Risk of Excess Maternal Folic Acid Supplementation in Offspring

Abstract

Folate, also known as vitamin B9, facilitates the transfer of methyl groups among molecules, which is crucial for amino acid metabolism and nucleotide synthesis. Adequate maternal folate supplementation has been widely acknowledged for its pivotal role in promoting cell proliferation and preventing neural tube defects. However, in the post-fortification era, there has been a rising concern regarding an excess maternal intake of folic acid (FA), the synthetic form of folate. In this review, we focused on recent advancements in understanding the influence of excess maternal FA intake on offspring. For human studies, we summarized findings from clinical trials investigating the effects of periconceptional FA intake on neurodevelopment and molecular-level changes in offspring. For studies using mouse models, we compiled the impact of high maternal FA supplementation on gene expression and behavioral changes in offspring. In summary, excessive maternal folate intake could potentially have adverse effects on offspring. Overall, we highlighted concerns regarding elevated maternal folate status in the population, providing a comprehensive perspective on the potential adverse effects of excessive maternal FA supplementation on offspring.

Keywords: behavioral changes; folate; folic acid; gene expression; maternal; neurodevelopment.

Figure 1

A simplified illustration of FA metabolism and the impact of maternal intake on offspring. Folate from food or folic acid (FA) from fortified food/supplements are converted by dihydrofolate reductase to form dihydrofolate (DHF) and then tetrahydrofolate (THF). THF is then converted to 5,10-methylenetetrahydrofolate (5,10-MTHF), which is required for nucleic acid synthesis. 5,10-MTHF is further converted by methylenetetrahydrofolate reductase to form 5-methyltetrahydrofolate (5-MTHF), which is necessary for neurotransmitter (NT) and nitric oxide (NO) synthesis. 5-MTHF is converted by methionine synthase back to THF. The methyl group is transferred from 5-MTHF to homocysteine to form methionine. Methionine can be converted to S-adenosylmethionine (SAM) and acts as the methyl donor in the methylation reactions. SAH, S-adenosylhomocysteine. Excess maternal FA intake induces changes at molecular, cellular, tissue, and organism levels in offspring.