Thyroid Hormones in Pregnancies At Elevated Risk of Autism Spectrum Disorders

Background:  There has been a long-standing speculation about the role of the hypothyroid state during pregnancy and risk of autism spectrum disorders (ASD) in the child.  Maternal thyroid autoimmune disease has been implicated in ASD.  Considering primarily toxicological evidence, a specific hypothesis about the role of maternal hypothyroxinemia was advanced.

Objectives:  To examine whether maternal thyroid hormones (thyroid stimulating hormone (TSH) and free thyroxin (fT4)) were in hypothyroid state (elevated TSH and depressed fT4) in mothers who previously gave birth to child with ASD compared with normative ranges from typical pregnancies in the US.

Methods: We determined levels of fT4 and TSH in samples of serum from the first 88 pregnant women enrolled in the Early Autism Risk Longitudinal Investigation (EARLI).  EARLI is a prospective pregnancy cohort study enrolling women who have previously given birth to a child subsequently diagnosed with autism.   Comprehensive data collection includes biospecimen collection throughout pregnancy.  Available 210 maternal pregnancy serum samples as of Feb-15-2011 were analyzed using standard immunoassays.  Levels of thyroid hormones were log-transformed prior to statistical analyses to account for skew in their distribution.  One-sided t-tests on trimester-specific logarithmic means were performed in reference to available normative ranges for the US (three reports).  Mixed effects models were used to correct for repeated measurements during pregnancy.

Results: The range of TSH and fT4 values and their variability were similar to what is seen in the normative pregnancy samples, although TSH appeared to be somewhat elevated in EARLI mothers. There were 13 (6%) measurements with TSH>3mIU/L and three measurements (1%) with TSH>5mIU/L suggesting a hypothyroid state in some women if the single reference range is used across trimesters.  There were no measurements with TSH<0.08mIU/L that would suggest a hyperthyroid state.  There was consistent evidence for elevated TSH in 2^nd trimester samples relative to reference ranges (n=123, median 1.47, IQR 0.99-1.89) with all p-values for one-sided t-tests <0.05.   The fT4 measurements were also depressed in 1^st and 2^nd trimesters relative to the general pregnancy population (p<0.01).  Consideration of repeated measurements of hormones in pregnant women using mixed effects models that accounted for within-mother random effect did not alter the overall pattern.

Conclusions: Comparisons to external reference ranges and clinical cut-off values for subclinical hypothyroidism revealed that high-risk pregnancies appear to be at an increased risk of deficiency in thyroid hormones.  Women enrolled in EARLI have a range of thyroid hormone levels detected in their prenatal serum, providing reassurance that it will be possible in the future to investigate variation in prenatal thyroid hormones in relation to child’s risk of ASD within a high-risk pregnancy cohort.