What medications can cause macrocytosis?

Medications That Cause Macrocytosis

The most common medications causing macrocytosis are methotrexate, azathioprine/6-mercaptopurine, hydroxyurea, sulfasalazine, anticonvulsants (particularly phenytoin and valproate), and zidovudine. 1, 2, 3

Mechanism-Based Classification

Megaloblastic Macrocytosis (Impaired DNA Synthesis)

Methotrexate is a primary cause through inhibition of dihydrofolate reductase, blocking conversion of dihydrofolic acid to tetrahydrofolic acid and impairing DNA synthesis. 1, 2 This produces megaloblastic changes with macro-ovalocytes and hypersegmented neutrophils on peripheral smear. 2

Sulfasalazine causes macrocytosis by blocking folate absorption in the intestine, leading to functional folate deficiency. 1, 2 This mechanism differs from methotrexate's direct enzymatic inhibition but produces similar megaloblastic morphology. 2

Trimethoprim-sulfamethoxazole inhibits dihydrofolate reductase similar to methotrexate, though this is less commonly recognized as a cause of macrocytosis. 1

Non-Megaloblastic Macrocytosis (Direct Myelosuppression)

Azathioprine and 6-mercaptopurine cause macrocytosis through direct myelosuppressive activity rather than vitamin deficiency. 1, 2 This is a critical distinction—these agents produce macrocytosis without megaloblastic changes and are often associated with concurrent leukopenia and/or thrombocytopenia. 1

Hydroxyurea is a well-established cause of drug-induced non-megaloblastic macrocytosis through direct effects on erythropoiesis. 1, 2

Anticonvulsants

Phenytoin causes macrocytosis and megaloblastic anemia, which usually respond to folic acid therapy. 3 The FDA label specifically notes that "macrocytosis and megaloblastic anemia have occurred" with phenytoin use. 3

Valproate is particularly important in pediatric populations, accounting for a substantial proportion of drug-induced macrocytosis cases. 4 In one pediatric study, valproate and other newer anticonvulsants accounted for 24% of all macrocytosis cases. 4

Immunosuppressive and Antiviral Agents

Zidovudine is a significant cause of macrocytosis, particularly in HIV-positive patients, and was identified as a major contributor in pediatric populations. 4

Sirolimus has dose-dependent association with anemia and may interfere with erythropoiesis by disrupting intracellular signaling pathways activated by erythropoietin. 1

Mycophenolate mofetil is myelosuppressive and can cause macrocytosis, typically with concurrent cytopenias. 1

Critical Clinical Pitfalls

Mixed Deficiency States

Concurrent iron deficiency with B12 or folate deficiency produces falsely normal MCV because microcytosis and macrocytosis cancel each other out. 2 In this scenario:

• Elevated red cell distribution width (RDW) suggests a mixed picture when MCV appears normal 2
• Mean corpuscular hemoglobin (MCH) is more sensitive than MCV for detecting iron deficiency 2
• In inflammatory conditions like IBD, ferritin <50-100 μg/L may indicate iron deficiency despite inflammation 1, 2

Folate Supplementation Hazard

Never give folic acid before excluding B12 deficiency—folate supplementation masks B12 depletion hematologically while allowing neurologic deterioration to progress, potentially precipitating subacute combined degeneration of the spinal cord. 2 This is particularly relevant when treating methotrexate or sulfasalazine-induced macrocytosis.

Diagnostic Approach for Drug-Induced Macrocytosis

Initial Assessment

• Peripheral blood smear distinguishes megaloblastic (macro-ovalocytes, hypersegmented neutrophils) from non-megaloblastic morphology 1, 2, 5
• Reticulocyte count differentiates production defects (low/normal) from hemolysis/hemorrhage (elevated) 1, 2
• Complete blood count with differential identifies concurrent cytopenias suggesting myelosuppression 1

Specific Laboratory Tests

• Vitamin B12 and folate levels are essential first-line tests even when drug etiology is suspected 2, 5
• Methylmalonic acid and homocysteine are useful when B12 deficiency is suspected despite normal serum B12 6
• Liver function tests help identify concurrent liver disease as a contributing factor 5, 6
• Thyroid function should be checked as hypothyroidism commonly causes macrocytosis 2, 5

Risk Stratification by MCV Value

MCV >120 fL is usually caused by B12 deficiency rather than medications alone, warranting aggressive investigation for vitamin deficiency. 6 Drug-induced macrocytosis typically produces MCV values between 100-115 fL. 5, 6

Management Considerations

Monitoring Requirements

Patients on long-term methotrexate require folate supplementation: 5 mg once weekly 24-72 hours after methotrexate, or 1 mg daily for five days per week. 1 This prevents macrocytosis without interfering with methotrexate's therapeutic effects.

Patients on sulfasalazine should receive prophylactic folic acid supplementation due to malabsorption mechanism. 1

Patients on azathioprine or 6-mercaptopurine with macrocytosis require complete blood count monitoring for concurrent cytopenias, as macrocytosis may herald more serious myelosuppression. 1

When to Discontinue Medication

Macrocytosis alone without anemia or other cytopenias generally does not require medication discontinuation. 1 However, development of:

• Pancytopenia with macrocytosis suggests serious bone marrow suppression requiring immediate drug cessation 1
• MCV >115 fL with megaloblastic changes warrants reassessment of medication necessity 5
• Symptomatic anemia (hemoglobin drop >2 g/dL) requires medication adjustment or discontinuation 1