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Dietary supplements: Active folate vs. folic acid

Supplement formulators using folate—a generic term used to identify a broad group of water-soluble B vitamins—need to consider which form best suits their intended application.

Because the human body can’t produce folate, people rely on their diets to introduce the levels required for optimal health—especially during pregnancy. However, folate is a generic term, used to identify a broad group of water-soluble B vitamins that includes the naturally occurring reduced folate found in food, as well as the oxidized synthetic folic acid found in supplements and fortified foods. To build a better folate-based product for pregnancy, it is critical to understand the correct type of folate needed.

In vivo, the body converts dietary folic acid and food folates to 5-MTHF (also named L-methylfolate or 5-methyltetrahydrofolate) through a multistep process where the enzyme methylenetetrahydrofolate reductase (MTHFR) owns a key role. However, unlike food folates, folic acid must first be reduced to tetrahydrofolate in a two-step reaction via dihydrofolate reductase (DHFR) and then further metabolized.

Due to unique genetic patterns and expression, some individuals present decreased activities of the MTHFR enzyme. They have polymorphic forms of this enzyme, which are associated with reduced plasma levels of the biologically active 5-MTHF folate. Active folate supplementation may help ensure that people have the same folate contribution without a genetic impact on the bioavailable blood folate. This directly provides a nutritionally active form of folate to the mother and fetus.

Folate intake is essential for adequate fetal and placental development during the periconceptional period and throughout pregnancy.1 Folate insufficiency in women of reproductive age can lead to pregnancies affected by neural tube defects (NTDs), such as spina bifida and anencephaly, which affect the development of the brain and spine and can lead to early death or lifelong disability.2,3 Folate deficiency has also been linked to a wide variety of disorders like anemia.4

Prevalence of NTD and folate deficiencies

Annually, more than 260,100 NTD‐affected pregnancies are estimated to occur worldwide.5 The prevalence of folate deficiency is over 20% in many countries with lower income economies and is typically less than 5% in countries with higher income economies.

Based on the data available, most health organizations recommend that women of reproductive age—especially those planning a pregnancy—take daily folic acid supplements (folic acid or methyl folate) at levels of 400 µg or higher beginning at least four weeks before conception and continuing throughout the first 12 weeks of pregnancy.

Factors influencing folate status

The World Health Organization (WHO) also reported that multiple factors influence folate status, including genetics such as the MTHFR gene polymorphism. Other factors include physiological status (e.g., age, pregnancy, lactation); biological factors (e.g., coexisting vitamin B6 and B12 status, homocysteine levels); contextual factors (e.g., comorbidities); and limited access to dietary folate sources.

Since the association between the MTHFR polymorphism and low folate concentration has been assessed, the direct supplementation of the active form 5-MTHF through prenatal vitamins can be strongly advantageous.

Folate EFSA claims

The European Food Safety Authority (EFSA) has granted health claims for folate related to psychological functions, reduction of tiredness and fatigue, cell division, normal homocysteine metabolism and the immune system well-function.

In order to identify the right form of folate for a pregnancy supplement, it is critical to work with a market expert who understands the differences between folic acid and active forms of folate.

Editor’s note: Additional content in the women’s health category is available in the “Natural women’s health solutions for every stage” digital magazine.

Silvia Pisoni is the global market manager for women’s health and reproduction at Gnosis by Lesaffre. She has a master’s degree in pharmaceutical science from the Department of Biomedical Sciences for Health – Milano University. Pisoni has more than 20 years of experience in various marketing positions, including scientific director, where she was responsible for presentations on scientific matters to physicians, individually or in groups.


1 Li B et al. “Folic Acid and Risk of Preterm Birth: A Meta-Analysis.” Front Neurosci. 2019;13:1284.

2 Obeid R et al. “Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?” J Perinat Med. 2013;41(5):469-483.

3 Scaglione F and Panzavolta G. “Folate, folic acid and 5-methyltetrahydrofolate are not the same thing.” Xenobiotica. 2014;44(5):480-488.

4 Greenberg JA et al. “Folic Acid Supplementation and Pregnancy: More Than Just Neural Tube Defect Prevention.” Rev Obstet Gynecol. 2011;4(2):52-59.

5 Rogers LM et al. “Global folate status in women of reproductive age: a systematic review with emphasis on methodological issues.” Ann N Y Acad Sci. 2018;1431(1):35-57.

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