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Maternal folic acid supplementation in the second and third trimesters shows a significant negative association with Kawasaki disease (KD) risk in infants under 12 months, according to a study analyzing data from 87,702 children in Japan’s JECS cohort, suggesting a potential protective role of folic acid in the development of KD.

1. In this large Japanese birth cohort, supplementing with folic acid at least once weekly and higher serum folic acid levels (≥10 ng/mL) in the second and third trimesters of pregnancy were associated with significantly decreased risk for developing Kawasaki disease (KD) in the first 12 months of life. 

Evidence Rating Level: 2 (Good)        

Study Rundown: Kawasaki disease (KD) is an acute systemic vasculitis that most often affects children under the age of 5. There has been a rise in KD incidence among infants below the age of 1 in Japan despite a declining birth rate. The mechanism of KD remains unknown, but some literature suggests associations between prenatal exposures. The current study sought to build on results from a prospective multicentre Japanese birth cohort (The Japanese Environment and Children’s Study [JECS]) that uncovered an association between folic acid supplementation and development of KD. Researchers investigated data from 87,702 children, with the primary outcome variable being the development of KD in the first 12 months of life. Maternal folic acid levels in the second and third trimesters of pregnancy were measured and frequency of folic acid supplementation in all trimesters was obtained via self-questionnaires. Data on several parental characteristics (including but not limited to maternal medical and social history, pregnancy BMI, other supplementation in pregnancy, mode of delivery, paternal medical history, and socioeconomic status [SES]) were also collected. Overall, this study found that higher maternal folic acid levels in the second and third trimesters demonstrated a significant negative association with KD risk for infants in the first 12 months of life. Dietary folic acid intake was controlled for and similar among mothers of both KD and non-KD infants, suggesting that folic acid supplementation specifically may reduce the risk of KD. From an epidemiological standpoint, as the incidence rate of KD has been rising, maternal folic acid supplementation has conversely been declining. It is proposed that this may partly explain the higher rates of KD in the Japanese pediatric population. 

Click to read the study in JAMA Network Open

Relevant Reading: Exposures Associated With the onset of Kawasaki Disease in Infancy from the Japan Environment and Children’s Study

In-Depth [prospective cohort]: In developed countries, KD is the leading cause of acquired heart disease in pediatric patients. A global decrease in KD incidence occurred during the COVID-19 pandemic (likely due to public health measures and a reduction in respiratory syncytial virus and influenza cases), suggesting a possible role of specific infectious agents. However, this phenomenon does not fully explain the etiology of KD. In Japan, one-fifth of KD cases occur in infants less than 12 months of age. This suggests a possible role for in-utero exposure, and the literature has suggested autoimmune status, smoking, and maternal age as potential contributors. However, these results have not been reproducible. Data from a large birth cohort study conducted in Japan has identified a possible correlation between folic acid supplementation and risk of KD. The current study is the first to investigate and demonstrate a direct association between maternal folic acid supplementation in pregnancy with the condition. The study included 87,702 infants born to mothers (35.7%; mean [SD] age, 31 [5] years) who provided theirs and their infant’s medical records for at least 1 year post-delivery and responded to self-questionnaires at 6 months and 1 year. Pregnancies resulting in miscarriages, stillbirths, and those lost to follow-up were excluded from data analyses. Serum folic acid levels in the first, second, and third trimester were measured in nanograms per milliliter (ng/mL; for conversion to nanomoles per liter, multiply by 2.266) and self-questionnaires on folic acid supplementation in all three trimesters were collected. Several other variables of interest (including several maternal and paternal characteristics/social history, prenatal and perinatal backgrounds, and infant characteristics) were collected. Maternal folic acid levels were classified as either ‘high’ (≥10 ng/mL) or ‘low’ (<10 ng/mL), and frequency of supplementation was recorded (at least once a week supplementation was classified as ‘exposed’, whereas less than once weekly supplementation was deemed ‘nonexposed’). Logistic regression adjusted for propensity scores and sensitivity analyses were conducted.  By 12 months of age, 336 infants (3.8% of the study population) developed KD. Infants born to mothers with higher serum folic acid levels (≥ 10 ng/mL) in the second and third trimesters were significantly less likely to develop KD than their low serum folic acid counterparts (0.27% versus 0.41% of infants developed KD, respectively; OR, 0.68; 95% CI 0.50-0.92). This finding of reduced incidence of KD was also present (but not statistically significant) for higher serum levels in the first trimester (0.34% versus 0.42% of infants; OR, 0.83; 95% CI, 0.66-1.04). Further, it was found that serum levels of 10-19 ng/mL led to significantly less risk for KD than levels lower than 10 ng/mL, but levels of ≥ 20 ng/ml did not result in a significant change in KD incidence compared to 10-19 ng/mL. This indicates that so long as the serum folic acid level was equal to or greater than 10 ng/mL, KD incidence would decrease. Finally, infants whose mothers supplemented with folic acid once or more per week in the second and third trimesters were at significantly reduced risk for developing KD (0.30% of exposed versus 0.43% of nonexposed infants; OR, 0.73; 95% CI, 0.57-0.94). There were similar findings, although nonsignificant, for folic acid supplementation in the first trimester (0.34% versus 0.42% of infants, respectively; OR, 0.83; 95% CI, 0.66-1.04). Overall, this study is the first to associate folic acid supplementation in the second and third trimesters with decreased risk for KD development by 12 months of life. However, future studies should aim to replicate these results indifferent geographical and epidemiological settings, and extend analyses past the 12-month mark to assess for long-term protection from KD. Another confounding variable is that folic acid was taken either alone or as part of a full prenatal vitamin with other supplements present. Thus, future studies should control for these factors where possible. 

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