Evidence-Based Medicine: Folic Acid, 5-MTHF, and the MTHFR Gene: What Pregnant Women (and Doctors) Should Know
And why the critics of 5-MTHF are missing the forest for the trees
Neural tube defects (NTDs) are serious birth defects of the brain and spine, including spina bifida and anencephaly. In the early 1990s, scientists discovered that daily folic acid before and during pregnancy could cut the risk of NTDs dramatically. This led to routine supplementation and food fortification, which reduced NTD rates worldwide.
Folic acid is a synthetic vitamin. Once swallowed, your body must convert it into 5-methyltetrahydrofolate (5-MTHF), the active form used in DNA building and cell growth. For most women, this conversion works smoothly.
Folic Acid vs 5-MTHF: Both Synthetic, But Not the Same
It’s a common misconception that 5-MTHF supplements are “natural” while folic acid is “synthetic.” The truth is that both are made in a lab. The difference is that 5-MTHF is chemically identical to the bioactive folate already circulating in your blood, while folic acid is an artificial precursor that the body must process first.
What about “natural” folate from food? Leafy greens, beans, and citrus are excellent sources, but natural folates are unstable and break down easily during storage and cooking. Even women with very healthy diets often don’t reach the protective levels needed to prevent NTDs. That’s why supplementation and food fortification became necessary in the first place.
The MTHFR Gene and Its Variants
Enter the MTHFR gene, which makes the enzyme that performs this conversion. Two common variants, C677T and A1298C, slow the process down. Nearly half of all women carry at least one of these variants. People with the “TT” type of C677T may have only 30% of normal enzyme activity.
The incidence varies: about 10–15% of African Americans, 20–25% of Caucasians, and 25–35% of Hispanics carry the higher-risk C677T variant. In some Asian populations, particularly Chinese and Japanese, it can reach 40–50%. Areas with high rates of these variants have historically reported higher rates of NTDs before folic acid fortification.
Genetic testing for MTHFR is available but not routinely recommended. Knowing your status can be useful if you have a history of pregnancy complications or NTDs, but for most women the advice is the same: take folate daily, starting before conception.
The Promise of 5-MTHF
5-MTHF bypasses the MTHFR conversion step completely. Studies show that it raises blood folate levels more reliably and lowers homocysteine better in people with these gene variants. On paper, it seems like the obvious choice.
But here’s the reality: no large pregnancy outcome trials have ever tested 5-MTHF versus folic acid for preventing NTDs. So while it seems to make sense to take 5-MTHF theoretically instead of folic acid, in practice it has never shown to actually work to prevent neural tube defects (NTDs). Only folic acid has been proven to work in practice, in scientific trials, not 5-MTHF.
ACOG and CDC: The Current Recommendations
Both the CDC and American College of Obstetricians and Gynecologists (ACOG) continue to recommend folic acid as the standard.
For all women of childbearing age: At least 400 mcg daily, starting before conception and continuing through early pregnancy.
During pregnancy: About 600 mcg daily.
If you’ve had a prior pregnancy affected by an NTD: 4 mg (4000 mcg) daily, starting 3 months before conception.
Why folic acid and not 5-MTHF? Their reasoning is simple: folic acid has decades of outcome data proving it prevents NTDs, while 5-MTHF has only biochemical evidence but no population-level trials. From a public health perspective, the safest choice is to stick with what has already saved thousands of lives.
The “Natural” Myth
Some supplement companies and wellness advocates call 5-MTHF “natural.” That’s only partly true. 5-MTHF is the natural form of folate circulating in your blood, but the 5-MTHF you buy in a prenatal vitamin is still manufactured in a lab—just like folic acid. The difference is that folic acid doesn’t exist in nature at all, while 5-MTHF does, so chemists can reproduce it exactly.
Dietary folates from leafy greens and beans are “natural,” but they are unstable and easily destroyed by cooking or storage. Even women who eat a very healthy diet usually don’t reach the high folate levels needed to prevent neural tube defects. That’s why public health authorities turned to stable, synthetic supplements and food fortification in the 1990s.
In short: both folic acid and 5-MTHF pills are synthetic. The real difference is that folic acid requires processing by the body, while 5-MTHF is already in the usable form.
So What Should Women Do?
Non-negotiable: Take 400–800 mcg of folate daily starting before conception. This is what prevents NTDs.
If cost isn’t an issue: Choosing a prenatal vitamin with 5-MTHF is reasonable. It may help those with MTHFR variants and carries no known risks.
If cost matters: Folic acid remains excellent and proven. Don’t feel pressured by marketing.
Who should especially consider 5-MTHF? Women with previous NTDs, pregnancy losses, or known MTHFR variants.
The key isn’t which form you take, it’s that you take it consistently—starting before you get pregnant.
A Note on Genetic Testing
Genetic testing for MTHFR variants (most often C677T and A1298C) is available, but it is not routinely recommended. That’s because the standard advice—daily folate )not 5-MTHF) supplementation—applies to everyone regardless of results.
C677T heterozygous (CT): Conversion is slowed but still functional. No change in recommendations beyond standard folic acid (400–800 mcg daily).
C677T homozygous (TT): Enzyme activity may drop to about 30%. These women may benefit from using 5-MTHF instead of folic acid, although ACOG and CDC still officially recommend folic acid.
A1298C variant: Generally has a milder effect on enzyme activity. No separate guideline beyond standard folic acid.
Compound heterozygotes (C677T/A1298C): Moderate reduction in enzyme activity. Again, 5-MTHF may be reasonable, though folic acid is considered sufficient by current guidelines.
In practice, a positive test rarely changes official recommendations, since population-level data show that folic acid fortification prevents NTDs even in women with these variants. Where testing can matter is in personalized care—especially for women with recurrent pregnancy loss, a prior NTD, or persistently elevated homocysteine despite folic acid use. For these patients, considering 5-MTHF is reasonable and safe.
📌 Professor Amos TIP
Don’t just trust the front of the bottle—read the label.
Look at the ingredient list and check whether your prenatal vitamin contains folic acid or 5-MTHF (sometimes listed as “L-methylfolate”). If you’re not sure how the amounts compare to the official recommendations, take a photo of the label or copy the ingredients from the website. Then you can upload it into ChatGPT or another AI tool to generate a table that shows whether your vitamin is complete, and how the doses match up against medical guidelines. This takes the guesswork out of comparing supplements.