Trending Clinical Topic: Folic Acid

Ryan Syrek


October 14, 2022

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News about the potential of folic acid supplementation to prevent or mitigate certain conditions, and a troubling finding about use in pregnant women, resulted in this week's top trending clinical topic. Perhaps most notably, a study that adjusted for multiple factors found that prescription folic acid, a synthetic form of vitamin B9, may aid in decreasing suicidal ideation (see Infographic below).

The study used a health claims database that included 164 million participants. The cohort comprised 866,586 adults (81.3% women; 10.4% aged 60 years or older) who filled a folic acid prescription between 2012 and 2017. Most folic acid prescriptions were associated with pain disorders. Nearly half (48%) were for a single agent at a dosage of 1 mg/d, the upper tolerable limit for adults. Participants were followed for 24 months. During the study, the overall suicidal event rate was 133 per 100,000 population. After adjusting for age, sex, diagnoses related to suicidal behavior and folic acid deficiency, history of folate-reducing medications, and history of suicidal events, the estimated hazard ratio (HR) for suicide events when taking folic acid was 0.56 (95% CI, 0.48-0.65), which represented a 44% reduction. The authors noted that this may be an underestimate, given that the study only captured prescription folic acid, and some may also have taken over-the-counter products. Experts caution that more analysis is needed prior to widespread use of folic acid in patients with depressive symptoms.

Folic acid may also have a role in preventing or delaying the progression of fatty liver disease. Researchers found that elevated blood levels of homocysteine correlate strongly with nonalcoholic steatohepatitis (NASH) severity. Thus, they suggest that vitamin B12 and folic acid supplementation may be beneficial. The investigators found that when homocysteine attaches to the syntaxin 17 (Stx17) protein, it blocks the protein from transporting and digesting fat, a process known as autophagy. This, in turn, induces the development and progression of fatty liver disease to NASH. In preclinical models, vitamin B12 and folic acid supplementation increased hepatic Stx17 levels, restored its role in autophagy, slowed NASH progression, and reversed liver inflammation and fibrosis.

Supplementation with folic acid may also improve histopathologic aspects of gastric precancerous conditions (GPCs), including intestinal metaplasia and gastric mucosal atrophy. The authors of a recent meta-analysis noted that evidence suggests the potential clinical use of folic acid in the management of GPCs. The analysis included 13 randomized controlled trials involving 1252 adults with GPCs living in China. A meta-analysis of five studies showed a statistically significant positive treatment effect of folic acid supplementation on gastric mucosal atrophy (relative risk [RR], 1.61; 95% CI, 1.07-2.41). A meta-analysis of two trials showed a statistically significant effect of folic acid on reversal of intestinal metaplasia (RR, 1.77; 95% CI, 1.32-2.37). However, supplementation did not appear to relieve GPC symptoms.

Not all of the current news on folic acid was as positive. A recent study involving data from a Scandinavian registry of more than 3 million pregnancies found that prenatal exposure to high-dose folic acid is associated with a more than twofold increased risk for cancer in children of mothers with epilepsy. Among the 27,784 children born to mothers with epilepsy, 5934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with 18 exposed cancer cases compared with 29 unexposed cancer cases, yielding an adjusted HR of 2.7 (95% CI, 1.2-6.3). The absolute risk with exposure was 1.5% (95% CI, 0.5%-3.5%) in children of mothers with epilepsy who were exposed to high-dose folic acid compared with 0.6% (95% CI, 0.3%-1.1%) in children of mothers with epilepsy who were not. Prenatal exposure to high-dose folic acid was not associated with an increased risk for cancer in children of mothers without epilepsy.

From the potential to mitigate suicidality, prevent or delay fatty liver disease progression, and improve GPCs to concerning news about its use in mothers with epilepsy, news about folic acid drew considerable interest this week and became our top trending clinical topic.

Learn more about folic acid.


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