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Hypothyroxinemia During Gestation and Offspring Schizophrenia in a National Birth Cohort

  • David Gyllenberg
    Correspondence
    Address correspondence to: David Gyllenberg, M.D., Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, Unit 23, New York, NY, 10032.
    Affiliations
    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
    Affiliations
    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
    Affiliations
    National Institute for Health and Welfare, Oulu, Finland
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  • Susanna Hinkka-Yli-Salomäki
    Affiliations
    Department of Child Psychiatry, Faculty of Medicine, University of Turku
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  • Ian W. McKeague
    Affiliations
    Department of Biostatistics, Columbia University Mailman School of Public Health, New York, New York
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  • Alan S. Brown
    Affiliations
    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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      Abstract

      Background

      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.

      Methods

      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.

      Results

      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).

      Conclusions

      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.

      Keywords

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