How folate as 5-MTHF supports reproductive health and pregnancy

Folic acid is the synthetic form of vitamin B9, commonly used in supplements. The body must reduce it into the bioactive folate derivative 5-MTHF by cell metabolism.

Moving straight from point A to point B without detours is always preferable. Such is the case for vitamin (or other) supplements. Yet, this is a core difference between folic acid and 5-MTHF (folate): folic acid needs to be converted to 5-MTHF through a multistep process.

Here’s how: Once consumed, folic acid is converted into di-hydro-folate (DHF) by the enzyme di-hydro-folate reductase (DHFR), which also converts DHF into tetra-hydro-folate (THF). It is then further converted into 5,10-methylene-THF by serine hydroxy-methyltransferase.

The final step is the reduction into 5-MTHF, the active form of folate, by methylene-tetra-hydro folate reductase (MTHFR). Supplementing with 5-MTHF bypasses those numerous exhaustive enzymatic conversion steps.

For millions of people folic acid is not adequately transformed into 5-MTHF so much of this nutrient is lost. Those with MTHFR polymorphism – approximately 40% of the world’s population – have a mutation in the gene that codes MTHFR, the enzyme which converts folic acid into folate.¹

They typically have only 30% of the activity of the normal MTHFR.² People with MTHFR polymorphisms are more susceptible to conditions arising from being folate deficient, including a heightened risk of birth defects.

Why 5-MTHF is critical for pregnant women

Women of reproductive age or who are pregnant, and especially women with MTHFR polymorphism, are at clear risk of folate deficiency. Folate supplementation is widely recommended to inhibit the development of embryonal neural tube defects (NTDs) in the developing fetus and is crucial for normalizing high homocysteine levels.

During pregnancy, demand for folate increases dramatically because of its role in nucleic acid synthesis. Women with insufficient folate intakes are at an increased risk of giving birth to infants with NTDs. Insufficient folate status during pregnancy has also been associated with low infant birth weight, preterm delivery, and fetal growth impairment.

5-MTHF supplementation during pregnancy can be preferred over folic acid because it effectively bypasses the block in folic acid metabolism in those with MTHFR polymorphism.

Managing homocysteine is another way 5-MTHR supplementation can support maternal and fetal health. In excessive levels, the amino acid homocysteine, created by methionine metabolism, is destructive. While normal levels of homocysteine help the body, elevated levels can impair health in several ways.³ Folate is an essential regulator of homocysteine metabolism and contributes to normalizing levels.

Proof of pregnancy benefits and superior bioavailability

A 5-MTHF glucosamine salt, Quatrefolic®, has been shown to be superior to folic acid in reducing homocysteine. In a 2016 study, this specific folate ingredient combined with B6 and B12 was able to lower homocysteine levels better than conventional supplementation of high-dose folic acid (5 mg/day).⁴

Four clinical studies involving more than 1,000 pregnant women evaluated supplementation of Quatrefolic in combination with other essential compounds for several weeks before conception and during pregnancy. These studies collectively demonstrated effectiveness in increasing blood folate levels and inhibiting adverse pregnancy outcomes.⁵⁻⁸

Meanwhile, PT. Simex Pharmaceutical Indonesia, the maker of a finished product HY-FOLIC® containing Quatrefolic, evaluated its pharmacokinetic profile compared to folic acid after one dose in healthy volunteers. The results showed that HY-FOLIC is twice as bioavailable compared to folic acid.⁹

While this study was not conducted with pregnant women, Merrylin Saragih, Head of Product Department at PT. Simex Pharmaceutical Indonesia, notes that its impact would make a world of difference to the childbearing population: “Our study findings suggest that HY-FOLIC increases 5-MTHF levels in the body more effectively than folic acid.

“This is especially important for individuals requiring enhanced folate bioavailability, such as pregnant women or those with genetic polymorphisms affecting folic acid metabolism,” adds Saragih.

Another bonus: Folate by itself provides full methylation benefits negating the need for a conjoined ingredient. To date, there are no known supporting studies suggesting that choline will boost the methylation of supplemental folates.

Liquid stability creates new prenatal formula opportunities

Given the solubility characteristics of folates, most liquid formulations are primarily aqueous. However, stability issues often compromise these known liquid formulations, significantly hindering their widespread application and utilization.

Quatrefolic Fine Powder, delivering active folate in tiny particles, was designed for oily liquid suspensions, oral sprays, and complex softgels, widening the formulation opportunities. Gnosis by Lesaffre recently filed a formulation patent for its use in oily liquid products.

Quatrefolic Fine Powder in the oily formulation is stable at temperatures up to 40° at a relative humidity of 75% without showing any drop in potency or detectable color changes. The unique formulation process eliminates the risk of sedimentation, ensuring high solubility and enhanced chemical and physical stability.

Recommending active folate

Because healthcare practitioners are more aware of the high incidence of MTHFR polymorphism, they are more frequently recommending active folate over folic acid, but for now folic acid remains that standard.¹⁰

This is especially true for women of reproductive age preparing themselves for pregnancy. Providing a folate that has been shown to exhibit desirable pharmacokinetics – proven in clinical studies in pregnant women – can reduce homocysteine and reduce the risk of adverse pregnancy outcomes.

References

1. Maulik, D.; et al. The effect of race and supplementation on maternal and umbilical cord plasma folates. J Matern Fetal Neonatal Med. 2019:1–9.
2. Frosst, P.; et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995; 10:111–3.
3. Cleveland Clinic. Homocysteine.
4. Mazza, A.; et al. Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial. Biol Regul Homeost Agents. 2016 Jul-Sep;30(3):921-927.
5. Dell’Edera, D.; et al. Prevention of neural tube defects and maternal gestational diabetes through the inositol supplementation: preliminary results. Euro Review Med and Pharmacological Sci. 2017. 21. 3305-3311.
6. Dell’Edera D, et al. Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms and susceptibility to recurrent pregnancy loss. Biomed Rep. 2018 Feb;8(2):172-175.
7. Bulavenko, O.V.; et al. Evaluation of clinical efficacy of preventive therapy in pregnant women with ulcerative colitis. Reports of Vinnytsia National Medical University. 2021 n. pag.
8. Cirillo, M.; et al. 5-Methyltetrahydrofolate and Vitamin B12 Supplementation Is Associated with Clinical Pregnancy and Live Birth in Women Undergoing Assisted Reproductive Technology. Int J Environ Res Public Health. 2021 No 23;18(23):12280.
9. Nafrialdi, N.; Pharmacokinetic study of HY-FOLIC and folic acid in health volunteers. International Journal of Applied Pharmaceutics. 2024 16(6), 64–68.
10. National Institutes of Health. Folate.