Effect of low thyroid hormone bioavailability on childhood cognitive development: data from the Avon Longitudinal Study of Parents and Children birth cohort

Abstract

BackgroundHypothyroidism is associated with impaired cognitive development. Whether free thyroxine (T4) concentrations at the lower end of the reference range also have a negative effect is less clear. A common genetic variant, the Thr92Ala substitution in deiodinase-2 can exacerbate low free T4 concentrations by reducing intracellular conversion of free T4 to free tri-iodothyronine. We aimed to see whether low thyroid hormone bioavailability (free T4 in the lowest quartile and the Thr92Ala substitution in deiodinase-2) in childhood adversely affects cognitive development. MethodsThe data from this study come from a retrospective cross-sectional analysis in a population-based birth cohort study, the Avon Longitudinal Study of Parents and Children. Children had thyroid function tested at age 7 years and extensive cognitive assessments at age 8 years. We assessed the odds of having a lower end intelligence quotient (IQ) (<85) if an individual had low thyroid hormone bioavailability. Analyses were adjusted for age, sex, other thyroid hormone variables, and social class. Findings422 (13·5%) of 3127 children had the Thr92Ala substitution, with 116 children (3·71%) having the combination of free T4 in the lowest quartile and the Thr92Ala substitution. We noted a strong association between children with free T4 in the lowest quartile and the Thr92Ala substitution and lower mean IQ (p=0·008, t test). Individuals with free T4 in the lowest quartile and the Thr92Ala substitution were more likely to have a total IQ score below 85 than individuals with free T4 above the lowest quartile without the substitution (odds ratio 3·03, 95% CI 1·38–6·67; p=0·006). There was no association with IQ below 85 in individuals with free T4 in the lowest quartile without the substitution (1·07, 0·82–1·39; p=0·59). When we considered total IQ as a continuous variable, children with free T4 in the lowest quartile and the Thr92Ala substitution had a lower IQ than did those with free T4 above the lowest quartile without the substitution (β=−0·34, −0·64 to −0·04, p=0·03). InterpretationCommon genetic variation in the intracellular thyroid hormone action pathway seems to substantially modify the effect of low serum thyroid hormone concentrations on IQ. This finding suggests that thyroid hormone concentrations alone do not entirely reflect thyroid status and raises the possibility that thyroxine supplementation in at-risk children might improve cognitive outcomes. FundingBupa Research Foundation, British Thyroid Foundation.