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Folic acid supplementation throughout pregnancy was correlated with a lower risk of early-onset Kawasaki disease in offspring, a Japanese observational study showed.

In a propensity score-matched model, children of women with above-average serum folic acid levels during the second and third trimesters had a significantly lower incidence of Kawasaki disease by 12 months of age compared with the children of those with below the 10 ng/mL median (0.27% vs 0.41%; OR 0.68, 95% CI 0.50-0.92), reported Shuichi Ito, MD, PhD, of Yokohama City University in Japan, and colleagues in .

The CDC and other federal agencies recommend that all women of childbearing age take a folic acid supplement to in unplanned pregnancies, but daily supplementation is also recommended through pregnancy to maintain stores of this B vitamin that has been of anemia, congenital heart disease, oral cleft, and possibly preterm birth.

In this study, folic acid supplementation was associated with a lower prevalence of Kawasaki disease, with a nonsignificant trend for first trimester use (0.34% vs 0.42%; OR 0.83, 95% CI 0.66-1.04) and a significant link during the second and third trimesters (0.30% vs 0.43%; OR 0.73, 95% CI 0.57-0.94).

"On the basis of these findings, we speculate that taking additional folic acid supplements with an appropriate diet during pregnancy may reduce the risk of [Kawasaki disease] in offspring," the researchers concluded.

Kawasaki disease, with its characteristic fever, rash, red eyes and tongue, and swollen soles and palms, is suspected to be an , although the exact cause remains uncertain.

In terms of mechanism, Ito's group noted the role of folic acid in DNA methylation, which could translate to an immunologic impact.

"For example, folic acid inhibits inflammation by suppressing cytokines and chemokines from inflammatory cells or by maintaining lymphocyte function," they wrote. Evidence suggests that "maternal serum folic acid levels may lead to epigenetic changes in immune cells, which, in turn, lead to differences in the risk of [Kawasaki disease] among offspring."

Proof would require a prospective randomized clinical trial to establish a causal relationship between maternal folic acid supplementation during pregnancy and children's subsequent risk of Kawasaki disease, Ito and colleagues noted.

The study used data from the Japan Environment and Children's Study, a nationwide birth cohort, with 87,702 children with 12-month follow-up since 2011.

Maternal serum folic acid levels of 10 ng/mL or greater (the 50th percentile in the cohort) were classified as exposed. Normal serum folate levels range from 2.7 to 17.0 ng/mL. Maternal folic acid supplementation once a week or more was classified as exposed for that measure. Not surprisingly, the 31.7% of women who took folic acid supplements averaged higher folate levels than those who didn't take the supplements.

In the study population, 336 children developed Kawasaki disease. Maternal dietary folic acid intake in both the Kawasaki disease and control groups averaged 260 μg per day, although the World Health Organization recommends dietary folic acid intake of at least 480 μg per day.

The researchers noted the need for further observational studies with a longer follow-up period beyond the 12 months in this study.

"In addition, we were unable to evaluate the effect of folic acid alone because the supplements taken by participating mothers may have been complex supplements, such as multivitamins, rather than supplements containing folic acid alone," they added. "There is also unmeasured confounding that was not adjusted in the propensity score analysis."

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