Maternal Serum Folic Acid Levels and Onset of Kawasaki Disease in Offspring During Infancy
Authors: Fukuda Sayaka , Tanaka Shiro , Kawakami Chihiro , Kobayashi Tohru , Ito Shuichi ,   Japan Environment and Children’s Study Group, Kamijima Michihiro , Yamazaki Shin , Ohya Yukihiro , Kishi Reiko , Yaegashi Nobuo , Hashimoto Koichi , Mori Chisato , Ito Shuichi , Yamagata Zentaro , Inadera Hidekuni , Nakayama Takeo , Sobue Tomotaka , Shima Masayuki , Kageyama Seiji , Suganuma Narufumi , Ohga Shoichi , Katoh Takahiko 
Published: December 2023

ImportanceKawasaki disease is an acute systemic vasculitis that primarily affects infants and young children. No reproducible risk factors have yet been identified, but a possible association between maternal folic acid supplementation and Kawasaki disease has been reported previously.ObjectiveTo investigate the associations of exposure to maternal serum folic acid levels and maternal folic acid supplementation with onset of Kawasaki disease during infancy among offspring.Design, Setting, and ParticipantsThis cohort study used data from the Japan Environment and Children’s Study, a nationwide birth cohort, which has enrolled children since 2011. This study used the data set released in October 2019, and analysis was performed in January 2023.ExposuresMaternal serum folic acid levels (≥10 ng/mL classified as exposed) during the second and third trimesters and the frequency of maternal folic acid supplementation during the first trimester and during the second and third trimesters of pregnancy (once a week or more was classified as exposed).Main Outcomes and MeasuresThe primary outcome was onset of Kawasaki disease in offspring up to age 12 months. Odds ratios (ORs) for each exposure were estimated, and propensity score–adjusted logistic regression was conducted on the basis of the sets of variables.ResultsThe study population comprised 87 702 children who were followed-up for 12 months. Of these, 336 children developed Kawasaki disease. Mothers who took folic acid supplements (31 275 mothers [35.7%]; mean [SD] age, 32 [5] years) had higher serum folic acid levels than those who did not take supplements. Higher maternal serum folic acid levels were associated with a significantly lower risk of Kawasaki disease in offspring than lower levels (folic acid ≥10 vs &amp;lt;10 ng/mL, 56 of 20 698 children [0.27%] vs 267 of 64 468 children [0.41%]; OR, 0.68; 95% CI, 0.50-0.92). Children whose mothers took folic acid supplementation during the first trimester had a lower prevalence of Kawasaki disease than children whose mothers did not take folic acid (131 of 39 098 children [0.34%] vs 203 of 48 053 children [0.42%]), although the difference was not statistically significant (OR, 0.83; 95% CI, 0.66-1.04). Supplementation during the second and third trimesters was associated with a significantly lower risk of Kawasaki disease compared with no supplementation (94 of 31 275 children [0.30%] vs 242 of 56 427 children [0.43%]; OR, 0.73; 95% CI, 0.57-0.94).Conclusions and RelevanceIn this cohort study, higher serum folic acid levels (≥10 ng/mL) and maternal folic acid supplementation more than once a week during the second and third trimesters were associated with reduced risk of Kawasaki disease in offspring during infancy.