Excess Folic Acid During Pregnancy Harms Brain Development

Summary: Study of pregnant mice found excess folic acid is detrimental to brain development in fetuses. Mice exposed in-utero to higher doses of folic acid had significant brain changes compared to those who were exposed to lower doses.

Source: UC Davis

A UC Davis MIND Institute study of pregnant mice found that high amounts of folic acid during pregnancy harmed the brain development of embryos. Researchers say the findings indicate that more investigation is needed about the best recommended dosage 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.

The research, published Sept. 30 in Cerebral Cortex, involved pregnant mice who were given either a normal amount of folic acid, 10 times the recommended amount, or none. The offspring of the mice that received the largest amount showed significant brain changes.

“It’s not subtle. It’s substantial,” said Konstantinos Zarbalis, associate professor in the Department of Pathology and Laboratory Medicine and also a corresponding author of the research. “It makes a marked difference in brain structure if you take very high amounts of folic acid.”

Paradoxically, changes in the brain due to too much folic acid mimicked those associated with a deficiency of folic acid. “This, to me, was an even more important insight,” said Zarbalis, who is also on the UC Davis MIND Institute faculty. He noted that in humans, research shows that impaired folate uptake into the brain can cause cerebral folate deficiency, a syndrome that is often associated with the development of autism.

Folic acid and pregnancy

Folic acid (the synthetic form of vitamin B9, or folate) supplementation is widely recommended for women of child-bearing age. It has been shown to substantially reduce the risk of neural tube defects, such as spina bifida, in children. Research, including studies at the MIND Institute, has also shown that prenatal vitamins that include folic acid have a protective effect against the development of autism and other disorders.

Green was on the panel with the National Academy of Sciences and the Institute of Medicine (now called the National Academy of Medicine) that determined the recommended daily intake of folic acid (400 mcg) and the maximum daily safe upper limit (1000 mcg). He was also on the Food and Drug Administration (FDA) panel that recommended adding folic acid to foods, which led to the fortification of all cereals and grains with folic acid mandated by the Federal Government in 1998.

“Addition of folic acid to the diet was a good thing, and I’ve supported fortification, but there is a ‘best amount’ of folic acid, and some people may be getting more than is optimal,” said Green.

This shows a pregnant woman
Paradoxically, changes in the brain due to too much folic acid mimicked those associated with a deficiency of folic acid. Image is in the public domain.

Women who have given birth to a child with neural tube defects or who have certain conditions like epilepsy and take anticonvulsants, have generally been advised to take much higher doses of folic acid.

“In animal models, we have indications that very high amounts of folic acid can be harmful to brain development of the fetus, and the clinical community should take this indication seriously, to support research in this area to reevaluate the amount of folic acid that is optimal for pregnant women,” said Zarbalis.

Zarbalis and Green suspect that the problem lies in the way folic acid is metabolized by the body and have plans to investigate the phenomenon further.

Co-authors on the study include Angelo Harlan De Crescenzo, now at the University of Nevada, Reno; Alexios Panoutsopoulos, Lyvin Tat, Zachary Schaaf and Shailaja Racherla in the UC Davis Department of Pathology and Laboratory Medicine; Lyle Henderson of the Institute for Pediatric Regenerative Medicine at Shriners Hospital for Children and Nicholas Greene and Kit-Yi Leung of the UCL Great Ormond Street Institute of Child Health, University College, London.

Funding: Funding for the study was provided 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.
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. Cerebral Cortex.


Deficient or Excess Folic Acid Supply During Pregnancy Alter Cortical Neurodevelopment in Mouse Offspring

Folate is an essential micronutrient required for both cellular proliferation through de novo nucleotide synthesis and epigenetic regulation of gene expression through methylation. This dual requirement places a particular demand on folate availability during pregnancy when both rapid cell generation and programmed differentiation of maternal, extraembryonic, and embryonic/fetal tissues are required. Accordingly, prenatal neurodevelopment is particularly susceptible to folate deficiency, which can predispose to neural tube defects, or when effective transport into the brain is impaired, cerebral folate deficiency. Consequently, adequate folate consumption, in the form of folic acid (FA) fortification and supplement use, is widely recommended and has led to a substantial increase in the amount of FA intake during pregnancy in some populations. Here, we show that either maternal folate deficiency or FA excess in mice results in disruptions in folate metabolism of the offspring, suggesting diversion of the folate cycle from methylation to DNA synthesis. Paradoxically, either intervention causes comparable neurodevelopmental changes by delaying prenatal cerebral cortical neurogenesis in favor of late-born neurons. These cytoarchitectural and biochemical alterations are accompanied by behavioral abnormalities in FA test groups compared with controls. Our findings point to overlooked potential neurodevelopmental risks associated with excessively high levels of prenatal FA intake.

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