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Observational Study
. 2018 Sep 1;75(9):918-928.
doi: 10.1001/jamapsychiatry.2018.1381.

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

Hamdi Eryilmaz  1 , Kevin F Dowling  1 , Franklin C Huntington  1 , Anais Rodriguez-Thompson  1 , Thomas W Soare  1 , Lauren M Beard  2 , Hang Lee  3 , Jeffrey C Blossom  4 , Randy L Gollub  1 , Ezra Susser  5   6   7 , Ruben C Gur  2 , Monica E Calkins  2 , Raquel E Gur  2 , Theodore D Satterthwaite  2 , Joshua L Roffman  1
Affiliations
Observational Study

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

Hamdi Eryilmaz et al. JAMA Psychiatry. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Roffman reported receiving grant support and consulting income from Pamlab for unrelated projects. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Fortification-Associated Cortical Thickness Changes in the Massachusetts General Hospital Cohort
A, Surface-wide maps of cortical thickness in fully exposed (n = 99) minus nonexposed (n = 97) individuals reveal higher thickness among youths who were exposed to folic acid fortification during gestation. Images are masked to show only clusters that survive correction for multiple comparisons. B, Dot plots showing cortical thickness in the left frontal cluster as a function of exposure group, suggesting intermediate effects in the partially exposed group. Horizontal lines in the boxes indicate median values, and shaded boxes indicate interquartile ranges. Cortical thickness values are z-transformed residuals after controlling for nuisance covariates. Cool colors (shades of blue) show regions for which cortical thickness is greater in the group that was not exposed to fortification, whereas hot colors (red, orange, and yellow) show regions where cortical thickness is greater in the fully exposed group. C, Age-centered regression analyses indicate clusters with significant between-group differences in thickness as a function of age at magnetic resonance imaging (MRI) scan. This analysis indicates that overall group differences largely reflect exposure-related associations within younger individuals. ITG indicates inferior temporal gyrus; L, left, and R, right.
Figure 2.
Figure 2.. Fortification-Associated Emergence of Nonlinear (Delayed) Cortical Thinning
A, Surface-wide maps of age-squared associations with cortical thickness in fully exposed (n = 99) minus nonexposed (n = 97) Massachusetts General Hospital (MGH) cohort scans reveal increased age-related quadratic thinning among individuals exposed to folic acid fortification during gestation. Nonexposed greater than fully exposed indicates that cool colors show regions for which β values are greater in the group that was not exposed to fortification. More negative β values reflect stronger quadratic thinning. The cool color (ie, shades of blue) reflects the negative age-squared term in the fully exposed group. B, Age-thickness scatterplot of MGH cohort, indicating emergence of quadratic (delayed) left inferior parietal lobule thinning in participants born after fortification was implemented. C, Surface-wide maps of age-squared associations with cortical thickness in the Philadelphia Neurodevelopmental Cohort (PNC) (n = 861) indicate age-related quadratic thinning in frontal, inferior parietal lobule (IPL), and inferior temporal gyrus (ITG) regions, again driven by delayed thinning in fully exposed individuals. D, Age-thickness scatterplot of the PNC cohort demonstrating delayed thinning in left (L) IPL and right (R) ITG. E, Within the L IPL cluster that demonstrated exposure-associated differences in quadratic thinning in the MGH cohort (A and B), analysis of the nonexposed National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development (NIH) cohort indicates linear thinning (evident at the earliest time point). F, Similarly, within the L IPL and R ITG clusters that demonstrated quadratic thinning in the PNC cohort (C and D), only linear thinning was seen in the NIH cohort (383 scans). A and B, Images are masked to show only clusters that survive correction for multiple comparisons (P < .05, clusterwise; for PNC cohort L IPL, the displayed cluster was too small to survive correction at P < .05 but is significant at P < .01). Cortical thickness values in scatterplots represent z-transformed residuals after controlling for nuisance covariates.
Figure 3.
Figure 3.. Local Slope Derivation and Association of Delayed Cortical Thinning With Individual Risk for Psychopathologic Conditions in Participants in the Philadelphia Neurodevelopmental Cohort (PNC)
A, In each of the 4 clusters exhibiting delayed cortical thinning in the PNC cohort, local cortical thinning slope was calculated for each individual based on the best-fit line of thickness vs age among all nearby individuals (±6 months). Insets demonstrate local slopes for an 11.0-year-old (left) and a 15.0-year-old (right) participant. B, Mean local slopes for participants in each diagnostic group, in each of the 4 clusters. For example, individuals with psychosis spectrum (PS) symptoms tended to have more negative slopes than those with other diagnoses. Local slopes reflect change in z-transformed cortical thickness scores (adjusted for nuisance covariates) during 1 year. C, Multinomial logistic regression models associated with diagnosis (PS, psychosis low [PL], or other psychopathologic condition [OP] relative to typically developing [TD]; n = 248) of each participant based on local slope, covarying for age, sex, total brain volume, and method of ascertaining diagnosis. Lower adjusted odds ratios indicate reduced odds of psychopathologic condition in the presence of flatter (less negative) local thinning slope, a pattern that was significant for PS in 3 of 4 regions tested. All P values are false discovery rate corrected. All error bars indicate 95% CIs. IPL indicates inferior parietal lobule; ITG, inferior temporal gyrus. aP < .001. bP < .01. cP < .05.
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