The MTHFR mutation and pregnancy: why standard folic acid isn't always enough

To properly understand the implications of the MTHFR gene mutation, it is first necessary to distinguish between two terms that are often used, incorrectly, interchangeably:

• Folates: these are the natural forms of vitamin B9, found in certain foods such as green vegetables and legumes.
• Folic acid: this is the synthetic form used in the majority of standard food supplements and fortified foods.

What is important to understand: in its existing form, folic acid is not biologically active. To be used by your cells and to cross the placenta, it must first undergo a complex transformation within your body to become 5-MTHF (5-methyltetrahydrofolate). This process is known as methylation.

The conversion of folic acid into active folates depends on a specific enzyme produced by the MTHFR gene. Everyone has two MTHFR genes: one inherited from the mother and one from the father. Some people inherit a variant (or gene mutation) that produces an MTHFR enzyme with impaired function. The most common MTHFR mutations are known as "677C>T" and "1298A>C".

For those who do not carry a mutation, this enzyme functions normally: it converts ingested folic acid into 5-MTHF, which can then fulfil its functions (DNA synthesis, neural tube closure, reduction of homocysteine).

The number of people affected by the MTHFR gene mutation varies across studies. According to some publications, 30–40%[1] to 60–70%[2] of the studied population carries at least one mutation. Other studies estimate that 55%[3] of the European population carries at least one of the 677C>T and 1298A>C mutations. As you can see, this is far from a rare occurrence!

If you carry this genetic variant, it means that the activity of your MTHFR enzyme is reduced by approximately 75% compared to a "normal" enzyme. In other words, it struggles to convert synthetic folic acid into its active form.

This has two major consequences:

• A cellular deficiency despite adequate intake: Even if you take your vitamins conscientiously, your body (and your baby) may be lacking active folates, as the conversion does not happen quickly enough. Standard blood tests can be misleading: they sometimes show a normal vitamin B9 level in the blood, while the cells are actually deficient.
• The accumulation of unmetabolised folic acid: Synthetic folic acid that is not converted remains in the bloodstream. It can then saturate cellular receptors and prevent the "good" natural folates from binding. 

Normal homocysteine levels, an indirect marker of healthy methylation, fall between 5 and 15 μmol/L. Although it is possible to carry out a genetic test or measure your homocysteine levels, checking your blood folate levels may not necessarily be of great help!

Indeed, even if your test results show a normal or elevated homocysteine level, you may still be facing a folate deficiency. This comes down to binding affinity, which refers to the strength with which a substance binds to a receptor. Surprisingly, folic acid (the synthetic form of B9) binds more readily to folate receptors than natural forms of folate[4]. The direct consequence: natural folate cannot always reach the cells, because folic acid blocks the receptors. This is referred to as a functional deficiency.

The current scientific consensus points towards pragmatism: since this mutation is very common and active (methylated) folates are safe and beneficial for everyone, it is simpler and more advantageous to opt directly for the right form of vitamin B9. So choose directly the best pregnancy food supplement with a 5-MTHF form. 

1. Your plate: the essential foundation

Before taking any supplement, aim to get folates from natural sources, which are found in a highly bioavailable form.

Where to find them? Many foods contain folates directly in the form 5-MTHF [5]. 

For example:

• Legumes (lentils, chickpeas, white beans): lentils contain 71 µg of folates in the active form 5-MTHF, and raw chickpeas contain 125 µg per 100 g.
• Green leafy vegetables (lettuce, spinach, watercress, cabbage…): 100 µg per 100 g for kale, of which half is in active form.
• Broccoli: 100 µg per 100 g, of which 67% is in the active form 5-MTHF.
• Citrus fruits (lemon, orange…): nearly 100% of folates in active form.
• Red berries (strawberries, raspberries, cherries): nearly 100% of folates in active form. For example, strawberries contain 79 µg of active folates per 100 g.

Practical tip: Folates are heat-sensitive and struggle to withstand light and heat. Excessive cooking can destroy up to 30% of them [6]. Where possible and if you can tolerate it, opt for gentle steaming or eating raw.

2. Targeted supplementation

Since diet alone rarely covers the increased folate requirements during pregnancy, supplementation is recommended. However, if you take a folate supplement, avoid folic acid, which requires conversion into its active form by the MTHFR enzyme.

Instead, opt for the following forms:

• (6S)-5-methyltetrahydrofolate as glucosamine salt or calcium salt
• Spinach extract standardised for vitamin B9
• Lemon extract standardised for vitamin B9