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Active folate versus folic acid
Date: 2018-05-25
Author: Belinda Reynolds BSc Nut & Diet (Hon)
Access: Public

Many individuals are familiar with the terms folate and folic acid, with each being recognised as important before and during pregnancy for the prevention of neural tube defects (NTD). For many years however there has been some confusion around the correct terminology, with the term folate and folic acid often being used interchangeably.

Folate is an umbrella term for a number of different compounds, and can include folic acid, folinic acid and 5-MTHF (also known as methylfolate, MTHF, and 5-methyltetrahydrofolate).

Folic acid is a synthetic form of folate which is often found in supplements and foods which have been fortified with the nutrient (e.g. breads and cereals). In September 2009, mandatory fortification of flour with folic acid was introduced in Australia. This followed voluntary fortification, and promotion of folic acid supplementation which had been recognised as achieving reductions in the number of NTD.2

An investigation one year after the initiation of mandatory fortification showed that the prevalence of low serum and red blood cell (RBC) folate status had reduced in women of child bearing age3, however a later paper questioned whether this was achieving levels sufficient enough to prevent NTD6, suggesting that supplementation should still be encouraged.

Another challenge is that folic acid does not occur naturally in foods, and in order to function within the body requires activation by a number of reactions catalysed by specific enzymes (e.g. dehydrofolate reductase (DHFR), methyltetrahydrofolate reductase (MTHFR)). On the contrary, folates such as folinic acid and 5-MTHF occur naturally in foods (e.g. green leafy/cruciferous vegetables) and are considered more biologically active. These are also available in supplement form.

The new debate is “which form is better”? Due to the low cost and accessibility of folic acid it is still widely used. However, the growing awareness of genetic variations, and other factors which impact folic acid utilisation has lead to the hypothesis that certain individuals will benefit more from taking the active forms of folate.

A paper published in 2014, stated that “Naturally occurring 5-MTHF has important advantages over synthetic folic acid - it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking haematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase (DHFR) and overcomes metabolic defects caused by methylenetetrahydrofolate reductase (MTHFR) polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation.” 7

Some additional findings:
A study comparing the effect of 7.5mg folic acid to 7.5mg 5-MTHF assessed the speed at which each option achieved desired increases in folate status in women with insufficient folate status. Serum total folate increased much more rapidly over the first four days in insufficient women given 7.5 mg doses of 5-MTHF than the same regimen of folic acid. Authors concluded that 5-MTHF enables repletion of folate stores more quickly and uniformly than folic acid and without exposure to unmetabolised folic acid.1
A study comparing daily ingestion of 1mg folic to 1mg 5-MTHF daily in women with MTHFR gene polymorphisms (C677T and A1298C) showed that the two supplements were equal in their ability to reduce homocysteine and spontaneous absorption, and to increase folate status (however 5-MTHF achieved a more rapid increase)4
“Analysis of the recent literature reposts suggests that metafolin (a supplement form of 5-MTHF) could be an effective and safe alternative to folic acid supplementation and could effectively prevent complications in pregnancy and serious birth defects in foetuses and newborns.”9

The more rapid improvement of folate status achieved in women with insufficient folate status using 5-MTHF (when compared to folic acid) is particularly relevant for women who have not planned pregnancy, or who have not used a folate supplement prior to conception. Once pregnancy becomes apparent due to a missed period and subsequent home pregnancy test, reactions involved in neural tube closure have begun, but are often not yet complete. Using 5-MTHF to rapidly achieve improved folate status may be the better option in these instances to support a greater reduction in the risk of NTD, but also in prevention of other folate-dependent defects, such as those of the heart, lip, and palate which develop later than closure of the neural tube.1

It is worth mentioning that, low vitamin B12 status, and elevated homocysteine have been identified as risk factors for recurrent pregnancy loss5. MTHFR polymorphisms have also been suggested as a contributor here, and one recent study on a small group of women found that supplementation with 5-MTHF (5mg/day), vitamin B6 (50mg/day) and vitamin B12 (1mg/week) had a beneficial effect on healthy pregnancy outcomes8. This is likely due, in part, to the role vitamin B12 and B6 play in supporting folate functioning, and maintenance of normal homocysteine.

In conclusion, the more active folate forms are emerging as useful supplements for women planning pregnancy, and nutrients beyond folate alone should also be considered, together with homocysteine status.

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  1. Bailey SW, Ayling JE. The pharmacokinetic advantage of 5-methyltetrahydrofolate for minimization of the risk for birth defects. Sci Rep. 2018;8(1):4096.
  2. Bower C, D'Antoine H, Stanley FJ. Neural tube defects in Australia: trends in encephaloceles and other neural tube defects before and after promotion of folic acid supplementation and voluntary food fortification. Birth Defects Res A Clin Mol Teratol. 2009;85(4):269-273.
  3. Brown RD, Langshaw MR, Uhr EJ, et al. The impact of mandatory fortification of flour with folic acid on the blood folate levels of an Australian population. Med J Aust 2011;194(2):65-67.
  4. Hekmatdoost A, Vahid F, Yari Z, et al. Methyltetrahydrofolate vs Folic Acid Supplementation in Idiopathic Recurrent Miscarriage with Respect to Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms: A Randomized Controlled Trial. PLoS One. 2015;10(12):e0143569
  5. Puri M, Kaur L, Walia GK, et al. MTHFR C677T polymorphism, folate, vitamin B12 and homocysteine in recurrent pregnancy losses: a case control study among North Indian women. J Perinat Med 2013;41(5):549-54.
  6. Rabovskaja V, Parkinson B, Goodall S. The cost-effectiveness of mandatory folic acid fortification in Australia. J Nutr 2013;143(1):59-66.
  7. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480-488.
  8. Serapinas D, Boreikaite E, Bartkeviciute A, et al. The importance of folate, vitamins B6 and B12 for the lowering of homocysteine concentrations for patients with recurrent pregnancy loss and MTHFR mutations. Reprod Toxicol;72:159-163.
  9. Seremak-Mrozikiewicz A. [Metafolin--alternative for folate deficiency supplementation in pregnant women]. [Article in Polish] Ginekol Pol 2013 Jul;84(7):641-646.

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