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(Folic acid)

by Larry E. Johnson, MD, PhD

Folate is now added to enriched grain foods in the US and Canada. Folate is also plentiful in various plant foods and meats, but its bioavailability is greater when it is in supplements or enriched foods than when it occurs naturally in food.

Folates are involved in RBC 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.

Folate supplements do not protect against coronary artery disease or stroke (even though they lower homocysteine levels); current evidence does not support claims that folate supplementation increases or reduces the risk of various cancers.

The upper limit for folate intake is 1000 μg; 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 anticonvulsants may need to take folate supplements to maintain birth control effectiveness.

Folate Deficiency

Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. 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.


The most common causes are

  • Inadequate intake (usually in patients with undernutrition or alcoholism)

  • Increased demand (eg, due to pregnancy or lactation)

  • Impaired absorption (eg, in tropical sprue or due to certain drugs)

Deficiency can also result from inadequate bioavailability and increased excretion (see Table: Causes of Folate Deficiency).

Causes of Folate Deficiency



Inadequate intake

Diet lacking fresh, green vegetables or enriched grains; chronic alcoholism; TPN

Impaired absorption

Celiac disease, sprue, other malabsorption syndromes, anticonvulsants, congenital or acquired folate malabsorption

Inadequate utilization

Folate antagonists (metformin, methotrexate, triamterene, trimethoprim), anticonvulsants, congenital or acquired enzyme deficiency, alcoholism

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 alcoholics). 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, sulfasalazine, triamterene, and trimethoprim impair folate metabolism.

In the US and Canada, many dietary staples (eg, cereals, grain products) are routinely enriched with folate, tending to reduce risk of deficiency.

Symptoms and Signs

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 (see Overview of Congenital Neurologic Anomalies).


  • CBC and serum vitamin B12 and folate levels

CBC may indicate megaloblastic anemia indistinguishable from that of vitamin B12 deficiency.

If serum folate is < 3 μg/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 (RBC) folate level better reflects tissue stores. A level of < 140 μg/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.


  • Supplemental oral folate

Folate 400 to 1000 μg po once/day replenishes tissues and is usually successful even if deficiency has resulted from malabsorption. The normal requirement is 400 μg/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 .)

For pregnant women, the recommended daily allowance (RDA) is 600 μg/day. For women who have had a fetus or infant with a neural tube defect, the recommended dose is 4000 μg/day, started 1 mo before conception (if possible) and continued until 3 mo after conception.

Key Points

  • Most commonly, folate deficiency results from reduced intake (eg, due to alcoholism), increased demand (eg, due to pregnancy), or impaired absorption (eg, due to drugs 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 μg po once/day.

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