Which medications are known to cause macrocytic anemia?

Medications Associated with Macrocytic Anemia

The most common medications causing macrocytic anemia are methotrexate, azathioprine/6-mercaptopurine, hydroxyurea, sulfasalazine, anticonvulsants (particularly phenytoin and phenobarbital), and zidovudine. 1

Mechanism-Based Classification

Megaloblastic Macrocytosis (Impaired DNA Synthesis)

Methotrexate causes megaloblastic macrocytosis by inhibiting dihydrofolate reductase, which blocks the conversion of dihydrofolic acid to tetrahydrofolic acid and impairs DNA synthesis. 1 Patients on long-term methotrexate require folate supplementation: 5 mg once weekly given 24-72 hours after methotrexate, or 1 mg daily for five days per week. 1

Sulfasalazine blocks folate absorption in the intestine, leading to functional folate deficiency and megaloblastic changes. 1 Patients on sulfasalazine should receive prophylactic folic acid supplementation due to this malabsorption mechanism. 1

Trimethoprim-sulfamethoxazole can cause megaloblastic anemia through folate pathway inhibition, and the drug is contraindicated in patients with documented megaloblastic anemia caused by folate deficiency. 2

Anticonvulsants (phenytoin, phenobarbital, carbamazepine) interfere with folate metabolism and can produce megaloblastic macrocytosis. 1

Fluoropyrimidines (5-FU, UFT, tegafur) can cause macrocytic anemia, with incidence rates of 30.3% in UFT group, 30.8% in 5-FU group, and 8.6% in tegafur group. 3 The MCV normalizes after cessation of these agents. 3

Non-Megaloblastic Macrocytosis (Direct Myelosuppression)

Azathioprine and 6-mercaptopurine cause macrocytosis through direct myelosuppressive activity rather than vitamin deficiency. 1 Patients on these medications require complete blood count monitoring for concurrent cytopenias. 1

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

Zidovudine causes macrocytosis through direct bone marrow suppression. 1

Additional Medication Classes

Hormonal contraceptives can cause folate deficiency and subsequent macrocytosis. 2

Proton pump inhibitors and H2 receptor antagonists used for more than 12 months can impair vitamin B12 absorption, leading to macrocytic anemia. 4, 5

Metformin use for more than 4 months poses a risk for vitamin B12 deficiency and macrocytosis. 4, 5

Colchicine can contribute to vitamin B12 deficiency. 5

Diagnostic Approach to Drug-Induced Macrocytosis

Peripheral blood smear distinguishes megaloblastic morphology (macro-ovalocytes, hypersegmented neutrophils) from non-megaloblastic patterns. 1

Reticulocyte count differentiates production defects (low or normal reticulocyte count) from hemolysis or hemorrhage (elevated reticulocyte count). 4, 1

Complete blood count with differential identifies concurrent cytopenias suggesting myelosuppression, particularly important for azathioprine, 6-mercaptopurine, and hydroxyurea. 1

Critical Clinical Pitfalls

Concurrent iron deficiency with folate or B12 deficiency produces a falsely normal MCV because microcytosis and macrocytosis cancel each other out. 1 An elevated red cell distribution width (RDW) suggests this mixed picture when MCV appears normal. 4, 1

Mean corpuscular hemoglobin (MCH) is more sensitive than MCV for detecting iron deficiency in these mixed states. 1

Never administer folic acid before treating B12 deficiency, as folic acid may mask anemia while allowing irreversible neurological damage to progress. 4, 5

MCV Severity Stratification

Medications can be categorized by the degree of MCV elevation they typically produce:

• Group 1 (MCV can exceed 130 fL): Megaloblastic anemia from vitamin deficiencies and medications like methotrexate and sulfasalazine 6
• Group 2 (MCV can exceed 114 fL but typically <130 fL): Hydroxyurea, azathioprine, and alcohol-related macrocytosis 6
• Group 3 (MCV typically <114 fL): Most other medication-induced macrocytosis 6