What causes macrocytosis in children?

Causes of Macrocytosis in Children

Primary Etiologies

The most common cause of macrocytosis in children is medication exposure, accounting for approximately 35% of cases, followed by congenital heart disease, Down syndrome, and reticulocytosis. 1

Medication-Induced Macrocytosis (Most Common)

• Anticonvulsants (particularly valproate), zidovudine, and immunosuppressive agents (azathioprine, methotrexate) represent the leading causes of macrocytosis in the pediatric population 1
• These medications collectively account for more than half of drug-related cases and approximately 24% of all pediatric macrocytosis 1
• Azathioprine and 6-mercaptopurine induce macrocytosis through myelosuppressive activity rather than vitamin deficiency 2
• Methotrexate causes macrocytosis by inhibiting dihydrofolate reductase, blocking conversion of dihydrofolic acid to tetrahydrofolic acid 2
• Sulfasalazine induces macrocytosis through folate malabsorption 2

Congenital and Structural Conditions

• Congenital heart disease represents the second most common association, found in approximately 14% of pediatric macrocytosis cases 1
• Down syndrome accounts for approximately 8% of cases 1
• Cyanotic heart disease specifically causes macrocytosis through compensatory erythrocytosis in response to chronic hypoxemia 2

Hematologic Causes

• Reticulocytosis (from hemolysis or hemorrhage) causes macrocytosis because immature reticulocytes are larger cells that shift into circulation 2, 1
• Bone marrow failure/myelodysplasia accounts for approximately 4% of cases and may present with macrocytosis and pancytopenia as the first manifestation 1
• This finding warrants urgent evaluation as it may indicate treatable disorders such as aplastic anemia 1

Nutritional Deficiencies

• Vitamin B12 deficiency causes megaloblastic macrocytic anemia, though it is notably rare in general pediatric populations 1, 3
• In children with inflammatory bowel disease and ileal involvement or resection >20-30 cm, B12 deficiency becomes more prevalent (5.6-38% in Crohn's disease) 2
• Folate deficiency similarly causes megaloblastic anemia but was not observed in a 13-month pediatric study of 146 children with macrocytosis 1
• In IBD patients, folate deficiency occurs from low intake, malabsorption, excess utilization from mucosal inflammation, and medications 2

Diagnostic Approach

Initial Laboratory Evaluation

• Reticulocyte count differentiates production versus destruction causes 4
• If reticulocyte count is normal or low with macrocytosis: consider vitamin B12 deficiency, folate deficiency, myelodysplastic syndrome, medications, or hypothyroidism 4
• If reticulocyte count is elevated with macrocytosis: consider hemolysis or recent hemorrhage 4
• Peripheral blood smear distinguishes megaloblastic (macro-ovalocytes, hypersegmented neutrophils) from non-megaloblastic causes 3

Specific Testing

• Serum vitamin B12 level should be obtained when macrocytosis is present 4, 3
• Serum folate and red blood cell folate levels complete the initial workup 4
• Medication review is essential given that drugs account for over one-third of pediatric cases 1
• Wide red cell distribution width (RDW) can identify coexisting iron deficiency when microcytosis and macrocytosis neutralize each other, resulting in falsely normal MCV 4

Important Clinical Pearls

Threshold Considerations

• Mean corpuscular volume (MCV) values of 91-92 fL likely represent the upper limit of normal in children, as 21 of 24 cases without apparent cause had only slight MCV elevation 1
• Macrocytosis is generally defined as MCV >100 fL in adults, but age-appropriate norms must be used in children 2, 3

Critical Pitfalls to Avoid

• Do not assume vitamin deficiency is the cause in general pediatric populations—medications and congenital conditions are far more common 1
• Pancytopenia with macrocytosis requires urgent bone marrow evaluation to exclude aplastic anemia or myelodysplasia 1
• In patients with inflammatory conditions, ferritin may be falsely elevated despite true iron deficiency, potentially masking concurrent deficiencies 4
• Always treat B12 deficiency before folate supplementation to avoid precipitating subacute combined degeneration of the spinal cord 4

Less Common Etiologies

• Hypothyroidism, liver disease, and primary bone marrow dysplasias represent additional causes 3
• Thiamine-responsive megaloblastic anemia syndrome, pure red cell aplasia, and bone marrow infiltration by malignancy are rare pediatric causes 4
• Benign familial macrocytosis exists as a genetic condition without underlying pathology 5