By Kate Yandell
A folic acid supplement is recommended during pregnancy and prior to conception because it reduces the risk of neural tube defects in babies. Social media posts have claimed that people should avoid folic acid in favor of a different form of the vitamin, but folic acid is the only one that has been established to help prevent birth defects.
Neural tube defects affect the spinal cord and brain. They occur very early in pregnancy when the neural tube doesn’t close properly. The most common types are spina bifida, a defect of the spine that can range from having little impact to causing intellectual disability or paralysis, and anencephaly, a fatal defect in which parts of the brain and skull do not form.
Taking a folic acid supplement prior to and during pregnancy — first broadly recommended in the U.S. in 1992 — can reduce the risk of these birth defects. The rate of neural tube defects fell in the U.S. after the government mandated in 1998 that certain grain products be fortified with folic acid.
Widely shared social media posts incorrectly claim that people should not ingest folic acid, particularly those who have a certain common gene variant.
“Folic acid is not a physiological active form of folate. It doesn’t do anything good,” one recent post stated, recommending that people take other folates. “If you have the mthfr gene mutation, avoid folic acid!” said another. People have made similar claims on multiple accounts over several years.
There is a common variant of the MTHFR gene, particularly prevalent in Hispanic individuals, that slightly reduces the body’s ability to process folic acid. But people with this variant can still process folic acid and should take folic acid supplements at the usual dose, according to the Centers for Disease Control and Prevention website.
Prenatal supplements that contain a different type of folate, often a stabilized version of 5-methyltetrahydrofolate, or 5-MTHF, are increasingly available. As with folic acid, taking 5-MTHF increases folate levels in the blood, so it could have a similar impact in theory. But folic acid “is the only type of folate shown to help prevent neural tube defects,” the CDC says.
“Is having another form of folate adequate? We don’t know because the studies have not been done,” Dr. Shannon Clark, a professor of maternal-fetal medicine at the University of Texas Medical Branch in Galveston, told us. Such a study, comparing folic acid to another form of folate prior to conception and in early pregnancy, would likely never be approved due to ethical reasons, she said.
“There are no clinical trials using 5-methyltetrahydrofolate as a substitute for folic acid to prevent birth defects,” said Patrick Stover, a metabolic biochemist and director of the Institute for Advancing Health through Agriculture at Texas A&M University. “That doesn’t mean it shouldn’t work, but it’s never been tested. … So likely it could be a substitute, but it’s never been tested, and it would be unethical to test it because there’s already a solution.” That solution, he explained, is consuming folic acid.
A wide array of government and expert organizations recommend that people who could get pregnant consume 400 micrograms (mcg) of folic acid daily. The U.S. Preventive Services Task Force — an independent group of experts on preventive medicine — recommends 400 to 800 mcg per day.
The organizations vary on whether the recommended amount of folic acid, a synthetic folate, is limited to supplements or refers to fortified foods and supplements combined. Some guidelines specify that people should make sure to get 400 mcg folic acid on top of eating a generally healthy diet with naturally occurring folate.
Expert groups representing physicians who treat pregnant people specify that folic acid supplementation should start at least a month prior to conception and continue through pregnancy week 12, since the neural tube is formed very early in pregnancy.
There are separate folate recommendations for people who aren’t pregnant or soon-to-be pregnant.
“For the general population there isn’t any recommendation from public health authorities about the folate versus folic acid versus [5-MTHF],” said Carol Haggans, a registered dietician and scientific and health communications consultant with the Office of Dietary Supplements at the National Institutes of Health. She noted that this group should focus on getting folate from food.
People With MTHFR Gene Variant Can Process Folic Acid
The most common MTHFR variant is MTHFR C677T, and approximately a quarter of people who are Hispanic, 10% of those who are white or Asian, and 1% of African Americans have two copies of this version of the gene. The variant is found at an even higher rate in some groups — reaching greater than 35% prevalence in people of Mexican or northern Chinese descent.
People with two copies of this MTHFR variant have about 16% lower amounts of folate in their blood on average than people with two copies of the predominant version after consuming the same amount of folic acid. People with one copy of the variant also have reduced blood folate, but to a lesser degree.
This is not enough of a reduction that people with the variant need to follow different instructions on supplementation. “Consuming 400 mcg of folic acid each day helps prevent neural tube defects, even if you have an MTHFR C677T variant. Taking a supplement with more than 400 mcg of folic acid each day is not necessarily better for preventing a neural tube defect,” the CDC says.
People who have previously had a baby with a neural tube defect or who have certain health conditions may be recommended to take more folic acid.
Folic Acid Versus Other Folates Like 5-MTHF
In recent years, the folates present in some prenatal supplements began to change, according to an analysis published in 2020 by researchers from the National Institutes of Health.
Between September 2015 and March 2019, 32% of prescription and a quarter of nonprescription prenatal supplements included in NIH databases contained stabilized salts of 5-MTHF, said Haggans, who co-authored the report. Prior to September 2015, no supplements in the databases reported having salts of 5-MTHF.
Like other vitamins and supplements, prenatal supplements are not approved for efficacy and safety by the Food and Drug Administration before companies can market them. Supplements do not have to contain particular vitamins and minerals to be marketed as prenatal, and their content varies.
When asked via email if the increasing prevalence of 5-MTHF in prenatal vitamins is a public health concern, the CDC told us: “Yes. Currently there is only research to support the use of folic acid to prevent neural tube defects. No scientific studies exist that show that supplements containing other types of folate (such as 5-MTHF) can help prevent neural tube defects. Therefore, we do not know if prenatal vitamins with 5-MTHF offer the same level of protection against neural tube defects as those with folic acid.”
Studies do show that taking 5-MTHF increases the concentration of folate in the blood. However, CDC scientists wrote in a review paper that to establish efficacy of 5-MTHF in preventing neural tube defects, there would need to be a randomized trial demonstrating that it was safe and effective and establishing the proper dose and timing.
Stover pointed out that 5-MTHF has two downsides. The first is that it is much more expensive to make than folic acid. The second is that 5-MTHF is less stable. This leads to concern that the level of intact folate found in some supplements at the time they’re consumed could differ from the amount listed on the label. Newer forms of 5-MTHF have improved stability, he said, but “it does not achieve the stability of folic acid.”
Someone could theoretically aim to get the equivalent of 400 mcg folic acid only from eating a healthy diet rich in natural food folate. However, getting this amount of folate from unfortified foods alone “requires consumption of a large quantity of foods not typically consumed,” the CDC scientists wrote in the review. “For example, a person would need to consume approximately 12 cups of raw spinach daily to reach the recommended level.”
Further, the researchers wrote, studies haven’t determined how much natural food folate is needed to reduce neural tube defects or how it interacts with other vitamins, “so it is not possible to recommend an intake of natural food folate that is certain to prevent [neural tube defects].”
Social media posts bring up that folic acid “doesn’t exist in nature” or “doesn’t occur anywhere naturally.” Indeed, it is a synthetic folate used in supplements and for food fortification due to its relative stability in the presence of heat and light compared with folate naturally found in food. (Folic acid only occurs in nature in trace amounts, Stover explained.)
But 5-MTHF supplements are also not the same as natural food folate. The folate found naturally in food is less bioavailable — meaning it’s less easily absorbed and used by the body — than either folic acid or 5-MTHF supplements.
“Just because something isn’t found naturally in food in high concentrations doesn’t mean it’s harmful,” Stover said.
How to Look for Folic Acid on Supplement Labels
The FDA does require supplements to have a “supplement facts” label including a list of dietary ingredients and the amount per serving.
Supplement labels can cause confusion, Haggans said, because folate is measured in various ways. The FDA requires that labels have in parentheses the mcg of folic acid to aid people who are trying to prevent neural tube defects.
“The number to look for is the number in parentheses,” Haggans said.
And again, experts generally recommend 400 mcg of folic acid for people who could become pregnant.
The parenthetical value should specify that it is talking about folic acid — some supplement makers include a number in parentheses referring to the mcg of other folates. These are usually versions of 5-MTHF, which is sometimes also referred to as L-5-MTHF or methylfolate.
“If the supplement label does not specifically say folic acid in the parentheses then it does not have folic acid,” Clark said.
No Known Risks From Recommended Levels of Folic Acid
Folic acid is safe when taken as recommended. “Folic acid taken at or up to the recommended amount of 400-800 micrograms per day (mcg/day) has not been shown to be harmful,” the CDC spokesperson told us.
The tolerable upper intake level for folate from fortified food or supplements in adults, including pregnant people, is 1,000 mcg daily, according to the Institute of Medicine, which provides these numbers to indicate the level under which a nutrient is unlikely to pose any health risks to “almost all individuals in the general population.”
One-third of U.S. pregnant women are estimated to consume amounts of folic acid from fortified foods and supplements that put them over the tolerable upper intake level, according to a 2019 study published in JAMA Network Open.
The limit was established because of concern that folate at high levels — over 5,000 mcg daily — could cause a B12 vitamin deficiency to go undiagnosed, leading to potential neurologic complications. The theory was that consuming high levels of folic acid could improve a type of anemia resulting from low B12 without correcting other problems associated with the deficiency. People of reproductive age have a low rate of B12 deficiency, especially compared with older adults.
However, the CDC spokesperson noted that people who have low B12 are unlikely to get as much benefit from 5-MTHF as from folic acid because “5-MTHF needs vitamin B-12 to work in the body, while folic acid can work without this vitamin.”
Some supplement companies argue that 5-MTHF is safer because when folic acid is not fully metabolized, it can circulate in the blood. But harms from circulating folic acid have not been established, Stover said. “That’s not an adverse effect. It just shows you’ve saturated the system,” he said. “It’s circulating. It’s not known to have any activity or function when it’s circulating.” Excess folic acid is eventually excreted in urine.
A separate possibility is that elevated folate status in general could have some negative impact, Stover said, meaning there could be some consequence to having large amounts of folate in the body no matter the type. Someone could have elevated folate status regardless of what form they consumed, he added.
But, observations that indicate elevated folate levels in the body or excess folic acid intake can have negative health impacts — mainly from animal and nonrandomized studies — are inconclusive, Stover and his colleagues wrote in a summary paper.
Still, “you should never take more than is recommended is the bottom line,” Stover said. “More isn’t always better, but you don’t want to be deficient.”