Association of gestational maternal hypothyroxinemia and increased autism risk

Authors

  • Gustavo C. Román MD,

    Corresponding author
    1. Methodist Neurological Institute, Houston, TX
    2. Department of Neurology, Weill Cornell Medical College, New York, NY
    • Address correspondence to Dr Román, Methodist Neurological Institute, 6560 Fannin Street, Suite 802, Houston, TX 77030. E-mail: GCRoman@tmhs.org

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  • Akhgar Ghassabian MD, PhD,

    1. Generation R Study Group, Rotterdam, the Netherlands
    2. Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
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  • Jacoba J. Bongers-Schokking MD, PhD,

    1. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
    2. Department of Endocrinology, Erasmus University Medical Center, Rotterdam, the Netherlands
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  • Vincent W. V. Jaddoe MD, PhD,

    1. Generation R Study Group, Rotterdam, the Netherlands
    2. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
    3. Department of Pediatrics, Erasmus University Medical Center, Rotterdam, the Netherlands
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  • Albert Hofman MD, PhD,

    1. Generation R Study Group, Rotterdam, the Netherlands
    2. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
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  • Yolanda B. de Rijke PhD,

    1. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
    2. Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands
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  • Frank C. Verhulst MD, PhD,

    1. Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
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  • Henning Tiemeier MD, PhD

    1. Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
    2. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
    3. Department of Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
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Abstract

Objective

Transient gestational hypothyroxinemia in rodents induces cortical neuronal migration brain lesions resembling those of autism. We investigated the association between maternal hypothyroxinemia (gestational weeks 6–18) and autistic symptoms in children.

Methods

The mother-and-child cohort of the Generation R Study (Rotterdam, the Netherlands) began prenatal enrollment between 2002 and 2006. At a mean gestational age of 13.4 weeks (standard deviation = 1.9, range = 5.9–17.9), maternal thyroid function tests (serum thyrotropin [TSH], free thyroxine [fT4], and thyroid peroxidase [TPO] antibodies) were assessed in 5,100 women. We defined severe maternal hypothyroxinemia as fT4 < 5th percentile with normal TSH. Six years later, parents reported behavioral and emotional symptoms in 4,039 children (79%) using the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist and/or the Social Responsiveness Scale (SRS). We defined a probable autistic child by a PDP score > 98th percentile and SRS score in the top 5% of the sample (n = 81, 2.0%).

Results

Severe maternal hypothyroxinemia (n = 136) was associated with an almost 4-fold increase in the odds of having a probable autistic child (adjusted odds ratio = 3.89, 95% confidence interval [CI] = 1.83–8.20, p < 0.001). Using PDP scores, children of mothers with severe hypothyroxinemia had higher scores of autistic symptoms by age 6 years (adjusted B = 0.23, 95% CI = 0.03–0.37); SRS results were similar. No risk was found for children of TPO-antibody–positive mothers (n = 308).

Interpretation

We found a consistent association between severe, early gestation maternal hypothyroxinemia and autistic symptoms in offspring. Findings are concordant with epidemiological, biological, and experimental data on autism. Although these findings cannot establish causality, they open the possibility of preventive interventions. Ann Neurol 2013;74:733–742

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