Association of Prenatal Exposure to Population-Wide Folic Acid Fortification With Altered Cerebral Cortex Maturation in Youths | Adolescent Medicine | JAMA Psychiatry | JAMA Network
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Age-Related Group Differences in Cortical Thickness

Lateral views of left and right cortex demonstrate dynamic effects of prenatal fortification exposure (fully exposed minus nonexposed) on cortical thickness between 8 and 18 years of age in the Massachusetts General Hospital cohort. In general, the most pronounced differences occurred at earlier ages. Color bar indicates effect size (Cohen d) and direction of effect.

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Original Investigation
September 2018

Association of Prenatal Exposure to Population-Wide Folic Acid Fortification With Altered Cerebral Cortex Maturation in Youths

Author Affiliations
  • 1Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown
  • 2Penn–Children’s Hospital of Philadelphia Lifespan Brain Institute, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 3Massachusetts General Hospital Biostatistics Center, Harvard Medical School, Boston
  • 4Center for Geographic Analysis, Harvard University, Cambridge, Massachusetts
  • 5Department of Epidemiology, Columbia University, New York, New York
  • 6Department of Psychiatry, Columbia University, New York, New York
  • 7New York State Psychiatric Institute, New York, New York
JAMA Psychiatry. 2018;75(9):918-928. doi:10.1001/jamapsychiatry.2018.1381
Key Points

Question  Is increased fetal exposure to folic acid, implemented through population-wide fortification of grain products, associated with clinically meaningful changes in postnatal brain development?

Findings  In a cohort of 292 youths 8 to 18 years of age with normative results of clinical magnetic resonance imaging, delayed age-associated thinning of the cerebral cortex, a pattern suggesting reduced risk for severe mental illness, emerged among individuals who gestated during and after the fortification rollout in the United States (1996-1997). Studies of 2 additional independent US cohorts (N = 1078) confirmed the reliability and temporal specificity of fortification-associated delays of cortical thinning and demonstrated an associated reduction in psychosis risk.

Meaning  Beyond its known association with the prevention of neural tube defects, increased gestational exposure to folic acid through food fortification may protect against psychosis through altered postnatal cortical development.


Importance  Presently, 81 countries mandate the fortification of grain products with folic acid to lessen the risk of neural tube defects in the developing fetus. Epidemiologic data on severe mental illness suggest potentially broader effects of prenatal folate exposure on postnatal brain development, but this link remains unsubstantiated by biological evidence.

Objective  To evaluate associations among fetal folic acid exposure, cortical maturation, and psychiatric risk in youths.

Design, Setting, and Participants  A retrospective, observational clinical cohort study was conducted at Massachusetts General Hospital (MGH) among 292 youths 8 to 18 years of age born between January 1993 and December 2001 (inclusive of folic acid fortification rollout ±3.5 years) with normative results of clinical magnetic resonance imaging, divided into 3 age-matched groups based on birthdate and related level of prenatal folic acid fortification exposure (none, partial, or full). Magnetic resonance imaging was performed between January 2005 and March 2015. Two independent, observational, community-based cohorts (Philadelphia Neurodevelopmental Cohort [PNC] and National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development [NIH]) comprising 1078 youths 8 to 18 years of age born throughout (PNC, 1992-2003) or before (NIH, 1983-1995) the rollout of folic acid fortification were studied for replication, clinical extension, and specificity. Statistical analysis was conducted from 2015 to 2018.

Exposures  United States–mandated grain product fortification with folic acid, introduced in late 1996 and fully in effect by mid-1997.

Main Outcomes and Measures  Differences in cortical thickness among nonexposed, partially exposed, and fully exposed youths (MGH) and underlying associations between age and cortical thickness (all cohorts). Analysis of the PNC cohort also examined the association of age–cortical thickness slopes with the odds of psychotic symptoms.

Results  The MGH cohort (139 girls and 153 boys; mean [SD] age, 13.3 [2.3] years) demonstrated exposure-associated cortical thickness increases in bilateral frontal and temporal regions (9.9% to 11.6%; corrected P < .001 to P = .03) and emergence of quadratic (delayed) age-associated thinning in temporal and parietal regions (β = –11.1 to –13.9; corrected P = .002). The contemporaneous PNC cohort (417 girls and 444 boys; mean [SD] age, 13.5 [2.7] years) also exhibited exposure-associated delays of cortical thinning (β = –1.59 to –1.73; corrected P < .001 to P = .02), located in similar regions and with similar durations of delay as in the MGH cohort. Flatter thinning profiles in frontal, temporal, and parietal regions were associated with lower odds of psychosis spectrum symptoms in the PNC cohort (odds ratio, 0.37-0.59; corrected P < .05). All identified regions displayed earlier thinning in the nonexposed NIH cohort (118 girls and 99 boys; mean [SD] age, 13.3 [2.6] years).

Conclusions and Relevance  The results of this study suggest an association between gestational exposure to fortification of grain products with folic acid and altered cortical development and, in turn, with reduction in the risk of psychosis in youths.