Table 1. Gaps in knowledge and studies needed to clarify the role of maternal folate in secondary birth outcomes.

Studies to confirm the association between folate intake (supported by maternal blood folate markers) and the risk of CHD, low birth weight, or preterm birth in different populations

Confirmatory studies on a possible role of folate in prevention of the most severe forms of CHD and the possible economic impact of this prevention

If folate supplementation is protective against secondary outcomes, is there a critical time window for folate supplementation in order to prevent a specific outcome (i.e., preconceptional, or in the first or second trimester)?

What are the mechanisms by which folate could prevent CHD or preterm birth?

Does low folate status interact with common genetic polymorphisms to increase the risk of CHD (gene-nutrient interaction)?

Does folate status interact with vitamin B12 status to increase the risk of CHD (i.e., could high folate/low B12 be an issue)?

May additional nutrients closely related to folate metabolism (or compensate for low folate or low B12) influence the risk by synergy in effects (i.e., choline)?

CHD, congenital heart defects.