The roles of folate, MTHFR genetics, vitamin B12 in pregnancy outcomes

Folate is essential for fetal development, and periconceptional folic acid (FA) supplementation is well-established for preventing neural tube defects. However, evidence regarding its role in other pregnancy outcomes, such as gestational diabetes mellitus, hypertensive disorders of pregnancy, fetal growth, miscarriage, and preterm birth, remains inconsistent. Current knowledge indicates that the effects of FA are not uniform but significantly influenced by the timing, dose, and duration of supplementation, frequently exhibiting U-shaped or timing-dependent relationships. Furthermore, methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and vitamin B12 levels are critical modifiers of folate metabolism and its association with pregnancy outcomes. Crucially, there is a lack of quantitative studies linking circulating folate levels to the risk of adverse outcomes, and no optimal threshold range has been established to balance the prevention of different complications. This review consolidates the existing evidence on the associations between FA supplementation, circulating folate levels, and non-structural pregnancy outcomes, while elucidating the modulating roles of MTHFR genetics and vitamin B12. Besides, it highlights possible underlying biological mechanism of hyperhomocysteinemia, alterations in DNA methylation, the presence of folate receptor antibody (FRAbs), and the direct anti-inflammatory effects of folate. This review aims to provide a foundation for a future precision nutrition strategy through individual physiological folate levels, MTHFR genetics, and vitamin B12 status.