What causes folate deficiency?

Causes of Folate Deficiency

Folate deficiency results from inadequate dietary intake, malabsorption, medication interference, or increased metabolic demands—with dietary insufficiency being the most common cause globally.

Primary Dietary Causes

Low dietary intake is the most frequent cause of folate deficiency worldwide. 1, 2, 3, 4

• Natural folate sources include pulses (legumes), leafy green vegetables, eggs, nuts, and whole grains 1
• Food folates have approximately 50% lower bioavailability than synthetic folic acid, making dietary correction challenging without careful food selection 2
• Populations consuming insufficient green leafy vegetables, legumes, and liver are at highest risk 3, 4
• Low-carbohydrate diets that restrict fortified grain products can inadvertently reduce folic acid intake 2

Malabsorption Conditions

Gastrointestinal diseases that impair small intestinal absorption are major contributors to folate deficiency. 1, 2, 3

• Crohn's disease demonstrates 22.3% prevalence of folate deficiency compared to 4.3% in ulcerative colitis 1, 2, 3
• Active intestinal inflammation increases folate consumption while simultaneously impairing absorption 1, 2, 3
• Celiac disease compromises folate absorption in the duodenum and jejunum 1, 5
• Bariatric surgery causes malabsorption, particularly when combined with poor adherence to multivitamin supplementation 2, 3

Medication-Induced Deficiency

Several commonly prescribed medications directly interfere with folate metabolism or absorption. 1, 2, 3, 6, 7

Methotrexate

• Inhibits dihydrofolate reductase, the enzyme converting dihydrofolic acid to the active tetrahydrofolic acid form 1, 2, 3, 6, 7
• Requires routine supplementation: 5 mg folic acid once weekly (24-72 hours post-methotrexate dose) or 1 mg daily for 5 days per week 1, 8

Sulfasalazine

• Causes direct folate malabsorption in the intestinal tract 1, 2, 3
• Requires routine supplementation: 1 mg daily for 5 days per week 1, 8

Anticonvulsants

• Phenytoin, primidone, and barbiturates interfere with folate metabolism 6, 7
• The anticonvulsant action of phenytoin is antagonized by folic acid, potentially requiring dose adjustments 6

Other Medications

• Azathioprine and 6-mercaptopurine cause macrocytosis through myelosuppressive activity rather than true folate deficiency 1
• Pyrimethamine, trimethoprim, triamterene, and nitrofurantoin act as folate antagonists 6, 7

Increased Metabolic Demands

Pregnancy and lactation dramatically increase folate requirements, doubling the daily needs. 1, 2, 9

• Pregnant women require approximately twice the folate intake of non-pregnant adults (600-800 μg DFE daily) 1
• Folate deficiency during pregnancy causes neural tube defects, growth retardation, preterm delivery, low birth weight, and fetal growth retardation 2, 9
• Lactation increases folate requirements markedly, though amounts in human milk are typically adequate for term infants 6
• Low birth-weight infants and those breast-fed by folate-deficient mothers may require supplementation (50 mcg daily) 6

High-Risk Populations

Older adults face multiple concurrent risk factors for folate deficiency. 2, 3, 10

• Age-related physiological changes, reduced food intake, limited dietary variety, and polypharmacy increase risk 3, 10
• Food-bound cobalamin malabsorption due to gastric atrophy is common in the elderly, often coexisting with folate deficiency 4
• Elderly patients are less responsive to folate repletion than younger adults and may require higher maintenance doses 8

Additional Contributing Factors

Alcohol consumption and chronic diseases significantly impair folate status. 1, 3, 4

• Alcoholic cirrhosis causes folate deficiency through multiple mechanisms including reduced intake, malabsorption, and altered metabolism 6, 4
• Renal dialysis increases folate loss 6
• Patients with chronic gastrointestinal disorders, cancer, or diabetes have altered nutrient absorption and metabolism 3
• Helicobacter pylori infection may contribute to malabsorption 4

Critical Clinical Pitfall

The most dangerous aspect of folate deficiency is its potential to mask vitamin B12 deficiency. 2, 8, 6

• Folic acid in doses above 0.1 mg daily may obscure pernicious anemia by alleviating hematologic manifestations while neurologic complications progress 6
• This can result in severe nervous system damage (subacute combined degeneration of the spinal cord) before correct diagnosis is made 8, 6
• Always check and treat vitamin B12 deficiency before or concurrently with initiating folic acid treatment 8, 6
• Total daily folate intake should not exceed 1000 μg (1.0 mg) unless prescribed by a physician, specifically to avoid masking B12 deficiency 2