Prenatal Vitamins and Folate: Navigating the Folic Acid versus Methylfolate Controversy

When it comes to prenatal vitamins, few topics are as polarizing as the debate over folic acid versus 5-methyltetrahydrofolate (5-MTHF). Discussions among dietitians, OBGYNs, and functional medicine practitioners often lack nuance, leaving many dietitians uncertain about the evidence and best practices for their clients. This article provides an evidence-based exploration of this complex topic.

What is Folate?

Folate (also referred to as folacin or Vitamin B9) is a water-soluble vitamin essential for DNA and RNA synthesis, amino acid metabolism, methylation reactions and the prevention of neural tube defects. It exists in multiple forms:

Dietary Folate:

Found naturally in leafy greens, beans, nuts, poultry, meat, seafood, and dairy

Folic Acid:

Synthetic monoglutamate form added to supplements and fortified foods (e.g., breads, cereals, enriched pastas)

5-Methyltetrahydrofolate (5-MTHF):

The active form of folate in the blood.
Also found in supplements as calcium or glucosamine salts

History of Folate In Public Health

Folate is an essential vitamin and is especially important for the prevention of neural tube defects.

The neural tube forms during the third and fourth weeks of pregnancy, and its proper closure is critical for brain and spinal cord development. Neural tube defects (NTDs), such as spina bifida and anencephaly, can result from insufficient folate levels.

The essential role of folate in supporting healthy neonatal outcomes has driven public health initiatives, including recommendations and mandates for folic acid fortification and supplementation.

Key historical milestones include:

1991: A study called the Medical Research Council Vitamin Study showed that women with a prior NTD-affected pregnancy reduced recurrence risk by 70% with 400 mcg/day folic acid.
1992: Another randomized control trial demonstrated a 100% reduced risk of an NTD-affected pregnancy in women who took a prenatal supplement containing 800 mcgs for folic acid. The same year, the Center for Disease Control in the US recommended 400 mcg/day folic acid for all women of childbearing age.
1998: Mandatory folic acid fortification of cereal grains in the U.S. and Canada was implemented. NTDs were reduced by 46% in Canada
2021: The UK and New Zealand announced mandatory folic acid fortification of non-wholemeal wheat flour.

By 2023, 69 countries globally have implemented folic acid fortification, 47 recommend voluntary fortification and 77 do not have fortification. Many countries also recommend prenatal supplementation with folic acid in females of childbearing age.

Daily Requirements and Recommendations

Group	*Daily Requirement (DFE)**	Upper Limit (Folic Acid)
Adults	400 mcg	1,000 mcg
Pregnant Individuals	600 mcg	1,000 mcg
Lactating Individuals	500 mcg	1,000 mcg

Special Populations

History of NTDs: 4 mg/day folic acid recommended.
Diabetes or epilepsy: 1–5 mg/day depending on country-specific guidelines.

*DFE stands for Dietary Folate Equivalent, a measure used to account for the differences in absorption between natural food folate and synthetic folic acid. For example, 1 mcg of food folate equals 1 mcg DFE, while 1 mcg of folic acid from supplements equals 1.7 mcg DFE when taken on an empty stomach. This system ensures accurate recommendations for meeting folate needs.

If public health recommendations recommend folic acid fortification and supplementation, then what is the controversy all about?

The controversy is rooted in the question of how different forms of folate are metabolized. Let’s take a closer look.

Folate Absorption and Metabolism

If you are a visual learner, I would recommend looking at Figure 1 of this study for a visual representation of the below mechanism.

Dietary Folate:

Food folate in the form of tetrahydrofolate. They usually have additional glutamate residues, making them polyglutamates
Polyglutamates need to be converted to monoglutamates in the small intestine for absorption via active transport
Once absorbed, the monoglutamates are then reconverted to polyglutamates again
Through several enzymatic reactions, these polyglutamates are then metabolized to 5-MTHF. Key enzymes in the process include dihydrofolate reductase (DHFR) and methylenetetrahydrofolate reductase (MTHFR)
5-MTHF is the active and primary form of folate in the blood. It has many important roles including:
- Synthesis of nucleic acids (DNA and RNA)
- Metabolism of amino acids
- Converting homocysteine (which can be detrimental to health if elevated) to methionine

The bioavailability of food folate is highly variable (50–90%) due to food preparation, gastrointestinal destruction, and folate type.

Folic Acid:

Unlike dietary folate, synthetic folate is already in the monoglutamate form and is absorbed directly in small intestine
The rest of the process is similar to what happens with food folate
The one concern that is brought up with folic acid, is that excess doses may saturate the DHFR enzyme, leading to unmetabolized folic acid (UMFA) in plasma. We discuss this more in a later section

The bioavailability of folic acid is nearly 100% bioavailable on an empty stomach; and 85% with food. It is stable and less prone to degradation than food folate.

5-Methyltetrahydrofolate (5-MTHF), also called methylfolate or methylated folate:

Either in the form of calcium or glucosamine salts in supplements. The glucosamine salt is the more stable and soluble form
Active form of folate and bypasses the DHFR and MTHFR steps.

New research is finding that 5-MTHF may be highly bioavailable and immediately usable by cells. However, as we will learn in the next section, there is limited data on long-term efficacy in NTD prevention compared to folic acid.

Markers of Folate Status:

Serum Folate: Reflects recent dietary intake but does not indicate long-term folate status

Red Blood Cell (RBC) Folate: Provides a more accurate measure of long-term folate status

Plasma Homocysteine: Elevated levels indicate possible 5-MTHF deficiency, as homocysteine cannot be converted to methionine. However, levels can also be influenced by other factors like kidney dysfunction or vitamin B12 deficiencies. A homocysteine cutoff of 10 micromol/L is often used to assess folate status in populations

Folate Deficiency Criteria:

Serum Folate: <7 nmol/L
RBC Folate: <360 nmol/L
RBC folate concentrations >906 nmol/L are linked to a very low risk of neural tube defects (NTDs).

The Controversy: Folic Acid vs. 5-Methyltetrahydrofolate (5-MTHF)

The debate over folic acid versus 5-MTHF has grown in recent years, driven by emerging research, genetic considerations, and marketing claims.

Here are the primary areas of controversy and what the actual research shows.

Argument 1: 5-MTHF "Natural" and more effective than synthetic folic acid

While 5-MTHF is often marketed as a “natural” alternative, it is still synthesized in a lab. However, it is the active form of folate and bypasses the metabolic steps required for folic acid. Studies have shown both forms are effective at increasing red blood cell (RBC) folate levels, with 5-MTHF potentially offering slightly greater efficiency.

In a 24-week, double-blind, placebo-controlled trial compared the effects of 400 μg folic acid/day, 416 μg 5-MTHF/day, 208 μg 5-MTHF/day, and placebo on RBC folate levels.

Results showed that

RBC folate levels increased more significantly in the 416 μg 5-MTHF group than in the 400 μg folic acid group (P < 0.001).
Mean RBC folate exceeded the protective threshold of 906 nmol/L after 8 weeks in groups receiving 400 μg folic acid or 416 μg 5-MTHF
Conclusion: 5-MTHF is effective and may raise folate levels more efficiently than folic acid. However, folic acid supplementation is still effective increasing the RBC folate levels to the protective threshold

Argument 2: People with the MTHFR Polymorphisms Can’t Metabolize Folic Acid

Recall from earlier that the methyltetrahydrofolate reductase (MTHFR) is a key enzyme in the process of converting folate to its active form, 5-MTHF.

The MTHFR gene provides instructions for making the MTHFR enzyme. Variants in the gene may impact enzyme efficiency and affect folate metabolism.

The most common genetic variant is C677T. This means that in the 677 position of the gene, there is a cytosine (C) replaced by a thymine (T).

Key MTHFR C677T genotypes:

CC: Normal enzyme activity, with no significant reduction in folate metabolism.
CT Genotype: Heterozygous variant with moderate reduction in enzyme efficiency
TT Genotype: Homozygous variant associated with the greatest reduction in MTHFR activity

Another common, but less prevalent, polymorphism is MTFHR A1298C. In this case, adenine (A) has been replaced by cytosine (C).

MTFHR variants are highly prevalent in the population. An estimated 40% or more of the population will have 1 or 2 copies of the MTHFR C677T variant. The prevalence is higher among Hispanics, Caucasians and East Asians.

So does this mean that 40% of the population can’t metabolize folic acid? That’s not quite the case. Let’s review what the research shows:

Individuals with the TT genotype have the greatest reduction in the efficiency of folate metabolism. This amounts to a ~16% reduction in folate levels compared to the CC genotype
Populations with a higher prevalence of the T allele (e.g., Hispanics, Northern Chinese) also show increased risks of NTDs. However, studies show 400 μg/day of folic acid in these populations can increase RBC folate levels sufficiently to protect against NTDs, regardless of MTHFR genotype
In a 6-month trial, women with the TT genotype achieved mean RBC folate levels of 927 nmol/L with 400 μg/day of folic acid, slightly lower than CC (1175.8 nmol/L) or CT (1087 nmol/L) genotypes.

Recall that the RBC folate concentrations >906 nmol/L are linked to a very low risk of neural tube defects (NTDs). This means that the folic acid supplementation was able to increase RBC folate concentrations to a safe level, though slightly less efficiently.

Also important to note that participants in this particular study were from a region where there was no mandatory fortification from grains, which may yield even more significant increases in levels.

The key takeaway: Folic acid is effective even with MTHFR variants.Those with the TT variant can benefit from consistent, long-term supplementation.

Argument 3: Masking Vitamin B12 Deficiency

Both folate and vitamin B12 are essential nutrients involved in red blood cell production and DNA synthesis. Deficiencies in either vitamin can lead to megaloblastic anemia, characterized by fatigue, weakness, and pale skin.

High doses of folic acid can mask a B12 deficiency by correcting anemia through improved red blood cell production. This masking effect can delay the diagnosis and treatment of the underlying B12 deficiency, allowing neurological damage to progress unnoticed.

A lack of vitamin B12 can also create a "folate trap," where folate becomes trapped in an unusable form, disrupting the methionine and folate cycles. This metabolic block exacerbates the effects of B12 deficiency, compounding both anemia and the risk of neurological complications.

Without timely intervention, untreated B12 deficiency can lead to irreversible neurological damage, including nerve problems and cognitive impairment

Proponents of 5-methylTHF claim that it is a safer alternative than folic acid because it does not mask the symptoms of B12 deficiency. This is because 5-methylTHF requires vitamin B12 to be utilized in key metabolic pathways, meaning it cannot bypass or hide a B12 deficiency.

Although these arguments are valid, here are some things to consider:

Although the theoretical concern of folic acid masking B12 deficiency is valid, studies suggest it is not a widespread problem in practice for pregnant individuals
Older adults, especially those over 60, are at greater risk of vitamin B12 deficiency due to common malabsorption issues
Awareness of this risk is essential, particularly for clinicians managing individuals with high folic acid intake and populations at risk of B12 deficiency

Argument 4: The risk of unmetabolized Folic Acid (UMFA) for fetal outcomes

The liver enzyme dihydrofolate reductase (DHFR) has a limited ability to process folic acid.

When intake exceeds 260–280 μg of folic acid, the liver’s capacity can be overwhelmed, leading to unmetabolized folic acid (UMFA) appearing in the blood. Research shows:

With single doses, folic acid is quickly cleared from the blood through tissue absorption and urine excretion. However, after taking 400 μg of folic acid daily for 8–14 weeks, studies found UMFA in fasting blood samples, showing that daily supplementation can overwhelm the liver’s ability to process
Interestingly, UMFA levels increased during the first 12 weeks of supplementation but then dropped by week 30, despite continued supplementation. This suggests the body may adjust over time by slowing down folic acid transport or speeding up its metabolism

Potential Risks of High Unmetabolized Folic Acid Levels:

Cancer Risk:

Some studies have found that people with a history of precancerous colon growths (adenomas) who were given high doses of folic acid had a higher risk of developing advanced adenomas compared to those taking a placebo. This might be due to folic acid promoting the growth of early, microscopic lesions.

However, other studies didn’t find the same increase in tumors. Scientists believe high folic acid levels might encourage tumor growth by speeding up DNA production, reducing immune activity, or causing inflammation in the colon.

More research is needed to explore these risks further.

Pregnancy and Fetal Health:

Maternal supplementation of 400 μg/day increases folate levels in both maternal and cord blood, as fetal folate concentrations correlate with maternal values.

Some observational studies from India suggested that very high folate levels during pregnancy might increase the baby’s risk of obesity and insulin resistance later in life. However, clinical trials didn’t confirm these results, and similar animal studies have shown mixed outcomes.

What we know and what’s missing about the risks of unmetabolized folic acid:

The body appears to have ways to limit how much unmetabolized folic acid builds up, even at high doses, by adjusting how it processes and clears folic acid
While some studies suggest possible risks from very high folic acid levels, there isn’t enough solid evidence to confirm harm in humans
More research is needed to understand whether affects long-term health and whether it causes any serious problems

Practical Suggestions:

Follow established folic acid supplementation guidelines, as they are based on decades of research showing their effectiveness in preventing neural tube defects (NTDs)
While 5-MTHF is likely to be a suitable alternative, there is limited long-term evidence supporting its use for NTD prevention. If a client chooses to use 5-MTHF, ensure it is combined with folic acid supplementation to meet current guidelines
Screen for vitamin B12 deficiency in high-risk populations, such as older adults or individuals with absorption issues, to prevent complications from undiagnosed B12 deficiency
Educate clients about the importance of evidence-based practices, emphasizing that folic acid remains the most studied and effective form of supplementation, even for individuals with MTHFR variants
Understand why RCTs are unlikely: Because folic acid is already a proven and effective treatment, conducting randomized controlled trials (RCTs) to compare it with 5-MTHF would be unethical, as it could withhold effective prevention from participants

Key takeaway:

Folic acid supplementation remains the cornerstone of neural tube defect (NTD) prevention, backed by decades of robust evidence. While 5-MTHF shows promise as an alternative, its long-term efficacy for NTD prevention is not yet fully understood, and current guidelines should remain the standard. Until more research is available, combining 5-MTHF with folic acid ensures both innovation and adherence to proven practices, safeguarding the health of future generations.