When Martha Field became pregnant in 2005, a singular fear weighed on her mind. Not long before, as a Cornell University graduate student researching how genes and nutrients interact to cause disease, she had seen images of unborn mouse pups smaller than her pinkie nail, some with brains bulging outside their skulls or with deformed and unfused faces. The mothers, which had genetic defects that made them more susceptible to having pups with these birth defects, had also not been given enough of the vitamin folate, nor been supplemented with folic acid, a stable form of folate.
Field was well aware of the connection between dietary folate deficits and neural tube defects, in which the part of the embryo that becomes the brain and spinal cord doesn't close properly. In the weeks before she conceived, she had taken supplements of folic acid, which is known to reduce the risk of having babies with these anomalies, most commonly spina bifida, which occurs when the spine doesn't form as it should. Even so, the harrowing images of the mice forced her to wonder: Was it enough?
As it happens, folic acid supplements are among the best studied and most widely endorsed nutritional recommendation for childbearing-aged women today. The Centers for Disease Control and Prevention recommends that all women who are of reproductive age take 400 micrograms of folic acid every day, and certain foods are fortified with folic acid.
Folate supplements are essential, experts say, because it's nearly impossible to get the amount known to prevent the birth defects by eating folate-rich foods alone. "Folic acid is actually the only type of folate that has been shown in studies to help the closure of the neural tube," says Stuart Shapira, the associate director for science and chief medical officer for the CDC's National Center on Birth Defects and Developmental Disabilities. As a result, at least 80 countries require that some foods be fortified with folic acid as a public health measure.
Despite the scientific consensus, some nutritionists and dieticians — along with prominent complementary health practitioners including naturopaths, chiropractors, and functional medicine doctors — are causing many people, and not just those who are or may become pregnant, to question whether they should be consuming any folic acid at all. Many medical experts worry that these vocal individuals are urging people who could become pregnant to avoid vital folic acid supplementation, putting unborn babies at unnecessary risk for neural tube defects.
Over half of Americans have variations in a gene known as methylenetetrahydrofolate reductase (MTHFR), which is involved in using folate to help make crucial cellular building blocks. In 2017, the direct-to-consumer genetic testing service 23andMe wrote in a blog post that MTHFR was the most asked-about gene among its customers. People have even created cookbooks targeted toward those who have MTHFR variants, as well as shirts that play on the acronym's resemblance to a vulgar term. The gene has also been the subject of more than 3,000 research articles, some of which study whether the common variations may be linked to over 600 disorders, including autism, anxiety, infertility, as well as neural tube defects.
But the links between MTHFR and the majority of the disorders are weak, according to Barry Shane, a nutrition researcher and professor emeritus at the University of California, Berkeley, who has been studying folate metabolism for over 45 years. MTHFR variations can make someone more likely to have low folate, which does carry risks, especially for having a baby with a neural tube defect. However, folic acid is a safe and proven way to raise folate levels, even in people with MTHFR variants, says Shapira.
Nonetheless, a search for MTHFR on YouTube, podcasts, search engines, and other social media channels turns up a host of articles, videos, and interviews warning, without solid evidence, that folic acid is poison for those with MTHFR variations (which they often call "mutations") or that the conditions associated with MTHFR variations are actually triggered or made worse by folic acid. They often recommend changing one's diet to include more folate-rich foods, avoiding foods fortified with folic acid, and replacing folic acid supplements with different, costlier ones in order to alleviate MTHFR-ascribed symptoms.
These warnings about folic acid appear widely on sites that feature heavy doses of science skepticism or dubious claims, among them that MTHFR variations justify medical exemptions from vaccines. Typically, those sites also sell supplements, genetic testing, and analysis, or related services including nutritional coaching sessions, books, and online courses centered on MTHFR.
Experts are frustrated by the proliferation of such offerings, which they see as misinformation that is spreading far faster than they can counter it. But Field, who is now a Cornell professor and has been studying folate nutrition and genes for over 15 years, understands why it may have taken hold. "Nutrition is not a great place in terms of trust in science," she says. "The science is complicated," she adds, and scientists "don't do a very good job of explaining it. And then when you're left with gaps to fill in, you fill them in any way you can."
Folic acid as been around since at least the 1940s as a version of the folate found naturally in foods like vegetables, legumes, fruits, eggs, and meat. Cooking can decrease or degrade natural folate, but folic acid's structure makes it highly stable: It can even be boiled without changing shape.
In the 1970s, researchers found that blood folate levels were lower in people who had babies with neural tube defects. By the early 1990s, researchers had shown folic acid's effectiveness in preventing neural tube defects. In 1992, the U.S. began recommending that those planning a pregnancy start taking folic acid before conceiving.
However, roughly half of all pregnancies in the U.S. are unplanned, and the neural tube closes in the first 28 days of pregnancy, before many people even find out they are pregnant. Ideally, someone would keep their folate levels up with a naturally high-folate diet and by taking supplements three months before they get pregnant, says Anne Parle-McDermott, a professor at Dublin City University in Ireland who studies folate genetics. But with many pregnancies unplanned, this advice alone is not enough, she says.
Before 1998, about 30 percent of Americans of childbearing age were considered to be folate deficient. That year, the FDA began requiring folic acid fortification of foods labeled as enriched, including wheat flour, corn meal, and rice. This gives the average adult about 140 micrograms of folic acid from fortified foods daily. A 2015 CDC report estimated that fortification alone prevents about 1,300 neural tube defects from occurring in the U.S. each year.
Fortification isn't perfect. If someone is eating a lot of processed foods, and also taking a multivitamin, they could exceed the recommended upper level of 1,000 micrograms per day, which was set so there wouldn't be a risk of folic acid masking the symptoms of a severe vitamin B12 deficiency called pernicious anemia. An estimated 33 percent of pregnant people exceed this threshold, possibly because many prenatal vitamins contain 800 to 1,000 micrograms of folic acid.
When fortification was introduced, concerns were raised about possible side effects in the general population: Could doses above the recommended levels of folic acid promote autism or cancer? These worries proved to be unfounded, according to Field, who co-authored a research review on the safety of folic acid, summarizing evidence from studies that investigated these issues. Interestingly, she says some studies show that the risk of autism, and some cancers, may even be reduced by taking the recommended amount of folic acid.
Folic acid is one of a few forms of folate that can come from diet. The body uses folate to transport carbon for numerous crucial processes in cells. The gene MTHFR codes for an enzyme that helps to get the carbon into forms necessary for these processes. (In the process MTHFR generates L-methylfolate, another kind of folate, which other enzymes further modify to make things that cells need.)
These processes can be less efficient in people with the common MTHFR variations. This can lead to lower blood folate levels, but folic acid can boost folate levels even in people with variations. "I think people get this idea that this enzyme doesn't work in them — it works, it just doesn't work as well," Field explains.
Some nutritionists and complementary health practitioners recommend avoiding folic acid. Christa Biegler, a registered dietician and podcaster, tells people with MTHFR variations to supplement with a synthetic version of L-methylfolate because it bypasses the MTHFR enzyme in the process of converting folate, so people with less functional MTHFR enzymes can put the supplement straight to use.
But Shane counters that this isn't how folates are processed; rather than an assembly line, it is a cycle, so even if MTHFR is skipped once, it will be involved as the folates get cycled through the pathway again and again. Because this cycling occurs hundreds or thousands of times a day, Shane explained that the advantage of giving L-methylfolate, compared to folic acid, is "absolutely minimal."
Also, L-methylfolate is more difficult, and therefore more costly, to make into a supplement and is less stable than folic acid. And because it is less stable, it can be hard to know exactly how much someone is getting if it's been sitting on the shelf, since over-the-counter supplements are largely unregulated by the FDA and are exempt from requirements demonstrating that their ingredients are made carefully — or that they even work.
Well-made L-methylfolate may be adequate for preventing neural tube defects, Shane says, though he doesn't recommend it. But folic acid is unlikely to be unseated as the recommended form of folate, because experts point out that it would be unethical to test a different form of folate through a randomized trial — considered the gold standard for medical research — which would require that some participants not get any folic acid and could put babies at risk. And scientists caution that neural tube closure is still something of a mystery.
Despite the broad medical agreement about folic acid's benefits, some people who find out about MTHFR on the internet decide to avoid folic acid supplements and foods fortified with folic acid. Tammy Rose-Townsend, a health coach, blogger, and mother of five, discovered MTHFR when she sought a diagnosis for her second-born, who had experienced anxiety and dramatic mood swings beginning in kindergarten.
The doctors and experts she consulted said that her son didn't meet the criteria for ADHD, dyslexia, bipolar disorder, or autism. But without a diagnosis, Rose-Townsend says she couldn't help her son's symptoms, and it was painful to see him struggling. She discovered blog posts by Ben Lynch, a Seattle-based naturopath, explaining the many symptoms attributed to MTHFR, "and everything just clicked," she wrote in an email. "The symptoms he described were evident in both of my older boys and some applied to me and others to my husband. It all just made sense."
Data from DNA tests revealed that everyone in the family had MTHFR variations. Rose-Townsend believes that these MTHFR variations, along with other genetic variations and nutritional factors, are the root cause of her son's behavior as well as symptoms in her other children. Now the whole family avoids folic acid fortified foods and some take supplements, including L-methylfolate. Rose-Townsend says their dietary changes have helped their MTHFR-ascribed symptoms, including her son's mood swings and anxiety.
Scott Hickey, a clinical geneticist at Nationwide Children's Hospital in Columbus, Ohio, believes that people like Rose-Townsend are seizing on the MTHFR gene variants because it may seem like they can be used to explain a wide range of symptoms. He says there are countless studies claiming a link between MTHFR variations and "just about every clinical outcome you could possibly imagine."
Around the turn of the millennium, when it got easier to read DNA, scientists were enthusiastic that research would reveal genetic risk factors in complex diseases, and were hopeful that this could advance medical care, Hickey explained. In many studies beginning around then, MTHFR variations popped up because they are so common in the population. But Shane and Hickey say that most of the correlations between MTHFR and the hundreds of diseases and conditions it became associated with were weak. So while scientists became less enthusiastic that these genetic studies were providing meaningful information, "in the general public, especially on the internet, it just took off in the other direction," Hickey says.
Hickey says we now know that there are few health risks that come from having common MTHFR variations, and there is no reason for these common variations to lead to any changes in medical care. Having MTHFR variations can contribute to low folate, which can have negative health effects, but these issues are uncommon due to food fortification, according to Shane.
The strongest, most well-established association between common MTHFR variants and a medical condition is that certain variations slightly increase the risk of neural tube defects in newborn babies. However, Shapira of the CDC says this association is due to low folate. Those who could become pregnant need higher levels of folate. "Consuming 400 micrograms of folic acid each day increases the amount of folate in a woman's blood to a level that's high enough to help prevent the formation of these neural tube defects," says Shapira. He added that folic acid is protective regardless of a person's MTHFR gene variants.
Hickey says people contact him "pretty regularly" to have MTHFR genes analyzed for the common variants. But he only orders gene testing for patients in cases where he suspects extremely uncommon MTHFR variants. The symptoms of these very rare variants are severe — intellectual disability, low muscle tone, concerning blood test results, and seizures. In his 11 years of clinical practice, Hickey says he has come across only one confirmed case that he knows of: two siblings who were diagnosed at the clinic where he did his residency. He estimates that these siblings represent 2 of about 100 to 200 people in the entire country that have the rare MTHFR variants causing these severe symptoms.
Many doctors and researchers are exasperated by the misinformation about folic acid and MTHFR on the internet. Field has seen such conversations on Facebook, but said "I just get so frustrated that I don't continue." An undergraduate student working with Parle-McDermott made a YouTube video about MTHFR and tongue tie (a condition that restricts tongue movement) — a connection which is not supported by scientific evidence but is popular on blogs — but it only had about 100 views as of Dec. 2020.
The CDC has a landing page on their website about MTHFR and folic acid, but has posted little, if anything, about the gene on social media channels. And Hickey co-authored practice guidelines for the American College of Medical Genetics and Genomics to recommend against MTHFR variant testing, but that doesn't prevent someone from using direct-to-consumer DNA testing services to discover their "MTHFR status" on their own.
In the early 1990s, long before the rise of commercial gene testing, Shane became one of the first people to find out his own MTHFR status after analyzing some of his own DNA in his lab. He learned he has a variation that slightly diminishes his body's ability to convert folates. But despite his long and intimate relationship with MTHFR, Shane has never been concerned about its effect on his life, because, he says, the data don't support it. He began taking a multivitamin several years ago when his diet suffered as meals he ate in his wife's absence were less nutritionally balanced. Those capsules, which he now takes once daily, contain 400 micrograms of folic acid. "Do I need it? Probably not," he said. "But it can't do any harm."
As for Field, she says she has no desire to know her MTHFR status or that of her children, now ages 11 and 14, because it wouldn't change what they eat, or anything else they do. But MTHFR seems to pursue her. Her mother underwent genetic testing sometime in the last few years, which revealed that she has duplicate MTHFR variants, meaning that Field inherited one of them.
Would she have done anything different when she was planning a pregnancy had she known? "I still would have taken the recommended amount of folic acid well before I became pregnant," she said.
Christina Szalinski is a freelance science writer with a Ph.D. in cell biology based near Philadelphia.
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