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Folic acid

Classification: A

Drug products: Folacin®, Folarell, Folix, Folsyra EQL Pharma, Folsyra Evolan, Folsyra Orifarm, Folsyra Pilum, Folsyra Vitabalans, Folsäure Injektopas, Folvidon

ATC code: B03BB01

Substances: folic acid, folic acid hydrated

Summary

Higher folic acid intake is associated with reduced ischemic stroke risk in men but not in women. There are contradictory data concerning the effect of folic acid on cancer incidence and whether there are sex differences or not. Large meta-analyses shown no reduced incidence of overall cancer or for colon cancer, neither in men nor in women. Results from observational studies vary between cancer forms, some describe no sex differences while others describe effect only in one sex. The clinically relevance is unclear.

Additional information

Pharmacokinetics and dosing

Based on data from a European population study (2889 men, 2557 women), the level of folate in plasma does not differ significantly between men and women [1]. Serum concentrations of folate biomarkers were measured in the US population in 2011-2012 (4463 men, 4493 women). Concentrations of 5-methylTHF concentrations were higher in women, while concentrations of the oxidation product of 5-methylTHF, that lacks biologic activity, were similar in men and women [2].Women who plan to become pregnant or are pregnant are recommended a folic acid intake of at least 400 µg/day to prevent neural tube defects on the fetus [3].

Effects

Stroke preventionMeta-analyses assessing the efficacy of folic acid supplementations for prevention of cardiovascular and cerebrovascular events have reported contradictory findings [4-7]. One meta-analysis performed a sex-stratified analysis showing a relative stroke risk of 0.84 (95% CI 0.74-0.94; p=0.03) in men predominant trials, while women predominate trials showed no change in relative risk (RR 1.11, 95% CI 0.84-1.49). The authors suggest this sex difference could be due to higher stroke event rates in men which increases study power to detect treatment effects. Another  reason might be sex differences in severity and treatment-responsiveness of hyper-homocysteinemia causing higher baseline homocysteine concentration in men and greater reductions in homocysteine levels in men [6]. Same findings have been reported in observational studies; higher folic acid intake was associated with reduced ischemic stroke risk in male US health professionals (43 732 men, RR 0.71, 95%CI 0.52-0.96, p=0.05) [8] and in male Finnish smokers (RR 0.80, 95% CI 0.70-0.91, p=0.001) [9], but not in female US nurses (83 272 women; RR 1.01, 95% CI 0.79-1.29, p=0.8) [10].

Cancer incidenceThe effect of folic acid on overall cancer incidence was analyzed in a meta-analysis with data from 13 placebo-controlled trials of folic acid for prevention of colorectal cancer (3 studies, n=2652) or cardiovascular disease (10 studies, n=46 969). The daily dose ranged between 0.5-5 mg folic acid (one trial 40 mg) and the average treatment duration was 5.2 years. The plasma folate was quadrupled (57.3 nmol/L for the folic acid group vs 13.5 nmol/L for the placebo group), but no effect on cancer incidence was observed, neither in men nor in women [11].Another meta-analysis of eight RCTs (n=34 598) found no effect of folic acid supplementation (0.5-2.5 mg) on colorectal cancer risk (RR 1.00, 95% CI 0.82-1.22, p=0.974), neither in men nor women [12]. Most observational studies report similar findings [13-17], while some report an association between low folic acid intake and colorectal cancer risk only in men [18, 19].High folic acid intake is associated with reduced risk of oral cavity and pharynx cancer [20] and head and neck cancer [21] in both men and women. High folic acid intake is associated with reduced risk of lung cancer only in men [22], and associated with increased risk of skin cancer only in women [23].

DeathAn observational study report that lower levels of folate are associated with higher risk of death in men and women, higher risk of death in cardiovascular diseases in men, and higher risk of death in tumor disease in women [24].

DepressionA meta-analysis of three randomized trials (n=247) showed beneficial effects of folic acid in depression [25]. One of the included trials (20 men, 40 women) reported an improved Hamilton depression rating scale in women, but not in men treated with folic acid [26].Observational studies are inconsistent whether patient’s sex influence the association between folate levels (or folic acid intake) and depressive symptoms. Low folate levels are associated with elevated depressive symptoms in US women [27, 28] and in elderly Latina women [29]. Contrary to this, Japanese studies found an association between low folate levels (or folic acid intake) and increased prevalence of depressive symptoms in men but not in women [30, 31]. One analysis in elderly >65 years found no association between folic acid intake and risk of depressive symptoms in men nor in women [32].

Adverse effects

See above, no further studies with a clinically relevant sex analysis regarding adverse effects of folic acid has been found.

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

Changes in folic acid intake as a result of fortification have been estimated in several countries. The 1998 FDA fortification policy contributed to an increased folic acid intake by approximately 100 µg/day in the US population, but consumption rates varied between ethnic groups with lower rates among Blacks and Mexican Americans [33]. Also, in a Brazilian study, folic acid intake increased after food fortification. Only 1.76% had folate deficiency, with no sex differences observed for any of the age groups [34].

Updated: 2020-08-28

Date of litterature search: 2017-12-10

References

  1. Eussen SJ, Nilsen RM, Midttun Ø, Hustad S, IJssennagger N, Meyer K et al. North-south gradients in plasma concentrations of B-vitamins and other components of one-carbon metabolism in Western Europe: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. Br J Nutr. 2013;110(2):363-74. PubMed
  2. Pfeiffer CM, Sternberg MR, Fazili Z, Lacher DA, Zhang M, Johnson CL et al. Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2. Br J Nutr. 2015;113(12):1965-77. PubMed
  3. Folacin (folic acid). Summary of Product Characteristics. Medical Products Agency Sweden; 2018.
  4. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA. 2006;296(22):2720-6. PubMed
  5. Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007;369(9576):1876-1882. PubMed
  6. Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. Stroke. 2010;41(6):1205-12. PubMed
  7. Yang HT, Lee M, Hong KS, Ovbiagele B, Saver JL. Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials. Eur J Intern Med. 2012;23(8):745-54. PubMed
  8. He K, Merchant A, Rimm EB, Rosner BA, Stampfer MJ, Willett WC et al. Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke. 2004;35(1):169-74. PubMed
  9. Larsson SC, Männistö S, Virtanen MJ, Kontto J, Albanes D, Virtamo J. Folate, vitamin B6, vitamin B12, and methionine intakes and risk of stroke subtypes in male smokers. Am J Epidemiol. 2008;167(8):954-61. PubMed
  10. Al-Delaimy WK, Rexrode KM, Hu FB, Albert CM, Stampfer MJ, Willett WC et al. Folate intake and risk of stroke among women. Stroke. 2004;35(6):1259-63. PubMed
  11. 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 50,000 individuals. Lancet. 2013;381(9871):1029-36. PubMed
  12. Qin T, Du M, Du H, Shu Y, Wang M, Zhu L. Folic acid supplements and colorectal cancer risk: meta-analysis of randomized controlled trials. Sci Rep. 2015;5(1):12044. PubMed
  13. Du W, Li WY, Lu R, Fang JY. Folate and fiber in the prevention of colorectal cancer: between shadows and the light. World J Gastroenterol. 2010;16(8):921-6. PubMed
  14. Kennedy DA, Stern SJ, Moretti M, Matok I, Sarkar M, Nickel C et al. Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis. Cancer Epidemiol. 2011;35(1):2-10. PubMed
  15. Keum N, Giovannucci EL. Folic acid fortification and colorectal cancer risk. Am J Prev Med. 2014;46(3):S65-72. PubMed
  16. Konings EJ, Goldbohm RA, Brants HA, Saris WH, van den Brandt PA. Intake of dietary folate vitamers and risk of colorectal carcinoma: results from The Netherlands Cohort Study. Cancer. 2002;95(7):1421-33. PubMed
  17. La Vecchia C, Negri E, Pelucchi C, Franceschi S. Dietary folate and colorectal cancer. Int J Cancer. 2002;102(5):545-7. PubMed
  18. Su LJ, Arab L. Nutritional status of folate and colon cancer risk: evidence from NHANES I epidemiologic follow-up study. Ann Epidemiol. 2001;11(1):65-72. PubMed
  19. Bird CL, Swendseid ME, Witte JS, Shikany JM, Hunt IF, Frankl HD et al. Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev. 1995;4(7):709-14. PubMed
  20. Galeone C, Edefonti V, Parpinel M, Leoncini E, Matsuo K, Talamini R et al. Folate intake and the risk of oral cavity and pharyngeal cancer: a pooled analysis within the International Head and Neck Cancer Epidemiology Consortium. Int J Cancer. 2015;136(4):904-14. PubMed
  21. Kawakita D, Lee YA, Gren LH, Buys SS, La Vecchia C, Hashibe M. The impact of folate intake on the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort. Br J Cancer. 2018;118(2):299-306. PubMed
  22. Zhang YF, Zhou L, Zhang HW, Hou AJ, Gao HF, Zhou YH. Association between folate intake and the risk of lung cancer: a dose-response meta-analysis of prospective studies. PLoS One. 2014;9(4):e93465. PubMed
  23. Donnenfeld M, Deschasaux M, Latino-Martel P, Diallo A, Galan P, Hercberg S et al. Prospective association between dietary folate intake and skin cancer risk: results from the Supplémentation en Vitamines et Minéraux Antioxydants cohort. Am J Clin Nutr. 2015;102(2):471-8. PubMed
  24. Peng Y, Dong B, Wang Z. Serum folate concentrations and all-cause, cardiovascular disease and cancer mortality: A cohort study based on 1999-2010 National Health and Nutrition Examination Survey (NHANES). Int J Cardiol. 2016;219(1):136-42. PubMed
  25. Taylor MJ, Carney SM, Goodwin GM, Geddes JR. Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol. 2004;18(2):251-6. PubMed
  26. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60(2):121-30. PubMed
  27. Beydoun MA, Fanelli Kuczmarski MT, Beydoun HA, Shroff MR, Mason MA, Evans MK et al. The sex-specific role of plasma folate in mediating the association of dietary quality with depressive symptoms. J Nutr. 2010;140(2):338-47. PubMed
  28. Beydoun MA, Shroff MR, Beydoun HA, Zonderman AB. Serum folate, vitamin B-12, and homocysteine and their association with depressive symptoms among US adults. Psychosom Med. 2010;72(9):862-73. PubMed
  29. Ramos MI, Allen LH, Haan MN, Green R, Miller JW. Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification. Am J Clin Nutr. 2004;80(4):1024-8. PubMed
  30. Nanri A, Mizoue T, Matsushita Y, Sasaki S, Ohta M, Sato M et al. Serum folate and homocysteine and depressive symptoms among Japanese men and women. Eur J Clin Nutr. 2010;64(3):289-96. PubMed
  31. Murakami K, Mizoue T, Sasaki S, Ohta M, Sato M, Matsushita Y et al. Dietary intake of folate, other B vitamins, and omega-3 polyunsaturated fatty acids in relation to depressive symptoms in Japanese adults. Nutrition. 2008;24(2):140-7. PubMed
  32. Skarupski KA, Tangney C, Li H, Ouyang B, Evans DA, Morris MC. Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time. Am J Clin Nutr. 2010;92(2):330-5. PubMed
  33. Bentley TG, Willett 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. 2006;96(11):2040-7. PubMed
  34. Steluti J, Selhub J, Paul L, Reginaldo C, Fisberg RM, Marchioni DML. An overview of folate status in a population-based study from São Paulo, Brazil and the potential impact of 10 years of national folic acid fortification policy. Eur J Clin Nutr. 2017;71(10):1173-1178. PubMed
  35. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2017 [cited 2018-12-06.] länk

Authors: Carl-Olav Stiller, Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson

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