Megaloblastic anemia is a type of macrocytic anemia characterized by large erythroblast cells with delayed nuclear maturation. In children, this could happen because of nutritional deficiency or intestinal malabsorption of vitamin B12 (cobalamin), folic acid or both. Pediatric megaloblastic anemia is rare compared to other types of anemia but more significant due to some major developmental disorders if left untreated. 

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Pediatric Megaloblastic Anemia

Image: “Vitamin B12 is a nutrient that helps keep the body’s nerve and blood cells healthy and helps make DNA, the genetic material in all cells. Vitamin B12 also helps prevent a type of anemia called megaloblastic anemia that makes people tired and weak.” by آرمین. License: Public Domain


Definition

Anemia refers to a state in which the blood hemoglobin (Hb) is two standard deviations lower than the reference range for specific age and it is prevalent in children throughout the world. Megaloblastic anemia is a type of macrocytic anemia characterized by large erythroblast cells with delayed nuclear maturation. In children, this could happen in the wake of nutritional deficiency or intestinal malabsorption of vitamin B12 (cobalamin), folic acid or both.

According to world health organization (WHO):

  • In children aged between 6–59 months, lower limit for Hb is 11 g/dL
  • In children aged between 5–11 years, lower limit for Hb is 11.5 g/dL
  • In children aged between 12–14 years, lower limit for Hb is 12 g/dL

In infants younger than 6 months, physiological anemia must be kept in mind while making diagnosis. However, hemoglobin is not expected to be lower than 9 g/dL in physiological anemia.

Epidemiology of Pediatric Megaloblastic Anemia

Pediatric megaloblastic anemia is rare compared to other types of anemia. The prevalence of megaloblastic anemia is unevenly distributed around the world. It is more prevalent in developing countries than in developed countries.

The World Health Organization reported that the rate of pediatric anemia in the United States is low around 6 % with the exception of children in low-income families. However, according to the data from federally funded programs, the prevalence of anemia has increased from 13.4 % in 2001 to 14.6 % in 2010 with the highest prevalence of 18.2 % in children aged between 12 and 17 months.

Etiology of Pediatric Megaloblastic Anemia

It was previously thought that common cause of megaloblastic anemia in infants and younger children is folate deficiency whereas vitamin B12 causes megaloblastic anemia in older children. However, recent evidence shows that vitamin B12 deficiency is the common cause in infants and early childhood. Usually, deficiency of both exists.

Deficiency of vitamin B12 (Cobalamin)

Common causes leading to vitamin B12 deficiency are as following:

Nutrition

Poor nutrition is the most common cause of vitamin B12 deficiency in developing countries. The primary sources of vitamin B12 are meat, fish, and dairy products. Infants of poor vegetarian mothers are most likely to develop vitamin B12 deficiency if they are solely dependent on breast milk.

Malabsorption (tropical sprue)

In older children, disease of the small intestine leads to malabsorption, i.e. tropical sprue is the common cause of vitamin B12 deficiency.

Gastritis/Gastrectomy

Both of these conditions lead to malabsorption of vitamin B12 from dietary sources.

Pernicious anemia

Pernicious anemia is the intrinsic factor deficiency of vitamin B12. It can be differentiated through Schilling Test. However, it is rarely found in children.

Fish tape worm infestation

Infestation of fish tape worm (Diphyllobothriumlatum) leads to deficiency of vitamin B12.

Folate Deficiency

Likewise vitamin B12 deficiency, folate deficiency is commonly caused by poor nutrition. In addition to meat, unlike vitamin B12, folate is found in vegetables and fruits as well.

Other causes of folate deficiency might include malabsorption due to tropical sprue and celiac disease, conditions with increase requirement such as rapid growth and chronic hemolytic anemias.

Moreover, goat milk feeding, maternal deficiency and certain anticonvulsant drugs (Phenytoin and Phenobarbital) can lead to folate deficiency megaloblastic anemia.

Classification of Pediatric Megaloblastic Anemia

Megaloblastic anemia can be classified into two types on the basis of the type of deficiency:

  1. Vitamin B12 (Cobalamin) deficiency

Nutrition related deficiency of cobalamin usually develops in breast feeding infants of mothers who are strictly vegetarian or have pernicious anemia. In older children, the cause of cobalamin deficiency is usually intestinal malabsorption. This might be the manifestation of Crohn’s disease, chronic pancreatitis or infection with fish tapeworm. Congenital defects in metabolism such as transcobalamin II deficiency and methylmalonic aciduria are reported in pediatric megaloblastic anemia. Pernicious anemia, i.e. deficiency of intrinsic factor leading to vitamin B12 deficiency is rare in pediatric cases.

  1. Folate deficiency

Various causes of folate deficiency might include nutritional, malabsorption and increased folate requirement. Some severely malnourished children might develop folate deficiency. However, infants feeding on goat’s milk, lacking folic acid are frequently reported to develop folate deficiency. Folic acid is absorbed in the jejunum, therefore, pathologies of the small intestine, such as celiac disease, lead to folate deficiency. In addition, conditions of increased requirement in children, i.e. rapid growth and chronic hemolytic anemia result in folate deficiency in the wake of low body stores of folate.

Pathophysiology of Pediatric Megaloblastic Anemia

The most common causes of pediatric megaloblastic anemia, a macrocytic anemia, include deficiency of vitamin B12, folate or both.

The major sources of cobalamin are meat fish and dairy products. It is not present in fruits and vegetables unlike folate. Cyanocobalamin, the form of vitamin B12 used in supplements, is readily converted into active forms (5’-Deoxyladenosyl-cobalamin, methyl-cobalamin) in the body.

Cobalamin is a cofactor for two enzymes in the body, i.e. methionine synthase and L-methylmalonyl-coA mutase. The products from these reactions inside the body are used for methylation of sites in DNA and RNA as well as for the production of energy. Deficiency of cobalamin can cause defective DNA maturation, megaloblastic changes and abnormal synthesis of hemoglobin.

The sources of folates are widespread such as vegetables, fruits and meat but the body stores less compared to vitamin B12. Folate is converted into dihydrofolate to tetrahydrofolate that along with methyl-cobalamin takes part in the synthesis of methionine.

Deficiency of these essential nutrients results in an abnormally large cell with delayed nuclear maturation. These anomalies occur in the wake of defect in DNA synthesis in rapidly dividing cells and, to a lower magnitude, RNA and protein synthesis result in an altered DNA to RNA ratio.

Morphological changes are not only confined to red blood cells but progress to the

Hyperlobated Neutrophil

Image: “As seen in the peripheral blood of a patient with megaloblastic anemia.” by Ed Uthman. License: CC BY 2.0

loosening of chromatin and asynchronous nuclear and cytoplasmic maturation. In addition, peripheral smear shows hypersegmented neutrophils, giant bands in bone marrow and abnormal myelination in the nervous system.

Clinical features of Pediatric Megaloblastic Anemia

Clinical features of megaloblastic anemia vary in significance depending on the severity of the disease. This ranges from mild signs and symptoms to developmental retardation. Following are the common symptoms and signs of megaloblastic anemia.

Symptoms

Symptoms might be starkly apparent in advanced stages of megaloblastic anemia. These include the involvement of skin, musculoskeletal system, nervous system and gastrointestinal system. Common symptoms of megaloblastic anemia in children are:

  • Yellowish skin
  • Fatigue
  • Irritability
  • Anorexia
  • Poor feeding
  • Weakness
  • Numbness

Signs

General Signs

  • Pallor due to ineffective erythropoesis
  • Fever due to infections resulting from neutropenia
  • Glossitis (smooth and beefy red inflamed tongue)
  • Hyperpigmentation of knuckles

Musculoskeletal signs

  • Musculoskeletal dysfunction
  • Unsteady gait
  • Hypotonia

Gastrointestinal system signs

  • Splenomegaly
  • Hepatomegaly
  • Mild jaundice

Neurological signs

  • Intellectual disability (ID) due to developmental retardation
  • Paresthesias
  • Diminished neurological sensations such as proprioception and vibratory sensations

Investigations of Pediatric Megaloblastic Anemia

Diagnosis of megaloblastic anemia is made on the presence of megaloblastosis and anemia. Blood studies and bone marrow examination is significant in diagnosing megaloblastic anemia. Moreover, serum cobalamin, serum folate, serum methylmalonic acid level and serum homocysteine level are used to differentiate the underlying type, i.e. vitamin B12 deficiency or folate deficiency.

Complete Blood Count

(CBC)

  • Hemoglobin and Hematoocrit would be low according to age
  • RBC: low
  • MCV (mean corpuscular volume): high
  • TLC: frequently reduced
  • Reticulocyte count: reduced
  • Platelet count: low
Peripheral Smear
  • Macrocytosis
  • Anisocytosis
  • Poikilocytosis
  • Large neutrophils with hypersegmented nuclei
Bone marrow examination
  • Hyperplasia
  • Ineffective erythropoesis
  • Megaloblastic changes
  • Delayed nuclear maturation
Blood serum investigations
  • Serum Cobalamin: reduced in cobalamin deficiency
  • Serum Folate: reduced in folate deficiency
  • Serum methylmalonic acid level: elevated in vitamin B12 deficiency
  • Serum homocysteine level: elevated in both vitamin B12 deficiency and folate deficiency

Differential Diagnosis of Pediatric Megaloblastic Anemia

Differential diagnosis of megaloblastic anemia is made with the conditions presenting similar signs and symptoms of megaloblastosis and other forms of macrocytic anemia. These include:

  • Pernicious anemia

In this type of megaloblastic anemia there is a deficiency of intrinsic factor of cobalamin due to malabsorption. The Schilling test is performed to differentiate the intrinsic factor deficiency. However, this type of anemia is rare in children.

  • Drug-induced anemia
  • Anemia in down syndrome
  • Hemolytic anemias
  • Fanconi anemia and Diamond-Blackfan anemia (bone marrow failure syndrome)
  • Liver disease
  • Hypothyroidism

Management of Pediatric Megaloblastic Anemia

Pediatric megaloblastic anemia is managed by correcting the deficiency and symptomatic treatment. Oral and parenteral routes are considered according to the conditions. The condition in which there is gastrointestinal dysfunction leading to malabsorption, parenteral route is effective.

Management of vitamin B12 (cobalamin) deficiency

Cobalamin deficiency is managed by giving cobalamin supplementation through oral or parenteral routes.

Oral cobalamin therapy

Oral supplementation is preferred in nutritional deficiency of cobalamin and in children compliant and adherent to oral medication.

Parenteral cobalamin therapy

Parenteral therapy is considered in very young infants and older children with intestinal malabsorption.

The commonly practiced dose is in the form of a 1000 mcg injection of vitamin B12 once or twice a day. This high dose inflicts tremors in some patients. Therefore, the newly recommended dose is 250 mcg weekly for infants and 500 mcg weekly for older children. The recommended treatment time is 6–8 weeks or longer.

Note: Parenteral therapy of vitamin B12 might cause life threatening hypokalemia and thus consequently requires supplemental potassium.

Management of folate deficiency

Folate deficiency is mostly managed through oral supplementation.

In addition to diets rich in folic acid, 200–500 mcg per day of folic acid is given orally in the form of supplements. Therapy for curing deficiency continues for 6–8 weeks.

Moreover, children with suspected prematurity or those diagnosed with chronic hemolysis are given folic acid supplementation for prophylactic measures.

Complications of Pediatric Megaloblastic Anemia

The prognosis of megaloblastic anemia is good and favorable if diagnosed in time and effectively treated. However, there are certain complications that might follow in megaloblastic anemic infants:

  • Neural tube defects in prenatal period
  • Developmental disorders in prenatal life
  • Intellectual Disability (ID)
  • Hypokalemia
  • Anemia-related cardiac complications
  • Risk of infection
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