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Prenatal Folic Acid Exposure Linked to Reduced Risk of Psychosis in Adolescence

Key findings

  • Fetal exposure to folic acid fortification was associated with greater cortical development in the brain among school-aged children
  • These cortical changes were associated with reduced risk of psychotic disorders in adolescence
  • The findings suggest that protective effects of prenatal folic acid exposure extend beyond the prevention of neural tube defects and span neurodevelopment during childhood and adolescence

Since January 1998, U.S. manufacturers of bread and other grain-based foods have been required to enrich their products with folic acid, which is critical to fetal neural tube development. As a result, neural tube defects in newborns have diminished substantially.

Based on epidemiologic studies of mental illness, researchers have wondered whether prenatal exposure to folic acid might also influence postnatal brain development. Now, for the first time, psychiatrists at Massachusetts General Hospital have substantiated that theory.

Led by psychiatry researcher Hamdi Eryilmaz, PhD, and Joshua L. Roffman, MD, MMSc, co-director of Mass General Neuroscience and director of the Brain Genomics Laboratory, the team found a link between fetal exposure to folate and greater cortical development in the brain, which is considered the key to mental health, until early adolescence. According to their report in JAMA Psychiatry, these cortical changes were associated with reduced risk of psychotic disorders in adolescence including schizophrenia.

The researchers studied 292 patients between the ages of eight to 18 at Mass General who had magnetic resonance imaging (MRI) of the brain between January 2005 and March 2015. The patients were divided into:

  • Those born before July 1, 1996, who were not exposed to folic acid fortification during any part of gestation (n=97)
  • Those born after June 30, 1998, who were exposed throughout gestation (n=99)
  • Those born between those dates, who were considered intermediately exposed (n=96)

Cortical thickness on MRI was used as a marker of brain development. The researchers found that cortical thickness in the bilateral frontal and inferior temporal regions was significantly higher in the group fully exposed to folic acid during gestation than in the nonexposed group. Intermediate effects were observed in the partially exposed group.

In children who were fully exposed to folic acid fortification during gestation, cortical thinning did not begin until ages 13 to 14.

The research team replicated their findings using data from two large prospective studies in which 8- to 18-year-olds underwent standardized MRI:

  • 217 children from the National Institutes of Health MRI Study of Normal Brain Development who were born before the time of folic acid fortification. As expected, only one brain region showed a significant delay in cortical thinning
  • 861 children from the Philadelphia Neurodevelopmental Cohort (PNC) who were born about the time that folic acid fortification began. As expected, four brain regions showed a significant delay in cortical thinning until ages 13 to 14

Altogether, 248 of the PNC participants were psychiatrically healthy, 199 had significant psychosis spectrum symptoms, 105 had attenuated psychosis spectrum symptoms and 309 had other psychopathologic conditions. By analyzing data for each individual participant, the research team found that delay of cortical thinning in three of the four regions was associated with significantly reduced risk of a psychosis spectrum diagnosis (adjusted odds ratio, 0.37–0.59; < .001 to = .02).

It is unknown, the researchers say, how prenatal exposure to folic acid affects postnatal cortical development. One possibility is that fetal folate programs cortical maturation via epigenetic modification of genes that regulate cortical development, repair de novo mutations or mitigate toxic exposures.

Learn more about the Schizophrenia Clinical and Research Program

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Joshua Roffman, MD, MMSc, discusses his recent work investigating folic acid’s potential neuroprotective effects that may guard against schizophrenia development.