Folic acid or folates: what's the difference?

Folates (vitamin B9) are present in our diet, particularly in green leafy vegetables, fruit, pulses, liver and brewer's yeast. However, dietary folates are not very stable — they do not withstand light or heat well. Naturally occurring folates can be lost by up to 30% during food processing, depending on the cooking method used [1]. 
 

Steaming fruit and vegetables results in virtually no loss of folates, unlike boiling in water.

In fruit and vegetables, folates are mainly present in the form of 5-MTHF equivalent, i.e. the form directly usable by the body, with a total folate concentration ranging from 1–2 µg/100 g for peach and watermelon to an average of 300 µg/100 g for spinach [2].

It is recommended to consume 600 micrograms of vitamin B9 per day during pregnancy or when trying to conceive, and it is often advised to take 400 micrograms in supplement form, in addition to a balanced diet. Folic acid and pregnancy are thus inseparable.

So check that your food supplement to help conceive or your pregnancy food supplement contains 400 micrograms of vitamin B9. We will see later that it also needs to be present in its methylated form. 

Folate supplements are generally available in 2 forms: folic acid and 5-MTHF (found as a calcium salt or glucosamine salt). 

The problem? Folic acid is not the same as natural folate.

Folic acid (pteroylmonoglutamate) is the synthetic, oxidised form of folate, which is NOT present in fresh, natural foods. Folic acid has no biological activity unless it is converted into folates.

The bioavailability of 5-MTHF in supplements is identical to or greater than that of folic acid [3].

The methylation cycle can be partially represented as follows: 

The different forms of folate, including folic acid, are converted to THF by the DHFR enzyme, then this THF is converted into the form 5-MTHF by the MTHFR enzyme, which subsequently allows 5-MTHF to donate its methyl group (M) and convert homocysteine, thereby helping to reduce its levels in the body. All of this requires a great deal of energy, and is not always possible.

Jolly Mama products contain only vitamin B9 in its active form!
 

Our pregnancy snack Vanifique contains folates from a spinach extract, naturally rich in 5-methyltetrahydrofolate, the directly active form! One snack provides 400 µg of folates. 
 

Baby bump, Bump essentials and Bump powder, our multivitamin supplements for conception and pregnancy, provide 400 µg of folates per day, in 5-methyltetrahydrofolate form (Quatrefolic®). Our post-partum food supplement also contains this form.

The role of the MTHFR gene 

The MTHFR gene is responsible for producing the enzyme methylenetetrahydrofolate reductase (MTHFR), an enzyme that enables folate metabolism and its conversion into its active form, 5-MTHF. 

Genetic alterations in the genes encoding key enzymes in folate metabolism can affect their activity and reduce folate availability, which may increase folate requirements [14]. 
 

There are two variations of the MTHFR gene: 677C>T and 1298A>C. In the general population, 60 to 70% of individuals carry at least one of these variants [15]. 

The MTHFR gene, 677C>T
 

People with a 677C>T genetic mutation have a reduced ability to convert folate into its active form, 5-MTHF. This leads to a decrease in the amount of biologically available 5-MTHF, which generates elevated homocysteine levels and has consequences for health, as it increases the risk of cardiovascular disease, thrombosis and stroke [16], and also presents an increased risk of neural tube defects [17].

The MTHFR gene, 1298A>C

Based on current data, this mutation would not cause raised homocysteine levels but does affect the activity of the MTHFR enzyme, which in turn reduces folate levels in their active form (5-MTHF). Furthermore, the 1298(A>C) mutation may also be expected to be a risk factor for neural tube defects, albeit with a lower relative risk than the 677(C>T) mutation [19].

One study highlighted that the 1298A>C mutation could be a cause of Turner syndrome (an exclusively female genetic condition in which only one normal X sex chromosome is present, affecting approximately 1 in 2,000 babies [20]). This mutation is more frequent in the group of patients with Turner syndrome [21].

Ingested folic acid is converted into various forms by the enzyme dihydrofolate reductase (DHFR). The first conversion step is slow; ultimately, folic acid ends up in the form of THF. THF can then be converted into other folates by the enzyme MTHFR, including 5-MTHF, the form normally found in circulation [10]. The capacity of the DHFR enzyme is limited, and when folic acid supplementation is excessive, a large proportion of the ingested folic acid appears in its unmetabolised form in the blood.

Another issue related to folic acid concerns binding affinity. Binding affinity refers to the strength with which a substance binds to a receptor. Interestingly, the body appears to prefer folic acid over natural folates. Indeed, folic acid binds more readily to folate receptors than natural forms of folate [26].
 

As a result, folic acid is transported and binds to receptors adequately, but the actual folate does not reach the cells to be used, because folic acid blocks the receptors. This is known as functional folate deficiency. In this case, your laboratory test results will be "normal" or even "elevated", yet symptoms of folate deficiency may still appear. This is because laboratory tests measure blood folate levels, not cellular folate levels [27].

What should I do?

You should have a test to assess your homocysteine levels, as a folate deficiency — even when blood test results appear elevated due to folic acid supplementation — can help reveal a potential functional folate deficiency [27] [28].

Low folate status is considered one of the most common nutritional deficiencies and, although inadequate dietary intake is the main cause, genetic alterations and drug interactions affecting folate metabolism can contribute to reduced folate availability. 

Furthermore, folate deficiency can result from low levels of vitamin B12, as this vitamin acts as a cofactor in folate metabolism. Folate deficiency has been associated with an increased risk of numerous health problems, including neural tube defects, cardiovascular disease, cancer and cognitive disorders. 

The 5-MTHF form is preferable to folic acid in its prenatal vitamins, however, it is still far better to supplement with folic acid than to take nothing at all!