Food is medicine: The science behind folic acid

Key takeaways:

• Folic acid supplementation is essential for reducing the risk for neural tube defects.
• The supplement could also offer other benefits, like for preeclampsia, but the evidence is far less certain.

Folic acid is critical for prenatal care, according to experts, and research has suggested its supplementation could also offer benefits in some other areas of health.

Folic acid is a form of folate — a B vitamin — that can be found in fortified foods as well as in dietary supplements, Jaime Gahche, PhD, MPH, director of the Population Studies Program at NIH’s Office of Dietary Supplements (ODS), told Healio.

“Folate is the generic term for naturally occurring food folates and folates in dietary supplements and fortified foods, including folic acid,” Gahche said. “Folate functions as a coenzyme or cosubstrate in single-carbon transfers in the synthesis of nucleic acids and metabolism of amino acids. It is also required for proper cell division and is critical for proper fetal development.”

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Edwina Wambogo, PhD, MPH, RD, a nutritional epidemiologist at ODS, told Healio that some of the best food sources of folate include dark green leafy vegetables, nuts, peas, beans, fruits and fruit juices.

“Folic acid, the form commonly found in dietary supplements, is also added to enriched breads, cereals, flours, corn meals, pastas, rice and other grain products in the United States,” Wambogo said.

When taken periconceptionally, Gahche said folic acid supplementation can reduce the risk for neural tube defects (NTDs) like spina bifida and anencephaly.

“For this reason, numerous professional societies and government agencies recommend folic acid supplementation before and during early pregnancy,” Gahche said.

The recommended dietary allowance (RDA) for folate varies by age group, according to Wambogo. For those aged 14 years and older, the RDA is 400 µg Dietary Folate Equivalents (DFE). However, the RDA increases to 600 µg DFE during pregnancy and lowers to 500 µg DFE during lactation. For those who have had a previous pregnancy impacted by an NTD, 4,000 µg per day of folic acid is recommended, beginning 1 month before pregnancy and during the first trimester of pregnancy.

“Folate DFEs take into account the bioavailability differences among foods and dietary supplements,” Wambogo said.

Summary of evidence

Evidence has continued to show the benefits of folic acid supplements in preventing NTDs.

For example, in a 2023 systematic review of 12 observational studies including 1,244,072 participants, researchers found a statistically significant reduction in the risk for NTDs associated with folic acid supplementation before pregnancy (adjusted RR = 0.54; 95% CI, 0.31-0.91) and during pregnancy (aRR = 0.62; 95% CI, 0.39-0.97). None of the studies reported statistically significant harms linked to supplementation.

Researchers have also evaluated the potential impacts folic acid supplementation may have on other conditions, although the evidence is much more limited.

In a 2022 meta-analysis of 11 observational studies and four randomized controlled trials including 26,275 participants, researchers found that continually using folic acid supplementation while pregnant might reduce the incidence of perinatal depressive symptoms. The overall OR for perinatal depression among those taking folic acid supplements was 0.74 (95% CI, 0.647-0.852), and the combined effect value was 0.84 (95% CI, 0.76-0.93).

Additionally, a 2018 meta-analysis of 13 cohort studies and one randomized controlled trial evaluating 309,882 participants revealed that taking folic acid supplements while pregnant had no effects on gestational hypertension risk but significantly lowered preeclampsia risk (RR=0.69; 95% CI, 0.58–0.83).

One 2019 systematic review and meta-analysis of 17 case-control studies including 28,292 participants even evaluated folic acid’s associations with childhood cancers. The researchers found a possible protective association between maternal folic acid supplementation and childhood acute lymphoblastic leukemia (OR = 0.75; 95% CI, 0.66-0.86) but noted limitations, including the fact that all studies evaluated were case-cohort designs.

More information

Like most supplements, excessive folic acid intake “could potentially cause adverse health effects,” Gahche said.

For those aged 19 years and older, Gahche said the tolerable upper intake level (UL) is 1,000 µg per day when taking a dietary supplement containing folate or folic acid.

“High doses of supplemental folate might precipitate or exacerbate the anemia and cognitive symptoms associated with vitamin B12 deficiency,” Gahche said. “Some studies have suggested that high doses may also increase the risk of colorectal cancer and possibly other cancers. In addition, there are concerns that high folic acid intake can lead to a buildup of unmetabolized folic acid in the body which may have negative health consequences.”

Wambogo added that some dietary supplements do not contain folic acid, but instead methylfolate (5-MTHF), one of folate’s active forms. This is notable, she said, because patients who have a specific genetic polymorphism — 677C>T, in the methylenetetrahydrofolate reductase (MTHFR) gene — “have a reduced ability to convert” folate to 5-MTHF.

“Only folic acid, not methylfolate, has been proven to reduce the risk of NTDs,” Wambogo said. “Therefore, CDC recommends folic acid, not methylfolate, for anyone who could become pregnant, even if they have a 677C>T MTHFR polymorphism.”

The ODS offers resources for health care providers and consumers. To learn more about folic acid and other products, check out the ODS Fact Sheets.

Editor’s Note: Healio is highlighting the clinical value of various supplements. See other installments of the series here:

• Melatonin
• Omega-3
• Zinc and other supplements for immune function
• Vitamin D
• Calcium
• Ashwagandha
• Magnesium
• Vitamin B12
• Iodine

References:

• Crider KS, et al. Annu Rev Nutr. 2022;doi:10.1146/annurev-nutr-043020-091647.
• Ismail WRW, et al. J Prev Med Public Health. 2019;doi: 10.3961/jpmph.19.020.
• Jin X, et al. J Affect Disord. 2022; doi:10.1016/j.jad.2022.01.080.
• Liu C, et al. Arch Gynecol Obstet. 2018;doi: 10.1007/s00404-018-4823-4.
• Folic acid supplementation to prevent neural tube defects: a limited systematic review update for the U.S. Preventive Services Task Force. https://www.ncbi.nlm.nih.gov/books/NBK593614/. Published Aug. 2023. Accessed April 3, 2024.