Folic acid is used for the treatment of megaloblastic and macrocytic anemias resulting from folate deficiency. The drug is usually indicated in the treatment of nutritional macrocytic anemia; megaloblastic anemias of pregnancy, infancy, and childhood; and megaloblastic anemia associated with primary liver disease, alcoholism and alcoholic cirrhosis, intestinal strictures, anastomoses, or sprue. Folate deficiency may also result from increased loss of folate secondary to renal dialysis or the administration of some drugs such as phenytoin, primidone, barbiturates, methotrexate, nitrofurantoin, or sulfasalazine.
Folic acid is not effective in the treatment of normocytic, refractory, or aplastic anemias or, when used alone, in the treatment of pernicious anemia. Folic acid antagonists (e.g., methotrexate, pyrimethamine, trimethoprim) inhibit folic acid reductases and prevent the formation of tetrahydrofolic acid. Therefore, folic acid is not effective as an antidote following overdosage of these drugs, and leucovorin calcium must be used.
In large doses, folic acid is used in the treatment of tropical sprue. In patients with this disease, the drug appears to exert a beneficial effect on the underlying mucosal abnormality as well as to correct folate deficiency.
Although prophylactic administration of folic acid is not required in most individuals, supplemental folic acid may be required to prevent deficiency of the vitamin in patients with conditions that increase folic acid requirements such as pregnancy, nursing, or chronic hemolytic anemia.
In some patients, such as those with nutritional megaloblastic anemia associated with vitamin B12 deficiency or tropical or nontropical sprue, a simultaneous deficiency of folic acid and cyanocobalamin may exist, and combined therapy may be warranted. Likewise, combined folic acid and iron therapy may be indicated for prevention or treatment of megaloblastic anemia associated with iron deficiency as may occur in conditions such as sprue, megaloblastic anemia of pregnancy, and megaloblastic anemia of infants.
The National Academy of Sciences (NAS) has issued a comprehensive set of Recommended Dietary Allowances (RDAs) as reference values for dietary nutrient intakes since 1941. In 1997, the NAS Food and Nutrition Board (part of the Institute of Medicine [IOM]) announced that they would begin issuing revised nutrient recommendations that would replace RDAs with Dietary Reference Intakes (DRIs). DRIs are reference values that can be used for planning and assessing diets for healthy populations and for many other purposes and that encompass the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL). DRIs apply to the healthy general population, with RDAs and AIs defining the nutrient levels necessary for healthy individuals. Intake at the level of the RDA or AI would not necessarily replete the nutrient in undernourished individuals nor would it be adequate for disease states marked by increased requirements of the nutrient.
The EAR is the nutrient intake value that is estimated to meet the requirement defined by a specific indicator of adequacy in 50% of individuals in a life-stage and gender group. In the past, recommended nutrient intake values (e.g., RDAs) often were based principally on levels needed to prevent deficiency, whereas EARs consider these levels as well as levels associated with disease risk reduction (e.g., osteoporosis). The RDA currently is defined as the daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97-98%) healthy individuals in a given life-stage and gender group; RDAs apply to individuals not to groups, and the EAR serves as the basis for establishing the RDA. Although RDAs also previously were defined as the level of intake of essential nutrients that, on the basis of scientific knowledge, were judged to be adequate to meet the known nutrient needs of practically all healthy individuals, the current methods for establishing RDAs differ from those used in the past and, together with EARs and other reference values, address increased understanding of both population and individual nutrient needs.
The RDA for a given nutrient, in a prescriptive sense, is the goal for dietary intake in individuals. If data are insufficient or too controversial to establish an RDA for a given life-stage group, an AI will be used instead. AIs are used when scientific evidence is insufficient to calculate a given EAR, which is needed for establishing the RDA. AIs are based on observed or experimentally determined approximations of the average nutrient intake, by a defined population or subgroup, that appears to sustain a defined nutritional state (e.g., usual circulating nutrient levels, nutrient levels for normal growth). In the absence of definitive data needed to establish the EAR and RDA, the AI may be used as the goal for nutrient intake in healthy individuals; however, the AI should not be considered equivalent to the RDA, and in some cases it actually may exceed the RDA that eventually gets established.
The NAS has established an EAR and RDA for folate for adults based principally on red cell folate, which reflects tissue folate stores. For some life-stage groups, plasma homocysteine and plasma or serum folate concentrations also were considered. Because evidence currently available on the role of folate in reducing the risk of vascular disease (by reducing plasma homocysteine concentrations), cancer, and psychiatric and mental disorders is limited, the NAS did not use risk reduction as a basis for setting the EAR and RDA. While NAS has issued recommendations on folate intake for women capable of becoming pregnant, NAS considered prevention of neural tube defects inappropriate for use as an indicator for setting the EAR for women of childbearing age.
(See Uses: Prevention of Neural Tube Defects.)The EAR and RDA for children and adolescents 1-18 years of age were established based on data in adults, since specific data in children and adolescents currently are unavailable. An AI has been set for infants up to 6 months of age based on the observed mean folate intake of infants fed principally human milk. An AI for infants 6-12 months of age has been set based on the AI for younger infants and data from adults. Data from research studies that measured folate intake and assessed infant status are compatible with the established AI.
The principal goal of maintaining an adequate intake of folate in the US and Canada is to prevent megaloblastic changes in the bone marrow and other rapidly dividing cells. The role of folate in reducing the risk of vascular disease and other chronic disorders remains to be determined. Adequate intake of folate can be accomplished through consumption of foodstuffs, including folate-fortified foodstuffs, use of dietary supplements, or both. In the US, folate principally is obtained from fortified ready-to-eat cereals and vegetables (e.g., green beans, vegetable soup). As of January 1998, all enriched grains (e.g., enriched bread, pasta, flour, breakfast cereal, rice) are required to be fortified with 1.4 mg of folic acid/kg. Since enriched cereal grains are widely consumed in the US, these foodstuffs are expected to become an important contributor of folate and to increase folate intake. The NAS cautions that most currently available information on food folate composition underestimates folate concentration because of limitations in the analytical methods used and recent changes in folate fortification, and conclusions regarding the EAR for folate intake should not be based on these data.
For specific information on currently recommended AIs and RDAs of folate for various life-stage and gender groups, see
Dosage: Dietary and Replacement Requirements, under Dosage and Administration.
Prevention of Neural Tube Defects
Because available evidence indicates that prophylactic therapy with folic acid initiated before pregnancy can reduce the risk of fetal neural tube defects, including spina bifida, anencephaly, and encephalocele, during gestation, the US Public Health Service, the US Preventive Services Task Force, the American Academy of Pediatrics (AAP), the NAS, and others currently recommend that adequate folic acid intake be ensured in all women of childbearing potential. At a minimum, current evidence indicates that adequate intake of folic acid for at least 1 month before conception and through early pregnancy is needed to reduce the risk of fetal neural tube defects. However, because most pregnancies in the US are unplanned, the US Public Health Service, the US Preventive Services Task Force, and the NAS currently state that it would be prudent for all such women to consume folic acid through fortified foods and/or supplements (in addition to consuming food folate from a varied diet) on a regular, continuous basis as long as they are capable of conception. A higher dose of folic acid has been recommended prior to and during the first 3 months after conception for women with a history of prior neural tube defect pregnancy who are again planning pregnancy.
While a level of 0.4 mg of folate daily generally can be obtained through careful selection of foods, evidence for the protective effect from folic acid is much stronger than that from food folate. As of January 1998, all enriched grains (e.g., enriched bread, pasta, flour, breakfast cereal, rice) are required to be fortified with 1.4 mg of folic acid/kg of grain.In contrast to previous recommendations that relied principally on food folate, NAS currently recommends that women capable of becoming pregnant consume 0.4 mg of folic acid daily from fortified food and/or supplements. The US Preventive Services Task Force recommends that women planning a pregnancy and women capable of becoming pregnant consume 0.4-0.8 mg of folic acid daily from supplements.
Women of childbearing potential should be advised of the various alternatives (i.e., fortified food, supplements) for ensuring adequate daily intake of folic acid and encouraged to meet a goal of 0.4 mg daily. Women with a history of prior pregnancy complicated by fetal development of a neural tube defect and women receiving certain anticonvulsants are at high risk of a pregnancy with neural tube defects; such women should consult a clinician for advice if pregnancy is contemplated. While the possibility exists that lower dosages may be comparably effective, the US Public Health Service recommends that an increase in folic acid intake to 4 mg daily during the period of greatest risk (1 month before and 3 months after conception) be considered for women with a history of prior pregnancy complicated by fetal development of a neural tube defect. This dosage currently is recommended because the most rigorous study to date demonstrating benefit in reducing the risk of neural tube defects in such women employed it rather than because of superiority to alternative dosages.Because this dosage is high and may be associated with some risk, such women should consult their clinician in weighing the benefits versus risks of such high-dose supplementation.
It should be recognized that the underlying cause(s) of neural tube defects remains to be elucidated more fully and that adequate intake of folic acid is expected only to avert some but not all cases of such defects.
There is substantial evidence linking homocysteine concentrations to risk of ischemic heart disease and stroke. Folate is an important regulator of the metabolism of homocysteine; blood concentrations of homocysteine are inversely related to blood concentrations of folate. Data from randomized studies indicate that dietary supplementation with folic acid reduces blood homocysteine concentrations. Whether supplemental folic acid alters the risk of cardiovascular disease in patients with preexisting vascular disease has been investigated in several small randomized studies. However, the studies have yielded inconsistent results, and interpretation is limited by statistical limitations (i.e., inadequate power). A meta-analysis of 12 studies published before July 2006 was undertaken to qualify the relationship between supplemental folic acid and the risk of cardiovascular disease and all-cause mortality in patients with vascular disease. This meta-analysis found no important benefit or harm of folic acid supplementation on the risk of cardiovascular disease, coronary heart disease, stroke, or all-cause mortality in this patient population.