Folic acid supplementation on congenital heart disease and its dual character

Pregnant women are vulnerable to folate deficiency as its requirement is substantially greater than folate requirements for non-pregnant women. Folic acid is a synthetic form of folate and has been used in the fortified foods and nutritional supplements. Since the 1990s, maternal folic acid supplementation has been adopted by the governments and health organizations around the world as the policy to prevent the birth defects, especially neural tube defects. Under the promotion of folic acid supplementation, however, the global prevalence of congenital heart disease continues to be increased. In the recent years, our research group has evaluated that the heterogeneity concerning the association between folic acid supplementation and congenital heart disease is high. Based on experiments with animal models such as zebrafish and mice, we have demonstrated that excessive folic acid supplementation led to cardiovascular development disorders and even early embryo death. In this review article, we first summarize the discovery of folic acid and the achievement of folic acid supplementation in the prevention of congenital diseases. We then discuss the transport and metabolism of folic acid particularly in the form of unmetabolized folic acid. Finally, we comment on the association of folic acid supplementation with congenital heart disease. Better understanding the dual character of folic acid supplementation on congenital heart disease may provide new insights into the potential role of folic acid and offer a fresh perspective on the prevention of congenital heart disease.