Folate is a vital component of a healthy diet, being essential for numerous bodily functions. Deficiency of folate is common, with studies suggesting prevalence of deficiencyas high as 85.5% as was shown in women between the ages of 16 and 49, living in the UK. Causes of folate deficiency range from diet and lifestyle, to pathological and pharmacological processes. Because of the well-known role of folate in prevention of neural tube defects, numerous countries have implemented strategies to increase folate intake, with programs such as mandatory grain fortification. As a result, the intake of folate in these countries is often higher than the recommended dietary allowance for many groups of people. Although folate is believed to be non-toxic, the potential adverse effects of excessive intake of folic acid (synthetic form of folate) have not been highlighted well by authorities to people taking supplements; despite this, many studies have addressed this issue. However, the results of these studies provide discrepant results, leading to confusion as to whether mandatory folic acid fortification should be introduced in other countries. The purpose of this review was to provide a summary of evidence related to high folic acid ingestion and to look at the unwanted effects it may have on the certain groups within the general population.
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Das KC, Herbert V . Vitamin B12—folate interrelations. Clin Haematol 1976; 5: 697–745.
The British Dietetic Association (BDA) Food Fact Sheet Folic Acid. Avaliable at: http://www.nhs.uk/ipgmedia/national/british%20dietetic%20association/assets/folicacid-howmuchyouneed.pdf (accessed on 30 July 2016).
Khoshnood B, Loane M, de Walle H, Arriola L, Addor MC, Barisic I et al. Long term trends in prevalence of neural tube defects in Europe: population based study. BMJ 2015; 351: h5949.
Scaglione F, Panzavolta G . Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica 2014; 44: 480–488.
Lucock M . Is folic acid the ultimate functional food component for disease prevention? BMJ 2004; 328: 211–214.
Sweeney MR, McPartlin J, Scott J . Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health 2007; 7: 41.
Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM . Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 1997; 65: 1790–1795.
Powers HJ . Folic acid under scrutiny. Br J Nutr 2007; 98: 665–666.
Pfeiffer CM, Sternberg MR, Fazili Z, Yetley EA, Lacher DA, Bailey RL et al. Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. J Nutr 2015; 145: 520–531.
Pfeiffer CM, Hughes JP, Lacher DA, Bailey RL, Berry RJ, Zhang M et al. Estimation of trends in serum and RBC folate in the U.S. population from pre- to postfortification using assay-adjusted data from the NHANES 1988-2010. J Nutr 2012; 142: 886–893.
Institute of Medicine (US). Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline 1998, Available at http://www.nap.edu/books/0309065542/html/index.html/ accessed on 20 July 2016.
B vitamin supplement Available at:http://www.tesco.com/groceries/product/details/?id=263466800 (accessed on 30 November 2015).
Sobczyńska-Malefora A, Harrington DJ, Gorska R, Shearer MJ, Lomer MC, Sobczyńska-Malefora A et al. Hyperhomocysteinaemia and B vitamin intakes in patients with a history of cardiovascular disease). 10th international conference 7/07/15-11/07/15 Page 51 University of Lorraine One Carbon Metabolism, Vitamins B and Homocysteine Conference 2015: Nancy, France.
Sobczynska-Malefora A, Harrington DJ, Lomer MC, Pettitt C, Hamilton S, Rangarajan S et al. Erythrocyte folate and 5-methyltetrahydrofolate levels decline during 6 months of oral anticoagulation with warfarin. Blood Coagul Fibrinolysis 2009; 20: 297–302.
Hauser WA . Folic acid supplementation: too much of a good thing? J Neurol Neurosurg Psychiatry 2009; 80: 468.
Kakar F, Henderson MM . Potential toxic side effects of folic acid. J Natl Cancer Inst 1985; 74: 263.
Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Federal Register 1996; 61: 8781–8789.
Boulet SL, Yang Q, Mai C, Kirby RS, Collins JS, Robbins JM et al. Trends in the postfortification prevalence of spina bifida and anencephaly in the United States. Birth Defects Res A Clin Mol Teratol 2008; 82: 527–532.
Atta CA, Fiest KM, Frolkis AD, Jette N, Pringsheim T St, Germaine-Smith C et al. Global birth prevalence of spina bifida by folic acid fortification status: a systematic review and meta-analysis. Am J Public Health 2016; 106: e24–e34.
Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007; 297: 2351–2359.
Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007; 16: 1325–1329.
Wright AJA, Dainty JR, Finglas PM . Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr 2007; 98: 667–675.
SACNFolate status of women in the United Kingdom and the risk of congenital neural tube defects (NTD) (2015). Available at: https://app.box.com/s/p66yloezimv7je6s0j9l962z3gizr381/1/4509873782/42609000313/1 (accessed on 20 February 2016)..
Bates B, Prentice A, Bates CJ, Page P, Steer T, Cox L et al. National Diet and Nutrition Survey rolling Programme (NDNS RP) supplementary report: blood folate results for the UK as a whole, Scotland and Northern Ireland (years 1 to 4 combined) and Wales (years 2 to 5 combined). Public Health England, London 2015.
Cordero AM, Crider KS, Rogers LM et al. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines. MMWR Morb Mortal Wkly Rep 2015; 64: 421–423.
Smith AD, Refsum H, Selhub J, Rosenberg IH . Decision on folic acid fortification in Europe must consider both risks and benefits. BMJ 2016; 352: i734.
Heseker HB, Mason JB, Selhub J, Rosenberg IH, Jacques PF . Not all cases of neural-tube defect can be prevented by increasing the intake of folic acid. Br J Nutr 2009; 102: 173–180.
Mensink GB, Fletcher R, Gurinovic M, Huybrechts I, Lafay L, Serra-Majem L et al. Mapping low intake of micronutrients across Europe. Br J Nutr 2013; 110: 755–773.
Deshmukh U, Katre P, Yajnik CS . Influence of maternal vitamin B12 and folate on growth and insulin resistance in the offspring. Nestle Nutr Inst Workshop Ser 2013; 74: 145–154.
Girotto F, Scott L, Avchalumov Y, Harris J, Iannattone S, Drummond-Main C et al. High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring. Sci Rep 2013; 3: 1465.
Christensen KE, Mikael LG, Leung KY, Levesque N, Deng L, Wu Q et al. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr 2015; 101: 646–658.
Choi SW, Mason JB . Folate status: effects on pathways of colorectal carcinogenesis. J Nutr 2002; 132: 2413S–2418S.
Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 2006; 136: 189–194.
Ulrich CM, Potter JD . Folate and cancer—timing is everything. JAMA 2007; 297: 2408–2409.
Hirsch S, Sanchez H, Albala C, de la Maza MP, Barrera G, Leiva L et al. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol 2009; 21: 436–439.
Stevens VL, McCullough ML, Sun J, Jacobs EJ, Campbell PT, Gapstur SM . High levels of folate from supplements and fortification are not associated with increased risk of colorectal cancer. Gastroenterology 2011; 141: 98–105.
Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR . Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 2008; 134: 29–38.
Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst 2009; 101: 432–435.
Vollset SE, Clarke R, Lewington S, Ebbing M, Halsey J, Lonn E et al. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50000 individuals. Lancet 2013; 381: 1029–1036.
Boyles AL, Yetley EA, Thayer KA, Coates PM . Safe use of high intakes of folic acid: research challenges and paths forward. Nutr Rev 2016; 74: 469–474.
Bailey RL, Dodd KW, Gahche JJ, Dwyer JT, McDowell MA, Yetley EA et al. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006. Am J Clin Nutr 2010; 91: 231–237.
Rycyna KJ, Bacich DJ, O'Keefe DS . Divergence between dietary folate intake and concentrations in the serum and red blood cells of aging males in the United States. Clin Nutr 2016; 35: 928–934.
Bruce A . Folic acid: an update on scientific developments European Union Publications Office January 2009. EFSA Meeting summary report. Available at http://www.efsa.europa.eu/sites/default/files/event/corporate090121-m.pdf accessed on 17 June 2016.
World Health Organization, Food and Agricultural Organization of the United Nations, Clugston GA World Health Organization, Food and Agricultural Organization of the United Nations, Tontisirin K World Health Organization, Food and Agricultural Organization of the United NationsVitamin and Mineral Requirements in Human Nutrition. FAO: Rome, Italy, 2004, pp 53–62.
Krishnaveni GV, Veena SR, Karat SC, Yajnik CS, Fall CH . Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children. Diabetologia 2014; 57: 110–121.
Keating E, Correia-Branco A, Araujo JR, Meireles M, Fernandes R, Guardao L et al. Excess perigestational folic acid exposure induces metabolic dysfunction in post-natal life. J Endocrinol 2015; 224: 245–259.
Xita N, Tsatsoulis A . Adiponectin in diabetes mellitus. Curr Med Chem 2012; 19: 5451–5458.
Popkin BM, Doak CM . The obesity epidemic is a worldwide phenomenon. Nutr Rev 1998; 56: 106–114.
Philip D, Buch A, Moorthy D et al. Dihydrofolate reductase 19-bp deletion polymorphism modifies the association of folate status with memory in a cross-sectional multi-ethnic study of adults. Am J Clin Nutr 2015; 102: 1279–1288.
Orjuela MA, Titievsky L, Liu X, Ramirez-Ortiz M, Ponce-Castaneda V, Lecona E et al. Fruit and vegetable intake during pregnancy and risk for development of sporadic retinoblastoma. Cancer Epidemiol Biomarkers Prev 2005; 14: 1433–1440.
Selhub J, Rosenberg IH . Excessive folic acid intake and relation to adverse health outcome. Biochimie 2016; 126: 71–78.
Sobczynska-Malefora A, Harrington DJ, Voong K, Shearer MJ . Plasma and red cell reference intervals of 5-methyltetrahydrofolate of healthy adults in whom biochemical functional deficiencies of folate and vitamin B 12 had been excluded. Adv Hematol 2014; 2014: 465623.
Selhub J, Morris MS, Jacques PF, Rosenberg IH . Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr 2009; 89: 702S–706SS.
Dwarkanath P, Barzilay JR, Thomas T, Thomas A, Bhat S, Kurpad AV . High folate and low vitamin B-12 intakes during pregnancy are associated with small-for-gestational age infants in South Indian women: a prospective observational cohort study. Am J Clin Nutr 2013; 98: 1450–1458.
Barker DJ . Maternal nutrition, fetal nutrition, and disease in later life. Nutrition 1997; 13: 807–813.
O’Hare J, O’Driscoll D, Duggan B, Callaghan N . Increase in seizure frequency following folic acid. Ir Med J 1979; 72: 241–242.
Steinweg DL, Bentley ML . Seizures following reduction in phenytoin level after orally administered folic acid. Neurology 2005; 64: 1982.
Arabelovic S, Sam G, Dallal GE, Jacques PF, Selhub J, Rosenberg IH et al. Preliminary evidence shows that folic acid fortification of the food supply is associated with higher methotrexate dosing in patients with rheumatoid arthritis. J Am Coll Nutr 2007; 26: 453–455.
Ashokkumar B, Mohammed ZM, Vaziri ND, Said HM . Effect of folate oversupplementation on folate uptake by human intestinal and renal epithelial cells. Am J Clin Nutr 2007; 86: 159–166.
We thank Mrs Renata Gorska (The Nutristasis Unit, Viapath) for preparation of the figure. We also thank the reviewers for their helpful comments. All of the information in this review is of original research and has not been published or submitted for publication to other journals.
The authors declare no conflict of interest.
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Patel, K., Sobczyńska-Malefora, A. The adverse effects of an excessive folic acid intake. Eur J Clin Nutr 71, 159–163 (2017). https://doi.org/10.1038/ejcn.2016.194
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