Exposure to intrauterine folic acid supplementation was associated with increased cortical thickness in bilateral frontal and temporal regions (9.9% to 11.6%, corrected P<0.001 to P=0.03) and slower age-associated thinning in the temporal and parietal regions, compared with lack of such exposure (β = –11.1 to –13.9, corrected P=0.002), reported Hamdi Eryilmaz, PhD, of Massachusetts General Hospital in Boston, and colleagues.

A second cohort using data from the Philadelphia Neurodevelopmental Cohort (PNC) showed flatter patterns of age-related cortical thinning — as seen with prenatal folic acid exposure — to be associated with a lower risk of psychosis spectrum symptoms (OR 0.37-0.59, corrected P<0.05), the authors wrote in JAMA Psychiatry.

Analysis of the PNC data also showed similar exposure associated delays in cortical thinning (β = –1.59 to –1.73, corrected P<0.001 to P=0.02) in similar regions as in the MGH cohort.

A National Institutes of Health study provided data for a third cohort. Participants in this group had received no folic acid supplementation. Patterns of early cortical thinning were apparent in all identified regions in this group.

“Adolescence directly precedes the period of greatest risk for psychiatric disorders, some of which are characterized by reductions in cortical thickness present at the onset of the illness,” stated Eryilmaz and colleagues. They speculated that folic acid’s role in regulating gene expression through histone methylation could account for the findings.

“Overall, it is plausible that exposure to folic acid in utero induces molecular effects, such as DNA methylation, that persist into adolescence. Such a phenomenon has been observed in association with maternal cigarette smoking during pregnancy,” commented Tomas Paus, MD, PhD, of the University of Toronto, in an accompanying editorial.

“But this folate methylation hypothesis needs to be tested empirically in large data sets, ideally in conjunction with relevant brain phenotypes, to replicate and expand the initial findings” in the current study, Paus cautioned.

As of 1998, all grain-based food products in the U.S. were required to be fortified with 140 mg of folic acid per 100 grams of food, following research showing increased risk of neural tube defects associated with folic acid deficiency. That provided an opportunity for a “natural experiment” to explore possible effects of fetal folic acid exposure on cortical development and risk of psychiatric illness in youths.

Measures of cortical thickness were gathered from MRI brain scans across the three independent cohorts of young people 8 to 18 years old.

Initial observations were made using data accessed via the MGH from 292 clinically normative brain scans of young people — 139 girls and 153 boys — born from 1993 through 2001.

Contemporaneous data was gathered from the two other community-based cohorts for replication, clinical extension, and specificity using data from national MRI scan repositories.

The PNC was used to explore scan data from 861 participants born between 1992 and 2003 who had demonstrated psychosis spectrum symptoms.

Participants in the MGH and PNC cohorts were identified as non-exposed, partially exposed, or fully exposed to folic acid fortification, depending on year of birth. Those born before July 1, 1996, when the fortification mandate was first announced, were considered non-exposed; those born after June 30, 1998, when the mandate’s implementation was completed, fully exposed; and those born in between as partially exposed.

The NIH cohort provided data on 217 otherwise healthy young people — 118 girls and 99 boys — who were born before the 1996 rollout of fortification.

In healthy individuals, the researchers explained, a steady, linear, age-associated decrease in cortical thickness is normally seen. An accelerated pattern of loss is associated with a heightened risk of psychopathological characteristics.

Collectively, this data suggests a further protective feature of folic acid supplementation through increased cortical thickness in early adolescence, delayed onset of cortical thinning, and reduced risk of psychosis.

“The present findings are consistent with recent reports of salutary behavioral outcomes after periconceptional intake of folic acid and with a recent study linking folate deficiency with reduced brain volume in a cohort of young European children,” wrote Eryilmaz and colleagues.

• Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 07.05.2018