Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Abstract

Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of > 200 μg. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6S)-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B 12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs.

Multiple Micronutrient Needs in Pregnancy in Industrialized Countries

“…Associations tended to be weaker in pregnant and lactating women. The biologically active derivate [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) has been found to be more effective than folic acid supplementation in improving folate status [49], and since it represents the main folate form in cord blood (mean 89.4% of total folate), it may be hypothesized that 5-MTHF can provide an immediate source for folate to be transported to the fetus [50]. …”

Primary Prevention of Congenital Anomalies: Recommendable, Feasible and Achievable

“…Additional scientific evidence could also refine and improve the undisputed effectiveness of folic acid supplementation. Issues for research include the characterization of effects on CA other than neural tube defects [38,39], the 5-methyl-tetrahydrofolate as possible alternative to folic acid [40] and the mechanisms (immune factors, inositol metabolism) and risk factors of the neural tube defects that are resistant to folic acid supplementation [41,42]. Most importantly, folic acid is also an issue for public health research, e.g., strategies to promote a community awareness on periconceptional supplementation [43] and a robust and consistent definition of recommended intake levels for folates [44].…”

Folic Acid Supplementation in Prevention of Neural Tube Defects

“…FA fortification of the food couldn't archive optimal folate level in the plasma. So, supplementation in preconceptional period at the moment is the best way to improve the folate status within a relatively short time (4-12 weeks) [13]. The use of MVs containing FA and other B vitamins in several studies showed high efficacy in the reduction of NTDs (about 90%), then the use of high or low dose of FA alone.…”

“…Although there are no clinical trials on the effectiveness of 5-MTHF in preventing NTDs, metabolic studies have shown that 5-MTHF is a biologically active form of the vitamin and it seems to be at least as effective as FA in improving folate biomarkers. The literature clearly shows that a better food folate intake is associated with better folate markers and that food folate can prevent NTDs (by increasing folate status) [6,[13][14][15].…”

“…At the time of the first missed menstrual period and on about the 15th post-conceptional day, when the possible pregnancy is recognized, the neural tube is preparing to close. Mandatory food fortification with FA to increase intake, as done in the United States and other countries, has not yet been introduced in any European country [6,[13][14]16]. …”