Summary: A UC Davis MIND Institute study in pregnant mice found that very high doses of folic acid during gestation produced notable changes in fetal brain development. Offspring exposed in utero to excessive folic acid showed significant structural and behavioral differences compared with those given standard or no supplementation.
Source: UC Davis
Overview
Researchers at the UC Davis MIND Institute report that excessive folic acid intake during pregnancy altered cortical neurodevelopment in mouse offspring. The study raises questions about the optimal prenatal folic acid dose and suggests further research is needed to refine recommendations for pregnant women.
“We believe there’s a Goldilocks effect with folic acid. Too little is not good, too much is not good; you have to get it just right,” said Ralph Green, UC Davis distinguished professor of pathology and medicine and a corresponding author of the study.
In the experiments, pregnant mice received either no folic acid, a standard recommended amount, or a dose ten times higher than recommended. Offspring of the high-dose group exhibited marked differences in brain structure and behavior compared with controls. “It’s not subtle. It’s substantial,” said Konstantinos Zarbalis, associate professor in the Department of Pathology and Laboratory Medicine and a corresponding author. He emphasized that very high maternal folic acid intake produced clear changes in cortical organization.
Surprisingly, several of the neurodevelopmental changes seen with excess folic acid resembled changes caused by folate deficiency. Zarbalis noted that impaired folate transport into the brain in humans is linked to cerebral folate deficiency, a condition that has been associated in some studies with an increased risk of neurodevelopmental disorders, including autism. The team cautions that parallels between mouse models and human development require careful interpretation and additional clinical research.
Folic acid and pregnancy
Folic acid, the synthetic form of vitamin B9 (folate), is widely recommended for women of childbearing age because it reduces the risk of neural tube defects, such as spina bifida. Prenatal vitamins containing folic acid have also been associated with protective effects against certain neurodevelopmental disorders in some studies. These public health measures, including food fortification, substantially increased folic acid intake in many populations.
Ralph Green served on panels that helped set the current recommended daily folic acid intake (400 mcg) and the upper safe limit (1000 mcg). He was also involved in the FDA advisory process that led to mandatory folic acid fortification of many grain products in 1998. “Fortification was an important public health measure, and I’ve supported it,” Green said. “But there may be a best amount for pregnancy, and some individuals could be receiving more than is optimal.”
Certain women—such as those who have previously given birth to a child with a neural tube defect, or those taking anticonvulsant medications—are commonly advised to take higher folic acid doses. The UC Davis team urges clinicians and researchers to consider animal model evidence that very high folic acid exposure could affect fetal brain development and to pursue studies that clarify safe, effective dosing during pregnancy.
The investigators suspect that altered folate metabolism—how the body processes folic acid—may explain the paradoxical findings, and they plan follow-up studies to explore metabolic pathways and transport mechanisms that influence fetal brain folate levels.
Co-authors of the study include Angelo Harlan De Crescenzo (now at the University of Nevada, Reno); Alexios Panoutsopoulos, Lyvin Tat, Zachary Schaaf and Shailaja Racherla (UC Davis Department of Pathology and Laboratory Medicine); Lyle Henderson (Institute for Pediatric Regenerative Medicine at Shriners Hospital for Children); and Nicholas Greene and Kit-Yi Leung (UCL Great Ormond Street Institute of Child Health, University College London).
Funding: The research was funded by Elissa Leonard, Powell Family Charitable Trust; Shriners Hospitals for Children; UC Davis Department of Pathology and Laboratory Medicine; UC Davis MIND Institute; National Institute of Mental Health (R21MH115347); and the UK Medical Research Council (N003713).
About this neurodevelopment research news
Source: UC Davis
Contact: Marianne Sharp – UC Davis
Image: The image is in the public domain.
Original Research: Open access. Title: “Deficient or Excess Folic Acid Supply During Pregnancy Alter Cortical Neurodevelopment in Mouse Offspring” by Angelo Harlan De Crescenzo, Alexios A. Panoutsopoulos, Lyvin Tat, Zachary Schaaf, Shailaja Racherla, Lyle Henderson, Kit‑Yi Leung, Nicholas D. E. Greene, Ralph Green, Konstantinos S. Zarbalis. Journal: Cerebral Cortex. DOI: 10.1093/cercor/bhaa248
Abstract (summarized)
Folate is essential for both DNA synthesis and epigenetic regulation through methylation, creating high demand during pregnancy when rapid cell division and differentiation occur. Prenatal folate insufficiency can lead to neural tube defects, and impaired folate transport into the brain causes cerebral folate deficiency. To prevent such outcomes, folic acid fortification and supplementation have increased maternal folate intake in many populations. This study shows that in mice, both maternal folate deficiency and excess folic acid disrupt folate metabolism in offspring and shift folate use from methylation toward DNA synthesis. Unexpectedly, both low and very high maternal folate produced similar delays in prenatal cortical neurogenesis, favoring later-born neurons, and these structural and biochemical changes were accompanied by behavioral differences in the high-dose groups. The results highlight potential neurodevelopmental risks associated with excessively high prenatal folic acid intake and support further study to define optimal dosing during pregnancy.