Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is essential for the body to make DNA and RNA and metabolize amino acids, which are required for cell division. As humans cannot make folate, it is required in the diet, making it an essential vitamin. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.
Folate is the form of folic acid is used to treat anemia caused by folate deficiency. Folic acid is also used as a supplement by women during pregnancy to reduce the risk of neural tube defects (NTDs) in the baby. Low levels in early pregnancy are believed to be the cause of more than half of babies born with NTDs. More than 80 countries use either mandatory or voluntary fortification of certain foods with folic acid as a measure to decrease the rate of NTDs. Long-term supplementation with relatively large amounts of folic acid is associated with small reduction in the risk of stroke and an increased risk of prostate cancer. There are concerns that large amounts of supplemental folic acid can hide vitamin B12 deficiency.
Folate is especially important during periods of frequent cell division and growth, such as infancy and pregnancy. Folate deficiency hinders DNA synthesis and cell division, affecting hematopoietic cells and neoplasms the most because of their greater frequency of cell division. RNA transcription and subsequent protein synthesis are less affected by folate deficiency, as the mRNA can be recycled and used again (as opposed to DNA synthesis, where a new genomic copy must be created).
Folate deficiency can be caused by unhealthy diets that do not include enough vegetables and other folate-rich foods; diseases in which folates are not well absorbed in the digestive system (such as Crohn’s disease or celiac disease); some genetic disorders that affect levels of folate; and certain medicines (such as phenytoin, sulfasalazine, or trimethoprim-sulfamethoxazole). Folate deficiency is accelerated by alcohol consumption, possibly by interference with folate transport.
Folate deficiency may lead to glossitis, diarrhea, depression, confusion, anemia, and fetal neural tube and brain defects. Other symptoms include fatigue, gray hair, mouth sores, poor growth, and swollen tongue. Folate deficiency is diagnosed by analyzing a complete blood count (CBC) and plasma vitamin B12 and folate levels. A serum folate of 3 μg/L or lower indicates deficiency. Serum folate level reflects folate status, but erythrocyte folate level better reflects tissue stores after intake. An erythrocyte folate level of 140 μg/L or lower indicates inadequate folate status. Serum folate reacts more rapidly to folate intake than erythrocyte folate.
Since folate deficiency limits cell division, erythropoiesis (production of red blood cells) is hindered. This leads to megaloblastic anemia, which is characterized by large, immature red blood cells. This pathology results from persistently thwarted attempts at normal DNA replication, DNA repair, and cell division, and produces abnormally large red cells called megaloblasts (and hypersegmented neutrophils) with abundant cytoplasm capable of RNA and protein synthesis, but with clumping and fragmentation of nuclear chromatin. Some of these large cells, although immature (reticulocytes), are released early from the marrow in an attempt to compensate for the anemia. Both adults and children need folate to make normal red and white blood cells and prevent anemia, which causes fatigue, weakness, and inability to concentrate.
Increased homocysteine levels suggest tissue folate deficiency, but homocysteine is also affected by vitamin B12 and vitamin B6, renal function, and genetics. One way to differentiate between folate deficiency and vitamin B12 deficiency is by testing for methylmalonic acid (MMA) levels. Normal MMA levels indicate folate deficiency and elevated MMA levels indicate vitamin B12 deficiency. Folate deficiency is treated with supplemental oral folic acid of 400 to 1000 μg per day. This treatment is very successful in replenishing tissues, even if deficiency was caused by malabsorption. People with megaloblastic anemia need to be tested for vitamin B12 deficiency before treatment with folic acid, because if the person has vitamin B12 deficiency, folic acid supplementation can remove the anemia, but can also worsen neurologic problems. Cobalamin deficiency may lead to folate deficiency, which, in turn, increases homocysteine levels and may result in the development of cardiovascular disease or birth defects.
Deficiency of folate in pregnant women has been implicated in neural tube defects (NTDs), with an estimate of 300,000 cases worldwide prior to the implementation in many countries of mandatory food fortification. NTDs occur early in pregnancy (first month), therefore women must have abundant folate upon conception and for this reason there is a recommendation that any woman planning to become pregnant consume a folate-containing dietary supplement before and during pregnancy. Compliance with this recommendation is not complete, and many women become pregnant without this being a planned pregnancy, or may not realize that they are pregnant until well into the first trimester, which is the critical period for reducing risk of NTDs. Countries have implemented either mandatory or voluntary food fortification of wheat flour and other grains, or else have no such program and depend on public health and healthcare practitioner advice to women of childbearing age. A meta-analysis of global birth prevalence of spina bifida showed that when mandatory fortification was compared to countries with voluntary fortification or no fortification program, there was a 30% reduction in live births with spina bifida. Some countries reported a greater than 50% reduction. The United States Preventive Services Task Force recommends folic acid as the supplement or fortification ingredient, as forms of folate other than folic acid have not been studied.
Folate contributes to spermatogenesis. In women, folate is important for oocyte quality and maturation, implantation, placentation, fetal growth and organ development.
One meta-analysis reported that multi-year folic acid supplementation, in amounts in most of the included clinical trials at higher than the UL of 1,000 μg/day, reduced the relative risk of cardiovascular disease by a modest 4%. Two older meta-analyses, which would not have incorporated results from newer clinical trials, reported no changes to the risk of cardiovascular disease.
The absolute risk of stroke with supplementation decreases from 4.4% to 3.8% (a 10% decrease in relative risk). Two other meta-analyses reported a similar decrease in relative risk. Two of these three were limited to people with pre-existing cardiovascular disease or coronary heart disease. The beneficial result may be associated with lowering circulating homocysteine concentration, as stratified analysis showed that risk was reduced more when there was a larger decrease in homocysteine. The effect was also larger for the studies that were conducted in countries that did not have mandatory grain folic acid fortification. The beneficial effect was larger in the subset of trials that used a lower folic acid supplement compared to higher.
Chronically insufficient intake of folate may increase the risk of colorectal, breast, ovarian, pancreas, brain, lung, cervical, and prostate cancers.
Early after fortification programs were implemented, high intakes were theorized to accelerate the growth of preneoplastic lesions that could lead to cancer, specifically colon cancer. Subsequent meta-analyses of the effects of low versus high dietary folate, elevated serum folate, and supplemental folate in the form of folic acid have reported at times conflicting results. Comparing low to high dietary folate showed a modest but statistically significant reduced risk of colon cancer. For prostate cancer risk, comparing low to high dietary folate showed no effect, but the same two studies reported a significant increased risk for prostate cancer correlating to elevated serum folate. Two reviews of trials that involved folic acid dietary supplements reported, respectively, a statistically significant 24% increase in prostate cancer risk and a not significant 17% increase in prostate cancer risk. Supplementation with folic acid at 1,000 to 2,500 μg/day – the amounts used in many of the supplement trials – would result in higher concentrations of serum folate than what is achieved from diets high in food-derived folate. The second study reported no significant increase or decrease in total cancer incidence, colorectal cancer, other gastrointestinal cancer, genitourinary cancer, lung cancer or hematological malignancies in people who were consuming folic acid supplements. A third supplementation meta-analysis limited to reporting only on colorectal cancer incidence showed that folic acid treatment was not associated with colorectal cancer risk.
Folinic acid, under the drug name leucovorin, a form of folate (formyl-THF), can help “rescue” or reverse the toxic effects of methotrexate. Folic acid supplements have little established role in cancer chemotherapy. The supplement of folinic acid in people undergoing methotrexate treatment is to give cells dividing less rapidly enough folate to maintain normal cell functions. The amount of folate given is depleted by rapidly dividing cells (cancer) quickly, so does not negate the effects of methotrexate.
Conversion of homocysteine to methionine requires folate and vitamin B12. Elevated plasma homocysteine and low folate are associated with cognitive impairment, dementia and Alzheimer’s disease. Supplementing the diet with folic acid and vitamin B12 lowers plasma homocysteine. However, several reviews reported that supplementation with folic acid alone or in combination with other B vitamins did not prevent development of cognitive impairment nor slow cognitive decline.
The relative risk of autism spectrum disorders was reduced by 23% when the maternal diet was supplemented during pregnancy. Subset analysis confirmed this among Asian, European and American populations.
Folic acid, B12 and iron
A complex interaction occurs between folic acid, vitamin B12, and iron. A deficiency of one may be “masked” by excess of another, so when taken as dietary supplements, the three need to be in balance.
Some studies show iron–folic acid supplementation in children under five may result in increased mortality due to malaria; this has prompted the World Health Organization to alter their iron–folic acid supplementation policies for children in malaria-prone areas, such as India