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Description
Folic acid is a water-soluble B vitamin found in a variety of foods, especially green leafy vegetables. Folium, the Latin word for leaf, is the source of the term folic acid. This vitamin is required for DNA synthesis and a variety of other key reactions in normal metabolism.
Folic acid has emerged as an important preventive nutrient, most notably for neural tube defects in pregnancy and atherosclerotic disease due to elevated homocysteine. Sexually active women of child-bearing potential should be encouraged to use folic acid supplements if dietary intake is not sufficient. Individuals with vascular disease risks should be tested for hyperhomocysteinemia or given prophylactic supplementation. Cancer prevention is inadequately supported, yet intriguing relationships exist at several sites, including the cervix, colon, and lung.
As a therapeutic intervention, the treatment of megaloblastic anemia has been the primary application of folic acid supplementation for some time in both traditional and alternative medicine, though a concerted attempt to rule out vitamin B12 deficiency is required before initiating monotherapy with folic acid. Deficiencies secondary to pharmaceutical therapy with anticonvulsants and oral contraceptives increase the need for folic acid supplementation. Topical folic acid solutions for use in periodontal disease are available but remain underutilized.
Other Names
folate, folinic acid, pteroylglutamic acid, vitamin B9
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Actions & Pharmacology
Effects
Folic acid has the following effects: antidepressant, antiproliferative, antiteratogenic, antihomocysteinemic, and anti-inflammatory (gingival). The coenzymes formed from folic acid are instrumental in the following intracellular metabolisms: conversion of homocysteine to methionine, conversion of serine to glycine, synthesis of thymidylate, histidine metabolism, synthesis of purines, and utilization or generation of formate (Gilman et al 2001).
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Clinical Trials
Cardiovascular Disease
Low folic acid status has been associated with cardiovascular disease (CVD) (Omenn et al 1998), and earlier epidemiological studies suggested that folic acid supplementation was associated with reduced risk of coronary heart disease (Rimm et al 1998). Prior to its institution, the plan to fortify cereal-grain products with 140 mcg of folate per 100 grams was projected to reduce the U.S. population risk of coronary artery disease by 5% (Tucker et al 1996), presumably by lowering blood homocysteine levels (Boers 1998).
Since hyperhomocysteinemia is an independent risk factor for CVD, it was believed that reducing plasma homocysteine levels with folic acid could reduce atherosclerosis progression and the risk of cardiovascular events. Unfortunately, current findings from clinical studies do not support this idea. A 2006 meta-analysis showed that folic acid supplementation conferred no benefits to those with preexisting vascular disease; the risk of CVDs or all-cause mortality remained unchanged during supplementation (Bazzano et al 2006). The analysis reviewed data from 12 randomized, controlled trials involving 16,958 subjects with a history of cardiovascular or renal disease who received supplemental folic acid for a period ranging from 6 months to 5 years. Dosages of folic acid used in the studies ranged from 0.5 mg/day to 15 mg/day. Folic acid supplementation reduced homocysteine levels in all trials (range: −1.5 to −26.0 µmol/L), but did not prevent cardiovascular events or reduce all-cause mortality. One multicenter trial mentioned in the analysis, the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST), examined 315 patients with chronic renal failure (CRF). Patients in the folic acid group (n=156) received 15 mg/day; at median follow-up 3.6 years later, plasma homocysteine levels were reduced by 19% in those receiving active treatment as compared to the group randomized to placebo (n=159). However, folic acid supplementation did not slow the progression of atherosclerosis, nor did it reduce cardiovascular events (Zoungas et al 2006). Even a large trial such as the Heart Outcomes Prevention Evaluation 2 study (HOPE-2)—which followed 5,522 subjects—yielded similar results. That study examined the effect of combined folic acid and vitamins B12 and B6 on cardiovascular events in patients with preexisting vascular disease.
Although mean levels of plasma homocysteine were reduced, the risk of major cardiovascular events was not (Lonn et al 2006). Given the discrepancies between results from earlier observational studies and those from clinical trials, the role of folic acid supplementation in primary prevention of vascular disease needs to be explored. Studies to date have only examined its effects in secondary prevention.
Other studies show that folic acid supplementation safely reduces elevated plasma homocysteine levels (Villa et al 2007; Huemer et al 2005). One review examined the effect of folic acid supplementation on plasma homocysteine levels in postmenopausal women and observed the relationship between supplementation with folic acid and various metabolic parameters. In one randomized, placebo-controlled study cited in the review, postmenopausal women were assigned to one of two groups: Group A (n=10) received folic acid 7.5 mg/day, and Group B (n=10) received placebo. By study end, Group A had lower plasma homocysteine levels compared with Group B. In addition, although some lipid profiles remained unchanged, significant improvements vs baseline were noted in levels of high-density lipoprotein (HDL, p<0.01), as well as in the ratios of total cholesterol/HDL cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)/HDL-C (p<0.02 and p<0.03, respectively), insulin sensitivity (p<0.02), and hepatic clearance of insulin (p<0.01). It was also noted that folic acid supplementation modifies impaired endothelial function due to hyperhomocysteinemia (Villa et al 2007). Interestingly, another study observed this effect independent of homocysteine-lowering. The randomized, placebo-controlled, crossover study enrolled 19 patients with type 2 diabetes; active treatment was 10 mg/day of folic acid for 2 weeks. Two weeks of folic acid supplementation was shown to improve endothelial dysfunction in these subjects, but no relationship was observed between changes in homocysteine levels and the significant improvements noted in flow-mediated dilatation (Title et al 2006). Another double-blind, randomized study examining children with epilepsy (n=123) found that of those receiving antiepileptic drugs (AEDs), 15.5% had elevated plasma homocysteine levels (ie, hyperhomocysteinemia).
Supplementation with 1 mg/day of folic acid for 3 months significantly reduced plasma homocysteine levels, while significantly increasing blood concentrations of folate. Levels of both remained unchanged in the group receiving placebo (Huemer et al 2005).
A 2005 meta-analysis studied the effect of folic acid supplementation, with and without vitamins B12 and B6, on levels of plasma homocysteine. Various doses were examined among the 25 randomized controlled trials involving 2,596 subjects. The authors concluded that, in general, daily doses of >0.8 mg folic acid are needed to achieve the maximal reduction in plasma homocysteine levels produced with supplementation. Doses of 0.2 and 0.4 mg/day correlate with 60% and 90% of the maximal effect, respectively. When vitamin B12 was combined with folic acid, an additional 7% reduction in plasma homocysteine levels was noted (Homocysteine Lowering Trialists' Collaboration, 2005). In earlier studies, folic acid was combined with vitamin B6 and vitamin B12 for greater effect on homocysteine levels. A meta-analysis of 12 trials examining the effects of supplemental folic acid on plasma homocysteine levels showed that supplements of 0.5 to 5 mg of folic acid could be expected to reduce plasma levels of homocysteine by a quarter to a third. Addition of vitamin B12 reduced plasma homocysteine concentrations by another 7%. Vitamin B6 did not lower these levels any further when added to the mix (Anon 1998).
Contraceptive-Induced Folic Acid Deficiency
Using oral contraceptives may result in folic acid deficiency that may occasionally manifest as megaloblastic anemia and thrombocytopenia. Administration of folic acid can correct the folic acid deficiency and thereby promptly reverse any abnormalities associated with the deficiency (Lewis 1974; Luhby et al 1971). The FDA-approved minimum optimal dose of oral folic acid is 2 milligrams/day for oral contraceptive-induced folate deficiency.
Depression
Folic acid deficiency may cause psychiatric disturbances such as depression. Low folate status is more common in depressed patients and has been linked with poor response to antidepressant therapy. Two controlled studies have suggested that supplementation of folate or its derivatives may improve clinical outcomes in the treatment of depression (Alpert et al 1997; Bottiglieri 1996).
Lung Cancer
Low folate status may increase lung cancer risk, and large doses may reduce precancerous changes in bronchial tissues. Epidemiological studies have suggested a relationship between low folate status and cancer of the lung (Glynn et al 1994). One study found that folic acid (10 mg) with vitamin B12 (500 mcg) reduced evidence of atypical bronchial squamous metaplasia in smokers. However, the authors cautioned that the spontaneous variation in sputum cytology results along with other limitations of this study temper the significance of these findings (Heimberger et al 1988).
Methotrexate Toxicity
A randomized study compared the effects of 5 mg/day of either folic acid or folinic acid added to current methotrexate (MTX) therapy on purine metabolism in patients with rheumatoid arthritis (RA). Specifically, researchers wanted to observe the effects of supplementation on urinary 5-amino-imidazole-4-carboxamide (AICA) and urinary adenosine excretion, two markers for MTX interference with purine metabolism. Blockages along this pathway may in turn affect immune cell function. Supplementation began concurrent with the sixth dose of MTX. Of the 40 subjects, 21 were randomized to treatment with folic acid and 19 were randomized to folinic acid. During MTX therapy, folinic acid, but not folic acid, normalized urinary AICA levels (Morgan et al, 2004). An earlier meta-analysis of published double-blind, randomized, controlled trials (n=7) testing the influence of folate supplementation in RA patients treated with MTX showed an 80% reduction of side effects (mainly gastrointestinal) with folic acid supplementation and no compromise of MTX efficacy. However, high-dose folinic acid was associated with an increase in tender and swollen joints (Ortiz et al 1998).
A more recently published study found that psoriasis patients treated with MTX had a marked deterioration in the disease following folic acid supplementation. This 12-week, double-blind clinical trial was originally designed to determine the effects of folic acid on the efficacy of MTX and its bearing on the frequency of side effects associated with MTX. Patients receiving long-term MTX therapy for their psoriasis were randomized to active treatment with 5 mg folic acid or placebo daily (n=11 in both groups). The addition of folic acid was associated with a decline in the efficacy of MTX for the treatment of psoriasis as measured by specific indices and visual analog scales. Given the small sample size and short duration of the trial, no conclusions could be made regarding the effect of folic acid on side effects associated with MTX therapy (Salim et al, 2006).
Prevention of Neural Tube Defects/Congenital Anomalies
The use of folic acid supplements by pregnant women to prevent neural tube defects is well established and supported by extensive clinical literature. Less known is the potential for reducing other congenital anomalies with folic acid supplementation. A 2006 meta-analysis reported that the use of folic acid–fortified multivitamins, beginning prior to conception and continuing throughout the first trimester of pregnancy, consistently provided protection against several serious congenital anomalies. In addition to neural tube defects, these included cardiovascular defects, limb defects, urinary tract anomalies, congenital hydrocephalus, and oral clefts. The meta-analysis identified 41 studies for inclusion, including 27 case-control studies, 10 cohort studies, and 4 randomized, controlled trials. All trials supplied a folic acid–fortified multivitamin to a group of pregnant subjects (Goh et al 2006). Oral clefts such as cleft palate alone (CP) or as cleft lip with or without cleft palate (CLP) are embryologically related to neural tube defects. A 2007 meta-analysis suggests that folic acid supplements taken during pregnancy protect against the development of oral clefts. From the 5 prospective studies that were analyzed, combined relative risks among those receiving supplementation were reported as 0.51 (95% CI: 0.32, 0.95) for CLP; 1.19 (95% CI: 0.43, 3.28) for CP; and 0.55 (95% CI: 0. 32, 0.95) for all clefts. From the 12 case-control studies, these combined risks were 0.77 (95% CI: 0.65, 0.90) for CLP; 0.80 (95% CI: 0.69, 0.93) for CP; and 0.78 (95% CI: 0. 71, 0.85) for all clefts. Although a negative association between supplementation and risk of CP was observed in 3 of the prospective studies, the reviewers note these studies, being the fewest in number, were underpowered.
For those women receiving supplementation in the case-control studies, the likelihood of having a child with an oral cleft was 33% less for any oral cleft, 29% less for CLP, and 20% less for CP. For their counterparts in the prospective studies, the likelihood of having a child with an oral cleft was 45% less for any oral cleft and 49% less for CLP. However, women in this group were 19% more likely to have a child with CP. This may be due to study limitations or the variation among studies regarding the distinction between syndromic vs nonsyndromic clefts (Badovinac et al 2007). The 2006 meta-analysis by Goh and colleagues, having been published just a few months earlier, was not included in this report (Goh et al 2006). It found that taking folic acid–fortified multivitamins beginning prior to conception and continued through the first trimester of pregnancy provided consistent protection against the development of cleft palate across studies. Case-control studies included in the analysis showed OR 0.76 (95% CI: 0.62-0.93) for CP; cohort and randomized, controlled trials showed OR 0.42 (95% CI: 0.06-2.84). For CLP, case-control studies showed OR 0.63 (95% CI: 0.54-0.73) while cohort and randomized, controlled trials showed OR 0.58 (95% CI: 0.28-1.19).
The 2006 meta-analysis by Goh and colleagues also showed that supplementation with folic acid–fortified multivitamins protects against neural tube defects (Goh et al 2006). For each study included in the analysis, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Among the eight case-control studies and 11 cohort and randomized, controlled trials included, women beginning supplementation prior to conception and taking it through the first trimester were consistently protected against neural tube defects (OR 0.67, 95% CI 0.58-0.77 in case-control studies; OR 0.52, 95% CI 0.39-0.69 in cohort and randomized, controlled trials). In six case-control studies, protection was even conferred to women who began supplementation in the first trimester, after learning they were pregnant (OR 0.80; 95% CI 0.72-0.89).
Ideally, folic acid should be administered at least 1 month before and during the first 3 months of pregnancy. The Centers for Disease Control and Prevention and various other committees recommend that all women of childbearing age who are capable of becoming pregnant receive 400 mcg/day. The reduction in neural tube defects in patients receiving folic acid therapy has been 60% to 70% (NHMRC 1994). Patients with previous history of neural tube defects during pregnancy should receive 4 milligrams/day starting 1 month before pregnancy and throughout the first 3 months of pregnancy (NHMRC 1991 and 1994; AAP 1993; Mulinare 1993).
In an earlier study, neural tube defects were decreased by approximately 60% in 3,051 pregnant mothers treated with 0.4 milligram of folic acid during the periconceptional period (28 days before the last menstrual period through 28 days after the last menstrual period) (Werler et al 1993).
A significant reduction in risk for first-time occurrence of neural tube defects was observed in 18,508 pregnant women consuming folic acid-containing multivitamins compared to no folic acid consumption (Milunsky et al 1989). Similar results were reported in another study (Czeizel et al 1992).
Ulcerative Colitis and Colonic Adenomas
Folate supplementation can reduce cell abnormalities in the rectal mucosa of patients with ulcerative colitis. Folic acid 15 mg/day (as calcium folate) or a placebo was taken (double-blind) for 3 months by 24 patients with UC of more than 7 years' duration. Patients had been in remission (no acute inflammation) for more than 1 month. In the placebo group, there was no difference in proliferative index between baseline and 3-month measures. In the folate group, proliferation was significantly reduced at 3 months compared to baseline (Biasco et al 1997).
Epidemiological studies have suggested a relationship between low folate status and colorectal cancer (Glynn et al, 1994). Folic acid supplementation had a nonsignificant but dose-response effect on protecting ulcerative colitis patients against colonic neoplasia. Use of higher doses (1,000 mcg daily) of folic acid was associated with greater risk reduction (46%, nonsignificant) (Lashner et al 1997).
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Indications & Usage
Approved by the FDA
- Prevention of neural tube defects in pregnancy
- Treatment of megaloblastic anemias caused by folic acid deficiency
- Treatment of folic acid deficiency caused by oral contraceptive or anticonvulsant therapy
Unproven Uses
Strong evidence shows that folic acid therapy can reduce high levels of homocysteine, which has been linked to coronary heart disease. Other studies have suggested that folic acid supplementation may be helpful for atherosclerosis, colon cancer prevention, coronary heart disease, depression, gingival hyperplasia, hyperhomocysteinemia, iron-deficiency or sickle-cell anemia, lung cancer prevention, methotrexate toxicity, prevention of restenosis following coronary angiography, ulcerative colitis, and vitiligo. Weaker evidence suggests that folic acid may be of some benefit for cervical cancer prevention (some studies were inconclusive), aphthous ulcers, geriatric memory deficit, and prevention of fragile X syndrome in children.
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Contraindications
Pernicious anemia and megaloblastic anemia caused by vitamin B12 deficiency (Prod Info: Folic acid tablets 1995).
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Precautions & Adverse Reactions
Folic acid doses above 0.1 mg/day may obscure pernicious anemia. Side effects of folic acid therapy include erythema, pruritus, urticaria, irritability, excitability, nausea, bloating, and flatulence.
A variety of central nervous system effects have been reported following 5 mg of folic acid three times a day, including altered sleep patterns, vivid dreaming, irritability, excitability, and overactivity (Hunter et al 1970). Discontinuation of the drug usually results in rapid improvement but in some cases may require 3 weeks before complete restoration.
Gastrointestinal disturbances following oral doses of 5 mg three times daily have been reported and include nausea, abdominal distention, discomfort, flatulence, and a constant bad or bitter taste in the mouth (Prod Info: Folic acid tablets 1995).
High-dose folic acid has been associated with zinc depletion. (Kakar et al 1985). Evidence suggests that up to 5 to 15 milligrams daily of folic acid does not have significant adverse effects on zinc status in healthy, nonpregnant individuals (Butterworth et al 1989).
Pregnancy
FDA-rated as Pregnancy Category A (relatively safe) at doses below 0.8 mg/day; doses higher than this are rated as Pregnancy Category C (effects unknown).
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Drug Interactions
Moderate Risk
Phenytoin and fosphenytoin
Concurrent use may decrease phenytoin or fosphenytoin levels, respectively, and increase seizure frequency. Clinical Management: If folic acid is added to phenytoin therapy, monitor patients for decreased seizure control.
Pyrimethamine
Concurrent use may reduce the effectiveness of pyrimethamine. Clinical Management: Folic acid should not be used as a folate supplement during pyrimethamine therapy as it is ineffective in preventing megaloblastic anemia. Leucovorin (folinic acid) may be added to pyrimethamine therapy to prevent hematologic toxicity without affecting pyrimethamine efficacy. However, the use of leucovorin may worsen leukemia.
Minor Risks
Sulfasalazine
Concurrent use may decrease the absorption of folic acid. Clinical Management: Monitor patient for signs of deficiency.
Potential Interactions
Colestipol
In vitro data has shown that colestipol may bind to cyanocobalamin/intrinsic factor complex, Folic Acid and iron citrate. Concurrent administration may decrease the bioavailability of vitamin and mineral preparations (Leonard et al, 1979).
Pancreatic enzymes
Concurrent use may interfere with the absorption of folic acid. Clinical Management: Patients taking pancreatin may require folic acid supplementation.
Triamterine
Concurrent use may cause decreased utilization of dietary folate. Clinical Management: Monitor patient for signs of deficiency.
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Dosage
Mode of Administration
Intramuscular, intravenous, oral, subcutaneous
How Supplied
Capsule, tablet, sterile solution for injection
Daily Dosage
All doses are for oral administration unless otherwise noted.
Adults
Recommended dietary allowance (RDA): adults and adolescents ≥ 14 years — 400 mcg/day; pregnancy — 600 mcg/day; lactation — 500 mcg/day.
Anticonvulsant-induced folate deficiency: 15 mg daily.
Aphthous ulcers (canker sores): treat folic acid deficiency.
Hyperhomocysteinemia: 500 to 5,000 mcg daily.
Methotrexate toxicity: 5 mg orally per week.
Oral contraceptive-induced folate deficiency: 2 mg daily.
Periodontal disease: 2 mg twice daily, or 5 mL of 0.1% topical mouth rinse twice daily.
Prevention of birth defects: 400 to 4,000 mcg orally daily beginning 1 month before conception.
Prevention of cerebrovascular disease: treat folic acid deficiency or hyperhomocysteinemia.
Prevention of cervical cancer: 800 to 10,000 mcg daily.
Prevention of colorectal cancer: 1 to 5 mg daily.
Prevention of lung cancer: 10 mg daily.
Prevention of neural tube defects (first occurrence prevention): 0.4 mg of folic acid daily. Doses from 0.5 to 1 mg daily are often administered during pregnancy.
Prevention of neural tube defects (prevention of recurrence): Patients with a previous history of neural tube defects during pregnancy should receive 4 mg daily starting 1 month before pregnancy and throughout the first 3 months of pregnancy.
Prevention of restenosis following coronary angiography: 1 mg in combination with 400 mcg vitamin B12 and 10 mg vitamin B6 daily.
Sickle cell anemia: 1 mg daily.
Treatment of folic acid deficiency (intramuscular, intravenous, or oral): Up to 1 mg daily until clinical symptoms of deficiency have resolved and blood levels have returned to normal.
Ulcerative colitis: 15 mg daily.
Vitiligo: 2,000 to 10,000 mcg daily.
PEDIATRICS
Recommended dietary allowance (RDA): Infants and children 0 to 6 months — 65 mcg/day; 7 to 12 months — 80 mcg/day; 1 to 3 years — 150 mcg/day; 4 to 8 years — 200 mcg/day; 9 to 13 years — 300 mcg/day.
Anticonvulsant-induced folate deficiency: 5 mg daily.
Folic acid deficiency (intramuscular, intravenous, subcutaneous, or oral): Up to 1 mg daily until clinical symptoms of deficiency have resolved and blood levels have returned to normal.
Folic acid deficiency in preterm neonates (intramuscular): 100 mcg daily from day 7 until discharge from hospital.
Gingival hyperplasia: 5 mg daily (Backman et al 1989).
Hyperhomocysteinemia: 500 to 5,000 mcg daily.
Storage
Store oral and parenteral folic acid at room temperature.
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