Why ACOG and CDC Continue to Recommend Folic Acid Over Folate Despite Research Advancements

We’ve been clear that we believe that Folate is superior to Folic Acid when it comes to perinatal supplementation. We’re also aware that many major organizations, including the American College of Obstetrics and Gynecology (ACOG) and Centers for Disease Control (CDC) continue to recommend the synthetic form of folate, Folic Acid. 

This disconnect has sparked a question in many of your minds, and we hear you.  Why do these organizations recommend Folic Acid instead of Folate? Which is really better? You’re confused and not sure what to believe. So, we want to address this head on. 

But first, let us be clear. We design our supplements with evidence-based information. We developed all of our products, including our Methylfolate-containing Prenatal Multi, from the ground up. We questioned common industry practices around every ingredient (that’s why we have the prenatal vitamin on the market with the most supportive amount of Choline!) Most companies look at what is cheapest or easiest to formulate--not us. Every ingredient and dosage choice we make is based on an exhaustive review of well-designed and peer-reviewed research. And, since there are limitations on women’s health research especially in the perinatal stage, we supplement this understanding with insights from the in-practice experience of our perinatal health practitioner community. We also gut check our clinical research and practice with a practical look at nature and history. In the case of Folate vs. Folic Acid, Folate is what is found in food and what has been consumed by pregnant women since the beginning of time to birth healthy babies. Yes, there have been cases of neural tube defects when women haven’t consumed enough Folate (hence the need for supplementation), but that concern is about nutrient quantity, NOT form.

This is all to say that, if the clinical research, or the in-practice experience of our practitioner community, or historical context showed that synthetic Folic Acid was preferable to the active form of Folate (Methylfolate), we would have utilized it. In fact, doing so would have been the far cheaper option. But the evidence isn’t there. There is a large and growing body of evidence suggesting that Methylfolate is effective in raising maternal folate status, and that excess Folic Acid (caused by poor absorption of the synthetic form) can build up and remain unmetabolized in the body. This is worrisome for mama and baby, as we’ll get into in further detail.

A Quick Refresher

In case you need a quick refresher on the difference between Folate and Folic Acid, here it is:

Folic Acid is the synthetic form of Folate. It does not occur in nature. The important distinction is that your body can’t just utilize Folic Acid as it is. It has to go through a conversion process in the body first before the body (and your baby) can actually use it. Food sources of Folate contain the already “active” form of Folate that does not need to be converted. 

The body converts Folic Acid into a form called Methyltetrahydrofolate (or MTHF or L-methylfolate), in order to be able to use it. This conversion happens in all bodies. However, approximately 40-60% of people have a genetic variant (the MTHFR variant) that prevents their body from appropriately making this conversion. That means if you have it and you take synthetic Folic Acid, you (and your baby) may not get the nutrition you need.

What Research Exists Around the Effectiveness of Folate Supplementation?

Since the argument of ACOG and the CDC is that “Folic Acid is the only type of Folate shown to help prevent neural tube defects,” you would be wise to wonder, what research is there around the effectiveness of L-methylfolate in pregnancy? 

While there isn’t as much research around L-methylfolate in pregnancy as there is Folic Acid (in part due to the higher cost of L-methylfolate), there is a growing body of compelling and reliable information.

In a Key Opinion Leader interview in Reviews in Obstetrics & Gynecology, James A. Greenberg, MD, from the Department of Obstetrics and Gynecology at Brigham and Women’s Hospital and the Department of Obstetrics, Gynecology, and Reproductive Biology at Harvard Medical School, discusses the form of Folate in prenatal supplementation with Stacey J. Bell DSc, RD. 

They acknowledge, “it is reasonable to question the safety and efficacy of L-methylfolate, because up until recently, only Folic Acid was available for prenatal vitamins." However, they point to a study in which healthy women were randomly assigned to consume 400 µg of folic acid, 416 µg of L-methylfolate (the bioequivalent dose of folic acid), and 208 µg of l-methylfolate (half dose). 

Each group experienced increases in plasma Folate and decreases in homocysteine concentrations (although unsurprisingly the half dose of l-methylfolate had a significantly smaller increase in plasma folate compared with the other two groups). These findings suggest that L-methylfolate is bioactive and behaves predictably by increasing plasma levels of Folate and decreasing homocysteine. (Note: Women with elevated homocysteine levels are believed to be at higher risk for miscarriage, preeclampsia, and preterm labor due to increased clotting caused by the elevated homocysteine levels, so decreasing homocysteine is ideal.)

Their conclusion, based on this and other research, is that due to “the high prevalence of [the MTHFR variant] and the importance of assuring that pregnant women get adequate supplementation, L-methylfolate may be the best option to avoid blood Folate deficiencies.”

Furthermore, the study notes that excessive intake of Folic Acid could mask an undiagnosed Vitamin B12 deficiency, and that it was “unlikely” that L-methylfolate would mask Vitamin B12 deficiency. Therefore, L-methylfolate may be a better option for supplementation.

Another review in the Journal of Perinatal Medicine looked at whether 5-methyltetrahydrofolate could be used as an alternative to folic acid for the prevention of neural tube defects. It reviewed a number of studies but ultimately concluded that “supplementation of the natural form is a better alternative to supplementation of Folic Acid. Supplemental [L-methylfolate] can effectively improve Folate biomarkers in young women in early pregnancy in order to prevent neural tube defects.” It specifically pointed to a study in the American Journal of Clinical Nutrition that concluded that a mean serum Folate level of approximately 50 nmol/L was achieved by supplementing with 400 μg of either 5-MTHF or Folic Acid for 12 weeks

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If I Know I Don’t Have the MTHFR Variant, is Folic Acid Better?

You don’t know for sure whether or not you have the MTHFR variant unless you have had genetic testing. But if you have, and you know that you don’t, you might be wondering if Folic Acid is better in that case. 

The short answer is no. 

Research has shown that excess Folic Acid supplementation can build up and remain unmetabolized in the body.

In fact, a study in the American Journal of Clinical Nutrition evaluated the effect of mandatory fortification, prevalent supplement use, and public health guidelines recommending periconceptional supplementation have increased folic acid intakes in North American pregnant women. The study found that unmetabolized folic acid (UMFA) was detectable in more than 90% of maternal and cord plasma samples tested. The study concluded that UMFA concentrations in maternal and fetal circulation warrant additional investigation, since this excess UMFA may affect long-term health outcomes of the baby. While these long-term ramifications are still being studied, we know enough to know that high doses of Folic Acid should be questioned for the sake of future health outcomes.

Another study notes, “It is now clear that the practice of prescribing high doses of synthetic folic acid should be at least a matter for debate. 5-MTHF, the “active” folate that is immediately available for conversion of homocysteine to methionine, should be proposed instead of Folic Acid for periconceptional support and even for nutritional supplementation in general.”

In addition, a retrospective, comparison study looked at supplementation with Folate and Folic Acid in pregnant women alongside Vitamin B12 with respect to hemoglobin levels. The women studied either used a prenatal supplement containing L-methylfolate or one with Folic Acid. Women were followed during pregnancy until term. In contrast with women who used a prenatal product that contained Folic Acid, those who had L-methylfolate in their prenatal supplement had significantly higher hemoglobin levels at the end of the second trimester and at delivery. Based on this study, it appeared that women benefited from L-methylfolate in their prenatal vitamin in terms of having a lower incidence of anemia.

Furthermore, research suggests that it may not be just mother and baby who are affected by high Folic Acid supplementation. One study found alterations of the human sperm epigenome (the “programming” of sperm that affects gene expression, or how genetics play out in baby’s health) associated with high-dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR.

It’s worth noting that research generally points to “high-dose” Folic Acid supplementation. While the definition of “high dose” varies, it generally refers to a dose that is consistent with a recommendation for preconception and/or pregnancy. 

In contrast, when we refer to “high doses” of L-methylfolate, we are referring to a specific amount: greater than 1,000mcg DFE (dietary Folate equivalent) as this amount can lead to mood imbalances in mama. Our Prenatal Multi contains an optimal dose of 918 mcg DFE (dietary Folate equivalent) for this reason.

If Folate Is Superior, Why Do Major Medical Organizations Recommend Folic Acid

So the big question: if plenty of evidence exists to suggest that Folate is superior to Folic Acid, why is Folic Acid still recommended? In short, it seems there’s only one explanation:

Official recommendations lag scientific research.

Think about it. We’ve had evidence for years that trans fats were bad for us. But it wasn’t until 2015 that the FDA got on board. And even then, food manufacturers weren’t required to change their practices until 2018. Choline has been studied for its importance in pregnancy dating back to the 1950s, and with respect to overall human health since at least the 1980s, but it wasn’t until 1998 that there was an official RDA, and it is still missing from the vast majority of supplements (despite over 95% of the population being deficient).

It takes a lot for an official recommendation to change, and rightfully so, these organizations don’t take recommendation updates lightly. So while the evidence is building, it’s not yet enough for major medical organizations to spend the time and money to change a decades-long recommendation.

There are simply more studies on Folic Acid. This is because when supplementation was introduced in 1998, synthetic Folic Acid was the only option. It was inexpensive and accessible, and so it was studied. Still to this day, synthetic Folic Acid remains a cheaper and more accessible option. And if it is the ONLY option for a pregnant woman to take, then yes, she is better off taking it than allowing herself to be deficient during pregnancy.

As a gut check on this, we can look to history too. Prior to Folic Acid supplements being available on the market, women relied on food sources of Folate to meet their needs. Yes, some women fell short, but these were women who were not eating enough Folate, not women who failed to supplement with Folic Acid (this was the catalyst for introducing Folic Acid supplementation in the first place). Women birthed healthy babies for hundreds of years before synthetic Folic Acid was available. If active Folate was not a sufficient way to prevent neural tube defects, we likely would have seen a much higher occurrence in prior generations. After all, most of the Folate in your body is in the form of L-methylfolate - this form represents 95–98% of Folate in your red blood cells (serum Folate).

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The Bottom Line

There is a growing body of research around the advantages of supplementing with the active form of Folate over Folic Acid:

• Folate is already a biologically active form that occurs in our food sources with no need for conversion/activation.
• It is the main type of folate in our blood (serum and red blood cells) as well as cord blood (fetal blood supply).
• It does not mask Vitamin B12 deficiency, unlike Folic Acid. Vitamin B12 is also critical in pregnancy.
• It does not build up to cause unmetabolized Folic Acid in the body (which may lead to negative downstream effects).
• Women with the MTHFR variant show a better response with plasma folate markers to methylfolate than to Folic Acid.
• There is no research to suggest that it is not effective at preventing neural tube defects, and a number of studies to show that it is at least as effective as Folic Acid.
• While too much is not desirable, there is a low risk for toxicity, unlike Folic Acid

While there may be a lag in official guidance on this topic, we continue to recommend Folate over Folic Acid. We are confident in this approach, but we are humble and nimble in our willingness to learn and adapt as new research and information becomes available. As always, our team of perinatal nutrition experts will continuously monitor the latest nutrition research and clinical experience, and update our approach to optimal perinatal nourishment as needed.