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Maternal Thyroid Anomalies and Risk of ASD
Thyroid hormones are essential for appropriate fetal brain development. The hormones play pivotal roles in numerous key neurodevelopmental processes, including fetal neural cells migration and synapse formation. Some preliminary evidence suggests that hypothyroidism or hypothyroxinemia is associated with autism spectrum disorders (ASD), but available data are inconsistent and rely heavily on cross-sectional observations. Moreover, the fetus is dependent on maternal supply of thyroid hormones during the first months of gestation. Very low levels of maternal thyroid hormones have been associated with reduced IQ and cretinism in the child, but the effects of more minor maternal thyroid conditions are less clear.
Objectives:
To evaluate the risk of ASD in children born to mothers with thyroid anomalies, and the relation between maternal thyroid hormone levels during pregnancy and risk of ASD.
Methods:
The study included 436,188 singleton pregnancies ending in a live birth occurring between January 1, 1999 through December 31, 2013 in a large sick fund in Israel. Data on ASD diagnoses, maternal thyroid conditions, drug dispensing information and lab results were obtained through December 31,2016. Mothers with thyroid conditions were identified through ICD-9 codes with subsequent validation of the diagnoses through review of medication dispensing data and laboratory results. ASD cases were identified through ICD-9 codes with further verification of case status through review of medical records. Analyses of thyroid abnormality diagnoses were performed using generalized estimating equation (GEE) logistic regression models with adjustment for potential confounders. Analysis of gestational lab test results was performed using general additive models using penalized splines.
Results:
Mothers who had ever experienced hypothyroidism were at a higher risk of giving birth to a child with ASD compared to women without thyroid conditions (OR=1.24, 95% C.I:1.08-1.41). Further stratification based on the time of first diagnosis relative to the birthdate of the child suggested that the effect was mostly driven by diagnoses given prior to birth (OR=1.27, 1.08-1.50), although borderline statistically significant effects were also seen with diagnoses first given post-birth (1.18, 0.98-1.42). Analysis of pregnancy TSH levels and ASD risk suggested an inverted U-shaped dose-response curve, with higher risks at moderately-elevated levels but not at the highest levels. Associations between hyperthyroidism and ASD were less consistent.
Conclusions:
The results suggest that maternal hypothyroidism could be a risk factor for ASD. The attenuated effects at the highest pregnancy TSH levels could be due to the higher prevalence of women subsequently treated with thyroid replacements, or indicate other differences in this subgroup. This attenuation may suggest that starting treatment for mothers with borderline low thyroid dysfunction could be beneficial and potentially indicate that thyroid screening in pregnant women, especially those with a history of thyroid anomalies, should be considered. Since thyroid levels are highly influenced by numerous environmental triggers, the possible role of maternal thyroid anomalies in ASD needs further exploration.