TL;DR

• Folic acid and 5-MTHF (active folate) are both legitimate, effective forms of folate. Folic acid has the strongest direct evidence for preventing neural tube defects of any folate form.
• Common MTHFR gene variants do not stop your body from processing folic acid. People with the most-studied variant still raise their blood folate on a standard 400 mcg dose. In people with the 677TT genotype, blood folate is on average about 16% lower than in people with the 677CC genotype at the same intake, not "unreliable."
• Active folate (5-MTHF) bypasses the MTHFR-dependent conversion step, which is a real, useful property, just not because folic acid fails for a large share of the population.
• Folate needs shift across life: before conception, during pregnancy, and again with age-related changes like rising homocysteine after menopause.
• Our Prenatal Core's AM sachet provides 500 mcg of folate as Quatrefolic®, within SAHPRA's regulatory maximum for a multi-ingredient supplement.

Folate and folic acid get used interchangeably so often that people assume "folic acid bad, active folate good" is settled science. It isn't. Folic acid has decades of outcome evidence behind it, including the evidence that first established folate's role in preventing neural tube defects. The real, more interesting story is what active folate does differently, and why we still chose it for Prenatal Core.

What are B vitamins, and what does "water-soluble" mean?

Folate is part of the B vitamin family, eight related nutrients (B1, B2, B3, B5, B6, B7, B9 and B12) that help the body convert food into usable energy and keep the nervous system running. Several B vitamins participate in interconnected pathways, particularly one-carbon metabolism and homocysteine regulation, which is part of why they're often discussed together.

Most water-soluble vitamins aren't stored in large amounts, so regular intake matters. Folate stores are relatively modest and typically last weeks to months. Vitamin B12 is a genuine exception here, the liver can store years' worth, which is why a B12 deficiency can take a long time to show up even after intake or absorption drops.

What folate actually does

Folate is a nutrient the body relies on for healthy cell growth, DNA synthesis and red blood cell formation. When folate is inadequate, rapidly dividing tissues are particularly vulnerable, since folate is required for normal DNA synthesis and cell division.

Common food sources, and why they're not always enough

Folate occurs naturally in leafy greens, legumes, citrus and liver. In theory, a varied diet gets you there. In practice, naturally occurring food folate is less bioavailable than folic acid from supplements or fortified food, and cooking degrades it further. Because adequate folate status matters most in a critical early window, before and just after conception, guidelines recommend supplementation rather than relying on diet alone, not because diet is inherently inadequate.

Folic acid and active folate: what's actually different

Folic acid, the synthetic form used in most supplements and fortified foods, has to be metabolised before it enters the body's main circulating folate pool as 5-MTHF. Active folate (5-MTHF) is already in that active form. One of the enzymes involved later in that pathway is MTHFR.

Here's where a lot of supplement marketing overstates things. You may have heard that people with an MTHFR variant "can't process folic acid," or that everyone should switch to methylfolate. According to the CDC, that isn't accurate. People with common MTHFR variants, including the most-studied one, C677T, can process folic acid. Getting 400 mcg of folic acid daily increases blood folate regardless of MTHFR genotype. Even people with two copies of the variant (the TT genotype) only show blood folate levels around 16% lower than the CC genotype at the same intake, a real but modest difference, not an inability to use folic acid. The CDC does not recommend changing the standard folic-acid recommendation simply because someone has a common MTHFR variant. Folic acid remains the folate form with direct population-level evidence demonstrating prevention of neural tube defects.

None of that makes active folate pointless. It bypasses the MTHFR-dependent step altogether, which is a genuinely useful property on its own terms, it just isn't a fix for a widespread inability to process folic acid, because that inability doesn't really exist at meaningful scale.

Folic acid can also appear in the bloodstream as unmetabolised folic acid (UMFA), particularly at higher intakes. This isn't primarily an MTHFR story either, the initial processing step is handled by a different enzyme. The long-term clinical significance of circulating UMFA remains genuinely uncertain. Active folate doesn't go through this particular pathway, but that's a difference whose importance isn't yet fully established rather than protection from a known harm.

Folate during conception and pregnancy

Folate is critical during pregnancy because it's involved in DNA synthesis and cell division, both of which accelerate as the foetus grows, particularly during the first few weeks, when the neural tube is forming. That's why folate is recommended before conception, not just after a positive test, since the neural tube closes early, often before someone knows they're pregnant.

The direct, population-level evidence for preventing neural tube defects is specifically for folic acid. Active folate raises folate status effectively and is an accepted supplemental folate source, but it doesn't carry that same scale of directly-studied outcome evidence.

Folate during perimenopause and menopause

Folate remains biologically important after the reproductive years. Homocysteine, an amino acid that folate helps the body regulate, tends to rise after menopause, and folate is one of the nutrients involved in that pathway. Elevated homocysteine is associated with cardiovascular risk, but that's not the same as proving that lowering it with folate reduces that risk directly.

Hot flushes are the most recognisable menopause symptom. The research on folic acid here is genuinely mixed, not the clean positive story it's sometimes presented as. A smaller earlier trial found folic acid improved hot flush severity and frequency compared with placebo. But the largest and most rigorous trial to date, a 2021 phase III randomised, placebo-controlled trial of 164 postmenopausal women in England, found folic acid did not produce a statistically significant improvement in hot flush severity over 12 weeks compared with placebo. The honest summary is that folic acid may help, but it isn't an established treatment for hot flushes, and the strongest available trial didn't clear that bar.

Those trials used folic acid, at doses considerably higher than what's in our formulation, not active folate. They can't be taken as evidence that Quatrefolic® itself affects hot flushes. The shared biochemical pathway makes it a scientifically reasonable area of interest, but that's different from clinical proof.

Why we use Quatrefolic®

Quatrefolic® is 5-MTHF, already in the active form the body needs, bound to glucosamine for stability and solubility. Because it doesn't require the MTHFR-dependent conversion step, the body can use it directly.

A pharmacokinetic study is sometimes cited as showing Quatrefolic is twice as bioavailable as folic acid. The actual study, a small trial of 12 healthy volunteers published in the International Journal of Applied Pharmaceutics in November 2024, tested a 5-MTHF product called HY-FOLIC®, not Quatrefolic® specifically. It found roughly double the peak concentration and overall exposure of active folate compared with an equivalent dose of folic acid, with lower UMFA levels. That's a useful data point for active folate as a category, single dose, small sample, healthy volunteers, blood levels rather than clinical outcomes, but it isn't a Quatrefolic-specific result. The broader, well-supported statement is that supplemental 5-MTHF is generally considered at least as bioavailable as folic acid, and in some formulations more so.

There's a second point sometimes raised: that high-dose folic acid can mask a vitamin B12 deficiency by correcting the associated anaemia while allowing neurological effects to continue unnoticed. It's worth keeping this in proportion. The CDC notes that getting the recommended amount of folic acid does not delay detection of vitamin B12 deficiency, and modern lab testing can identify B12 status directly, regardless of folate intake. The masking concern is more relevant to sustained, very high folic acid intakes well above the amounts in a typical prenatal, so at ordinary doses it isn't a strong reason to prefer one folate form over another. Maintaining adequate B12 intake matters regardless of which folate form you're taking.

Where we use it

Our Prenatal Core's AM sachet provides 500 mcg of folate as Quatrefolic®. That figure sits within the adult maximum SAHPRA specifies for folate in this health-supplement category, under Annexure E guidance. This is a regulatory ceiling, not a claim that 500 mcg is the one biologically optimal dose for every person, individual circumstances, including higher-risk pregnancies, are worth discussing with a doctor.

It's paired in the same sachet with choline, B12, B6 and B1, since folate works alongside other B vitamins in the same interconnected pathways rather than in isolation.

Quatrefolic® is a registered trademark of Gnosis by Lesaffre.

This article is for general educational purposes and isn't medical advice. Please consult a doctor, gynaecologist or fertility specialist before starting any new supplement or treatment.

Sources

1. Centers for Disease Control and Prevention. MTHFR Gene Variant and Folic Acid Facts. National Center on Birth Defects and Developmental Disabilities. https://www.cdc.gov/folic-acid/data-research/mthfr/index.html

2. Centers for Disease Control and Prevention. Folic Acid Safety, Interactions, and Health Outcomes. https://www.cdc.gov/folic-acid/about/safety.html

3. National Institutes of Health, Office of Dietary Supplements. Folate: Fact Sheet for Health Professionals. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

4. Nafrialdi N, Suyatna FD. Pharmacokinetic study of HY-FOLIC® and folic acid in healthy volunteers. International Journal of Applied Pharmaceutics, 2024;16(6):64-68. https://journals.innovareacademics.in/index.php/ijap/article/view/51874

5. Bani S, Hasanpour S, Farzad Rik L, Hasankhani H, Sharami SH. The effect of folic acid on menopausal hot flashes: a randomized clinical trial. Journal of Caring Sciences, 2013;2(2):131-140.

6. Ewies AAA, Ahmed I, Al-Azzawi F, et al. Folic acid supplementation in postmenopausal women with hot flushes: phase III randomised double-blind placebo-controlled trial. BJOG, 2021;128(12):2024-2033. https://pubmed.ncbi.nlm.nih.gov/33982872/

7. Gnosis by Lesaffre. Quatrefolic: the trusted folate solution for a healthy pregnancy. https://gnosisbylesaffre.com/blog/quatrefolic-the-trusted-folate-solution-for-a-healthy-pregnancy/

8. SAHPRA. Complementary Medicines, Health Supplements: Safety and Efficacy, Annexure E (Vitamins). https://www.sahpra.org.za/wp-content/uploads/2022/03/7.04_CM_SE_Health_Supplements_Mar22_v4_3.pdf