Hypothyroxinemia During Gestation and Offspring Schizophrenia in a National Birth Cohort

  • David Gyllenberg
    Address correspondence to: David Gyllenberg, M.D., Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, Unit 23, New York, NY, 10032.
    Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, New York

    Department of Child Psychiatry, Faculty of Medicine, University of Turku
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  • Andre Sourander
    Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, New York

    Department of Child Psychiatry, Faculty of Medicine, University of Turku

    Department of Child Psychiatry, Turku University Hospital, Turku
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  • Heljä-Marja Surcel
    National Institute for Health and Welfare, Oulu, Finland
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  • Susanna Hinkka-Yli-Salomäki
    Department of Child Psychiatry, Faculty of Medicine, University of Turku
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  • Ian W. McKeague
    Department of Biostatistics, Columbia University Mailman School of Public Health, New York, New York
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  • Alan S. Brown
    Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, New York

    Department of Epidemiology, Columbia University Mailman School of Public Health, New York, New York
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      Evidence from animal and human studies indicates that thyroid hormone deficiency during early gestation alters brain development. As schizophrenia is associated with prenatal brain insults and premorbid cognitive deficits, we tested the a priori hypothesis that serologically defined maternal thyroid deficiency during early gestation to mid-gestation is associated with schizophrenia in offspring.


      The investigation is based on the Finnish Prenatal Study of Schizophrenia, a nested case-control study that included archived maternal sera from virtually all pregnancies since 1983 (N = >1 million). We identified all offspring in the cohort with a diagnosis of schizophrenia based on the national inpatient and outpatient register and matched them on sex, date of birth, and residence in Finland at time of onset of the case to comparison subjects (1:1) from the cohort. Maternal sera of 1010 case-control pairs were assessed for free thyroxine, and sera of 948 case-control pairs were assessed for thyroid-stimulating hormone.


      Maternal hypothyroxinemia (free thyroxine ≤10th percentile, normal thyroid-stimulating hormone) was associated with an increased odds of schizophrenia (odds ratio = 1.75, 95% confidence interval = 1.22–2.50, p = .002). When adjusted for maternal psychiatric history, province of birth, and maternal smoking during pregnancy, the association remained significant (odds ratio = 1.70, 95% confidence interval = 1.13–2.55, p = .010).


      In a large, national birth cohort, prospectively documented hypothyroxinemia during early gestation to mid-gestation was associated with increased odds of schizophrenia in offspring. This information can inform translational studies of maternal hypothyroxinemia examining molecular and cellular deviations relevant to schizophrenia.


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        • Henrichs J.
        • Ghassabian A.
        • Peeters R.P.
        • Tiemeier H.
        Maternal hypothyroxinemia and effects on cognitive functioning in childhood: How and why?.
        Clin Endocrinol (Oxf). 2013; 79: 152-162
        • Zoeller R.T.
        • Rovet J.
        Timing of thyroid hormone action in the developing brain: Clinical observations and experimental findings.
        J Neuroendocrinol. 2004; 16: 809-818
        • Gilbert M.E.
        • Rovet J.
        • Chen Z.
        • Koibuchi N.
        Developmental thyroid hormone disruption: Prevalence, environmental contaminants and neurodevelopmental consequences.
        Neurotoxicology. 2012; 33: 842-852
        • Auso E.
        • Lavado-Autric R.
        • Cuevas E.
        • Del Rey F.E.
        • Morreale De Escobar G.
        • Berbel P.
        A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration.
        Endocrinology. 2004; 145: 4037-4047
        • de Escobar G.M.
        • Obregon M.J.
        • del Rey F.E.
        Maternal thyroid hormones early in pregnancy and fetal brain development.
        Best Pract Res Clin Endocrinol Metab. 2004; 18: 225-248
        • Calvo R.M.
        • Jauniaux E.
        • Gulbis B.
        • Asuncion M.
        • Gervy C.
        • Contempre B.
        • et al.
        Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development.
        J Clin Endocrinol Metab. 2002; 87: 1768-1777
        • Haddow J.E.
        • Palomaki G.E.
        • Allan W.C.
        • Williams J.R.
        • Knight G.J.
        • Gagnon J.
        • et al.
        Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.
        N Engl J Med. 1999; 341: 549-555
        • Willoughby K.A.
        • McAndrews M.P.
        • Rovet J.F.
        Effects of maternal hypothyroidism on offspring hippocampus and memory.
        Thyroid. 2014; 24: 576-584
        • Pop V.J.
        • Kuijpens J.L.
        • van Baar A.L.
        • Verkerk G.
        • van Son M.M.
        • de Vijlder J.J.
        • et al.
        Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy.
        Clin Endocrinol (Oxf). 1999; 50: 149-155
        • Li Y.
        • Shan Z.
        • Teng W.
        • Yu X.
        • Fan C.
        • Teng X.
        • et al.
        Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25-30 months.
        Clin Endocrinol (Oxf). 2010; 72: 825-829
        • Henrichs J.
        • Bongers-Schokking J.J.
        • Schenk J.J.
        • Ghassabian A.
        • Schmidt H.G.
        • Visser T.J.
        • et al.
        Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: The generation R study.
        J Clin Endocrinol Metab. 2010; 95: 4227-4234
        • Welham J.
        • Isohanni M.
        • Jones P.
        • McGrath J.
        The antecedents of schizophrenia: A review of birth cohort studies.
        Schizophr Bull. 2009; 35: 603-623
        • Canetta S.
        • Sourander A.
        • Surcel H.M.
        • Hinkka-Yli-Salomäki S.
        • Leiviska J.
        • Kellendonk C.
        • et al.
        Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort.
        Am J Psychiatry. 2014; 171: 960-968
        • M’kikyro T.
        • Isohanni M.
        • Moring J.
        • Hakko H.
        • Hovatta I.
        • Lönnqvist J.
        Accuracy of register-based schizophrenia diagnoses in a genetic study.
        Eur Psychiatry. 1998; 13: 57-62
        • Stagnaro-Green A.
        • Abalovich M.
        • Alexander E.
        • Azizi F.
        • Mestman J.
        • Negro R.
        • et al.
        Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum.
        Thyroid. 2011; 21: 1081-1125
        • Männisto T.
        • Surcel H.M.
        • Ruokonen A.
        • Vaarasmaki M.
        • Pouta A.
        • Bloigu A.
        • et al.
        Early pregnancy reference intervals of thyroid hormone concentrations in a thyroid antibody-negative pregnant population.
        Thyroid. 2011; 21: 291-298
        • Männisto T.
        • Surcel H.M.
        • Bloigu A.
        • Ruokonen A.
        • Hartikainen A.L.
        • Järvelin M.R.
        • et al.
        The effect of freezing, thawing, and short- and long-term storage on serum thyrotropin, thyroid hormones, and thyroid autoantibodies: Implications for analyzing samples stored in serum banks.
        Clin Chem. 2007; 53: 1986-1987
        • van Os J.
        • Kapur S.
        Lancet. 2009; 374: 635-645
        • Cannon M.
        • Jones P.B.
        • Murray R.M.
        Obstetric complications and schizophrenia: Historical and meta-analytic review.
        Am J Psychiatry. 2002; 159: 1080-1092
        • Brown A.S.
        The environment and susceptibility to schizophrenia.
        Prog Neurobiol. 2011; 93: 23-58
        • Haddow J.E.
        • McClain M.R.
        • Lambert-Messerlian G.
        • Palomaki G.E.
        • Canick J.A.
        • Cleary-Goldman J.
        • et al.
        Variability in thyroid-stimulating hormone suppression by human chorionic [corrected] gonadotropin during early pregnancy.
        J Clin Endocrinol Metab. 2008; 93: 3341-3347
        • Kooistra L.
        • Crawford S.
        • van Baar A.L.
        • Brouwers E.P.
        • Pop V.J.
        Neonatal effects of maternal hypothyroxinemia during early pregnancy.
        Pediatrics. 2006; 117: 161-167
        • Craig W.Y.
        • Allan W.C.
        • Kloza E.M.
        • Pulkkinen A.J.
        • Waisbren S.
        • Spratt D.I.
        • et al.
        Mid-gestational maternal free thyroxine concentration and offspring neurocognitive development at age two years.
        J Clin Endocrinol Metab. 2012; 97: E22-E28
        • Männisto T.
        • Vaarasmaki M.
        • Pouta A.
        • Hartikainen A.L.
        • Ruokonen A.
        • Surcel H.M.
        • et al.
        Thyroid dysfunction and autoantibodies during pregnancy as predictive factors of pregnancy complications and maternal morbidity in later life.
        J Clin Endocrinol Metab. 2010; 95: 1084-1094
        • Cleary-Goldman J.
        • Malone F.D.
        • Lambert-Messerlian G.
        • Sullivan L.
        • Canick J.
        • Porter T.F.
        • et al.
        Maternal thyroid hypofunction and pregnancy outcome.
        Obstet Gynecol. 2008; 112: 85-92
      1. Official Statistics of Finland (2015): Population structure. Available at: Accessed May 6, 2015.

        • Hernan M.A.
        • Hernandez-Diaz S.
        • Robins J.M.
        A structural approach to selection bias.
        Epidemiology. 2004; 15: 615-625
        • Greenland S.
        Modeling and variable selection in epidemiologic analysis.
        Am J Public Health. 1989; 79: 340-349
        • Rothman K.
        • Lash T.L.
        • Greenland S.
        Modern Epidemiology.
        3rd ed. Lippinicott Williams & Wilkins, Philadelphia2012
        • Stagnaro-Green A.
        • Pearce E.
        Thyroid disorders in pregnancy.
        Nat Rev Endocrinol. 2012; 8: 650-658
        • Rapoport J.L.
        • Giedd J.N.
        • Gogtay N.
        Neurodevelopmental model of schizophrenia: Update 2012.
        Mol Psychiatry. 2012; 17: 1228-1238
        • Insel T.R.
        Rethinking schizophrenia.
        Nature. 2010; 468: 187-193
        • Mangelsdorf D.J.
        • Thummel C.
        • Beato M.
        • Herrlich P.
        • Schutz G.
        • Umesono K.
        • et al.
        The nuclear receptor superfamily: The second decade.
        Cell. 1995; 83: 835-839
        • Bernal J.
        • Guadano-Ferraz A.
        • Morte B.
        Perspectives in the study of thyroid hormone action on brain development and function.
        Thyroid. 2003; 13: 1005-1012
        • Alvarez-Dolado M.
        • Ruiz M.
        • Del Rio J.A.
        • Alcantara S.
        • Burgaya F.
        • Sheldon M.
        • et al.
        Thyroid hormone regulates reelin and dab1 expression during brain development.
        J Neurosci. 1999; 19: 6979-6993
        • Lavado-Autric R.
        • Auso E.
        • Garcia-Velasco J.V.
        • Arufe Mdel C.
        • Escobar del Rey F.
        • Berbel P.
        • et al.
        Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny.
        J Clin Invest. 2003; 111: 1073-1082
        • Harrison P.J.
        The hippocampus in schizophrenia: A review of the neuropathological evidence and its pathophysiological implications.
        Psychopharmacology (Berl). 2004; 174: 151-162
        • Negro R.
        • Formoso G.
        • Mangieri T.
        • Pezzarossa A.
        • Dazzi D.
        • Hassan H.
        Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: Effects on obstetrical complications.
        J Clin Endocrinol Metab. 2006; 91: 2587-2591
        • MacSweeney D.
        • Timms P.
        • Johnson A.
        Thryo-endocrine pathology, obstetric morbidity and schizophrenia: Survey of a hundred families with a schizophrenic proband.
        Psychol Med. 1978; 8: 151-155
        • Zimmermann M.B.
        The effects of iodine deficiency in pregnancy and infancy.
        Paediatr Perinat Epidemiol. 2012; 26: 108-117
        • Brucker-Davis F.
        • Panaia-Ferrari P.
        • Gal J.
        • Fenichel P.
        • Hieronimus S.
        Iodine supplementation throughout pregnancy does not prevent the drop in FT4 in the second and third trimesters in women with normal initial thyroid function.
        Eur Thyroid J. 2013; 2: 187-194
        • Erkkola M.
        • Karppinen M.
        • Jarvinen A.
        • Knip M.
        • Virtanen S.M.
        Folate, vitamin D, and iron intakes are low among pregnant Finnish women.
        Eur J Clin Nutr. 1998; 52: 742-748
        • Schaefer C.A.
        • Brown A.S.
        • Wyatt R.J.
        • Kline J.
        • Begg M.D.
        • Bresnahan M.A.
        • et al.
        Maternal prepregnant body mass and risk of schizophrenia in adult offspring.
        Schizophr Bull. 2000; 26: 275-286
        • Klaning U.
        • Mortensen P.B.
        • Kyvik K.O.
        Increased occurrence of schizophrenia and other psychiatric illnesses among twins.
        Br J Psychiatry. 1996; 168: 688-692
        • Sirugo G.
        • Ashenbrenner J.
        • Odunsi K.
        • Morakinyo O.
        • Page G.
        No evidence of association between the genetic predisposition for dizygotic twinning and schizophrenia in West Africa.
        Schizophr Res. 2004; 70: 343-344
        • Gejman P.V.
        • Sanders A.R.
        • Kendler K.S.
        Genetics of schizophrenia: New findings and challenges.
        Annu Rev Genomics Hum Genet. 2011; 12: 121-144
        • Craddock N.
        • Owen M.J.
        The Kraepelinian dichotomy—going, going … but still not gone.
        Br J Psychiatry. 2010; 196: 92-95
        • Roman G.C.
        • Ghassabian A.
        • Bongers-Schokking J.J.
        • Jaddoe V.W.
        • Hofman A.
        • de Rijke Y.B.
        • et al.
        Association of gestational maternal hypothyroxinemia and increased autism risk.
        Ann Neurol. 2013; 74: 733-742
        • Brown A.S.
        • Surcel H.
        • Hinkka-Yli-Salomaki S.
        • Cheslack-Postava K.
        • Bao Y.
        • Sourander A.
        Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort.
        Prog Neuropsychopharmacol Biol Psychiatry. 2015; 57: 86-92
        • Cannon M.
        • Clarke M.C.
        • Cotter D.R.
        Priming the brain for psychosis: Maternal inflammation during fetal development and the risk of later psychiatric disorder.
        Am J Psychiatry. 2014; 171: 901-905
        • Giovanoli S.
        • Engler H.
        • Engler A.
        • Richetto J.
        • Voget M.
        • Willi R.
        • et al.
        Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice.
        Science. 2013; 339: 1095-1099