Revisiting Folic Acid

Published on: March 13, 2018

A look at the science behind folic acid, and why it’s relevant.

When the British researchers Richard Smithells and Elizabeth Hibbard first noticed that mothers of children with neural tube defects (NTDs) had lower levels of the B vitamin folate than did mothers of unaffected children, the Iron Curtain was still closed and FDA had only recently approved “the pill” (yes, that one).

Which is to say, it was a long time ago. In the intervening decades, considerable research has not only corroborated their observations, but shown that raising mothers’ folic acid levels via supplementation genuinely prevents neural tube defects. And the message of that finding has spread so thoroughly that prenatal folic acid supplementation is as much a matter of public awareness as it is of public health policy. Not for nothing has the U.S. mandated folic acid fortification of so basic a staple as flour.

And yet in an era of superfoods and short attention spans, a vitamin like folic acid can be something of a sleeper: easy to overlook, but impossible to dismiss. It may not be “the cutting-edge ingredient of the month,” says Douglas “Duffy” MacKay, ND, senior vice president, scientific and regulatory affairs, Council for Responsible Nutrition (CRN; Washington, DC), but it challenges critics who question supplementation’s benefits for a population.

“What’s nice about the folic acid story,” says MacKay, “is that you can usually stop someone in their tracks just by reminding them that the recommendations provide a very strong foundation for why supplements are valuable, and for why they have an important public health role.”

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Making the Connection
Researchers first started elucidating that role-and making the connection between folic acid and NTDs-in the mid-1960s. “Then there were some critical randomized controlled trials in 1991 and ’92 which were the turning points where the evidence became rock solid,” MacKay recalls.

The evidentiary summary boils down to this: folic acid, which acts as both a vitamin and a coenzyme and is essential to DNA and RNA synthesis and repair, the regulation of cell division and more, helps prevent major congenital deformities of the brain and spine. These include conditions like anencephaly, or the failure of brain development, and spina bifida, which is the failure of the spinal column to close in the early stages of embryonic development.

Precisely how it does so we don’t yet know. But, says Jayesh Chaudhari, MS, CNS, senior director, R&D, Prinova Solutions (Carol Stream, IL), “Although spina bifida is believed to result from a combination of genetic and environmental factors,” the fetus’s increasing folic acid requirement over the gestational period suggests that “most spina bifida cases can be prevented by addressing the nutritional deficiency through folic acid supplementation early in pregnancy.”

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A Clear Statement
No wonder the CDC recommended in 1991 that women with a family history of neural tube defects supplement with folic acid-a recommendation that the agency extended to all women in 1992.

And though the 1992 recommendation prescribed consuming 400 to 800 mcg of folic acid through a combination of dietary, fortified and supplementary sources, by 1998 the recommendation was to get 400 to 800 mcg via supplements and fortification in addition to whatever came from the diet.

That recommendation still stands and was reaffirmed in 2009 when the United States Preventative Services Task Force (USPSTF) issued an authoritative public health recommendation that all women either planning or capable of pregnancy- “that’s all women,” MacKay emphasizes-take a daily supplement that contains 400 to 800 mcg of folic acid. “And fairly new news,” he adds, “is that the USPSTF in 2017 reaffirmed and updated their 2009 statement.”

The USPSTF is “a very conservative organization,” MacKay notes, and its folic acid guidelines qualify as one of what he calls its “Grade A” recommendations. In other words, if the data supporting supplementation weren’t there, the USPSTF wouldn’t make the recommendation. Thus, MacKay concludes, “This is one of those situations where the data’s so clear that they’re willing to go down this road.”

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Critical Moment
And yet. “Despite great efforts,” MacKay continues, “women in the U.S. tend to fall short in their folic acid consumption.” Data from the CDC’s National Health and Nutrition Examination Survey (NHANES) show that from 2003 to 2006-when it last reviewed folic acid status-75% of non-pregnant women ages 15 to 44 did not consume the recommended daily intake of folic acid from diet and supplements combined for preventing neural tube defects.

“So, there is a nutrient gap there that’s prudent to fill,” MacKay says. “That’s a real public health issue-making sure that the vast majority of women have enough folic acid onboard to prevent neural tube defects.”

And remember: fully 50% of pregnancies in the U.S. are unplanned, MacKay adds. It’s within the first 28 days of conception-often before a woman knows she’s pregnant-that the neural tube closes. “So you have this critical moment in which folic acid is really important,” he continues. “When you translate all that, most young adult women should be taking a supplement unless they’re actively preventing pregnancy. That’s a large amount of people.”

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Closing the Gap
The evidence for supplementation is undeniable. “Based on birth defect surveillance programs in the United States, the introduction of mandatory folic acid fortification resulted in an initial decrease followed by the relatively stable prevalence of NTD births,” Chaudhari says. “Additionally, implementation of mandatory folic acid fortification of staple foods including flour, grain, and cereal products in a large number of countries has led to a significant reduction in the occurrence of NTDs.”

But opportunities remain to prevent and reduce NTD prevalence further through supplementation and fortification, particularly among women from under-developed countries, Chaudhari says, who may have yet to benefit from the U.S.s’ public health policies.

All of which makes folic acid a real good-news story. “Nutrients of the week come and go,” MacKay says. “Folic acid has been here since the beginning, and it has continued to be a very important reason why we supplement to fill that gap. We should all recognize that it’s the cornerstone of why dietary supplements are important and have become a household name.”

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Folic Acid or Folate?
Folic acid, folate: What’s the difference-and does it even matter? To some extent, it does.

Folate or folacin-or, even more technically, pteroylpolyglutamate-is the water-soluble form of vitamin B9 as it occurs naturally in foods, like green leafy vegetables, citrus fruits, and legumes. Folic acid-or pteroylmonoglutamic acid-is folate in synthetic form.

While “synthetic” can be a four-letter word these days, it so happens, says Jayesh Chaudhari, MS, CNS, senior director, research and development, Prinova Solutions (Carol Stream, IL), that “the synthetic folic acid form is more stable and thus more commonly found in supplements and fortified foods.”

But our bodies need to metabolize and activate folic acid once we’ve consumed it. “And we’ve learned,” says CRN’s MacKay, “that there are genetic variants wherein some people do not activate folic acid as well as do others.”

Thus, a commercial product (Quatrefolic; Gnosis SPA, Milan, Italy) delivers folic acid in the already-activated 5-methyltetrahydrofolate form, which allows those with the genetic predisposition to use the folic acid found in supplements and fortified foods.

And while the ingredient is a game changer for consumers who can’t otherwise activate synthetic folic acid, MacKay notes that, like folic acid, it too “is not ‘natural.’ The only natural form comes from eating food. And in the end, we have to remember that it’s regular-old synthetic folic acid that’s part of the public health recommendations.”

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The Labels, They are A-Changin’
Food labels are going through a revamp once again, and among the nutrients that’ll look different on-pack going forward is folic acid.

To this point, it’s appeared on Nutrition Facts panels in metric units-400 mcg, say. But once the changes kick in, consumers will see totals expressed as dietary folate equivalents, or DFEs. Per FDA, the new folate RDI for adults and children aged four and above will be 400 mcg DFE, or 240 mcg folic acid, says Chaudhari, with 1 mcg DFE equaling 1 mcg of food folate and 0.6 mcg synthetic folic acid.

“This change is going to require some education,” MacKay notes. “But luckily, we and others commented on this proposed change.” And the result is that while consumers will see the new DFE listing, they’ll also continue to see, in parenthesis, the actual microgram amount, says MacKay- “so that women who are trying to achieve the public health recommendation of 400 mcg can identify the products that they’re looking for.”

Enough is Enough?
Folic acid is a water-soluble vitamin, making excretion of any excess a “relatively straightforward” matter, says Chaudhari.

But, notes MacKay, “Floating around for a while was concern that with fortified food, dietary supplements, fortified energy drinks-might people be getting too much folic acid?” The concern arises from folic acid’s critical role in cellular division. “So, if you have a precancerous lesion like a colon polyp,” MacKay asks, “would feeding that precancerous cell folic acid help it grow into a full-blown cancerous lesion?”

For about a decade, that theory “kicked around,” he says-but over the past few years, “some authoritative papers have come out that really put that theory to rest. Even in the era of fortification, folic acid is still important.”

The Homocysteine Connection
Because so much awareness around folic acid centers on NTDs and prenatal supplementation, it’s easy to forget that protecting babies’ neural development isn’t all that folic acid does. It plays a role in everything from cardiovascular health to Alzheimer’s disease-and it appears to do so in partnership with homocysteine.

Homocysteine is an amino acid byproduct of the body’s methylation reactions. Folic acid, too, is a critical player in methylation. Increasingly, evidence hints that 1) disturbances in folic acid metabolism, and 2) the elevated homocysteine levels that those disturbances precipitate may help explain not only NTDs, but other congenital deformities, cognitive disorders, infertility, heart disease, osteoporosis, cancer, and more.

And here’s the good news: “To the extent that elevated homocysteine levels have been linked to these other conditions,” MacKay says, “getting more folic acid is one of the ways whereby we lower homocysteine levels.”

Chaudhari agrees. “Supplementation with folate/folic acid, along with vitamins B6 and B12, would be the prudent approach to reducing homocysteine levels. This, in turn, would minimize the damage to the inner arterial lining, for example, to lessen the possibility of cardiovascular and other diseases, such as congestive heart failure, stroke, age-related macular degeneration, brain atrophy and Alzheimer’s disease.”

Solving the Mystery of NTD Prevention
The science behind folic acid’s ability to prevent NTDs is rock solid: randomized, controlled clinical trials corroborate it time and again, and supplementation’s public health outcomes prove it in real time. But as for how folic acid works its neat trick, “We don’t know,” says MacKay. “Still. To this day.”

That may be changing. As mentioned in the previous slide, folic acid’s relationship to homocysteine levels and methylation may provide a big clue.

According to Chaudhari, recent research seems to implicate disordered methioninesynthase activity in NTD pathogenesis. What is methioninesynthase? It’s an enzyme that converts homocysteine to methionine using a methyl group that folic acid provides. “If this transformation fails to take place,” Chaudhari says, “be it because of an enzyme anomaly or lack of folic acid, homocysteine levels increase. And this appears to prevent the closures of the neural tube.”

It goes to show that methylation-and compounds like folic acid and homocysteine that take part in it-could be the common denominator in many disorders. “It’s a very important metabolic step that happens thousands of times per second,” MacKay says. “If your body’s not able to do it, there could be any number of challenges.”