Maternal Thyroid Function in Early Pregnancy and Child Neurodevelopmental Disorders: A Danish Nationwide Case-Cohort Study

Background: Maternal thyroid dysfunction may adversely affect fetal brain development, but more evidence is needed to refine this hypothesis. The aim of this study was to evaluate potential fetal programming by abnormal maternal thyroid function on child neurodevelopmental disorders. Methods: The design was a case-cohort study within the Danish National Birth Cohort (1997-2003). From the eligible cohort of 71,706 women, a random 12% sub-cohort (n = 7624) was selected, and all women (n = 2276) whose child was diagnosed with seizures, specific developmental disorder (SDD), autism spectrum disorder (ASD), and/or attention-deficit/hyperactivity disorder (ADHD) up to December 31, 2010, were identified. All women had a blood sample drawn in early pregnancy (median week 9), and the stored sample was used for measurement of free thyroxine and thyrotropin. Method- and week-specific reference ranges were used for classification of maternal thyroid function. A weighted Cox proportional hazards model was used to estimate adjusted hazard ratio (aHR) with 95% confidence intervals (CI) for neurodevelopmental disorders in children exposed to maternal thyroid dysfunction. Results: The overall frequency of abnormal maternal thyroid function was 12.5% in the sub-cohort and significantly higher among cases of ASD (17.9%; aHR = 1.5 [CI 1.1-2.1]), but not among other types of neurodevelopmental disorders (febrile seizures: 12.7%; epilepsy: 13.1%; SDD: 12.6%; and ADHD: 14.0%). However, evaluation of subtypes of maternal thyroid dysfunction showed that maternal overt hypothyroidism (thyrotropin >10 mIU/L) was a risk factor for epilepsy in the child (aHR = 3.5 [CI 1.2-10]), as was overt hyperthyroidism for cases diagnosed within the first year of life (aHR = 3.0 [CI 1.03-8.4]). Furthermore, both maternal hypothyroidism (aHR = 1.8 [CI 1.1-2.7]) and overt hyperthyroidism (aHR = 2.2 [CI 1.1-4.4]) were risk factors for ASD in the child, and isolated low free thyroxine was associated with ASD (aHR = 4.9 [CI 2.03-11.9]) and ADHD (aHR = 2.3 [CI 1.2-4.3]) in girls but not in boys. Conclusions: Abnormal maternal thyroid function in early pregnancy was associated with epilepsy, ASD, and ADHD in the child, but associations differed by subtypes of exposure and by child age and sex. More evidence on subtypes and severity of maternal thyroid function is needed, and alternative outcomes of child neurodevelopment may be warranted.