The Importance of Maternal Folate Status for Brain Development and Function of Offspring

Abstract

The importance of an adequate periconceptional maternal folate status to prevent fetal neural tube defects has been well demonstrated and resulted in the recommendation for women to use folic acid supplements during the periconception period. The importance of maternal folate status for offspring neurodevelopment and brain health is less well described. We reviewed the current evidence linking maternal folate status before conception and during pregnancy with neurodevelopment and cognition of the offspring. We discuss both animal and human studies. Preclinical research revealed the importance of maternal folate status for several key processes required for normal neurodevelopment and brain functioning in the offspring, including DNA synthesis, regulation of gene expression, synthesis of phospholipids and neurotransmitters, and maintenance of healthy plasma homocysteine concentrations. Human observational studies are inconclusive; about half have shown a positive association between maternal folate status and cognitive performance of offspring. Whereas some studies suggest a positive association between maternal folate intake and cognition of offspring during childhood, data from interventional studies are too limited to conclude that there is a direct effect. Future preclinical studies are needed to help us characterize the behavioral effects, understand the underlying mechanisms, and to establish an optimal dosage and time window of folate supplementation. Moreover, more conclusive data from well-designed human observational studies and randomized controlled trials are needed to determine whether current recommendations for folic acid supplementation during pregnancy cover the needs for normal cognitive development in the offspring.

Keywords: brain; cognition; developmental; folate; folic acid; maternal; neuropsychological; prenatal.

FIGURE 1

Folate and methionine cycle (simplified). Folates from food and folic acid from fortification/supplementation are converted in the liver by the enzyme dihydrofolate reductase to form dihydrofolate (DHF) and then tetrahydrofolate (THF). THF enters the folate cycle where its vitamin B-6-dependent conversion to 5,10-methylenetetrahydrofolate (5,10-MTHF) is required for nucleic acid synthesis. The vitamin B-2-dependent enzyme methylenetetrahydrofolate reductase catalyzes reduction of 5,10-MTHF to 5-methyltetrahydrofolate (5-MTHF), in an irreversible reaction. As 5-MTHF is converted by methionine synthase into THF in a vitamin B-12-dependent reaction, vitamin B-12 deficiency can cause a functional folate deficiency. The interconnected methionine cycle is depicted on the right: 5-MTHF is required for the vitamin B-12-dependent formation of homocysteine into methionine. Methionine, once converted to S-adenosyl methionine (SAM) acts as a methyl donor in many biological methylation reactions. SAH, S-adenosylhomocysteine.