Folate and Folic Acid
Folate, also known as B19, is a water-soluble vitamin found naturally in foods. Dark green leafy vegetables, like spinach, are among the best sources of this vitamin, however, it is also found in liver, fortified breakfast cereals and other grain products, legumes and in lesser quantities in eggs, dried beans, and oranges. Food processing and preparation can destroy 50-90% of the folate in food. Folate is extremely susceptible to destruction by heat, oxidation, and ultraviolet light. Consequently, it is important to eat fresh fruits and lightly cooked or raw vegetables on a regular basis. If vegetables must be cooked, this should be done quickly in a minimum amount of water by steaming, stir-frying, or microwave.
Folic acid is the synthetic form of folate found in vitamins and supplements. When folic acid is consumed as a supplement and without food, it is nearly 100% bioavailable, consumed with food as in fortified cereal grains, absorption is slightly reduced. The liver changes the absorbed monoglutamate form of folate to the polyglutamate form. Alcohol interferes with this process which is one reason alcoholics often become folate deficient.
Functions of Folate
In cells, all forms of folate are readily converted to the basic coenzyme form tetrahydrofolic acid. It functions as a coenzyme involved in one-carbon transfer reactions that include the synthesis of nucleic acids and several amino acids. Nucleic acids are needed for the synthesis of DNA and the metabolism of various amino acids and their derivatives. Because THFA is needed for DNA synthesis, folate deficiency may be induced during periods of rapid cell division as in pregnancy and cancer treatments.
Humans cannot synthesize folate, therefore, it must be extracted from the food, vitamins, and supplements that pass through the small intestine. The recommended daily allowance (RDA) for folate for adults, especially women of childbearing age, is 0.4 mg/day and for pregnant women 0.6 mg/day, as is the daily value used on food and supplement labels. This is based on the amount needed to maintain red blood cell folate, control blood homocysteine and maintain normal blood folate concentrations. Adequate levels of dietary folate are important during early pregnancy to support rapid cell growth, replication, cell division, and nucleotide synthesis for fetal and placental development. It is also needed for maternal erythropoiesis, mainly during the second and third trimesters. The recommended upper limit of folate ingestion is 1mg/day, however, it may be required for pregnant women to reach and on occasion surpass this amount to prevent neural tube defects in high-risk pregnancies. Excess folic acid can mask vitamin b12 deficiencies.
Folate deficiency can result from a low intake, inadequate absorption which is often associated with alcoholism, increased requirement as in during pregnancy, compromised utilization typically associated with vitamin B-12 deficiency, use of certain chemotherapy medications and excessive excretion linked to long-standing diarrhea.
A deficiency in folate first affects cell types that are actively synthesizing DNA, such cells have a short lifespan and rapid turnover rate. Thus, one of the major folate deficiency signs is changes in the early phases of red blood cell synthesis, as these cells turn over every 120 days. Without folate, the precursor cells cannot divide normally to become mature red blood cells because they cannot form new DNA. These cells grow larger because there is a continuous formation of RNA, leading to increased synthesis of protein and other cell components to make new cells. Hemoglobin synthesis also intensifies, however, when it is time for the cells to divide, they lack sufficient DNA for normal division and thus remain in a large, immature form in the bone marrow, known as megaloblasts. Unlike normal, mature red blood cells, megaloblasts retain their nuclei and once they enter the blood stream they are called macrocytes. This results in a form of anemia called megaloblastic anemia. White blood cell synthesis also is disrupted by a folate deficiency because these cells are made in rapid bursts during immune challenges like infections. The GI tract is also impaired, leading to decreased absorptive capacity and persistent diarrhea.
Neural Tube Defects
Neural tube defects account for the largest proportion of congenital anomalies of the CNS resulting from a failure of the neural tube to close spontaneously between the 3rd and 4th week on in utero development. Neural tube defects including spina bifida and anencephaly can be easily avoided with adequate folate in most cases. Spina bifida may exhibit paralysis, incontinence, hydrocephalus, and learning disabilities while children with anencephaly die shortly after birth. The neural tube closure begins 21 days after conception and is completed by day 28 before or around the time when most women are realizing they are pregnant. As many as 70% of defects could be avoided with adequate folate ingestion and therefore, adequate folate is crucial for all women of childbearing years.
Hispanic women have highest rates of neural tube defects while lowest rates found in African American and Asian women. Women who have had a previous pregnancy with a neural tube defect or who are personally affected by a neural tube defect are at a higher risk for having an offspring with a neural tube defect in a subsequent pregnancy. Other factors include siblings with a neural tube defect, maternal diabetes and antiseizure medications such as valproic acid or carbamazepine. A higher risk of a neural tube defect is also associated with increased maternal weight. However, 95% of children with neural tube defects are born to couples without any family history of neural tube defects.
- US Preventive Services Task Force, Agency for Healthcare Research and Quality: Folic acid for the prevention of neural tube defects: US Preventive Services Task Force recommendation statement. Ann Intern Med 150:626, 2009.
- De Wals P, Tairu F, Van Allen MI, et al: Reduction in neural-neural tube defects after folic acid fortification in Canada. N Engl J Med 357:135, 2007.
- Bentley TG, Willet WC, Weinstein MC, Kuntz KM: Population-level changes in folate intake by age, gender, and race/ethnicity after folic acid fortification. Am J Public Health 96:2040, 2006.
- Green NS: Folic acid supplementation and prevention of birth defects. Journal of Nutrition 132:2356S, 2002.