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.

1.
US Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Fed Regist. 1996;61:8781-8797. https://www.federalregister.gov/documents/1996/03/05/96-5014/food-standards-amendment-of-standards-of-identity-for-enriched-grain-products-to-require-addition-of. Published March 5, 1996. Accessed November 21, 2016.
2.
Pfeiffer  CM, Hughes  JP, Lacher  DA,  et al.  Estimation of trends in serum and RBC folate in the US population from pre- to postfortification using assay-adjusted data from the NHANES 1988-2010.  J Nutr. 2012;142(5):886-893.PubMedGoogle ScholarCrossref
3.
Czeizel  AE.  Folic acid in the prevention of neural tube defects.  J Pediatr Gastroenterol Nutr. 1995;20(1):4-16.PubMedGoogle ScholarCrossref
4.
Canfield  MA, Collins  JS, Botto  LD,  et al; National Birth Defects Prevention Network.  Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study.  Birth Defects Res A Clin Mol Teratol. 2005;73(10):679-689.PubMedGoogle ScholarCrossref
5.
Susser  E, St Clair  D.  Prenatal famine and adult mental illness: interpreting concordant and discordant results from the Dutch and Chinese Famines.  Soc Sci Med. 2013;97:325-330.PubMedGoogle ScholarCrossref
6.
Surén  P, Roth  C, Bresnahan  M,  et al.  Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children.  JAMA. 2013;309(6):570-577.PubMedGoogle ScholarCrossref
7.
Roth  C, Magnus  P, Schjølberg  S,  et al.  Folic acid supplements in pregnancy and severe language delay in children.  JAMA. 2011;306(14):1566-1573.PubMedGoogle ScholarCrossref
8.
Schmidt  RJ, Tancredi  DJ, Ozonoff  S,  et al.  Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study.  Am J Clin Nutr. 2012;96(1):80-89.PubMedGoogle ScholarCrossref
9.
Levine  SZ, Kodesh  A, Viktorin  A,  et al.  Association of maternal use of folic acid and multivitamin supplements in the periods before and during pregnancy with the risk of autism spectrum disorder in offspring.  JAMA Psychiatry. 2018;75(2):176-184.PubMedGoogle ScholarCrossref
10.
Virk  J, Liew  Z, Olsen  J, Nohr  EA, Catov  JM, Ritz  B.  Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders.  Autism. 2016;20(6):710-718.PubMedGoogle ScholarCrossref
11.
Ducharme  S, Albaugh  MD, Nguyen  TV,  et al; Brain Development Cooperative Group.  Trajectories of cortical thickness maturation in normal brain development—the importance of quality control procedures.  Neuroimage. 2016;125:267-279.PubMedGoogle ScholarCrossref
12.
Sowell  ER, Peterson  BS, Thompson  PM, Welcome  SE, Henkenius  AL, Toga  AW.  Mapping cortical change across the human life span.  Nat Neurosci. 2003;6(3):309-315.PubMedGoogle ScholarCrossref
13.
Sowell  ER, Thompson  PM, Leonard  CM, Welcome  SE, Kan  E, Toga  AW.  Longitudinal mapping of cortical thickness and brain growth in normal children.  J Neurosci. 2004;24(38):8223-8231.PubMedGoogle ScholarCrossref
14.
Yakovlev  P, Lecours  A. The myelinogenetic cycles of regional maturation of the brain. In: Minokowski  A, ed.  Regional Development of the Brain Early in Life. Oxford, England: Blackwell Scientific Publications; 1967:3-70.
15.
Shaw  P, Greenstein  D, Lerch  J,  et al.  Intellectual ability and cortical development in children and adolescents.  Nature. 2006;440(7084):676-679.PubMedGoogle ScholarCrossref
16.
Thompson  PM, Vidal  C, Giedd  JN,  et al.  Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia.  Proc Natl Acad Sci U S A. 2001;98(20):11650-11655.PubMedGoogle ScholarCrossref
17.
Mattai  AA, Weisinger  B, Greenstein  D,  et al.  Normalization of cortical gray matter deficits in nonpsychotic siblings of patients with childhood-onset schizophrenia.  J Am Acad Child Adolesc Psychiatry. 2011;50(7):697-704.PubMedGoogle ScholarCrossref
18.
Zielinski  BA, Prigge  MB, Nielsen  JA,  et al.  Longitudinal changes in cortical thickness in autism and typical development.  Brain. 2014;137(pt 6):1799-1812.PubMedGoogle ScholarCrossref
19.
Murphy  SN, Herrick  C, Wang  Y,  et al.  High throughput tools to access images from clinical archives for research.  J Digit Imaging. 2015;28(2):194-204.PubMedGoogle ScholarCrossref
20.
Jacques  PF, Selhub  J, Bostom  AG, Wilson  PW, Rosenberg  IH.  The effect of folic acid fortification on plasma folate and total homocysteine concentrations.  N Engl J Med. 1999;340(19):1449-1454.PubMedGoogle ScholarCrossref
21.
US Census Bureau. Decennial census of population and housing. https://www.census.gov/programs-surveys/decennial-census/data/datasets.2010.html. Accessed May 8, 2018.
22.
Satterthwaite  TD, Elliott  MA, Ruparel  K,  et al.  Neuroimaging of the Philadelphia Neurodevelopmental Cohort.  Neuroimage. 2014;86:544-553.PubMedGoogle ScholarCrossref
23.
Calkins  ME, Moore  TM, Merikangas  KR,  et al.  The psychosis spectrum in a young US community sample: findings from the Philadelphia Neurodevelopmental Cohort.  World Psychiatry. 2014;13(3):296-305.PubMedGoogle ScholarCrossref
24.
Satterthwaite  TD, Wolf  DH, Calkins  ME,  et al.  Structural brain abnormalities in youth with psychosis spectrum symptoms.  JAMA Psychiatry. 2016;73(5):515-524.PubMedGoogle ScholarCrossref
25.
Evans  AC; Brain Development Cooperative Group.  The NIH MRI study of normal brain development.  Neuroimage. 2006;30(1):184-202.PubMedGoogle ScholarCrossref
26.
Wong  IC, Murray  ML, Camilleri-Novak  D, Stephens  P.  Increased prescribing trends of paediatric psychotropic medications.  Arch Dis Child. 2004;89(12):1131-1132.PubMedGoogle ScholarCrossref
27.
Govindarajan  KA, Freeman  L, Cai  C, Rahbar  MH, Narayana  PA.  Effect of intrinsic and extrinsic factors on global and regional cortical thickness.  PLoS One. 2014;9(5):e96429.PubMedGoogle ScholarCrossref
28.
Han  X, Jovicich  J, Salat  D,  et al.  Reliability of MRI-derived measurements of human cerebral cortical thickness: the effects of field strength, scanner upgrade and manufacturer.  Neuroimage. 2006;32(1):180-194.PubMedGoogle ScholarCrossref
29.
Gur  RC, Calkins  ME, Satterthwaite  TD,  et al.  Neurocognitive growth charting in psychosis spectrum youths.  JAMA Psychiatry. 2014;71(4):366-374.PubMedGoogle ScholarCrossref
30.
Narr  KL, Bilder  RM, Toga  AW,  et al.  Mapping cortical thickness and gray matter concentration in first episode schizophrenia.  Cereb Cortex. 2005;15(6):708-719.PubMedGoogle ScholarCrossref
31.
Roza  SJ, van Batenburg-Eddes  T, Steegers  EA,  et al.  Maternal folic acid supplement use in early pregnancy and child behavioural problems: the Generation R Study.  Br J Nutr. 2010;103(3):445-452.PubMedGoogle ScholarCrossref
32.
Ars  CL, Nijs  IM, Marroun  HE,  et al.  Prenatal folate, homocysteine and vitamin B12 levels and child brain volumes, cognitive development and psychological functioning: the Generation R Study  [published online January 22, 2016].  Br J Nutr. doi:10.1017/S0007114515002081PubMedGoogle Scholar
33.
Centers for Disease Control and Prevention (CDC).  Knowledge and use of folic acid by women of childbearing age—United States, 1995 and 1998.  MMWR Morb Mortal Wkly Rep. 1999;48(16):325-327.PubMedGoogle Scholar
34.
Kirkbride  JB, Susser  E, Kundakovic  M, Kresovich  JK, Davey Smith  G, Relton  CL.  Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects?  Epigenomics. 2012;4(3):303-315.PubMedGoogle ScholarCrossref
35.
McClellan  JM, Susser  E, King  MC.  Maternal famine, de novo mutations, and schizophrenia.  JAMA. 2006;296(5):582-584.PubMedGoogle ScholarCrossref
36.
Dolinoy  DC, Huang  D, Jirtle  RL.  Maternal nutrient supplementation counteracts bisphenol A-induced hypomethylation in early development.  Proc Natl Acad Sci U S A. 2007;104(32):13056-13061.PubMedGoogle ScholarCrossref
37.
Brown  AS, Bottiglieri  T, Schaefer  CA,  et al.  Elevated prenatal homocysteine levels as a risk factor for schizophrenia.  Arch Gen Psychiatry. 2007;64(1):31-39.PubMedGoogle ScholarCrossref
38.
Schmidt  RJ, Kogan  V, Shelton  JF,  et al.  Combined prenatal pesticide exposure and folic acid intake in relation to autism spectrum disorder.  Environ Health Perspect. 2017;125(9):097007.PubMedGoogle ScholarCrossref
39.
Bjørk  M, Riedel  B, Spigset  O,  et al.  Association of folic acid supplementation during pregnancy with the risk of autistic traits in children exposed to antiepileptic drugs in utero.  JAMA Neurol. 2018;75(2):160-168.PubMedGoogle ScholarCrossref
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.

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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