Maternal folate levels for the prevention of neural tube defects are considered a mainstay message for women of childbearing age. Side effects of synthetic folic acid supplementation have received some attention recently due to potential side effects. The most familiar is the potential to interfere with the diagnosis of a vitamin B12 deficiency related neurologic disease. This potential masking effect of folic acid supplementation occurs because megaloblastic anemia resulting from folate deficiency is not clinically distinguishable from megaloblastic anemia due to vitamin B12 deficiency. The megaloblastic anemia caused by a B12 deficiency responds to folic acid as does the megaloblastic anemia caused by folate deficiency. The problem is that the neurologic disease caused by a B12 deficiency does not respond to folic acid, only to Vitamin B12. As a result, a B12 deficient megaloblastic anemia and related neurologic problems will remain untreated and get worse if only folic acid is given. While this potentially harmful effect of masking is the primary reason that the Institute of Medicine (IOM) recommends that daily folic acid should not exceed 1,000 mcg per day,[i] synthetic L-5-methyl-THF, the bioavailable form of folate, does not have this masking effect.
In the last five years, some studies have suggested that high levels of unmetabolized folate may be associated with an increase in the risk for colorectal cancer. [ii], [iii]
In those individuals with premalignant colorectal lesions, excess folate, and in particular the thymidylate, a component of DNA that is synthesized from folate, could facilitate cell division of these premalignant lesions and lead to cancer. On the other hand, in those individuals without a premalignant lesion, folate may actually protect normal cells from becoming neoplastic. 3
Some evidence now exists for this “dual-modulator” effect of folate and colorectal neoplasia, whether dietary or supplemental. [iv],[v] This dual effect of folate, prevention vs. proliferative effect of premalignant lesions has been raised with prostate and breast cancer but recent studies have shown that appropriate folate intake does not significantly increase or decrease risks for breast[vi] and prostate cancer.[vii]
Adequate maternal intake of folic acid reduces the frequency of neural tube defects by up to 75%, and may also reduce the frequency of other birth defects such as ventricular septal defects, tetralogy of Fallot and transposition of the great vessels,[viii] urinary tract abnormalities [ix] and possibly even cleft lip and/or cleft palate.[x]
Currently, the average intake of folic acid from the diet of women of childbearing age is about 170mcg/day.[xi] A diet without folic acid fortified grains is typically 140 mcg/day. Clearly, too few women are achieving adequate serum folate levels through diet alone and do require supplementation. The RDA for folate in non-pregnant women is 400 mcg per day. [xii]The RDA for folate in pregnancy is 600 mcg per day[xiii] although the latest US Preventive Services Task Force recommendation is 400mcg-800 mcg per day for women of childbearing age.[xiv] The American College of Obstetricians and Gynecologists recommends that non pregnant women of childbearing aged consume 400 mcg/day. [xv] This variability reflects the uncertainty about the exact dose that is option for the prevention of neural tube defects. For women with a previous pregnancy resulting in a neural tube defect, 4,000 mcg is necessary to achieve these prevention benefits.15
While there is some concern about long term folic acid supplementation for a select number of individuals, the benefits for reproductive aged women, pre-pregnancy and pregnant, outweighs any concerns. A cautionary approach in terms of benefits and risks might be to meticulously track dietary intake to assure adequate levels, or to supplement with folic acid in combination with L-5-methyl-THF or L-5-methyl-THF alone.
[i] Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 1998.
[ii] Mason J, Dickstein A, Jacques P, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates myay be illuminating important biological principles : a hypothesis. Cancer Epidemiol Biomarkers Prev 2007;16(7):1325-1329
[iii] Sanjoaquin M, Allen N, Couto E, et al. Folate intake and colorectal cancer risk : a meta-analytical approach. Int J Cancer. 2005;113(5):825-828.
[iv] Mathers J. Folate intake and bowel cancer risk. Genes Nutr 2009;4(3)::173-178.
[v] Hubner R, Houlston R. Folate and colorectal cancer prevention. Br J Cancer. 2009;100(2):233-239.
[vi] Kim Y. Does a high folate intake increase rhe risk of breast cancer? Nutr Rev. 2006;64(10 pt 1):468-475
[vii] Figueiredo J, Grau M, Haile R, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009;101(6):432-435.
[viii] Botto L, Mulinare J, Erickson J. Do multivitamin or folic acid supplements reduce the risk for congenital heart defects? Evidence and gaps. Am J Med Genet. 2003;121A(2):95-101.
[ix] Czeizel A. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Am J Med Genet. 1996;62(2):179-183.
[x] Badovinac R, Werler M, Williams P, et al. Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth Defects Res A Clin Mol Teratol. 2007;79(1):8-15.
[xi] US Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Final rule. 212 CFR Parts 136, 137, 139. Fed Regist. 1996;61(44):8781-8797
[xii] Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington DC: National Academy Press; 1998.
[xiii] Simpson J, Bailey L, Pietrzik K, Shane B, Holzgreve . Micronutrients and women of reproductive potential: required dietary intake and consdquences of dietary deficiency or escess. Part !-Folate, Vitamin B12, Vitamin B6. J Matern Fetal Neonatal Med 2010.
[xiv] US Preventive Services Task Force. Folic acid for the prevention of neural tube defects: US preventive services task force recommendation statement. Ann Intern Med 2009;150(9):626-631
[xv] Cheschier N. ACOG Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin. Neural tube defects. November 44, July 2003. Int J Gynecol Obstet 2003;83(1):123-133.
