serum Fe |
АВО-system or Rh–factor incompatibility; complicated genetical history
After birth, on the 1st day
jaundice, splenomegaly, in hard cases – kernicterus
Nonconjugated hyperbilirubin-emia, positive Coombs test, reticulocytosis
|
Prematurity
before 2 months
skin and mucus membranes pallor, loss of appetite, height and weight retardation moderate hepatosplenomegaly, CNS depression
hypochromic and normochromic hyporegenerative anemia, anisocytosis, |
Prematurity
In 4-5 months
syderopenic, astenoneurotic cardiovascular syndromes, hepatosplenomegaly, depression of immune system
hypochromic anemia, decreasing of the serum Fe, increasing of the Fe conjugating ability of the serum |
complicated genetical history, toxin or medicine influence
gradual, with maximal clinical feature on the 2-3 months
progressive pallor, hemorrhages, hepatosplenomegaly, stigmas of dysembriogene-sis,
normochromic anemia, leucopenia, thrombocyto-penia, reticulocito-penia, erythroid shoot hypoplasia |
Lab Studies:
1. Complete blood count
· The CBC demonstrates normal white blood cell (WBC) and platelet lines.
· The hemoglobin is less than 10 g/dL but may descend to a nadir of 6-7 g/dL; the lowest levels generally are observed in the smallest infants.
· RBC indices are normal (eg, normochromic, normocytic) for age.
2. Reticulocyte count
· The reticulocyte count is low when the degree of anemia is considered as a result of the low levels of EPO.
· The finding of an elevated reticulocyte count is not consistent with the diagnosis of AOP.
3. Peripheral blood smear: No abnormal forms are observed.
4. Maternal and infant blood typing: In the evaluation of anemia, consider the possibility of hemolytic processes, such as the ABO blood group system and Rh incompatibility.
5. Direct antibody test (Coombs): This test may be coincidentally positive; however, with such a finding, ensure that an immune-mediated hemolytic process is not ongoing.
6. Serum bilirubin: With an elevated serum bilirubin level, consider other possible explanations for the anemia.
TREATMENT
Dietary sources of Iron Other factors affecting iron sufficiency are the amount and the bioavailability of dietary iron. The form of the iron influences its absorption: absorption is good from ferrous sulfate (the iron source generally used in infant formulas) and elemental iron of small particle size (e.g., the electrolytic iron used in infant cereals). In general, iron absorption from foods of animal origin surpasses that from foods of plant origin. Vitamin C, meat, fish and poultry facilitate iron absorption.
One litre of human milk contains only 0.3 to 0.5 mg of iron. About 50% of the iron is absorbed, in contrast to a much smaller proportion from other foods. Term infants who are breast-fed exclusively for the first 6 months may not be at risk for iron depletion or for the development of iron deficiency. However, if solid foods are given they may compromise the bioavailability of iron from human milk. Although some term infants who are exclusively breast-fed may remain iron-sufficient until 9 months of age, a source of dietary iron is recommended starting at 6 months (or earlier if solid foods are introduced into the diet) to reduce the risk of iron deficiency.
Infant formulas based on cow’s milk contain 1.0 to 1.5 mg of iron per litre; soy-based formula and iron-fortified formula based on cow’s milk contain 12 to 13 mg of iron per litre. The iron source of fortified formulas is ferrous sulfate, which is significantly more available than the iron used in infant cereals. The availability of iron from soy-based formulas appears to be lower than that from milk-based products. The optimal amount of iron in formula based on cow’s milk remains to be determined. Formulas in North America contain higher amounts of iron than those suggested in the United Kingdom (1.0 mg/100 kcal) and France (1.5 mg/100 kcal).
The decreased incidence of iron deficiency anemia in the United States since 1969 has been attributed to the increased and longer use of iron-fortified formulas, an increase in breast-feeding and the use of iron-fortified infant cereals. Contrary to popular belief, significant behavioural or gastrointestinal problems do not develop in most infants fed iron-fortified formulas. Theoretically, the iron from neonatal reserves in term babies is sufficient to cover their needs during the first 3 months of life. However, in order to avoid possible confusion with formula changes during the first few months, iron-fortified formulas should be used from birth.
Cow’s milk is not recommended for infants younger than 9 to 12 months of age. Although it contains approximately the same amount of iron as human milk (0.5 mg/L) the iron is poorly absorbed. Even when given iron-fortified cereals and other foods, some infants fed cow’s milk from 6 months of age have significantly lower mean serum ferritin levels and corpuscular volume and a greater incidence of hemoglobin concentration below 6.8 mmol/L at 12 months of age than infants fed iron-supplemented formula. In addition, cow’s milk compromises the absorption of dietary and medicinal iron.
Occult blood loss from the gastrointestinal tract has been demonstrated in infants younger than 4 months of age fed exclusively with unmodified cow’s milk. A more recent study of the effects of cow’s milk on infants from 168 to 252 days old showed significant gastrointestinal blood loss in the experimental group, as measured by a sensitive quantitative method; however, this group’s iroutritional status was not significantly different from that of the control (formula-fed) group.
Iron-fortified cereals are an important source of iron: they contain approximately 30 to 50 mg per
Term infants who are exclusively breast-fed do not need supplemental iron until they are 6 months of age. If solid foods are introduced earlier, they should contain an adequate amount of iron. After 6 months of age, breast-fed infants should receive extra iron in the form of iron-fortified infant cereals and other iron-rich foods. These infants should be offered an iron-fortified infant formula after they have been weaned from breast milk.
Term infants who are not breast-fed should be given an iron-fortified infant formula from birth. Studies are still under way to determine the optimal iron content of these formulas: and further studies are encouraged. Until the results are known, the use of currently available iron-fortified formulas seems appropriate. After 4 to 6 months of age, iron-fortified infant cereals provide a good additional source of iron.
For premature infants, an iron supplement should be started by at least 8 weeks of age and continued until the first birthday. Iron-fortified formula for bottle-fed infants or commercial iron drops for breast-fed infants are the recommended source of supplemental iron.
Cow’s milk should not be introduced until an adequate amount of solid food containing iron and vitamin C is included in the diet, preferably at 9 to 12 months of age.
For children over 1 year of age, the recommended daily nutrient intake of iron should be given. Iron-containing foods such as meats, some vegetables, legumes, fruits and iron-fortified infant or toddler cereals provide iron in sufficient amounts. Supplemental iron is not required unless the diet is lacking in these foods.
Medical Care: The medical care options available to the clinician treating an infant with AOP are prevention, blood transfusion, and recombinant EPO treatment.
Prevention
· Reducing the amount of blood taken from the premature infant diminishes the need to replace blood. When caring for the premature infant, carefully consider the need for each laboratory study obtained. Hospitals with care for premature infants should have the ability to determine laboratory values using very small volumes of serum.
· Manufacturers are developing an array of technologies that require extremely small amounts of blood for a steadily increasing number of tests. Likewise, devices that allow blood gases and serum chemistries to be determined at bedside via an analyzer attached to the umbilical artery catheter without loss of blood recently have been developed. The impact of such devices on the development of anemia and/or the need for transfusions has yet to be determined.
· The use of noninvasive monitoring devices, such as transcutaneous hemoglobin oxygen saturation, partial pressure of oxygen, and partial pressure of carbon dioxide, may allow clinicians to decrease blood drawing; however, no data currently support such an impact of these devices.
Blood transfusion
· Packed red blood cell (PRBC) transfusions: Despite disagreement regarding timing and efficacy, PRBC transfusions continue to be the mainstay of therapy for the individual with AOP. The frequency of blood transfusions varies with gestational age, degree of illness, and, interestingly, the hospital evaluated.
· Reducing the number of transfusions: Studies derived from individual centers document a marked decrease in the administration of PRBC transfusions over the past 2 decades, even before the use of EPO. This decrease in transfusions is almost certainly multifactorial in origin. One frequently mentioned component is the adoption of transfusion protocols that take a variety of factors into account, including hemoglobin levels, degree of cardiorespiratory disease, and traditional signs and symptoms of pathologic anemia. Using various audit criteria and indications for transfusions suggested by Canadian, American, and British authorities, the Medical University of South Carolina has instituted the following transfusion guidelines:
o Do not transfuse for phlebotomy losses alone.
o Do not transfuse for hematocrit alone, unless the hematocrit level is less than 21% with a reticulocyte count less than 100,000.
o Transfuse for shock associated with acute blood loss.
o For an infant with cyanotic heart disease, maintain a hemoglobin level that provides an equivalent fully saturated level of 11-
o Transfuse for hematocrit levels less than 35-40% in the following situations:
§ Infant with severe pulmonary disease (defined as requiring >35% supplemental hood oxygen or continuous positive airway pressure [CPAP] or mechanical ventilation with a mean airway pressure of >
§ Infant in whom anemia may be contributing to congestive heart failure
o In the following situations, transfuse for a hematocrit level that is 25-30% or less:
§ The patient requires nasal CPAP of
§ The patient has significant apnea and bradycardia (defined as >9 episodes in 12 h or 2 episodes in 24 h, requiring bag-mask ventilation while receiving therapeutic doses of methylxanthines).
§ The patient has persistent tachycardia or tachypnea without other explanation for 24 hours.
§ Weight gain of patient is deemed unacceptable in light of adequate caloric intake without other explanation, such as known increases in metabolic demands or known losses in metabolic demands (malabsorption).
§ The patient is scheduled for surgery; transfuse in consultation with the surgery team.
· Reducing the number of donor exposures: In addition to reducing the number of transfusions, reducing the number of donor exposures is important. This can be accomplished as follows:
o Use PRBCs stored in preservatives (eg, citrate-phosphate-dextrose-adenine [CPDA-1]) and additive systems (eg, Adsol). Preservatives and additive systems allow blood to be stored safely for up to 35-42 days. Infants may be assigned a specific unit of blood, which may suffice for treatment during their entire hospitalization.
o Use volunteer-donated blood and all available screening techniques. The risk of cytomegalovirus (CMV) transmission can be reduced dramatically (but not entirely) through the use of CMV-safe blood. This can be accomplished by using either CMV serology-negative cells or blood processed through leukocyte-reduction filters. This latter method also reduces other WBC-associated infectious agents (eg, Epstein-Barr virus, retroviruses, Yersinia enterocolitica). The American Red Cross now is providing exclusively leukocyte-reduced blood to hospitals in the United States.
Recombinant erythropoietin treatment
1. Multiple investigations have established that premature infants respond to exogenously administered recombinant human EPO with a brisk reticulocytosis. Modest decreases in the frequency of PRBC transfusions have been documented primarily in premature infants who are relatively large.
2. Recent trials have evaluated the impact of EPO treatment in populations of the most immature neonates. These studies likewise have demonstrated that infants with VLBW are capable of responding to EPO with a reticulocytosis and that the drug appears to be safe. Conversely, the hemoglobin level of infants treated with EPO falls to at or below the hemoglobin level of the control group within 1 week of treatment cessation, and the impact on transfusion requirements ranges from nonexistent to small.
3. No agreement regarding timing, dosing, route, or duration of therapy exists. In short, the cost-benefit ratio for EPO has yet to be clearly established, and this medication is not accepted universally as a standard therapy for the individual with AOP. When the family has religious objections to transfusions, the use of EPO is advisable.
Diet: Provision of adequate amounts of vitamin E, vitamin B-12, folate, and iron are important to avoid exacerbating the expected decline in hemoglobin levels in the premature infant.
MEDICATION
Epoetin alfa (Epogen, Procrit) Adult Dose Mother: 400 U/kg/dose IV/SC 3 times/wk until postconceptional age 35 wk. Pediatric Dose 72 hours: 200 U/kg/d IV for 14 d; 10 days: 200 U/kg/dose SC 3 times/wk for 6 wk; 10-35 days: 100 U/kg/d IV 2 times/wk for 6 wk.
Ferrous sulfate (Feosol) 5 mg/kg/wk (based on elemental iron content) IV; alternatively, 6 mg/kg/d PO.
Vitamin E (Aquasol E, Vitec) 25 IU/d PO initially; measure plasma tocopherol within 1 wk and adjust dose accordingly.
Folic acid (Folvite) 50 mcg/d PO
Further Outpatient Care: After discharge from the hospital, ensure regular determination of hematocrit levels in infants with APO. Once a steady increase in the hematocrit level has been established, only routine checks are required.
Deterrence/Prevention:
· Limit diagnostic blood draws to a minimum.
Complications:
1. Transfusion-acquired infections (eg, hepatitis, CMV, HIV, syphilis)
2. Transfusion-associated fluid overload and electrolyte imbalances
3. Transfusion-associated exposure to plasticizers
4. Transfusion-associated hemolysis
5. Posttransfusion graft versus host disease
Prognosis: Spontaneous recovery in the individual with AOP occurs by age 3-6 months.
What is iron deficiency?
Jennifer Rothman, MD Iron deficiency is the most commoutritional deficiency in the world. The World Health Organization (WHO) estimates that nearly one third of the world’s population may have low red blood cell numbers due to insufficient iron.
In the United States, iron deficiency remains common with 9 percent of toddlers between the ages of 12-36 months having inadequate iron stored in their bodies.
What is iron deficiency anemia?
Anemia is when a person has a significantly lower-than-average red blood cell number or a decrease in the protein called hemoglobin (oxygen carrier) for his or her age and gender.
In toddlers, that is defined by the WHO as lower than 11 gm/dL for both boys and girls. In the U.S., 5 percent of toddlers between the ages of 12-36 months have anemia, and iron deficiency is the cause of anemia in 40 percent of those children.
Why do we need iron?
Iron is important for many processes in our body including carrying oxygen to all of our organs. Most of the iron in our body is found in hemoglobin, a protein in our red blood cells. Iron is also stored in our liver, bone marrow, and spleen in a storage form called ferritin.
Iron is necessary to make red blood cells, as well as for normal growth and development. Iron deficiency in infancy may be associated with developmental delays or behavioral problems.
What causes iron deficiency?
A developing fetus gets all of its iron from its mother during pregnancy. Most of the iron stores are given to the fetus in the third trimester.
A full-term infant born from a healthy mother will have enough iron to support growth and development until four to six months of age. After that, iroeeds to be absorbed through the diet in the form of breast milk, iron-fortified formula, solid foods, or vitamin supplements.
Iron deficiency is most often caused by not enough iron absorbed through the diet. Sometimes people lose a lot of iron from the body in the form of blood loss. A good example of that is very heavy menstrual bleeding or bloody diarrhea from inflammatory bowel disease.
What are the symptoms of iron deficiency?
Symptoms of iron deficiency include:
· Pale skin, lips, or hands
· Fatigue or sleepiness
· Not wanting to eat
· Fast heart rate
· Pica — eating non food items like ice, paper, dirt, or couch cushions
Who is at risk for iron deficiency?
Infants, toddlers, teenagers, pregnant women, and, primarily, menstruating females are at risk for iron deficiency.
Special risk factors include:
· Preterm infants born before the third trimester (before 37 weeks gestation)
· Infants born to mothers with diabetes or severe anemia
· Vegan or vegetarians without a source of iron-rich foods
· Exclusive breast feeding beyond four to six months (not receiving iron-fortified solid foods in addition to breast milk)
o At four to six months, an infant has outgrown his or her stored iron, and, while breast milk does have iron, it is not enough to keep up with an infant’s rapid growth.
· Early introduction of cow’s milk (before 12 months) or excessive cow’s milk intake (more than
o Cow’s milk is low in iron and can actually prevent iron from being absorbed from the diet. In addition, some children develop small amounts of bleeding from their intestines when they have too much cow’s milk.
· Continued use of bottle feeding after 12 months of age
· Blood loss through heavy menses or bloody diarrhea
· Children with special health care needs
How do you screen for iron deficiency anemia?
Due to how common anemia is in childhood and the potential impact of anemia on growth and development, the American Academy of Pediatrics recommends screening for iron deficiency anemia at 12 months of age by checking a hemoglobin level as well as getting a good history for iron deficiency risk factors.
If the hemoglobin is low, then it is helpful to get a full blood count to look at the size and shape of the blood cells. Iron deficiency anemia is associated with small red blood cells, or cells that have a low MCV.
Another helpful test includes a serum ferritin which measures the amount of iron stored in the body. The serum ferritin may be falsely high if your child has recently been sick.
Screening for iron deficiency is recommended at any age for a child who has symptoms or significant risk factors.
How do you treat and monitor iron deficiency anemia?
If anemia is identified in a child with risk factors for iron deficiency, then it is reasonable to start iron replacement without sending a serum ferritin.
Iron replacement consists of an iron vitamin, either liquid or pill, at a dose of 6 mg/kg/day of elemental iron. Taking the iron supplement with a vitamin C-fortified liquid, such as orange juice, will help the iron be better absorbed. Milk intake should be limited and an iron-rich diet should be encouraged.
If iron deficiency is the cause of the anemia, then an increase in the hemoglobin by 1 gm/dL after four to six weeks is expected. Iron supplementation should be continued for at least six weeks after normalization of the hemoglobin in order to refill the child’s iron stores.
A repeat blood count should be performed three to six months after the iron supplement is stopped to make sure the child is maintaining his or her iron stores. If there is not an improvement in hemoglobin while taking iron supplementation, then further investigation is recommended.
Sometimes the lack of improvement is because the iron is not being taken as prescribed or the child’s diet has not changed. Other times, the cause of the anemia may not be iron deficiency.
How do you prevent iron deficiency?
Preterm infants who did not receive many red blood cell transfusions during the newborn period, should receive an iron-containing preterm infant formula or breast milk with an iron-containing vitamin.
Full-term infants can get iron from iron-fortified formula or breast milk. Breast-fed infants should start a vitamin with iron (1mg/kg/day) at four months of age until iron-containing solid foods, like iron-fortified rice cereal, are introduced.
Infants should be weaned to a cup around 12 months and should not start cow’s milk until older than 12 months. Cow’s milk should be limited to no more than
Toddler diets should include good sources of iron included red meat, beans, green vegetables, and iron-fortified cereals. Parents raising their children as vegetarians should take special care to identify iron-rich foods.
Anemia in Children
Am Fam Physician. 2001 Oct 15;64(8):1379-1387.
Anemia in children is commonly encountered by the family physician. Multiple causes exist, but with a thorough history, a physical examination and limited laboratory evaluation a specific diagnosis can usually be established. The use of the mean corpuscular volume to classify the anemia as microcytic, normocytic or macrocytic is a standard diagnostic approach. The most common form of microcytic anemia is iron deficiency caused by reduced dietary intake. It is easily treatable with supplemental iron and early intervention may prevent later loss of cognitive function. Less common causes of microcytosis are thalassemia and lead poisoning. Normocytic anemia has many causes, making the diagnosis more difficult. The reticulocyte count will help narrow the differential diagnosis; however, additional testing may be necessary to rule out hemolysis, hemoglobinopathies, membrane defects and enzymopathies. Macrocytic anemia may be caused by a deficiency of folic acid and/or vitamin B12, hypothyroidism and liver disease. This form of anemia is uncommon in children.
Anemia is a frequent laboratory abnormality in children. As many as 20 percent of children in the United States and 80 percent of children in developing countries will be anemic at some point by the age of 18 years.1
Physiology of Hemoglobin Production
Erythropoietin is the primary hormone regulator of red blood cell (RBC) production. In the fetus, erythropoietin comes from the monocyte/macrophage system of the liver. Postnatally, erythropoietin is produced in the peritubular cells of the kidneys. Key steps in red blood cell differentiation include condensation of red cell nuclear material, production of hemoglobin until it amounts to 90 percent of the total red blood cell mass and the extrusion of the nucleus that causes loss of RBC synthetic ability. Normal RBCs survive an average of 120 days, while abnormal RBCs can survive as little as 15 days.1
The hemoglobin molecule is a hemeprotein complex of two pairs of similar polypeptide chains. There are six types of hemoglobin in developing humans: the embryonic, Gower-I, Gower-II, Portland, fetal hemoglobin (HbF) and normal adult hemoglobin (HbA and HbA2). HbF is the primary hemoglobin found in the fetus. It has a higher affinity for oxygen than adult hemoglobin, thus increasing the efficiency of oxygen transfer to the fetus. The relative quantities of HbF rapidly decrease to trace levels by the age of six to 12 months and are ultimately replaced by the adult forms, HbA and HbA2
General Approach to Management
Most children with anemia are asymptomatic and have an abnormal hemoglobin or hematocrit level on routine screening (Table 1).2 Infrequently, a child with anemia may have pallor, fatigue and jaundice but may or may not be critically ill. Key historical points and findings on physical examination can reveal the underlying cause of the anemia.
The newborn’s body reclaims and stores iron as the hematocrit levels decrease during the first few months of life. Therefore, in full-term infants, iron deficiency is rarely the cause of anemia until after six months of age. In premature infants, iron deficiency can occur only after the birth weight has been doubled. X-linked causes of anemia, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, should be considered in males. Pyruvate kinase deficiency is autosomal recessive and associated with chronic hemolytic anemia of variable severity. A history of nutritional deficiency, pica or geophagia suggests iron deficiency. Recent prescription drug use may suggest G6PD deficiency or aplastic anemia. A recent viral illness may suggest red cell aplasia. Recurrent diarrhea raises suspicion of malabsorption and occult blood loss occurring in celiac sprue and inflammatory bowel disease.
TABLE 1 Screening Recommendations for Anemia in Children
TABLE 1
Screening Recommendations for Anemia in Children
|
1. U.S. Preventive Services Task Force recommends screening hemoglobin or hematocrit between the ages of six to 12 months in high-risk infants. High-risk includes the following: blacks, Native Americans, Alaska natives, infants living in poverty, immigrants from developing countries, preterm and low-birth-weight infants and infants whose principle dietary intake is unfortified cow’s milk. Newborns should be screened for hemoglobinopathies with hemoglobin electrophoresis. Selective screening is appropriate in areas of low prevalence. 2. The recommendations of the American Academy of Family Physicians are the same as the U.S. Preventive Services Task Force. 3. American Academy of Pediatrics recommends screening hemoglobin or hematocrit at the six-, nine-, or 12-month visit for all infants. Universal screening for anemia iewborns is not warranted. |
Information from U.S. Preventive Services Task Force. Guide to clinical preventive services: report of the U.S. Preventive Services Task Force. 2d ed. Baltimore, Md.: Williams & Wilkins, 1996; American Academy of Family Physicians. Summary of AAFP policy recommendations and age charts. Retrieved October 2000, from: http://www.aafp.org/exam; and the American Academy of Pediatrics. AAP policy statements, clinical practice guidelines, and model bills. Retrieved October 2000, from: http://www.aap.org/policy/pcyhome.cfm.
The physical examination is important but will be unremarkable in most children with anemia. Findings that suggest chronic anemia include irritability, pallor (usually not seen until hemoglobin levels are less than
Laboratory Evaluation
Anemia is defined as a decreased concentration of hemoglobin and RBC mass compared with that in age-matched controls. In screening situations, such as the one-year check-up, only a hemoglobin level is usually obtained. When anemia is encountered during this screening, the specimen should be upgraded to a complete blood cell count (CBC), because some laboratories store blood samples for up to seven days. Physicians should first look at the mean corpuscular volume (MCV), which allows placement of the anemia into one of the standard classifications of microcytic, normocytic and macrocytic (Table 2).3,4 After narrowing the differential diagnosis based on the MCV, the clinician can proceed with additional diagnostic work-up.
The next step of the anemia work-up should include a peripheral smear and a measurement of the reticulocyte count. Pathologic findings on the peripheral smear can indicate the etiology of the anemia based on red cell morphology. Basophilic stippling (Figure 1a) representing aggregated ribosomes can be seen in thalassemia syndromes, iron deficiency and lead poisoning. Howell-Jolly bodies (Figure 1b) are nuclear remnants seen in asplenia, pernicious anemia and severe iron deficiency. Cabot’s ring bodies (Figure 1c) are also nuclear remnants and are seen in lead toxicity, pernicious anemia and hemolytic anemias. Heinz’s bodies (Figure 1d) are from denatured aggregated hemoglobin and can be seen in thalassemia, asplenia and chronic liver disease.
The reticulocyte count (or percentage) helps distinguish a hypoproductive anemia (decreased RBC production) from a destructive process (increased RBC destruction). A low reticulocyte count may indicate bone marrow disorders or aplastic crisis, while a high count generally indicates a hemolytic process or active blood loss. The corrected reticulocyte count corrects for differences in the hematocrit and is a more accurate indicator of erythropoietic activity. To calculate corrected reticulocyte count, multiply the patient’s reticulocyte count (or percentage) by the result of dividing the patient’s hematocrit level by the normal hematocrit level. A corrected reticulocyte count above 1.5 suggests increased RBC production. In the case of decreased RBC survival, the bone marrow normally responds with increased reticulocyte production, usually greater than 2 percent or with an absolute count of greater than 100,000 cells per mm3 (100 × 106 per L). This is presumptive evidence of chronic hemolysis if the reticulocytosis is sustained.
FIGURE 1.
Depiction of red blood cell morphologies that may appear on a peripheral smear, showing: (A) basophilic stippling, (B) Howell-Jolly bodies, (C) Cabot’s ring bodies and (D) Heinz’s bodies.
If, after analysis of the initial laboratory findings, the diagnosis is still unclear, other confirmatory studies may be required. Tests to determine if the MCV is too low include serum iron level, total iron binding capacity (TIBC) and lead level. A serum ferritin level would be an acceptable substitute for the serum iron or TIBC levels. Serum ferritin levels are the first to decrease in patients with iron deficiency and are sensitive and specific. However, because serum ferritin is an acute phase reactant, it can be falsely elevated. If hemolysis is suspected, a direct Coombs’ test, G6PD assay, hemoglobin electrophoresis, and lactate dehydrogenase (LDH), haptoglobin and bilirubin (indirect) determinations may help to confirm the diagnosis. For the anemic child with an elevated MCV, the physician should test the vitamin B12, folate and thyroid-stimulating hormone levels.
Other tests for diagnostic confirmation include an RBC enzyme panel to diagnose enzymopathies, osmotic fragility to diagnose hereditary spherocytosis, hemoglobin isoelectric focusing to diagnose hemoglobin variants, membrane protein studies to diagnose membranopathies, and cytogenetic studies.3 In certain circumstances, such as a suspected hematologic malignancy, a bone marrow aspiration may be indicated. Hematology consultation before ordering these more sophisticated tests is usually warranted.
Types of Anemia Based on the MCV
MICROCYTIC ANEMIAS
The most prevalent and preventable form of microcytic anemia is iron deficiency anemia.1 The prevalence of iron deficiency anemia in the United States ranges from 3 to 10 percent and may be as high as 30 percent in low-income populations.5 Researchers in a 1997 study6 of a private pediatric office in New York City evaluated 504 consecutive children, ages one to three years, for anemia. Children with a chronic or acute illness, premature birth or with a known blood dyscrasia were excluded from participating in the study. The authors found that approximately 7 percent of the children in this population were iron deficient without anemia and 10 percent had iron deficiency anemia.6
Table 3. Age-Specific Blood Cell Indexes
|
Age |
Hemoglobin, g/dL (g/L) |
Hematocrit (%) |
MCV, µm3(fL) |
MCHC, g/dL (g/L) |
Reticulocytes |
|
|
26 to 30 weeks’ gestation* |
13.4 (134) |
41.5 (0.42) |
118.2 (118.2) |
37.9 (379) |
— |
|
|
28 weeks’ gestation |
14.5 (145) |
45 (0.45) |
120 (120) |
31.0 (310) |
(5 to 10) |
|
|
32 weeks’ gestation |
15.0 (150) |
47 (0.47) |
118 (118) |
32.0 (320) |
(3 to 10) |
|
|
Term† (cord) |
16.5 (165) |
51 (0.51) |
108 (108) |
33.0 (330) |
(3 to 7) |
|
|
1 to 3 days |
18.5 (185) |
56 (0.56) |
108 (108) |
33.0 (330) |
(1.8 to 4.6) |
|
|
2 weeks |
16.6 (166) |
53 (0.53) |
105 (105) |
31.4 (314) |
|
|
|
1 month |
13.9 (139) |
44 (0.44) |
101 (101) |
31.8 (318) |
(0.1 to 1.7) |
|
|
2 months |
11.2 (112) |
35 (0.35) |
95 (95) |
31.8 (318) |
|
|
|
6 months |
12.6 (126) |
36 (0.36) |
76 (76) |
35.0 (350) |
(0.7 to 2.3) |
|
|
6 months to 2 years |
12.0 (120) |
36 (0.36) |
78 (78) |
33.0 (330) |
|
|
|
2 to 6 years |
12.5 (125) |
37 (0.37) |
81 (81) |
34.0 (340) |
(0.5 to 1.0) |
|
|
6 to 12 years |
13.5 (135) |
40 (0.40) |
86 (86) |
34.0 (340) |
(0.5 to 1.0) |
|
|
12 to 18 years |
||||||
|
|
Male |
14.5 (145) |
43 (0.43) |
88 (88) |
34.0 (340) |
(0.5 to 1.0) |
|
|
Female |
14.0 (140) |
41 (0.41) |
90 (90) |
34.0 (340) |
(0.5 to 1.0) |
|
Adult |
||||||
|
|
Male |
15.5 (155) |
47 (0.47) |
90 (90) |
34.0 (340) |
(0.8 to 2.5) |
|
|
Female |
14.0 (140) |
41 (0.41) |
90 (90) |
34.0 (340) |
(0.8 to 4.1) |
MCV = mean corpuscular volume; MCHC = mean corpuscular hemoglobin concentration.
*— Values are from fetal samplings.
†— Less than one month, capillary hemoglobin exceeds venous: 1 hour–3.6 g difference; 5 days–2.2 g difference; 3 weeks–1.1 g difference.
Adapted with permission from Siberry GK, Iannone R, eds. The Harriet Lane handbook: a manual for pediatric house officers. 15th ed. St. Louis: Mosby, 2000.
Severe iron deficiency is usually easily diagnosable; however, the milder forms of iron deficiency offer a greater challenge. The normal values for the age-matched red cell indexes are listed in Table 37.
If the history and laboratory findings suggest iron deficiency anemia, a one-month empiric trial of iron supplementation is appropriate in asymptomatic infants nine to 12 months of age. A low MCV and elevated red cell distribution width (RDW) suggest iron deficiency.8 The RDW is an index of the variability in the size of the red blood cells (anisocytosis), which is the earliest manifestation of iron deficiency.9 Table 48 illustrates how the RDW helps distinguish iron deficiency from other causes of microcytosis.10
Iron supplements are given to the child at a dosage of 3 to 6 mg per kg per day in the form of ferrous sulfate before breakfast. An increase in hemoglobin levels of greater than
It is widely accepted that iron deficiency can have long-term consequences that are often irreversible. Several studies have found that reversal of the anemia did not improve standardized test scores.12,13 One study14 examined a group of Costa Rican children at five years of age. Children who had moderately severe iron deficiency anemia (hemoglobin less than
The indications listed in Table 48 can help differentiate the other microcytic anemias. Thalassemias are genetic deficiencies in the gene coding for globin chains. In patients with thalassemia, either the α-chain or the β-chain cannot be synthesized in sufficient quantities, lending to the nomenclature α-thalassemia or β-thalassemia. This deficiency produces an unbalanced globin chain synthesis that leads to premature RBC death (Table 618(p1403)). There are about 100 mutations of varying severity that cause thalassemia. They are more prevalent in persons of Mediterranean, African, Indian and Middle-Eastern descent. They cause disruption of hemoglobin polypeptide synthesis that can be asymptomatic, mildly symptomatic or cause severe anemia.
Referral is appropriate for cases in which the diagnosis is unclear and for treatment of the more severe types of anemia.
The clinician is often confronted with microcytic anemia in a population with a higher prevalence of thalassemias. The Mentzer index was developed to help distinguish thalassemia from iron deficiency. It is calculated by dividing the RBC count into the MCV. When the quotient is less than 13, thalassemia is more likely, and if the quotient is greater than 13, iron deficiency is more likely.19 Therefore, in the child with risk factors for iron deficiency, and a Mentzer index indicating iron deficiency, a trial of iron supplementation is warranted as outlined above. When the CBC is rechecked at four to six weeks, extra tubes of blood can be drawn and held depending on the CBC results. They can then be sent for hemoglobin electrophoresis or other clinically pertinent tests, if there has been an inadequate response to the iron supplementation trial.
Table 4. Relation of Red Cell Distribution Width and Mean Corpuscular Volume
|
Red cell distribution width |
Mean corpuscular volume |
||||
|
|
|
Low |
Normal |
High |
|
|
Normal (11.5 to 14.5)* |
Heterozygous α- or ß-thalassemia |
— |
Aplastic anemia |
|
|
|
|
Chronic disease |
Normal |
Preleukemia |
|
|
|
High (greater than 14.5) |
Iron deficiency, HgH disease or sickle-ß-thalassemia |
Chronic disease |
Folate deficiency |
|
|
|
|
|
Red cell fragmentation |
Liver disease |
Vitamin B12 deficiency |
|
HgH = hemoglobin H.
Other causes of microcytic anemia are lead poisoning and sideroblastic anemia. Lead poisoning is diagnosed in a child with elevated serum lead level. The acquired and hereditary forms of sideroblastic anemia are very rare in children.
Table 6. Clinical and Hematologic Features of the Principal Forms of Thalassemia
|
Type of thalassemia |
Globin-gene expression |
Hematologic features |
Clinical expressions |
Hemoglobin findings |
|
|
β-Thalassemias |
|
||||
|
|
β° homozygous |
β°/β ° |
Severe anemia; normoblastemia |
Cooley anemia |
HbF greater than 90 percent No HbA HbA2 increased |
|
|
β+ homozygous |
β+/β+ |
Anisocytosis, poikilocytosis; moderately severe anemia |
Thalassemia intermedia |
HbA: 20 to 40 percent HbF: 60 to 80 percent |
|
|
β° heterozygous |
β/β° |
Microcytosis, hypochromia, mild to moderate anemia |
May have splenomegaly, jaundice |
Increases HbA2 and HbF |
|
|
β+ heterozygous |
β/β+ |
Microcytosis, hypochromia, mild anemia |
Normal |
Increased HbA2 and HbF |
|
|
β silent carrier, heterozygous |
β/β+ |
Normal |
Normal |
Normal |
|
|
δβ heterozygous |
δβ/(δβ)° |
Microcytosis, hypochromia, mild anemia |
Usually normal |
HbF: 5 to 20 percent HbA2: normal or low |
|
|
γδβ heterozygous |
γδβ/(γδβ)° |
Newborn: microcytosis hemolytic anemia normoblastemia Adult: similar to heterozygous δβ |
Newborn: hemolytic disease with splenomegaly Adult: similar to heterozygous δβ |
Normal |
|
α -Thalassemias |
|||||
|
|
α silent carrier |
−, α/α,α |
Mild microcytosis or normal |
Normal |
Normal |
|
|
α trait |
−, α/−, α or −, − / α α |
Microcytosis, hypochromia, mild anemia |
Usually normal |
Newborn: Hb Barts (γ4) 5 to 10 percent Child or adult: normal |
|
|
HbH disease |
−, α /−, − |
Microcytosis, inclusion bodies by supravital staining; moderately severe anemia |
Thalassemia intermedia |
Newborn: Hb Barts (γ4) 20 to 30 percent Child or adult: HbH (β4) 4 to 20 percent |
|
|
α−hydrops fetalis |
−, −/ −, − |
Anisocytosis, poikilocytosis; severe anemia |
Hydrops fetalis; usually stillborn or neonatal death |
Hb Barts (y4) 80 to 90 percent; no HbA or HbF |
β= gene completely suppresses globin chain synthesis; β+ = gene produces a demonstrable globin chain product; HbF = fetal hemoglobin; HbA = normal adult hemoglobin; HbA2 = minor fraction of normal adult hemoglobin; HbH = hemoglobin H.
Adapted with permission from Nelson WE, Behrman RE, Kliegman R, Arvin AM, eds. Nelson Textbook of pediatrics. 15th ed. Philadelphia: Saunders,1996:1403.
NORMOCYTIC ANEMIAS
Determining a diagnosis of normocytic anemia in a child can be clinically difficult. First, obtain a reticulocyte count to determine whether there is decreased production or increased destruction of red blood cells. When there is increased destruction, the reticulocyte count will be high, the LDH and indirect bilirubin levels will increase, and there may be signs of red cell destruction on the peripheral smear (i.e., schistocytes, sickle cells, tear forms and poikilocytes). With decreased red cell production, the reticulocyte count will be depressed relative to the hemoglobin concentration. Depending on the severity of the anemia, the evaluation may ultimately warrant a bone marrow aspiration (Table 7).18(p1399)
The physiologic anemia of infancy is often confused with a pathologic condition. During the first weeks of life, erythropoietin synthesis abruptly decreases. In the ensuing six to eight weeks, the hemoglobin reaches a low point of 9 to
Table 7. Clinically Important Sickle Cell Syndromes
|
Sickle cell disorder |
Hemoglobin composition (%) |
HbA2 level |
Erythrocyte volume (MCV) |
Clinical severity |
Clinical features |
|
HbSS |
HbS: 80 to 95 |
Normal |
Normal |
+ + to + + + + |
Severe disease |
|
HbF: 2 to 20 |
|||||
|
HbS-β°-thalassemia |
HbS: 75 to 90 |
Increased |
Decreased |
+ + to + + + + |
Generally indistinguishable from SS |
|
HbF: 5 to 25 |
|||||
|
HbS-β+-thalassemia |
HbS: 5 to 85 |
Increased |
Decreased |
+ to + + + |
Generally milder than SS |
|
HbA: 10 to 30 |
|||||
|
HbF: 5 to 10 |
|||||
|
HbSS with α-thalassemia trait (−, α/ −, α) |
HbS: 80 to 90 |
Normal |
Decreased |
+ + to + + + + |
May be milder than SS |
|
HbF: 10 to 20 |
|||||
|
HbSC |
HbS: 45 to 50 |
Normal |
Normal |
+ to + + + |
Generally milder than SS; higher frequency of bone infarcts and proliferative retinal disease |
|
HbC: 45 to 50 |
|||||
|
HbF: 2 to 5 |
|||||
|
HbSo Arab |
HbS: 50 to 55 |
Normal |
Normal |
+ + to + + + + |
Generally indistinguishable from SS |
|
HbO: 40 to 45 |
|||||
|
HbF: 2 to 15 |
|||||
|
HbSD Los Angeles |
HbS: 45 to 50 |
Normal |
Normal |
+ + to + + + + |
May be as severe as SS |
|
HbD: 30 to 40 |
|||||
|
HbF: 5 to 20 |
|||||
|
HbS/HPFH* |
HbS: 65 to 80 |
Normal |
Normal |
0 to + |
Usually asymptomatic |
|
HbF: 15 to 30 |
|||||
|
HbAS* |
HbS: 32 to 45 |
Normal |
Normal |
0 to + |
Asymptomatic |
|
HbA: 52 to 65 |
HbA2 = normal adult hemoglobin; MCV = mean corpuscular volume; Hb = hemoglobin; HPFH = hereditary persisitence of fetal hemoglobin.
*— These conditions do not ordinarily produce sickle cell disease.
Adapted with permission from Nelson WE, Behrman RE, Kliegman R, Arvin AM, eds. Nelson Textbook of pediatrics. 15th ed. Philadelphia: Saunders, 1996:1399.
Infection with human parvovirus B19 (fifth disease) is a common cause of bone marrow suppression, typically causing four to eight days of aplasia.20 In healthy children, there are rarely hematologic complications; however, in children with sickle-cell disease or hereditary spherocytosis or elliptocytosis, the consequences of this viral-induced red cell aplasia can be catastrophic. This is because the average lifespan of a spherocyte or elliptocyte is markedly decreased from an average of 120 days to as low as 10 to 30 days. The circulating blood volume is therefore significantly more dependent on bone marrow production. Children with acute parvovirus infection are typically admitted to the hospital for intravenous immune globulin and blood transfusions if the anemia is symptomatic or severe (hemoglobin less than
Enzyme deficiencies, such as G6PD and pyruvate kinase are characterized by bouts of hemolysis during some form of stress. Deficiency of G6PD is the most common enzymopathy and is present in 13 percent of black males, 2 percent of black females and in some children of Mediterranean and Southeast Asian descent.22 In the case of G6PD deficiency, an oxidative stress may initiate a hemolytic anemia that can be dramatic. It will be manifested clinically by jaundice as well as other signs and symptoms of low hemoglobin levels. A reduced G6PD level will confirm the diagnosis but may be normal in the face of acute hemolysis. If this occurs, the test should be repeated several months after resolution of the episode. Currently, most hospitals test for G6PD and pyruvate kinase as part of newborn screening before discharge from the hospital.
MACROCYTIC ANEMIAS
Macrocytic anemias in children are relatively uncommon, but are usually caused by a deficiency of vitamin B12 and folate. Other possible causes include chronic liver disease, hypothyroidism and myelodysplastic disorders.
Folic acid deficiency is usually a secondary cause to inadequate dietary intake. Human and cow’s milk provide adequate sources of folic acid. The treatment of this deficiency is with parenteral or oral folate in a dosage of 1 to 3 mg once daily.23 A hematologic response to folate supplementation can be seen within 72 hours.
Vitamin B12 deficiency from nutritional deprivation is rare in the United States. Congenital pernicious anemia arises from the inability to secrete the gastric intrinsic factor. Neurologic symptoms become present at about nine months of age depending on vitamin B12 stores from birth.4 The preferred treatment is lifelong vitamin B12 supplementation.
Final Comment
The treatment modalities and diagnostic work-up for anemias in children have been well delineated. One major area for improvement in primary care is the prevention of iron deficiency, because it has been associated with permanent delays in psychomotor development. Appropriate screening and subsequent diagnostic testing will allow the family physician to appropriately diagnose most cases of anemia in children. Hematology referral is always appropriate for complicated or less defined cases.
The Authors
JOSEPH J. IRWIN, M.D., is in private practice in Ephrata, Pa. Dr. Irwin is a graduate of the University of Pennsylvania School of Medicine, Philadelphia, and completed a residency in family practice at Lancaster (Pa.) General Hospital.
JEFFREY T. KIRCHNER, D.O., is associate director of the family practice residency program at Lancaster General Hospital. Dr. Kirchner is a graduate of the Philadelphia College of Osteopathic Medicine and completed a residency in family practice at Abington (Pa.) Memorial Hospital. He is a former associate editor of American Family Physician.
Address correspondence to Joseph J. Irwin, M.D., Lancaster General Hospital, 555 W. Trout Run Rd., Ephrata, PA 17522 (e-mail: [email protected]). Reprints are not available from the authors.
The authors indicate that they do not have any conflicts of interest. Sources of funding: none reporte.
REFERENCES
1. Martin PL, Pearson HA. The anemias. In: Oski FA. Principles and practices of pediatrics. 2d ed. Philadelphia: Lippincott, 1994:1657.
2. U.S. Preventive Services Task Force. Guide to clinical preventive services. 2d ed. Baltimore: Williams & Wilkins, 1996.
3. Nathan DG, Orkin SH, Oski FA, Ginsburg D. Nathan and Oski’s Hematology of infancy and childhood. 5th ed. Philadelphia: Saunders, 1998:382.
4. Bessman JD, Gilmer PR, Gardner FH. Improved classification of anemias by MCV and RDW. Am J Clin Pathol. 1983803226.
5. Earl RO, Woteki CE. Iron deficiency anemia: recommended guidelines for the prevention, detection, and management among U.S. children and women of childbearing age. Washington, D.C.: National Academy Press, 1993.
6. Eden AN, Mir MA. Iron deficiency in 1- to 3-year-old children. A pediatric failure? Arch Pediatr Adolesc Med. 19971519868.
7. Siberry GK, Iannone R, eds. The Harriet Lane handbook. 15th ed. St. Louis: Mosby, 2000.
8. Oski FA. Iron deficiency in infancy and childhood. N Engl J Med. 19933291903.
9. Patton WN, Cave RJ, Harris RI. A study of changes in red cell volume and haemoglobin concentration during phlebotomy induced iron deficiency and iron repletion using the Technion H1. Clin Lab Haematol. 19911315361.
10. Bessman JD, Feinstein DI. Quantitative anisocy-tosis as a discriminant between iron deficiency and thalassemia minor. Blood. 19795328893.
11. Reeves JD. Prediction of therapeutic response to iron. In: Oski FA, Pearson HA, eds. Iroutrition revisited: infancy, childhood, adolescence. Columbus, Ohio: Ross Laboratories, 1981:114–25.
12. Walter T, DeAndraca I, Chadud P, Perales CG. Iron deficiency anemia. Pediatrics. 198984717.
13. Lozoff B, Brittenham GM, Wolf AW, McClish DK, Kuhnert PM, Jimenez E, et al. Iron deficiency anemia and iron therapy effects on infant developmental test performance. Pediatrics. 19877998195[Published erratum appears in Pediatrics 1988;81:683]
14. Lozoff B, Jimenez E, Wolf AW. Longterm developmental outcome of infants with iron deficiency. N Engl J Med. 199132568794.
15. Ben-Shachar D, Ashkenazi R, Youdim MB. Long-term consequences of early iron-deficiency on dopaminergic neurotransmission in rats. Int J Dev Neurosci. 19864818.
16. Yehuda S, Youdim ME, Mostofsky DI. Brain iron-deficiency causes reduced learning capacity in rats. Pharmacol Biochem Behav. 1986251414.
17. American Academy of Pediatrics Committee on Nutrition. The use of whole cow’s milk in infancy. Pediatrics. 19928911059.
18. Nelson WE, Behrman RE, Kliegman R, Arvin AM, eds. Nelson Textbook of pediatrics. 15th ed. Philadelphia: Saunders, 1996.
19. Mentzer WC. Differentiation of iron deficiency from thalassemia trait. Lancet. 19731882.
20. Brown KE, Young NS. Parvoviruses and bone marrow failure. Stem Cells. 19961415163.
21. Koch WC. Parvovirus B19. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of pediatrics. 16th ed. Philadelphia: Saunders, 2000:964–6.
22. Segel GB. Enzymatic defects. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of pediatrics. 16th ed. Philadelphia: Saunders, 2000:1488–91.
23. Schwartz E. Anemias of inadequate production. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of pediatrics. 16th ed. Philadelphia: Saunders, 2000:1463–72.
Iron deficiency anemia – children
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Anemia is a condition in which the body does not have enough healthy red blood cells. Red blood cells bring oxygen to body tissues.
There are many types of anemia. Iron deficiency anemia is a decrease in the number of red blood cells in the blood due to a lack of iron.
This article focuses on iron deficiency anemia in children.
Causes
Iron deficiency anemia is the most common form of anemia. You get iron through certain foods, and your body also reuses iron from old red blood cells.
Iron deficiency (too little iron) may be caused by:
· An iron-poor diet (this is the most common cause)
· Body not being able to absorb iron very well, even though you’re eating enough iron
· Long-term, slow blood loss — usually through menstrual periods or bleeding in the digestive tract
· Rapid growth (in the first year of life and in adolescence), when more iron is needed
Babies are born with iron stored in their bodies. Because they grow rapidly, infants and childreeed to absorb an average of 1 mg of iron per day.
Since children only absorb about 10% of the iron they eat, most childreeed to receive 8-10 mg of iron per day. Breastfed babies need less, because iron is absorbed 3 times better when it is in breast milk.
Cow’s milk is a common cause of iron deficiency. It contains less iron than many other foods and also makes it more difficult for the body to absorb iron from other foods. Cow’s milk also can cause the intestines to lose small amounts of blood.
The risk of developing iron deficiency anemia is increased in:
· Infants younger than 12 months who drink cow’s milk rather than breast milk or iron-fortified formula
· Young children who drink a lot of cow’s milk rather than eating foods that supply the body with more iron
Iron deficiency anemia most commonly affects babies 9 – 24 months old. All babies should have a screening test for iron deficiency at this age. Babies born prematurely may need to be tested earlier.
Iron deficiency in children also can be related to lead poisoning.
Symptoms
· Blue-tinged or very pale whites of eyes
· Blood in the stools
· Decreased appetite (especially in children)
· Fatigue
· Headache
· Irritability
· Pale skin color (pallor)
· Sore tongue
· Unusual food cravings (called pica)
· Weakness
Note: There may be no symptoms if anemia is mild.
Exams and Tests
The health care provider will perform a physical exam. A blood sample is taken and sent to a laboratory for examination. Iron-poor red blood cells appear small and pale when looked at under a microscope.
Tests that may be done include:
· Total iron binding capacity (TIBC)
A measurement called iron saturation (serum iron/TIBC) often can show whether you have enough iron in your body.
Treatment
Treatment involves iron supplements (ferrous sulfate), which are taken by mouth. The iron is best absorbed on an empty stomach, but many people need to take the supplements with food to avoid stomach upset. Another way to increase iron absorption is to take it together with vitamin C.
If you cannot tolerate iron supplements by mouth, you may get iron by injection into a muscle or through a vein (IV).
Milk and antacids can interfere with iron absorption and should not be taken at the same time as iron supplements.
Iron-rich foods include raisins, meats (especially liver), fish, poultry, egg yolks, legumes (peas and beans), and whole-grain bread.
Outlook (Prognosis)
With treatment, the outcome is likely to be good. In most cases, the blood counts will return to normal in 2 months. It is essential to determine the cause of the iron deficiency. If it is being caused by blood loss other than monthly menstruation, further investigation will be needed.
You should continue taking iron supplements for another 6 to 12 months after blood counts return to normal, or as your health care provider recommends. This will help the body rebuild its iron storage.
Iron supplementation improves learning, memory, and cognitive test performance in adolescents who have low levels of iron. Iron supplementation also improves the performance of athletes with anemia and iron deficiency.
Possible Complications
Iron deficiency anemia can affect school performance. Low iron levels are an important cause of decreased attention span, reduced alertness, and learning difficulties, both in young children and adolescents.
Excess amounts of lead may be absorbed by people with iron deficiency.
Prevention
The American Academy of Pediatrics (AAP) recommends that all infants be fed breast milk or iron-fortified formula for at least 12 months. The AAP does NOT recommend giving cow’s milk to children under 1 year old.
Diet is the most important way to prevent and treat iron deficiency.
Good sources of iron include:
· Apricots
· Kale and other greens
· Oatmeal
· Prunes
· Raisins
· Spinach
· Tuna
Better sources of iron include:
· Chicken and other meats
· Dried beans and lentils
· Eggs
· Fish
· Molasses
· Peanut butter
· Soybeans
· Turkey
The best sources of iron include:
· Baby formula with iron
· Breast milk (the iron is very easily used by the child)
· Infant cereals and other iron-fortified cereals
· Liver
· Prune juice
Alternative Names
Anemia – iron deficiency – children
References
Glader B. Iron-deficiency anemia. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, Pa: Saunders Elsevier; 2007: chap 455.
Stettler N, Bhatia J, Parish A, Stallings VA. Feeding healthy infants, children, and adolescents. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 19th Ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap 42.
O’Connor NR. Infant formula. Am Fam Physician. 2009;79:565-570.
Pediatric Acute Anemia
Background
Pediatric anemia refers to a hemoglobin or hematocrit level lower than the age-adjusted reference range for healthy children. Physiologically, anemia is a condition in which reduced hematocrit or hemoglobin levels lead to diminished oxygen-carrying capacity that does not optimally meet the metabolic demands of the body. (See Etiology.)
Anemia is not a specific disease entity but is a condition caused by various underlying pathologic processes. It may be acute or chronic. This article provides a general overview of anemia, with an emphasis on the acute form. In addition, conditions are emphasized in which anemia is the only hematologic abnormality. The combination of anemia with leukopenia, neutropenia, or thrombocytopenia may suggest a more global failure of hematopoiesis, caused by conditions such as aplastic anemia, Fanconi anemia, myelofibrosis, or leukemia, or may suggest a rapid destruction or trapping of all blood elements, such as hypersplenism, localized coagulopathy in a large hemangioma, or hemophagoctic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). (See Etiology.)
The main physiologic role of red blood cells (RBCs) is to deliver oxygen to the tissues. Certain physiologic adjustments can occur in an individual with anemia to compensate for the lack of oxygen delivery. These include (1) increased cardiac output; (2) shunting of blood to vital organs; (3) increased 2,3-diphosphoglycerate (DPG) in the RBCs, which causes reduced oxygen affinity, shifting the oxygen dissociation curve to the right and thereby enhancing oxygen release to the tissues; and (4) increased erythropoietin to stimulate RBC production.
The clinical effects of anemia depend on its duration and severity. When anemia is acute, the body does not have enough time to make the necessary physiologic adjustments, and the symptoms are more likely to be pronounced and dramatic. In contrast, when anemia develops gradually, the body is able to adjust, using all 4 mechanisms mentioned above (1, 3, and
Please see the following for more information:
· Anemia
· Emergent Management of Acute Anemia
Complications
Acute and severe anemia can result in cardiovascular compromise. Moreover, if individuals with acute anemia are not treated immediately and appropriately, the resulting hypoxemia and hypovolemia can lead to brain damage, multiorgan failure, and death. Long-standing anemia can result in failure to thrive. (See Prognosis.)
Many studies have shown the deleterious effects of iron deficiency anemia or iron deficiency without anemia on the neurocognitive and behavioral development in children. Other complications can include congestive heart failure, hypoxia, hypovolemia, shock, seizure, and acute silent cerebral ischemic event (ASCIE; see Magnetic resonance imaging in research settings in Workup).[1]
Patient education
Girls with heavy and/or prolonged menstrual periods should seek medical attention (should tell parents to obtain CBC count). One of the most common reasons for fainting spell or syncope in adolescent girls is rapidly developing anemia due to menstrual blood loss.
Toddlers who drink more than
Children diagnosed with anemia should be taught to look at their stool color and to report to their parents if it is tarry or bloody.
Educate the patient and/or the family about the specific disease that causes the anemia. For example, provide a list of drugs, food, and other agents to avoid because of their effect of triggering acute hemolysis in glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.
In pediatrics beyond the immediate neonatal period, acute anemia is rare in otherwise healthy children. In most instances, it is due to blood loss usually through the GI tract or via a heavy menstrual period. The most common reason for hospitalization because of acute anemia is due to the so-called aplastic crisis in children with chronic hemolytic anemia who otherwise had been stable. The most common varieties are herediatrary spherocytosis and sickle cell disease. Therefore, it would be prudent to educate parents regarding this complication, at the time when the diagnosis is established.
Etiology
Causes of anemia are either inherent in the RBCs or related to an external factor. The underlying pathologic processes that cause anemia can be broadly categorized as (1) decreased or ineffective red cell production, (2) increased red cell destruction (hemolysis), and (3) blood loss, although more than 1 mechanism may be involved in some anemias.
Anemia caused by decreased red cell production
This generally develops gradually and causes chronic anemia. Marrow failure may result from the following:
· Diamond-Blackfan anemia (congenital pure red cell aplasia)
· Transient erythroblastopenia of childhood
· Aplastic crisis caused by parvovirus B19 infection (in patients with an underlying chronic hemolytic anemia)
· Marrow replacement (eg, leukemia, neuroblastoma, medulloblastoma, retinoblastoma, Ewing sarcoma, soft tissue sarcoma, myelofibrosis, osteopetrosis)
· Aplastic anemia
· Paroxysmal nocturnal hemoglobinuria (PNH)
Impaired erythropoietin production may result from the following:
· Anemia of chronic disease in renal failure
· Chronic inflammatory diseases
· Hypothyroidism
· Severe protein malnutrition
Defect in red cell maturation and ineffective erythropoiesis may result from the following:
· Nutritional anemia secondary to iron, folate, or vitamin B-12 deficiency
· Congenital dyserythropoietic anemia
· Erythropoietic protoporphyria
· Myelodysplastic syndromes[2]
Anemia caused by increased red cell destruction
Extracellular causes may include the following:
· Mechanical injury (hemolytic-uremic syndrome, cardiac valvular defects, Kasabach-Merritt phenomenon or hemangioma with thrombocytopenia)
· Antibodies (autoimmune hemolytic anemia)
· Infections, drugs, toxins
· Thermal injury to RBCs (with severe burns)
Intracellular causes may include the following:
· Red cell membrane defects (eg, hereditary spherocytosis, elliptocytosis)
· Enzyme defects (eg, G-6-PD deficiency, pyruvate kinase deficiency)
· Hemoglobinopathies (sickle cell disease, unstable hemoglobinopathies)
· PNH
Anemia caused by blood loss
Obvious or occult sites of blood loss may include the GI tract or intra-abdominal, pulmonary, or intracranial (in neonates) sites. Patients with bleeding disorders are at particular risk for massive hemorrhage (internal or external).
Acute anemia caused by multiple mechanisms
Anemia associated with acute infection is common. This may be mediated by increased destruction by erythrophagocytosis[3] and suppression of erythropoiesis by the infection.
Epidemiology
In adolescents and adults, normal values for the hemoglobin and hematocrit levels vary according to sex. Racial differences are also apparent, with black children having lower normal values than white and Asian children of the same age and socioeconomic background.
Occurrence in the United States
Among all races, ages, and socioeconomic groups studied, an overall steady decline (from 7.8% in 1975 to 2.9% in 1985) in prevalence of anemia in the US pediatric population (aged 6 mo to 6 y) has been observed. Data showed continued decline in the prevalence of anemia from the mid-1980s to the mid-1990s.[4] Iron deficiency is the most common etiology.
International occurrence
In developing nations, the prevalence of anemia is extremely high. This is particularly true in preschool-aged children, in whom the prevalence reached as high as 90% of the sample population studied. Although iron deficiency is identified as the major factor, the etiology is often multifactorial, including recurrent or chronic infections (bacteria, parasites), malnutrition, and reduced immunity.
In addition, the prevalence of certain hereditary forms of anemia (eg, thalassemia, sickle cell disease) varies with ethnicity and, thus, with geography. For instance, α thalassemia, which may be the most common single gene disorder in the world, has a frequency of as much as 68% in the southwest Pacific, 20-30% in western Africa, and 5-10% in the Mediterranean region. Beta thalassemia mutations have high frequencies in the Mediterranean, northern Africa, Southeast Asia, and India, but they have low frequencies in Great Britain, Iceland, and Japan.
Racial-related demographics
Acute anemia is universal, but the likely underlying etiologies are influenced by race. Inherited red cell disorders are predominant in certain racial populations, such as sickle cell disease in black persons, β thalassemia in persons of Mediterranean ethnicity, and α thalassemia in Asians, African Americans, and others.[5]
Sex-related demographics
Sex predisposition to anemia varies according to the underlying etiology. For instance, certain hereditary X-linked red cell disorders (eg, G-6-PD deficiency) are observed in males. Anemia caused by blood loss can be observed in males with an X-linked bleeding disorder (eg, hemophilia).
Females with the autosomally inherited von Willebrand disease may be anemic because of heavy blood loss during menstruation. Even without this disorder, they have a high risk of developing iron deficiency and iron deficiency anemia, quite often worsened by acute blood loss. Acquired hemolytic anemia related to autoimmune disorders such as systemic lupus erythematosus is more common in females because of their relative predisposition to autoimmune disease.
Age-related differences in incidence
Acute anemia most commonly occurs among newborns. Significant blood loss can occur from birth trauma or blood exchange from the baby’s mother (feto-maternal transfusion) or the placenta. Isoimmune anemia can result from maternal antibodies crossing the placenta. Neonates have a shorter red cell life span and limited erythropoiesis that can aggravate any hemolytic process. Abnormalities of fetal hemoglobin may cause anemia that resolves with the normal shift to adult-type hemoglobins. Deletion of α globin gene, unlike β globin gene mutation, causes anemia in neonates. Hemoglobin H disease is a good example (ieonates Hb Barts is the abnormal hemoglobin rather than Hb H).
Nutritional anemia is common in infancy because of the associated rapid growth (necessitating an increase in red blood cell mass) and dietary adjustments.
With exposure to new infections in early childhood, the anemia of acute infection is common. Rarely, severe autoimmune hemolytic anemia can be triggered by certain infections. Adolescence is characterized by rapid growth and vulnerability to nutritional anemia. In addition, blood loss with heavy menstruation can be observed in adolescent girls.
Prognosis
The prognosis depends on the severity and acuteness with which the anemia develops and the underlying cause of the anemia.
Mortality and morbidity rates vary according to the underlying pathologic process causing the anemia, the degree of severity, and the acuteness of the process. When a precipitous drop in the hemoglobin or hematocrit level occurs (eg, due to massive bleeding or acute hemolysis), the clinical presentation is typically dramatic and can be fatal if the person is not immediately treated. In addition to the signs and symptoms of anemia, patients can present with congestive heart failure (CHF) or hypovolemia. Cerebral injury has been reported in perioperative patients with anemia.[6]
History
The acute development of anemia in the pediatric age group commonly occurs in 2 situations, (1) acute blood loss and (2) acute hemolysis.
Acute blood loss
Ieonates, blood loss can occur through the placenta, abruption, placenta previa, and fetomaternal transfusion. The former 2 can be known by history, while fetomaternal transfusion cannot be discerned from history findings. Iatrogenic blood loss through multiple blood samplings in extremely low birth weight infants can cause anemia rapidly.
In older children, the GI tract is the most common site of blood loss; common causes include esophageal and gastric varices (inquire about a history of umbilical vein catheterization during neonatal ICU stay), ulcerative colitis, and Crohn disease. Menstruating girls’ blood loss due to dysmenorrhea is an extremely common cause of acute blood loss (may or may not be associated with von Willebrand disease; ask about easy bruisability, frequent epistaxis, and family history of similar bleeding history).
A history of trauma is important (eg, rupture of spleen)
Rapid hemolysis
When taking the history, keep the following factors in mind:
· Isoimmune or alloimmune hemolytic anemia (ABO incompatibility or Rh incompatibility ieonates) – (1) Mother’s blood group (ABO) and type (Rh); (2) minor Rh antigen incompatibility such as c, E, may cause severe hemolytic anemia (even if there is no ABO or D incompatibility), therefore do direct antiglobulin test (DAT) whenever there is a suspicion
· Autoimmune hemolytic anemia – (1) History of a viral infection such as mycoplasma or Ebstein-Barr virus (EBV) may precede paroxysmal cold hemoglobinuria; (2) an infection with Streptococcuspneumoniae may cause autoimmune hemolytic anemia due to exposure of cryptic T antigen on the red blood cells by the bacterial neuraminidase
· Transfusion reaction due to major blood group incompatibility – Usually due to clerical error or misidentification of patient delayed transfusion reaction due to previously unrecognized antibodies to red blood cell antigens (may occur a few days to 1 wk after previous transfusion)
· Ingestion of strong oxidants in a child with G-6-PD deficiency – Ingestion or sniffing of a mothball is most common
· Splenic sequestration in a child with sickle cell anemia or hereditary spherocytosis – Sudden onset of severe abdominal pain; shocklike state with a drop in hemoglobin and platelet count
Other history considerations
Symptoms of anemia include pallor, fatigue, lethargy, dizziness, and anorexia. Jaundice and, occasionally, dark urine may be present with significant hemolysis. Syncope and fainting is quite common in a teenager.
Patients with acute anemia are overtly symptomatic when the condition is severe, whereas those with chronic anemia may go undiagnosed because they are asymptomatic relative to the degree of anemia.
Age is an important clue to the etiology of the anemia. For example, blood loss, isoimmunization, and congenital red cell disorders are common causes of anemia iewborns. Although observed in older infants, toddlers, and adolescent girls, iron deficiency anemia is unlikely iewborns or infants in whom iron stores from the mother are usually adequate and in prepubertal school-aged children in whom no rapid growth and expansion of blood volume occurs.
Review dietary history, including milk intake in infants and toddlers and the sources of other nutrients (eg, iron, folate, vitamin B-12). Note details about sources of blood loss, recent infections, travel, drug exposures, chemicals (eg, lead), toxins, and oxidants. Inquire about symptoms of hypothyroidism (eg, cold intolerance, constipation, lethargy, poor growth).
Inquire regarding a neonatal history of anemia, jaundice, phototherapy, transfusion, any other chronic medical illnesses or complaints, and medications.
When reviewing the family history, include questions regarding anemia, jaundice, gallbladder surgery, splenomegaly or splenectomy, autoimmune diseases, or a bleeding disorder.
Physical Examination
Check vital signs. Patients with acute and severe anemia appear in distress, with tachycardia, tachypnea, and hypovolemia. Patients with chronic anemia are typically well compensated and usually asymptomatic.
To evaluate chronicity, plot growth parameters; this may affect the urgency of treatment. Also, note pallor, jaundice, edema, and signs of bleeding (eg, stool occult blood, frequent epistaxis, petechiae, bruising).
Patients with significant anemia often have a systolic ejection murmur. Look for signs of congestive heart failure (CHF), such as tachycardia, gallop rhythm, tachypnea, cardiomegaly, wheezing, cough, distended neck vein, and hepatomegaly.
Splenomegaly can be found in many hemolytic anemias or may reflect infiltration in malignancy. In young patients with sickle cell disease, splenic sequestration can manifest with a sudden enlargement of the spleen and/or abdominal pain and distension together with an exacerbation of anemia and thrombocytopenia. Passive congestion of the spleen may complicate CHF.
Note any dysmorphic features and other congenital anomalies. Facial bony prominences (eg, frontal bossing) are signs of extramedullary hematopoiesis associated with chronic, severe, hemolytic anemias and thalassemias. Some congenital bone marrow failure syndromes (eg, Diamond-Blackfan anemia and Fanconi anemia) are associated with facial, limb, and other anomalies. Signs of hypothyroidism include low body temperature, failure to thrive, dry skin, constipation, and thinning of the hair.
Diagnostic Considerations
Conditions to consider, aside from those in the next section, in the differential diagnosis of acute anemia include the following:
· Acute hemorrhage
· Anemia of inflammation/infection
· Aplastic anemia, due to blood loss
· Autoimmune hemolytic anemia with acute hemolysis
· Erythrophagocytosis (hemophagocytic lymphohistiocytosis [HLH])
· G-6-PD deficiency, hemolytic episode
· Hereditary spherocytosis, splenic sequestration, or acute hemolytic episode
· Microangiopathic hemolytic anemia (DIC, Kasabach-Merritt phenomenon)
· Paroxysmal cold hemoglobinuria
· Paroxysmal nocturnal hemoglobinuria (PNH)
· Hemolytic disease of newborn
· Hemolytic-uremic syndrome
· Acute porphyria
Conditions to consider, aside from those in the next section, in the differential diagnosis of chronic anemia include the following:
· Chronic renal failure
· Congenital dyserythropoietic anemia
· Fanconi anemia
· Iron deficiency anemia
· Diamond-Blackfan anemia
· Osteopetrosis
· Sideroblastic anemia
· Unstable hemoglobinopathy
· Thymoma
· Transient erythroblastopenia of childhood
· Pyruvate kinase deficiency
· Evans syndrome (ITP and autoimmune hemolytic anemia)
· Hemoglobin H disease
· Hypothyroidism
· Myelofibrosis
· Aplastic or hypoplastic anemia
· Autoimmune hemolytic anemia
· Pure red cell aplasia
· PNH
Many anemias may be due to a combination of several mechanisms. For example, anemia due to acute infection is due to temporal suppression of erythropoiesis and some degree of hemolysis.
Differential Diagnoses
· Hereditary Elliptocytosis and Related Disorders
· Paroxysmal Cold Hemoglobinuria
· Systemic Lupus Erythematosus
Approach Considerations
To evaluate anemia, obtain initial laboratory tests, including the complete blood count (CBC), reticulocyte count, and review of the peripheral smear. (See the diagram below.)
An overwhelming majority of acute anemia is normocytic, although marked reticulocytosis may raise mean corpuscular volume (MCV). If microcytic, it has an underlying chronic anemia component, and one needs to know the cause.
Algorithm for diagnostic approach and workup of anemia in children. Hb=hemoglobin; Hct=hematocrit; HS=hereditary spherocytosis; HE=hereditary elliptocytosis; G-6-PD=glucose-6-phosphate dehydrogenase; PK=pyruvate kinase; HUS=hemolytic uremic syndrome; TTP=thrombotic thrombocytopenic purpura; DIC=disseminated intravascular coagulation; DBA=Diamond-Blackfan anemia.
Chest radiography is performed in patients who may have CHF and to rule out mediastinal mass (associated with acute leukemia).
Abdominal ultrasonography is used to assess for gallstones or splenomegaly in hemolytic anemia, while computed tomography (CT) scanning is used to evaluate occult bleeding in blunt trauma (eg, splenic rupture, subcapsular hemorrhage of the liver) or a bleeding disorder. Abdominal Doppler study is used to detect portal vein thrombosis.
Radioactively tagged RBC radionuclide scans are occasionally used to localize the site of GI bleeding when the source is unclear (a common example in pediatrics is the Meckel scan, used in the diagnosis of Meckel diverticulum).
Family studies, such as sending the CBC count, smear review, and hemoglobin electrophoresis from parents, may be helpful in making a diagnosis of conditions such as hereditary spherocytosis or thalassemia.
Rarely indicated in isolated acute anemia, bone marrow aspiration and biopsy are indicated in the evaluation of possible bone marrow failure or malignancy. Suppression of the platelet count or white blood cell (WBC; neutrophil) count, in association with anemia, often warrants an examination of the bone marrow.
Magnetic resonance imaging in research settings
Recently an MRI change termed acute silent cerebral ischemic events (ASCIE) in patients who developed acute anemia with and without sickle cell disease has been described.[1] The MRI abnormality is detected by diffusion-weighted imaging. The lesion may be temporary or long-lasting. If it is a permanent MRI lesion and the patient has no over clinical symptoms attributable to that lesion, then it is called a silent infarct. The fact that it occurs in children without sickle cell disease may indicate that in acutely severely anemic children regardless of the cause, ASCIE may not be a very rare event, and it does raise a question if some of these lesions are permanent and may cause subtle neurological dysfunction. Although MRI cannot be a routine imaging study for acute severe anemia, it may be a worthwhile test under a research setting.
Complete Blood Count
Base interpretation of the hemoglobin and hematocrit levels on the reference range for the specific age group. Some laboratories provide only a uniform reference range for the entire pediatric age group and not for specific age groups. Hemoglobin and hematocrit levels can be used interchangeably, depending on professional preference and familiarity. Essentially, the hematocrit level is 3 times the hemoglobin value.
If the patient is anemic, look at the red cell indices (mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH] and mean corpuscular hemoglobin concentration [MCHC]). Note that reference ranges for these parameters also vary with age. Of these, the MCV is particularly helpful in classifying anemia. Microcytic anemia suggests iron deficiency, lead poisoning, or thalassemia; macrocytosis suggests folate/B-12 deficiency or reactive reticulocytosis.
Another valuable parameter in classifying anemia is the RBC distribution width (RDW). This is the statistical description of the heterogeneity of RBC sizes. It is increased in anisocytosis (variable sizes of red cells), such as when increased reticulocytes are present.
Reticulocyte Count
Reticulocytes are immature, nonnucleated RBCs that indicate active erythropoiesis. The relative reticulocyte count is useful in differentiating whether the anemia is caused by decreased production, increased destruction, or loss of RBCs. An elevated number of reticulocytes (eventually) is observed in individuals with anemia caused by hemolysis or blood loss; note that the absence of reticulocytosis may simply reflect a “lag” in the response to the acute onset of anemia. Note that in some autoimmune hemolytic anemias, reticulocytopenia is present due to lysis of reticulocytes by the same antibodies.
The term reticulocyte count is often used inaccurately to refer to the percentage of reticulocytes, a value that must be interpreted in light of the degree of anemia. Thus, a finding of 2-3% reticulocytes (vs the normal value of approximately 1%) in a patient whose hemoglobin is only one third to one half of normal does not indicate a reticulocyte “response.” Some clinicians prefer to use either the absolute number of reticulocytes per µL of blood or a reticulocyte percentage “corrected” for the degree of anemia, as follows: corrected reticulocyte count = patient hematocrit/normal hematocrit x %reticulocyte count.
Peripheral Smear
Examination of the peripheral smear helps to identify the cause of the anemia through recognition of abnormal cell morphology (this is particularly helpful iormocytic anemia). The following are examples of abnormal cell morphology:
· Schistocytes or fragmented cells (microangiopathic hemolytic anemia)
· Spherocytes (hereditary spherocytosis, autoimmune hemolytic anemia)
· Ghost, helmet, blister, or bite cells (G-6-PD deficiency)
· Sickle-shaped cells (sickle cell disease)
· Target cells (hemoglobin C): These can be seeonspecifically in other conditions, such as thalassemia, other hemoglobinopathies, and with liver disease; however, hemoglobin C is the classic, most common example
· Stippled red blood cells (nonspecific, but may suggest lead poisoning; occurs in any condition with reticulocytosis)
· Increased polychromasia (reticulocytosis)
· Crenated or spiculated cells (liver disease, uremia, abetalipoproteinemia)
Recognizing that normal RBC morphology does not rule out hemolysis is important.
Additional Laboratory Tests
Additional laboratory tests that may be indicated in the diagnosis and treatment of patients with acute anemia include the following:
· Bilirubin level, lactate dehydrogenase (hemolytic anemia)
· Direct antiglobulin or Coombs test (autoimmune hemolytic anemia)
· Hemoglobin electrophoresis (hemoglobinopathies) (many unstable hemoglobins, such as Hb KÖLN, cannot be detected by hemoglobin electrophoresis)
· Red cell enzyme studies (eg, G-6-PD, pyruvate kinase)
· Osmotic fragility (spherocytosis)
· Iron, total iron-binding capacity (TIBC), ferritin (iron deficiency anemia)
· Folate, vitamin B-12 (macrocytic/megaloblastic anemia)
· Blood typing and crossmatching to assess possible isoimmune anemia in a neonate and to prepare for transfusion
· Bone marrow aspiration and biopsy
· Viral titers (eg, Epstein-Barr virus, cytomegalovirus)
· Blood urea nitrogen (BUN) and creatinine levels to assess renal function
· Thyroxine (T4)/thyroid-stimulating hormone (TSH) to rule out hypothyroidism
· “Fetaldex test” on maternal blood (Kleihauer-Betke test), when fetomaternal transfusion is suspected
· Stool for occult blood (on multiple specimens)
Approach Considerations
Acute anemia usually warrants immediate medical attention. Treatment depends on the severity and underlying cause of the anemia.
Initial treatment begins with careful assessment of the signs and symptoms of the anemia that indicate therapy. Guidelines for the treatment of patients with critical illness apply to children with severe anemia who are in acute distress and unstable. Supportive measures, such as supplemental oxygen for decreased oxygen-carrying capacity, fluid resuscitation for hypovolemia, and bed rest or activity restriction for fatigue, may be required. Inpatient care is indicated in patients with CHF who are severely anemic and in those with unstable vital signs (eg, hypotension, active bleeding). Most of these patients require admission to the intensive care unit (ICU). Patients who may be stable but who have severe anemia may also be admitted for diagnostic workup.
Except in cases of uncontrolled hemorrhage, surgery is very rarely indicated in acute anemia. Splenectomy is occasionally considered in persons with autoimmune hemolytic anemia that is refractory to medical treatment.
Activity restriction or bed rest may be indicated in symptomatic individuals with severe anemia.
Transfusion
Transfusion with packed RBCs (PRBC) is the universal treatment for most individuals with severe acute anemia. The British Committee for Standards in Hematology Transfusion Task Force has established guidelines for transfusions ieonates and older children.[7] and its amendments[8] The indication to transfuse should not be based solely on the hemoglobin or hematocrit levels; more importantly, one must consider the clinical effects or the signs and symptoms of the individual with anemia.[9]
A recently published article summarizing 19 randomized controlled studies in adults concluded that transfusions at a low Hb threshold level (7-9) compared with transfusions at a high Hb threshold level (9-13.3) showed a significantly reduced risk of 30-day all-cause mortality.[10] In another adult study with acute GI hemorrhage, restricted blood transfusion (Hb threshold of 7) versus a liberal transfusion strategy resulted in significantly reduced morbidity and mortality in the former group of patients.[11] While these are adult studies, the same principle may apply to children. Thus, one may consider these clear-cut study results when considering blood transfusion for a patient.
If transfusion is indicated, the packed RBC (PRBC) dose is 10-15 mL/kg over 3-4 hours. The rate of transfusion can be modified according to the clinical situation. Transfusion can be administered faster in individuals with acute blood loss or slower or in smaller aliquots in persons with CHF. Be aware of the risks of of inciting heart failure by rapid transfusion in patients with severe chronic anemia and patients in a compromised cardiovascular state.
In individuals with autoimmune hemolytic anemia, blood must be given with extreme caution, using the blood unit that is least reactive on crossmatch.
Consultations
Except for patients who have acute anemia secondary to blood loss from obvious trauma or injury, a hematology consultation is ideal for most patients with acute anemia to determine the underlying RBC disorder and provide the appropriate therapy.
In particular, the following features in an individual with acute anemia indicate the need for a hematology consultation:
· Concomitant abnormality in WBC and/or platelet counts (eg, neutropenia, thrombocytopenia, presence of immature WBCs)
· Positive Coombs test result
· Hepatosplenomegaly
· History of underlying hematologic disorder
· Excessive blood loss relative to the degree of injury in individuals who may have an underlying bleeding disorder
Consider a gastroenterology consult for GI blood loss, particularly in suspected esophageal varices, inflammatory bowel disease, and other conditions.
Consider a surgical consult for possible trauma to spleen, liver, and/or kidneys.
Medication Summary
Medications for specific forms of anemia may be indicated in addition to blood transfusion (eg, corticosteroids for autoimmune hemolytic anemia, iron therapy for iron deficiency anemia).
Recombinant erythropoietin has been available for the treatment of certain forms of anemia. Its use can allow for avoidance or minimization of the need for blood transfusion. Indications include anemias of chronic disease (eg, renal failure), chemotherapy, acquired immunodeficiency syndrome (AIDS) treatment, preparation for surgery with anticipated significant blood loss, prematurity,[12] and hyporegenerative anemia of erythroblastosis fetalis. It is important to note that erythropoietin is not indicated for the immediate correction of anemia. The correction of anemia with erythropoietin occurs after about 2-8 weeks.
Blood Products
Class Summary
The goal of therapy in acute anemia is to restore the hemodynamics of the vascular system and replace lost red-blood cells. To achieve this, the practitioner may use blood transfusions. Major complications of acute anemia can be prevented by providing timely transfusion to restore hemoglobin to safe levels.
Packed red blood cells
Packed red blood cells (PRBCs) are used preferentially to whole blood since they limit volume, immune, and storage complications. PRBCs have 80% less plasma, are less immunogenic, and can be stored about 40 days (versus 35 days for whole blood). PRBCs are obtained after centrifugation of whole blood. Whole blood is not available in many blood banks.
Corticosteroids
Class Summary
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body’s immune response to diverse stimuli. They may be used in autoimmune hemolytic anemia.
Prednisolone (Prelone, Millipred)
Prednisolone decreases autoimmune reactions, possibly by suppressing key components of the immune system.
Dosing Forms & Strengths
Inflammation
0.1-2 mg/kg/day PO in single daily dose or divided q6hr or q12hr; not to exceed 80 mg/day
Acute Asthma
1-2 mg/kg/day in single daily dose or divided q12hr for 3-5 days
Nephrotic Syndrome
First 4 weeks: 60 mg/m²/day or 2 mg/kg/day PO divided q8hr; not to exceed 80 mg/day
Subsequent 4 weeks: 40 mg/m² or 1-1.5 mg/kg PO every other day; not to exceed 80 mg/day
Maintenance in frequent relapses: 0.5-1 mg/kg PO every other day for 3-6 months
Treatment may have to be individualized
Methylprednisolone (Depo Medrol, Medrol, Solu-Medrol)
This agent is used for initial management of acute hemolytic anemia. Intravenous methylprednisolone is recommended when the most rapid and reliable treatment of hemolytic anemia is required.
ron Salts
Class Summary
Iron salts are used for treating patients with iron deficiency anemia.
Ferrous Sulfate (Feosol, Fer-Iron, Slow FE)
Dosing Forms & Strengths
Iron-deficiency Anemia, Treatment
Dosage recommendations expressed as elemental iron
Preemie: 2-4 mg Fe/kg/day PO divided q12hr, not to exceed 15 mg/day
Children: 3-6 mg Fe/kg/day PO divided q8hr
Iron-deficiency Anemia, Prophylaxis
Preemie: 2 mg Fe/kg/day PO divided q8hr, not to exceed 15 mg/day
Children: 1-2 mg Fe/kg/day PO divided q8hr, not to exceed 15 mg/day
Recommended Daily Allowance
Males >10 years old: 12 mg/day Fe PO
Females >10 years old: 15 mg/day Fe PO
Administration
For maximum absorption take on empty stomach, but may take with or after meals to minimize GI irritation
Vitamin C may enhance absorption
Iron salts are used as building blocks for hemoglobin synthesis in treating anemia. They allow transportation of oxygen via hemoglobin and are necessary for oxidative processes of living tissue. Treatment should continue for about 2 months after correction of anemia and etiological cause in order to replenish body stores of iron. Ferrous sulfate is the most common and inexpensive form of iron utilized. Tablets contain 50-60 mg of iron salt. Other ferrous salts are used and may cause less intestinal discomfort because they contain smaller doses of iron (25-50 mg). Oral solutions of ferrous iron salts are available for use in pediatric populations.
LITERATURE:
Nelson Textbook of Pediatrics, 16e edition.
Hoffman R, Benz EJ, Shattil SJ, et al: Hematology: Basic Principles and Practices, 3rd ed. New York
Miller DR
, Baehner RL: Blood Diseases of Infancy and Childhood, 7th ed. St. Louis
Nathan DG, Orkin SH: Nathan and Oski’s Hematology of Infancy and Childhood, 5th ed. Philadelphia
Williams WJ, Beutler E, Erslev AJ, Lichtman MA: Hematology, 4th ed. New York
WEB–adresses
http://www.meadline
http://www.neonatology.org/neo.clinical.html
