Folic Acid: An Overview of Metabolism, Dosages, and Benefits of Optimal Periconception Supplementation

Folic Acid

Folic acid is the synthetic form of folate, a water-soluble B vitamin that takes part in several critical functions in the human body. The active form of folate is tetrahydrofolic acid. It serves in one carbon reductions reactions. These reactions are involved in synthesis of nucleotides and amino acids1. The amino acids requiring folic acid for metabolism are methionine, cysteine, serine, glycine, and histidine. Folic acid also serves as a coenzyme in conversion of methionine to homocysteine. Methionine conversion also requires vitamin B12 and B6. Thus, folate or B12 deficiency can result in an elevated homocysteine level. Methionine, as S-adenylmethionine (SAM), serves as the donor of one carbon units to methylate sites within DNA, RNA, proteins, and phospholipids2. The enzyme responsible for conversion is dependent on riboflavin (B3). There are multiple level interactions among the B vitamins required for DNA synthesis3. Folic acid is required for erythropoiesis, thus folic acid deficiency leads to megaloblastic anemia. Adequate dietary intake of folic acid is critical for DNA repair and normal cell growth. 

When folic acid is deficient in the diet, oral supplementation is required. The dosage for supplementation varies by age and underlying conditions. For the general population, supplementation for folic acid deficiency is maintained at a dose of 0.4 mg/day. This dose can be increased to 0.8 mg/day for pregnant and lactating women. In non-deficient individuals for pregnancy prophylaxis, the recommended dose is 0.4 mg/day to 1 mg/day. Recommended dietary allowance for folic acid is 400 µg/day for men and women and 600 µg/day for pregnant woman. Lactating women should consume 500 µg/day of folic acid from their diet4. The dosages may have to be increased in alcoholics and patients on anticonvulsant therapy.

In pediatric patients, the recommended dietary allowance varies by age. For children aged 1 to 3 years, the RDA is 150 µg/day. It increases to 200 µg/day for children aged 4 to 8 years of age and 300 µg/day for ages 9 to 13. Infants of breastfeeding mothers do not require additional folic acid supplementation if the maternal diet is sufficient in folic acid. The content of folic acid in milk was found to be 15.2 ng/mL in colostrum, 16.3 ng/mL in transitional, and 33.4 ng/mL in mature milk5. For infants who are not breastfeeding, 65-80 µg of dietary folate equivalents are required per day6. Excessive doses of folate supplementation are not encouraged in pregnant females.  Folic acid doses higher than 5000 µg in pregnant females have shown to be associated with adverse affects including respiratory allergies, delayed psychomotor development, and insulin resistance7, 8.

Folic acid levels are a concern with several drugs. Methotrexate is a folic acid antagonist and therapy needs to be supplemented with folic acid to decrease toxicity. Methotrexate therapy is supplemented with leucovorin. Leucovorin (folinic acid) is a vitamer of folic acid and has its full vitamin activity. Leucovorin is given with methotrexate in order to prevent the cells from undergoing side effects of therapy9, 10. It can be used in cancer chemotherapy as well as for patients taking methotrexate for rheumatoid arthritis. Leucovorin is also used in combination with 5-fluorouracil for cancer chemotherapy. It enhances the effects of 5-fluorouracil by inhibiting the same enzyme that 5-fluorouracil targets: thymidylate synthase11. Leucovorin is also prescribed with pyrimethamine and sulfadiazine to enhance the effects of treatment of cerebral toxoplasmosis12, 13. Valproic acid, phenytoin, carbamazepine, primidone, and phenobarbital are known to decrease folate levels14. In addition to anti-convulsants, the anti-tumor agents aminopterin, pemetrexed, pralatrexate, and raltitrexed have also shown to decrease folic acid serum levels15. Dosage adjustments for folic acid supplementation may be necessary in pregnant females who are taking anti-convulsants16. Previous studies had shown concern regarding oral contraceptives’ interaction with folic acid. This has since resolved to conclude that OCPs do not affect folic acid levels17.

Neural tube defects (NTD) due to folic acid deficiency have been established with numerous randomized controlled trials. Supplementation, when begun preconception, has been shown to decrease the risk of first incidence of NTDs. These include anencephaly and spina bifida. Anencephaly is the absence of the forebrain and skull vault. Spina bifida is the caudal pole defect. Spina bifida has various clinical manifestations including spina bifida aperta (open), cystica, closed, or spina bifida involving more than one vertebra. It is important to note that NTDs associated with folic acid deficiency are isolated and not associated with syndromes involving NTDs18. Women who have a history of NTDs in the family are at higher risk of having children with NTDs. With that in mind, prevention of the first occurrence of NTDs in a family becomes a matter of utmost importance. Thus, preconception adequate serum folate levels are essential. In addition to NTDs, studies have shown that folic acid supplementation also decreases the likelihood for having a small for gestational age infant19. Congenital heart defects (CHD) are also associated with folic acid deficiency. Studies have shown a reduced risk of CHDs in mothers with adequate multivitamin and folic supplementation20.

NTDs have been shown by multiple studies to be preventable with folic acid supplementation preconception. Thus, all women who are likely to become pregnant should be receiving adequate folic acid through their diet or with supplementation from oral tablets21. The periconception supplementation in this incidence refers to at least one month before conception and two months after conception. As embryogenesis very early on the pregnancy is involved in closure of the neural tube and heart formation, early supplementation is essential. This poses a problem for unplanned pregnancies, as most women would not have started prenatal supplements. This can be countered with flour fortification of folic acid to overcome dietary deficiencies22. Keeping this in mind, an emphasis must be placed on adequate serum folic acid levels in all women likely to become pregnant.

Folic acid is not only deserving of attention from the medical community due to its essential functions in the body, but it also requires focus due to its preventive abilities. If NTDs and CHDs can be significantly reduced, then more effort should be made for public education of benefit and requirements of folic acid. All reproductive aged women should receive awareness on importance of multi vitamins and folic acid preconception. As Benjamin Franklin said, “An ounce of prevention is better than a pound of care.”

 

Saneea Almas, MD

InfantRisk Center

 

References:

1. Bailey L, Gregory JF., 3rd. Folate metabolism and requirements. 1999;129(4):779782

2. Wagner C. Biochemical role of folate in cellular metabolism Bailey, L.B. eds Folate in Health and Disease; 23-42. New York, NY: Marcel Dekker; 1995.

3. Gerhard G, Duell, PB. Hoocysteine and atherosclerosis. 1999;10(5):417-428

4. Food and Nutrition Board IoM. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington DC: National Academy Press; 1998:196-305.

5. Cooperman J, Dweck, HS., Newman, LJ., Garbarino, C., Lopez, R. The folate in human milk. 1982;36(4):576-580

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9. Keshava C, Keshava, N., Whong, W., Nath, J., Ong, T. Inhibition of methotreate-induced chromosal damage by folinic acid in V79 cells. 1998;397(2):221-228

10. McGuire B, Sia, L., Leese, P., Gutierrez, M., Stokstad, E. Pharmakokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration. 1988;7(1):52-58

11. Moran R, Keyomarsi, K. Biochemical rationale for the synergism of 5-fluorouracil and folinic acid. 1987;5:159-163

12. van der Ven A, et al. . Anti-toxoplasma effect of pyrimethamine, trimethoprim and sulphonamides alone and in combination: implications for therapy. 1996;38:75-80

13. Van Delden C, Hirschel, B. Folinic Acid Supplements to Pyrimethamine-Sulfadiazine for Toxoplasma Encephalitis Are Associated with Better Outcome. 1996;173:1294-1295

14. Morrell M. Folic acid and epilepsy. 2002;2:31-34

15. Desmoulin S, Wang, L., Polin, L., et al. Functional loss of reduced folate carrier enhances the antitumor activities of novel antifolates with selective uptake by the proton-coupled folate transporter. 2012;2(4):591-600

16. Battino D, Tomson, T. Management of epilepsy during pregnancy. 2007;67(2727-2746)

17. Wilson S, Bivins, BN., Russell, KA., Bailey, LB. Oral contraceptive use: impact on folate, vitamin B(6), and vitamin B(1)(2) status. 2011;69(10):572-583

18. Czeizel A, Dudas, I. Prevention of the first occurance of neural-tube defects by periconceptional vitamin supplementation. Dec 24 1992;327:1832-1835

19. Hodgetts V, Morris, RK., Francis, A., Gardosi, J., Ismail, KM. Effectiveness of folic acid supplementation in pregnancy on reducing the risk of small-for-gestational age neonates: a population study, systematic review and meta-analysis. 2015;122:478-490

20. van Beynum I, Kapusta, L., Bakker, MK., den Heijer, M., Blom, HJ., de Walle, HE. Protective effect of periconceptional folic acid supplements on the risk of congenital heart defects: a registry-based case -control study in the northern Netherlands. 2010;31(4):464-471

21. Ray JG, Singh, G. and Burrows, RF. Evidence for suboptimal use of periconceptional folic acid supplements globally. 2004;111:399-408

22. Bestwick JH, W., Morris, JK. ,Wald, NJ. Prevention of Neural Tube Defects: A Cross-Sectional Study of the Uptake of Folic Acid Supplementation in Nearly Half a Million Women. Rosendeld CS, ed. 2014;9(2):e89354

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