Prenatal Folic Acid Associated With Lower Psychosis Risk

In 1996, the United States began requiring that enriched grain products (refined grains such as white flour or white rice with nutrients added back) be fortified with folic acid to help prevent neurological birth defects such as spina bifida. Numerous studies over the years have also suggested that children who were exposed to folic acid in utero have lower risks of other neurodevelopmental problems, including language delays and autism.

A study published July 3 in JAMA Psychiatry provides the first biological evidence to support the idea that folic acid may also mediate schizophrenia risk. Researchers compared MRI brain scans of children who were born before, during, and after the full implementation of folic acid fortification of U.S. grain products (1996-1998). They found that increased gestational exposure to folic acid was associated with positive changes in childhood brain development and reduced the occurrence of psychotic symptoms later in life.

“With schizophrenia, as with any illness, you want to identify modifiable risk factors that might help prevent or delay symptoms,” said lead author Joshua Roffman, M.D., an associate professor of psychiatry at Harvard Medical School.

“We’ve known for a while that complications during pregnancy and childbirth increase schizophrenia risk, but it’s not like you can tell women to not have a complicated birth,” he continued. “You can help them make choices that will enhance resilience during pregnancy, and one way is to remind them that there is a global recommendation that pregnant women take 400 to 800 micrograms of folic acid daily because it has neuroprotective effects.”

Roffman, who also heads the Brain Genomics Lab at Massachusetts General Hospital, and colleagues first analyzed 292 MRI scans taken of children aged 8 to 18 at Massachusetts General Hospital. This group included 97 children born before folic acid enrichment, 96 born during the rollout (partially exposed to folic acid), and 99 born after the fortification was implemented nationwide.

They used the scans to measure the thickness of the cortical mantle (the outer layer of the brain’s cerebral cortex) in the children. This region gradually thins as children mature, reflecting the carefully regulated pruning of excess neuronal connections to make the brain more efficient. If neuron pruning starts too early, though, it can increase the risk of disorders such as schizophrenia.

The analysis by Roffman and colleagues showed that the brains of children exposed to folic acid exhibited slower age-related cortical thinning than children who were not exposed, with the partially-exposed children falling somewhere in between. These findings were confirmed in two additional batches of MRI images made available by the University of Pennsylvania (UPenn) and the National Institutes of Health (NIH), respectively. The UPenn study included 861 children born across the folic acid rollout timeframe (1992-2003) while the NIH study was exclusively composed of 217 children born before the fortification requirement was made (1983-1995).

The overall data suggested thinning begins shortly after age 13 in folic acid−exposed children, and about a year earlier in non-exposed children.

As part of the UPenn study, the children who received MRIs also underwent clinical tests to assess potential psychiatric conditions, including early psychosis symptoms. The investigators found that the children who had delayed thinning were at less risk of having psychosis symptoms.

Does this mean we might soon see a lower prevalence of psychotic disorders like schizophrenia as folic-acid fortified children start reaching adulthood?

“That would be encouraging, but we have to remember that there are many other risk factors for schizophrenia that can emerge between birth and adulthood. So, it’s not necessarily a direct correlation,” Roffman told Psychiatric News.

Roffman noted that the United States is imperfect when it comes to nationwide monitoring of mental illness rates and trends. And unfortunately, the places that track health information the best—Northern European countries including Sweden and Denmark—do not mandate folic acid fortification. He said he hopes that studies like his might persuade U.S. authorities to improve mental health surveillance while also convincing other countries to join the 81 nations already fortifying foods with folic acid.

Camille Hoffman-Schuler, M.D., a psychiatrist and obstetrician at Colorado University Anschutz Medical Center, said the findings of the study by Roffman and colleagues affirm the U.S. decision to fortify foods with folate.

“If future studies fall along the same lines and show an association between prenatal folic acid and reduced risk of schizophrenia and other mental illnesses, then the population impact could be huge,” Hoffman-Schuler said.

She noted that folic acid supplementation during the first trimester of pregnancy reduces the risk of neural tube defects (which are rare to begin with) by a factor of 10. If folic acid had anywhere close to that effect on schizophrenia, which is much more common, it would be a tremendous public health impact.

This study was funded by MQ: Transforming Mental Health, with additional support from the National Institute of Mental Health. ■

“Association of Prenatal Exposure to Population-Wide Folic Acid Fortification With Altered Cerebral Cortex Maturation in Youths” can be accessed here.