Medical Examiner

Is B9 Benign?

Some pregnant women may be taking too much folic acid.

newborn baby.
An assistant measures a baby’s head at a checkup on Feb. 23, 2010, in Aurora, Colorado. A small head can be a sign of abnormality, sometimes caused by vitamin deficiency.

John Moore/Getty Images

The world is scrambling to understand whether and how the Zika virus might have caused the birth of numerous infants with abnormally small heads in Latin America. Meanwhile, in the U.S., the Hispanic population already suffers the highest rates of a different group of birth abnormalities that include anencephaly, a fatal condition in which large parts of the brain or skull are missing. Here we know part of the cause: not a virus but a vitamin. The story goes back almost two decades, to when the U.S. began fortifying grain flours with folic acid, which is converted by the body to active vitamin B9, in 1998. Almost immediately, the country witnessed a 23 percent drop in babies born with neural tube defects. According to estimates released in December, the program saves about $400 million to $603 million a year when health care savings are taken into account. But the regulation did not apply to corn masa flour, the key ingredient in corn tortillas. In the large communities where tortillas are a staple food, these benefits were tempered.

Last week the March of Dimes and other advocacy groups sent a letter to the Food and Drug Administration urging the agency to allow fortification of corn masa with folic acid. It’s a wise measure, and the FDA says it plans to review the petition for the change “as expeditiously as possible.” Meanwhile, countries that don’t yet have folic acid fortification are considering the measure. Public health officials in Scotland have grown so frustrated by the lack of action on the issue in the U.K. that they may go it alone. But all of this important action on folic acid raises another, unexpected question: Could some people be getting too much of this life-saving vitamin?

Folate, the compound produced in the body from folic acid and found in leafy greens and other foods, helps with cell division in a rapidly growing embryo in the early weeks after conception. It’s this timing that makes things so tricky: By the time many women discover they are pregnant, they’ve already missed the window during which folic acid supplements would make a difference. That’s why adding the vitamin to the food supply makes sense. So far it has saved an estimated 1,300 babies annually from neural tube defects in this country, and it could have an even greater benefit if it’s added to corn masa flour.

But scientists have dubbed folic acid a “double-edged sword” because data suggest it might not always be doing good in the body. As with most anything, the dose makes the poison. A review published last week described intriguing reports of neurological harm  from excessive folic acid in the scientific literature and said there is an “urgent need” to figure out the upper limit that can be tolerated. The unease extends beyond the nervous system: A study published last month found an association between daily folic acid supplementation and gestational diabetes. And there remains vigorous discussion among nutritionists and epidemiologists about whether too much folic acid can encourage the growth of cancers already in the body. A 2013 meta-analysis suggested that this latter issue is probably not a concern—but the jury is still out, and some epidemiologists still worry over the possible link.

There are also hints that folic acid may mess with the immune system. A rodent study published last month found that the vitamin reduces the function of so-called natural killer cells of the immune system. Meanwhile, Rima Rozen, a geneticist at McGill University, recently reported that high dietary folate also made mice more vulnerable to malaria. She says that there is good reason for scientists to study whether high intake of this vitamin among pregnant women may make them more vulnerable to pathogens such as the Zika virus.

Mouse studies of folic acid don’t provide a perfect stand-in for human studies, though, because they metabolize it differently than we do. And while there was a human study from 2006 showing an association between high folic acid and diminished function of natural killer cells, it has not been replicated, according to R.J. Berry, an epidemiologist at the Centers for Disease Control and Prevention. Still, a retrospective study from November found women who took folic acid during pregnancy had a slightly higher chance of giving birth to a child with asthma, underscoring that there may be a lot about folic acid’s effect on immunity that we don’t yet understand.

For the time being, says Rozen, all this research is speculative, and pregnant women should continue taking folic acid without concern. An ounce of prevention is worth a pound of cure, as the saying goes. But in the case of folic acid, just about 400 micrograms taken during pregnancy will do the trick and help protect babies against neural tube defects. Yet evidence is mounting that some women are taking too much. In November, the epidemiologist Jesus Vioque and his colleagues published a study looking at data from more than 2,300 pregnant Spanish women. One-quarter of them had taken folic acid in doses greater than 1 milligram (1,000 micrograms), without medical rationale. That’s troubling, Vioque says, because his group has also found that mothers on high doses delivered a higher proportion of children with small weight and height than other women. They have also found that children whose mothers took high dosages had slightly lower scores on psychomotor development.

Young-In Kim of St. Michael’s Hospital in Toronto reported finding unexpectedly high levels of unmetabolized folic acid in a study last year of blood samples from more than 360 pregnant women. Kim says he was shocked at the results and blames the combination of food fortification—which contributes about 100 to 150 micrograms of folic acid to the average diet—mixed with high-dose supplements. And thanks to the Internet, a folic megadose is only a click away: Companies in the U.S. sell supplements containing as much as 20,000 micrograms online, advertising that this “provides an essential nutrient for all stages of life.”

Large doses of folic acid aren’t always a bad idea. The vitamin is water-soluble, and excreted in urine, so the thinking is that the body can pass any excess amounts. For certain people who are taking drugs, such as the diabetes medication metformin, that diminish folate in the blood, ample supplementation might make sense. Doses of folic acid as high as 5 milligrams (5,000 micrograms) are recommended for women who have had prior pregnancies with neural tube defects.

But even Berry notes that for pregnant women with no such history, a more moderate dose of about 400 micrograms will suffice to prevent neural tube defects. In light of this, and the unresolved questions about whether too much folic acid can cause harm, it seems like enough really is enough.