Folic acid

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Bottom line: Low-risk women: 0.4-0.8mg qd one month before and 3 months after conception. High-risk: 4mg qd 3 months before and 3 months after conception.

Folic acid (aka folate or folicin) is a water-soluble vitamin from the vitamin B complex (Structure). It is essential to several important biochemical reactions in 'one-carbon' metabolism (where 1C fragments are added to, or removed from, molecules). THF (Tetrahydrofolic acid), the coenzyme form of folate, is a cofactor in several important reactions, such as converting glycine to serine, thymine synthesis, purine synthesis, and methionine synthesis.

There are three possible consequences of poor folate nutrition:

  1. Impaired or less-than-optimal DNA synthesis
  2. Poor ability to carry out methylation reactions
  3. Toxic effects of increased homocysteine levels
Folate pathway in DNA synthesis


Tetrahydrofolate is the coenzyme of folate, which means that it can exist in several metabolically-active forms which are specific for certain biochemical reactions.

Methyl tetrahydrofolate is the most abundant form of TFA (trifatty acids). It is required for the conversion of homocysteine to methionine, and is the circulating form in body fluids. It is formed by an irreversible reaction that also requires B12. It is therefore the link between folate and B12 metabolism.

Two other typesof tetrahydrofolate are methenyl and formyl TFA, and are employed in purine synthesis. Methylene TFA is required for the conversion of deoxyuridylate to thymidylate, a rate-limiting reaction in DNA synthesis.


Folate deficiency can occur through dietary insufficiency, impaired absorption, defective utilization, or competitive interactions with several kinds of drugs such as dilantin and barbiturates. Sulfa drugs are especially significant here, since they do not allow bugs to make folate. This does not bother humans, since they consume folate whole, whereas microorganisms have to create folate from little bits.

At-risk populations

Several populations are especially at risk for folate deficiency.

An additional 200μg is recommended for reproductive females on top of the dietary requirement (120-330μg/day). All women of childbearing age should consume at least 400μg/day. Folate supplements are associated with a reduced risk of birth defects and with lowering homocysteine levels. There is a lot of empirical evidence on the link between vitamin deficiency — especially folate — and neural tube defects. Compromised folate status also increases the risks of cleft palate, cleft lip, congenital malformations, and miscarriage.

Alcoholics are also at risk — 40% of hospitalized alcoholics are folate deficient — since they usually have a poorer diet and nutritional status. Alcohol also impairs the absorption of folate.

Prophylactic uses

Folate supplementation can be used prophylactically to prevent defects, and in reducing cancer and coronary heart disease, is supported by epidemiological evidence.

For pregnant women, periconceptual supplementation has been shown to reduce the risk of NTDs in high-risk women and in women who had no history of NTD.

Inadequate folate intake is also associated with increased risk of cell dysplasia and of developing certain cancers. Interventions showed lower risk of dysplasia in the colon, cervix, lung and esophagus. Folate plays an important role in the prevention of chromosome breaks, which are crucial to oncogenic development.

For those who eat lots of KFC, there may be a connection between folate and cardiovascular disease, mediated by homocysteine levels. Excessive homocysteine may cause desquamation of endothelial cells, lipoprotein oxidation, or increase the adhesion of monocytes to the vessel wall. Metabolism of homocysteine is affected by several enzymes which use vitamins B6 and B12. The link is not direct, but there are studies linking folate intake to reduced plasma homocysteine and studies linking increased plasma homocysteine to increased cardiovascular risk.