The results of three prospective studies suggested that increased folate intake may reduce the risk of breast cancer in women who regularly consume alcohol Thus, high folate intake might be associated with a risk reduction only in women whose breast cancer risk is raised by alcohol consumption. A very large prospective study in more than 88, nurses reported that folic acid intake was not associated with breast cancer in women who consumed less than one alcoholic drink per day.
Nevertheless, whether and how alcohol consumption increases breast cancer risk is still subject to discussion , Finally, recent meta-analyses evaluating the influence of polymorphisms in one-carbon metabolism on cancer risk found that specific variants in the gene encoding thymidylate synthase increased the risk of breast cancer in certain ethnic populations , The incidence of Wilms' tumors kidney cancer and certain types of brain cancers neuroblastoma, ganglioneuroblastoma, and ependymoma in children has decreased since the mandatory fortification of the US grain supply in However, incidence rates were unchanged between the pre- and post-fortification periods for leukemia—a predominant childhood malignancy.
Despite earlier studies linking maternal folic acid supplementation during pregnancy with the reduced risk of childhood leukemia, more recent investigations have found little evidence to support a preventive effect of folic acid Several meta-analyses have also found little to no protective effect with MTHFR polymorphisms ; however, the most recent meta-analysis of 22 case-control studies found a reduction in the risk of acute lymphoblastic leukemia ALL with the c. Alzheimer's disease AD is the most common form of dementia , affecting more than 5 million individuals over 65 years old in the US One study associated increased consumption of fruit and vegetables, which are abundant sources of folate, with a reduced risk of developing dementia and AD in women Through its role in nucleic acid synthesis and methyl donor provision for methylation reactions, folate is critical for normal brain development and function, not only during pregnancy and after birth, but also later in life In one cross-sectional study of elderly women, AD patients had significantly higher homocysteine and lower red blood cell folate concentrations compared to healthy individuals.
However, there was no difference in the level of serum folate between groups, suggesting that long-term folate status, rather than recent folate intake, may be associated with the risk of AD Several investigators have described associations between increased homocysteine concentrations and cognitive impairment in the elderly , but prospective cohort studies have not found higher folate intakes to be associated with improved cognition , Higher homocysteine concentrations were found in individuals suffering from dementia, including AD and vascular dementia , compared to healthy subjects , Although deficiencies in folate, vitamin B 12 , and vitamin B 6 could increase homocysteine concentrations, a reduction in vitamin concentrations in the serum of AD patients compared to healthy individuals could not be attributed to decreased vitamin intakes It is not presently clear whether serum homocysteine is a risk factor for developing dementia or simply associated with the cognitive decline.
In the last decade, a number of clinical trials have tested the use of B-vitamins to lower homocysteine and prevent or delay cognitive decline. A meta-analysis of nine randomized, placebo-controlled trials of folic acid supplementation 0. More recently, a meta-analysis of 19 randomized , placebo -controlled trials of B-vitamin supplementation found no difference in cognitive parameters between the treatment and placebo groups, despite the treatment effectively lowering homocysteine concentrations Inconsistent findings across trials may be due to differences in design and methodology reviewed in Atrophy of specific brain regions affected by AD was observed in individuals of both groups, and this atrophy correlated with cognitive decline; however, the B-vitamin treatment group experienced a smaller loss of gray matter compared to the placebo group 0.
A greater benefit was seen in subjects with higher baseline homocysteine concentrations, suggesting the importance of lowering circulating homocysteine in prevention of cognitive decline and dementia.
Although encouraging, the effect of B-vitamin supplementation needs to be further studied in larger trials that evaluate long-term outcomes, such as the incidence of AD. Folinic acid see Figure 1 above , a tetrahydrofolic acid derivative, is used in the clinical management of rare inborn errors that affect folate transport or metabolism reviewed in Such conditions are of autosomal recessive inheritance, meaning only individuals receiving two copies of the mutated gene one from each parent develop the disease.
Hereditary folate malabsorption is caused by mutations in the SLC46A1 gene coding for the folate transporter PCFT and typically affects gastrointestinal folate absorption and folate transport into the brain Patients present with low to undetectable concentrations of folate in serum and cerebrospinal fluid , pancytopenia low number of all blood cells , impaired immune responses that increase susceptibility to infections, and a general failure to thrive Neurologic symptoms, including seizures , have also been observed Clinical improvements have been recorded following parenteral provision of folinic acid CFD is characterized by low levels of folate coenzymes in cerebrospinal fluid despite normal concentrations of folate in blood.
Neurologic abnormalities, along with visual and hearing impairments, have been described in children with CFD; autism spectrum disorder ASD is present in some cases. Folinic acid also known as leucovorin can enter the brain and normalize the level of folate coenzymes and has been shown to normalize folate concentrations and improve various social interactions in CFD, including mood, behavior, and verbal communication in children with ASD , , DHFR deficiency is characterized by megaloblastic anemia and cerebral folate deficiency causing intractable seizures and mental deficits.
Although folinic acid treatment can alleviate the symptoms of DHFR deficiency, early diagnosis is essential to prevent irreversible brain damage and improve clinical outcomes , Green leafy vegetables foliage are rich sources of folate and provide the basis for its name. Citrus fruit juices, legumes , and fortified foods are also excellent sources of folate 1 ; the folate content of fortified cereal varies greatly.
The principal form of supplementary folate is folic acid. It is available in single-ingredient and combination products, such as B-complex vitamins and multivitamins.
Doses of 1 mg or greater require a prescription Additionally, folinic acid, a tetrahydrofolic acid derivative, is used to manage certain metabolic diseases see Disease Treatment.
No adverse effects have been associated with the consumption of excess folate from food. Concerns regarding safety are limited to synthetic folic acid intake. Deficiency of vitamin B 12 , though often undiagnosed, may affect a significant number of people, especially older adults see the article on Vitamin B One symptom of vitamin B 12 deficiency is megaloblastic anemia , which is indistinguishable from that associated with folate deficiency see Deficiency.
Large doses of folic acid given to an individual with an undiagnosed vitamin B 12 deficiency could correct megaloblastic anemia without correcting the underlying vitamin B 12 deficiency, leaving the individual at risk of developing irreversible neurologic damage.
The saturation of DHFR metabolic capacity by oral doses of folic acid has been associated with the appearance of unmetabolized folic acid in blood A small study conducted in postmenopausal women also raised concerns about the effect of exposure to unmetabolized folic acid on immune function In a small, randomized , open-label trial in 38 women of reproductive age receiving 30 weeks of daily multivitamin supplements, daily supplementation with either 1.
However, unmetabolized folic acid concentrations returned to baseline levels at the end of the study, suggesting that adaptive mechanisms eventually converted folic acid to reduced forms of folate. Nonetheless, the use of supplemental levomefolate 5-methyl THF may provide an alternative to prevent the potential negative effects of unconverted folic acid in older adults.
When nonsteroidal anti- inflammatory drugs NSAIDs , such as aspirin or ibuprofen, are taken in very large therapeutic dosages i. The anticonvulsant , phenytoin, has been shown to inhibit the intestinal absorption of folate, and several studies have associated decreased folate status with long-term use of the anticonvulsants, phenytoin, phenobarbital, and primidone However, few studies controlled for differences in dietary folate intake between anticonvulsant users and nonusers.
Also, taking folic acid at the same time as the cholesterol -lowering agents, cholestyramine and colestipol, may decrease the absorption of folic acid Methotrexate is a folate antagonist used to treat a number of diseases, including cancer , rheumatoid arthritis , and psoriasis. Some of the side effects of methotrexate are similar to those of severe folate deficiency, and supplementation with folic or folinic acid is used to reduce antifolate toxicity.
Other antifolate molecules currently used in cancer therapy include aminopterin, pemetrexed, pralatrexate, and raltitrexed Further, a number of other medications have been shown to have antifolate activity, including trimethoprim an antibiotic , pyrimethamine an antimalarial , triamterene a blood pressure medication , and sulfasalazine a treatment for ulcerative colitis.
Early studies of oral contraceptives birth control pills containing high doses of estrogen indicated adverse effects on folate status; however, this finding has not been supported in more recent studies that used low-dose oral contraceptives and controlled for dietary folate The available scientific evidence shows that adequate folate intake prevents neural tube defects and other poor outcomes of pregnancy; is helpful in lowering the risk of some forms of cancer , especially in genetically susceptible individuals; and may lower the risk of cardiovascular disease.
Originally written in by: Jane Higdon, Ph. Updated in April by: Jane Higdon, Ph. Updated in September by: Victoria J. Drake, Ph. Updated in June by: Barbara Delage, Ph. Food and Nutrition Board, Institute of Medicine. Washington, D.
National Academy Press. Folate and carcinogenesis: an integrated scheme. J Nutr. Folate metabolism and requirements. Homocysteine and atherosclerosis. Curr Opin Lipidol. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr. The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring cohort is influenced by folate status and the CT transition in the methylenetetrahydrofolate reductase gene.
L-ascorbic acid improves the serum folate response to an oral dose of [6S]methyltetrahydrofolic acid in healthy men. Eur J Clin Nutr. Vitamin C-related nutrient-nutrient and nutrient-gene interactions that modify folate status. Eur J Nutr. The human proton-coupled folate transporter: Biology and therapeutic applications to cancer.
Cancer Biol Ther. Expression of folate transporters in human placenta and implications for homocysteine metabolism. Metabolic interactions of alcohol and folate. Dietary supplement use and smoking are important correlates of biomarkers of water-soluble vitamin status after adjusting for sociodemographic and lifestyle variables in a representative sample of US adults. Maternal smoking is associated with decreased 5-methyltetrahydrofolate in cord plasma.
Folic acid transport to the human fetus is decreased in pregnancies with chronic alcohol exposure. PLoS One. Herbert V. Folic acid. Modern Nutrition in Health and Disease.
Stabler SP. Clinical folate deficiency. In: Bailey LB, ed. Folate in Health and Disease. Bailey LB. Dietary reference intakes for folate: the debut of dietary folate equivalents. Nutr Rev. Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Med Genet. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia.
Nat Struct Biol. Thermolabile variant of 5,methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase MTHFR.
Thromb Haemost. Shane B. Folic acid, vitamin B, and vitamin B In: Stipanuk M, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W. Saunders Co. Eskes TK. Open or closed? A world of difference: a history of homocysteine research. Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation.
N Engl J Med. Talaulikar VS, Arulkumaran S. Folic acid in obstetric practice: a review. Obstet Gynecol Surv. Neural tube defects. Washington, DC. The vitamin helps form red and white blood cells.
It also helps produce DNA, the building block of the human body, which carries genetic information. Folic acid is a water-soluble type of vitamin B. This means it is not stored in the fat tissues of the body. Leftover amounts of the vitamin leave the body through the urine. Because folate is not stored in the body in large amounts, your blood levels will get low after only a few weeks of eating a diet low in folate.
Folate is found primarily in legumes, leafy greens, eggs, beets, bananas, citrus fruits, and liver. Folate deficiency can be diagnosed with a blood test. Pregnant women commonly have this blood test at prenatal checkups. In folate-deficiency anemia , the red blood cells are abnormally large megaloblastic.
Pregnant women need to get enough folic acid. The study did not find a negative impact of the folate fortification program on cancer risk and even suggested a protective role. When teasing out the relationship between any vitamin supplement and cancer, it is important to remember that cancer cells are essentially our own cells on overdrive, growing and rapidly dividing, and they have a greater need for nutrients than most of our normal cells do.
Studies done decades ago show that folate is needed for tumor cell growth. Indeed, one successful chemotherapy agent works as a folate antagonist, since rapidly dividing cells require folate to maintain their fast pace of cell division.
So for people who have cancer or precancerous growths, nutritional supplements may be a double-edged sword. If you have cancer, make sure to check with your doctor before beginning any vitamin supplement regimen. Some observational studies have found a link between low blood levels of folate and higher risk of dementia. However, clinical trials have not found that folic acid supplementation prevents the development of dementia or improves cognitive function even if it reduces homocysteine levels.
A wide variety of foods naturally contain folate, but the form that is added to foods and supplements, folic acid, is better absorbed. In January , the U. Food and Drug Administration required food manufacturers to add folic acid to foods commonly eaten, including breads, cereals, pasta, rice, and other grain products, to reduce the risk of neural tube defects.
A folate deficiency is rare because it is found in a wide range of foods. However, the following conditions may put people at increased risk:. Signs of deficiency can include: megaloblastic anemia a condition arising from a lack of folate in the diet or poor absorption that produces less red blood cells, and larger in size than normal ; weakness, fatigue; irregular heartbeat; shortness of breath; difficulty concentrating; hair loss; pale skin; mouth sores.
However, an upper limit for folic acid is set at 1, mcg daily because studies have shown that taking higher amounts can mask a vitamin B12 deficiency. This deficiency occurs most often in older adults or those eating a vegan diet in whom a B12 deficiency is more common.
Both folate and B12 are involved in making red blood cells, and a shortage of either can result in anemia. A person taking high-dosage supplements of folic acid may be able to correct the anemia and feel better, but the B12 deficiency still exists. If you choose to use a folic acid supplement, stick with the lower range available of mcg a day or less, as you will likely obtain additional folic acid from fortified foods like cereals and breads, as well as natural folate in food.
Overall, the evidence suggests that the amount of folic acid in a typical multivitamin does not cause any harm—and may help prevent some diseases, especially among people who do not get enough folate in their diets, and among individuals who drink alcohol. Folate is also referred to as vitamin B9. Despite the number, there are only eight B vitamins in total. B Vitamins Vitamins and Minerals. The contents of this website are for educational purposes and are not intended to offer personal medical advice.
You should seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The Nutrition Source does not recommend or endorse any products. Skip to content The Nutrition Source. Harvard T. The Nutrition Source Menu. Search for:. Folate and Health Neural tube defects One of the advances that changed the way we look at vitamins was the discovery that too little folate is linked to birth defects of the spine spina bifida and brain anencephaly.
Heart disease In , a Boston pathologist investigated the deaths of two children from massive strokes. A Cochrane review of 15 randomized controlled trials found that folic acid supplements, taken alone or with other B vitamins, compared with a placebo did not show a significant difference on rates of heart attack and cardiovascular disease deaths but it did reduce the risk of stroke.
Thus folate appears to be absorbed both in the small intestine and colon, with a decreasing absorptive gradient from jejunum to colon. The long absorptive pathway could be a consequence of the very important function of folate in maintaining genetic body homeostasis. After Roux-en-Y gastric bypass, many patients develop folate deficiency. This highlights the importance of the high absorptive capacity for folate in the acidic milieu in duodenum and proximal jejunum, which is eliminated by the operation Folate deficient rats did not thrive compared to their folate replete mates Wani et al 17 studied the aspects of intestinal folate uptake in folate replete and folate deficient rats using the technique of intestinal brush border membrane vesicles BBMV from isolated small intestinal epithelial cells.
The uptake of folic acid was p H dependent with a maximum at acidic p H of 5. It followed the enzyme kinetics of Michaelis-Menten consistant with a carrier-mediated transport.
The results of Wani et al 17 showed that folic acid uptake increased with increasing maturity of the enterocytes and was highest in the cells located at the tip of the villus. Furthermore, using labelled S-adenosylmethionine, there was evidence of a decreased methylation rate of DNA in folate deficient rats in comparison with their folate replete mates. Hopefully, their findings can be interpreted and employed to elaborate a better prevention and combat against the global problem of human folate deficiency.
National Center for Biotechnology Information , U. Indian J Med Res. Nils Milman. Author information Copyright and License information Disclaimer. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3. See the article " Diabetes prevention - the global hope on the horizon " in volume on page This article has been cited by other articles in PMC.
Open in a separate window. References 1. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate's role. Adv Nutr.
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