Maternal Sub-Clinical Hypothyroidism and Risk of Autistic Endophenotype in a Risk-Enriched Pregnancy Cohort

Background: There has been a long-standing speculation about prenatal hypothyroid state as an ASD risk factor.  Animal models suggest that maternal hypothyroidism is associated with dysregulated myelination, synaptogenesis, neuronal migration, and arborization in the fetus and there is clear evidence of associations with other disorders involving the brain.

Objectives: To investigate the association between the concentration of maternal thyroid hormones during pregnancy and early ASD-related phenotype in an ASD high-risk pregnancy cohort (the EARLI cohort – comprised of mothers of a child with ASD followed from the start of a subsequent pregnancy).  Specifically, we assessed whether elevated prenatal levels of thyroid stimulating hormone (TSH) and reduced levels of free thyroxin (fT4) (indicative of a hypothyroid state) were associated with elevated scores on the Autism Observation Scale for Infants (AOSI) at 12 months.

Methods: Thyroid hormone levels were measured in the earliest available prenatal serum samples for 180 mothers (29, 124, and 27 from the 1^st, 2^nd and 3^rd trimesters, respectively).   The association between ln(thyroid hormone concentration) and AOSI score alternatively parameterized as continuous (ln(total AOSI+1)) and dichotomous (total AOSI≥7) outcomes was estimated using regression approaches with adjustment for potential confounders.

Results: There were 56 (31%) children with total AOSI score ≥ 7. None of the mothers had both hormones outside clinical norms (TSH within 0.35 – 3.30 µ-IU/mL and fT4 within 0.56 – 1.64 ng/dL).  However, cases had higher maternal TSH and lower maternal fT4 concentrations compared to referents (table).  After adjusting for potential confounding by child’s sex and gestational age at birth, maternal pre-pregnancy BMI, parity, maternal age, race, ethnicity, and income, we still observed an increased risk of ASD endophenotype with increased concentration of TSH and decreased concentration of fT4. As shown in the figure (displaying predicted mean and 95%CI),within normative ranges a doubling of TSH concentration increases risk of a child having an AOSI ≥7 by about 35% (adjusted RR=1.4, 95%CI: 1.0-2.0) and the corresponding effect of halving fT4 doubled the risk (adjusted RR=1.9, 95%CI: 0.9-4.0).  The adjustment for potential confounders had negligible impact on effect estimates.  Similar results were seen when AOSI was parameterized as a continuous variable or dichotomized AOSI ≥ 6 (68 cases). 

Conclusions: Although effect estimates from this analysis are imprecise and should be interpreted with some caution, results support the hypothesis that subclinical maternal hypothyroidism is associated with early ASD-related phenotype.   Other findings from our cohort suggest that 12month AOSI is predictive of 36 month ASD diagnosis (i.e., AOSI≥7 having 70% sensitivity and 90% specificity for 36mos best estimate clinical diagnosis).   The relationship between subclinical maternal prenatal hypothyroidism and ASD risk remains of interest because maternal hypothyroidism is amenable to treatment and there are numerous environmental exposures implicated in causing hypothyroidism which could suggest strategies for primary prevention.