Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various medications. Deficiency causes megaloblastic anemia (indistinguishable from that due to vitamin B12 deficiency). Maternal deficiency increases the risk of neural tube birth defects. Diagnosis requires laboratory testing to confirm. Measurement of neutrophil hypersegmentation is sensitive and readily available. Treatment with oral folate is usually successful.
Folate is plentiful in various plant foods and meats, particularly raw green leafy vegetables, fruits, organ meats (eg, liver), but its bioavailability is greater when it is in supplements or enriched foods than when it occurs naturally in food (see table Sources, Functions, and Effects of Vitamins). In the United States and Canada, many dietary staples (eg, cereals, grain products) are routinely enriched with folate, tending to reduce risk of deficiency.
Folates are involved in red blood cell maturation and synthesis of purines and pyrimidines. They are required for development of the fetal nervous system. Absorption occurs in the duodenum and upper jejunum. Enterohepatic circulation of folate occurs.
Data do not convincingly show that folate supplements protect against coronary artery disease or stroke (even though they lower homocysteine levels) (1). Current evidence does not support claims that folate supplementation increases or reduces the risk of various cancers (2). Any role for using supplemental folate, methyltetrahydrofolate, or L-methylfolate, or for testing for mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene in patients with depression is uncertain at this time.
The upper limit for folate intake is 1000 mcg; higher daily doses (up to 4 mg) are recommended for women who have had a baby with a neural tube defect. Folate is essentially nontoxic.
Women taking both oral contraceptives and antiseizure medications may need to take folate supplements to maintain birth control effectiveness.
(See also Overview of Vitamins.)
References
1. Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FBJ Am Heart Assoc. 2016;5(8):e003768. Published 2016 Aug 15. doi:10.1161/JAHA.116.003768
2. Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp MBMJ Open. 2012;2(1):e000653. Published 2012 Jan 12. doi:10.1136/bmjopen-2011-000653
Etiology of Folate Deficiency
The most common causes of folate deficiency are
Inadequate intake (usually in patients with undernutrition or alcohol use disorder)
Increased demand (eg, due to pregnancy or lactation)
Impaired absorption (eg, in celiac disease or due to certain medications)
Deficiency can also result from inadequate bioavailability and increased excretion (see table Causes of Folate Deficiency).
Causes of Folate Deficiency
Cause | Source |
|---|---|
Inadequate intake | Diet lacking raw green vegetables or enriched grains, chronic alcohol use disorder, parenteral nutrition |
Impaired absorption | Celiac disease, sprue, other malabsorption syndromes, antiseizure medications, congenital or acquired folate malabsorption |
Inadequate utilization | Folate antagonists (metformin, methotrexate, triamterene, trimethoprim), antiseizure medications, congenital or acquired enzyme deficiency, alcohol use disorder |
Increased demand | Pregnancy, lactation, infancy, increased metabolism |
Increased excretion | Renal dialysis (peritoneal or hemodialysis) |
Prolonged cooking destroys folate, predisposing to inadequate intake. Intake is sometimes barely adequate (eg, in people with alcohol use disorder). Liver stores provide only a several-month supply.
Alcohol interferes with folate absorption, metabolism, renal excretion, and enterohepatic reabsorption and reduces healthy food intake. 5-Fluorouracil, metformin, methotrexate, phenobarbital, phenytoin, triamterene, and trimethoprim impair folate metabolism.
Symptoms and Signs of Folate Deficiency
Folate deficiency may cause glossitis, diarrhea, depression, and confusion. Anemia may develop insidiously and, because of compensatory mechanisms, be more severe than symptoms suggest.
Folate deficiency during pregnancy increases the risk of fetal neural tube defects and perhaps other brain defects.
Diagnosis of Folate Deficiency
Complete blood count and serum vitamin B12 and folate levels
Complete blood count may indicate megaloblastic anemia indistinguishable from that of vitamin B12 deficiency.
If serum folate is < 3 mcg/L or ng/mL (< 7 nmol/L), deficiency is likely. Serum folate reflects folate status unless intake has recently increased or decreased. If intake has changed, erythrocyte (red blood cell) folate level better reflects tissue stores. A level of < 140 mcg/L or ng/mL (< 305 nmol/L) indicates inadequate status.
Also, an increase in the homocysteine level suggests tissue folate deficiency (but the level is also affected by vitamin B12 and vitamin B6 levels, renal insufficiency, and genetic factors). A normal methylmalonic acid (MMA) level may differentiate folate deficiency from vitamin B12 deficiency because MMA levels rise in vitamin B12 deficiency but not in folate deficiency.
Treatment of Folate Deficiency
Supplemental oral folate
Folate 400 to 1000 mcg orally once a day replenishes tissues and is usually successful even if deficiency has resulted from malabsorption. The normal requirement is 400 mcg/day. (CAUTION: In patients with megaloblastic anemia, vitamin B12 deficiency must be ruled out before treating with folate. If vitamin B12 deficiency is present, folate supplementation can alleviate the anemia but does not reverse, and may even worsen, neurologic deficits.)
1). For women who have had a fetus or infant with a neural tube defect, the recommended dose is 4000 mcg/day, started 3 months before conception (if possible) and continued until 12 weeks of gestation (2).
Treatment references
1. US Preventive Services Task Force, Barry MJ, Nicholson WK, et alJAMA. 2023;330(5):454-459. doi:10.1001/jama.2023.12876
2. American College of Obstetricians and Gynecologists (ACOG): Practice Bulletin No. 187: Neural Tube Defects. Obstet Gynecol. 2017 (reaffirmed 2021); 130(6):e279-e290. doi:10.1097/AOG.0000000000002412
Key Points
Most commonly, folate deficiency results from reduced intake (eg, due to alcohol use disorder), increased demand (eg, due to pregnancy), or impaired absorption (eg, due to medications or malabsorption disorders).
Prolonged cooking destroys folate, but many dietary staples are supplemented with folate.
Deficiency causes megaloblastic anemia and sometimes glossitis, diarrhea, depression, and confusion.
Measure serum folate and vitamin B12 levels in patients who have megaloblastic anemia.
To treat deficiency, give patients supplemental folate 400 to 1000 mcg orally once a day.
