Folic Acid vs. Methylfolate When Trying To Conceive

Those in the camp of folic acid point to a mountain of evidence showing this form reduces the risk of fetal neural tube defects. Those in the camp of methylfolate (5-MTHF) say this form is more bioavailable, especially if you have a very common gene variant that may make it harder for your body to "absorb" other forms.

We looked into the science around this "debate." We also asked the question to our advisors, Harvard Professor Jorge Chavarro and Emory Professor Audrey Gaskins, who collectively have conducted numerous studies and metareviews on this exact topic.

⁠⁠The TL;DR? Though folic acid is the only form clinically proven to prevent neural tube defects, both forms are likely effective.

Here are the other key takeaways:

• Look for 800 mcg folate in your prenatal.

• ⁠From the clinical evidence, whether or not you have MTHFR gene variants, you can supplement with folic acid.

• The effectiveness of non-folic-acid forms (including 5-MTHF or methylfolate) in preventing fetal defects have not been studied. But theoretically they should offer similar benefits.

• Don't fall for the sales tactic of designer prenatals that try get you to pay more for the "superior" format of methylfolate.

Let's break down the science — and the viral hype on this topic.

In August 2023, the US Preventive Services Task Force on Folic Acid Supplementation to Prevent Neural Tube Defects came out with their updated recommendation in the peer-reviewed Journal of the American Medical Association. From their review of the literature, they stick to the folic acid recommendation, saying:

"There is high certainty that folic acid supplementation has a substantial net benefit to prevent neural tube defects in their offspring. The USPSTF recommends that all persons planning to or who could become pregnant take a daily supplement containing 0.4 to 0.8 mg (400 to 800 μg) of folic acid.”

This recommendation of the folic acid format is consistent with the those of major medical and public health bodies like ACOG, ASRM, and the CDC.  

Why do all these public bodies recommend folic acid over methylfolate? Folic acid is the only form of folate shown to be effective in preventing fetal neural tube defects in randomized control trials and food fortification programs. The effectiveness of other forms (including 5-MTHF or methylfolate) in preventing fetal defects have not been studied.

A quick note on dose: If you're trying to conceive, the dose of 400 to 800 mcg in these recommendations is focused on reducing the risk of neural tube defects in a growing fetus. But it is on the lower end of what some of the studies show can support fertility specifically (1, 2, 3, to name a few). So, we recommend at least 800 mcg daily in our fertility programs.

The brands/influencers in the 5-MTHFR camp spin a lot of misinformation about the methylenetetrahydrofolate reductase (MTHFR) “gene variations” — sometimes called, inaccurately, gene “mutations” to make it sound more scary and serious.

But the truth is, t⁠hese variations are extremely common — more than half of Americans probably have them. The question, then, is about whether these variations impact folic acid absorption, which could put people with the variation at greater risk of fetal neural tube defects.

More research is needed to better understand how genetic variants such as MTHFR slow folate metabolism and how these variants affect strategies for folic acid supplementation (this was something the recent JAMA recommendation calls out as well).

Though we’d be happy to see this research, our response here is that (I) the results of this research wouldn't really matter for people TTC because people with MTHFR gene variations can still safely process folic acid, and (II) these studies in the fertility/pregnancy use case will likely never happen.

Let's break down why.

Contrary to what most designer supplement brands will tell you, people with these common MTHFR gene variants can safely and effectively process folic acid.

While there is some research showing that neural tube defects are more common among people with the MTHFR 677 CT and TT genotypes, these studies are generally conducted in countries without folic acid fortification. Plus, studies have shown that women who consume enough folic acid each day generally have enough folate in their blood to help prevent neural tube defects, regardless of their MTHFR C677T genotype.

This means folic acid intake is more important than your MTHFR genotype for determining the amount of folate in your blood (1, 2, 3, 4). This is why the CDC urges all women of reproductive age who could become pregnant to consume 400 mcg of folic acid each day, including those with an MTHFR C677T variant.

Testing the efficacy of a different form of folate through the gold standard randomized trial would require that some participants not get any folic acid, which could put babies at risk. This would be extremely unethical, and so it's unlikely that studies looking at this would ever be funded.

For this reason, folic acid is unlikely to be unseated as the recommended form of folate for those trying to become pregnant (and those already pregnant).

Despite all the debate, both forms of the nutrient are likely effective and safe. Whether you're choosing a prenatal with folic acid or methylfolate, the most important thing is that you get enough of folate daily — at least 800 mcg if you're trying to conceive.

This format "debate" online is designed to stress people out and sell more products. The evidence for folic acid is so strong, regarless of any gene variation, that it's just not worth going down a stress/complication/hype rabbit hole.

In our opinion, fear about this gene variant is used to sell more gene variant testing services as well as designer prenatals using this as a "reason to believe" hook for “superior absorption” pseudoscience. 

So, keep it simple, and stick to the unbiased fertility science.