Folate Supplementation in Pregnancy: The Benefits of Using Active Folate

Folate is an essential water-soluble B-vitamin, also known as vitamin B9. It plays a crucial role in cell growth and the formation of DNA, as well as many other roles highlighted below. Folate is a generic term used to describe multiple types of vitamin B9, including:

• dihydrofolate (DHF)

• tetrahydrofolate (THF)

• 5,10-methylenetetrahydrofolate (5,10-MTHF)

• 5-methyltetrahydrofolate (5-MTHF) also known as L-methylfolate

Folate is available from food in its natural form or from supplements or fortified grains and cereals in its chemically synthesized form, folic acid. In dietary supplements folate is generally in the form of folic acid, but it can also be found as L-methylfolate (5-MTHF), which is the biologically active form of folate. I will discuss the studies that look at 5-MTHF and it’s potential to be a better source than folic acid for certain individuals below, but for now, here is a link to the NIH Office of Dietary Supplements, which says this exact thing.

Recommended intakes of folate are given in dietary folate equivalents (DFE), which are units that account for the differences in absorption between food folate and synthetic folate in supplements and food fortification. The RDA is 400mcg DFE for women of childbearing age and 600mcg DFE for pregnant and lactating women or 4,000mcg per day for pregnant women with a previous history of NTDs.

Importantly, recommendations are not made for folic acid alone. There is nothing unique about folic acid that would suggest that this is the only safe source of folate to raise levels to a place that prevents deficiencies and subsequent neural tube defects in the fetuses of pregnant women.

Folic Acid vs L-Methylfolate

Folic acid is the stable synthetic form of the vitamin used in drugs, supplements, and fortified foods. It is heat stable and costs much less, so it is the generally preferred form for supplementation and fortification. Metabolically, it needs to be reduced in the body in order to become biologically active. Folic acid has no biological activity unless converted into active folates. The simplified conversion for this is below:

Folic acid → DHF → THF → 5,10-MTHF → (reduced by MTHFR) → 5-MTHF

5-MTHF, also known as, L-methylfolate, is the folate derivative normally found in blood circulation (1). It is the active form of folate used by the body. Supplementing with L-methylfolate bypasses the folic acid metabolism cycle because you are supplementing with the biologically active form that requires no reduction (as shown in the simple conversion above).

For those with an MTHFR polymorphism, which can significantly reduce one’s ability to convert 5,10-MTHF to 5-MTHF (2), supplementing directly with 5-MTHF can be beneficial (3).

Why folate is important in pregnancy

Folate is essential for brain development and function. Deficiencies in the general population are known to cause megaloblastic anemia (4), and have been associated with increased oxidative stress (5) and cognitive dysfunction in aging (6).

In pregnancy, specifically, deficiencies of folate are known to cause neural tube defects (NTD) in the fetus (7). Neural tube defects include problems with the formation of the skull, scalp, brain tissue, spinal cord, and vertebrae.

In 1991, a study was published demonstrating that women with a history of NTD in previous pregnancies who took 4mg of folic acid daily before pregnancy and through the 12th week of gestation experienced a 72% reduction in their risk of recurrent NTD (8). Subsequently, in 1992, the CDC recommended that all women of childbearing age consume 0.4mg of folic acid to ensure adequate levels of folate when pregnancy occurs (9). Finally, in 1998, the FDA mandated fortification of grain products with folic acid (10), which resulted in a 28% reduction in anencephaly and spina bifida, the 2 most common NTDs (11).

Bioavailability of L-Methylfolate vs Folic Acid

As opposed to folic acid, the bioavailability of methylfolate does not rely on metabolic conversions in the folate metabolism cycle. As such, its intake does not lead to masking vitamin B12 deficiency (12, 13), or the potentially harmful accumulation of the highly oxidized form of folate in the blood (14, 15), which is a risk of folic acid supplementation. Importantly, the bioavailability of methylfolate is also not affected by polymorphisms in the genes that encode the enzyme MTHFR.

Polymorphisms in the genes that encode for MTHFR have been identified as a genetic risk factor for NTD (16, 17, 18, 19). Because folic acid does not bypass the conversion that requires MTHFR, supplementation with folic acid could be doing a disservice to individuals who have this polymorphism (3).

Although there are no RCTs assessing the effectiveness of L-methylfolate on specifically preventing NTDs (see the last paragraph for why), metabolic studies have shown that L-methylfolate is overwhelmingly effective in improving folate biomarkers, which is the goal of folate supplementation.

Multiple studies have shown that methylfolate is at least as effective at increasing plasma folate compared with folic acid (20, 21, 22, 23). And many additional studies have actually found it to be more effective at increasing plasma folate in individuals (24, 25, 26, 27), as well as breastfeeding women (28).

Importantly, I did not come across a single study that showed that L-methylfolate was less effective than folic acid at increasing plasma folate levels.

L-Methylfolate in Pregnancy

A retrospective, comparison study of different forms of folic acid in pregnant women assessed a prenatal supplement containing L-methylfolate or one with folic acid and found that those who had L-methylfolate in their prenatal supplement had significantly higher hemoglobin levels at the end of the second trimester and at delivery (29).

A recent article that reviewed the advantages and disadvantages of folate supplementation with folic acid versus methylfolate, with a focus on fetal and maternal health, highlighted several benefits of supplementing with methylfolate and concluded that supplementation with 5-MTHF in pregnancy could be advantageous over that with folic acid, because 5-MTHF is immediately active, does not require metabolic activation, is directly bioavailable to the mother and fetus, and is not influenced by the possible MTHFR gene mutations (30).

Another review article (31) looking specifically into 5-MTHF as an alternative to folic acid for the prevention of neural tube defects concluded that “supplementing with 5-methylTHF for NTD prevention seems to be rational. In contrast to the MRC study, testing the efficacy of 5-methylTHF against a placebo would be unethical. Comparing the preventive effect of FA with a proposed better alternative (5-methylTHF) will require following several thousands of pregnancies over a long time. The costs of testing 5-methylTHF against FA would be extremely high. We do not have any reason to assume that a randomized controlled trial is justified before recommending 5-methylTHF.”

Final Thoughts

I included a direct quote in that last study because I think it is important to highlight the specific justification of why there are no RCTs completed yet and why this does not justify avoiding 5-MTHF or, especially, stating that it could in some way be dangerous. There is absolutely no evidence to suggest this. Research on nutrients and nutrition is often different than research on pharmaceutical drugs and those differences greatly influence the design and conduct of clinical trials as well as their interpretation. We know deficiencies of folate cause the issues I highlight above, as well as NTDs in pregnancy. We know that adequate plasma folate prevents or significantly decreases the risk of NTDs. We know that methylfolate is as adequate, if not more adequate, in increasing plasma folate levels when compared to folic acid supplementation. Therefore, it is more than reasonable, to propose and use 5-MTHF to increase folate levels and prevent NTD in pregnancy.