Childhood Thyroid Function Reference Ranges and Determinants: A Literature Overview and a Prospective Cohort Study

Background: Reported cutoffs for childhood thyrotropin (TSH) and free thyroxine (fT4) reference ranges vary widely, and knowledge on the determinants of childhood thyroid function is sparse. This study aimed to summarize the existing studies on thyroid function reference ranges in children. Furthermore, the objective was to investigate the determinants of childhood TSH and fT4 concentration in a population based-prospective cohort. Methods: First, to identify studies on childhood thyroid reference ranges, The National Library of Medicine's PubMed, Embase, Ovid Medline, Web of Science, and Google Scholar databases were systematically searched. Second, in a non-selected sample of 4273 children (median age 6.0 years, range 4.9–9.1 years) from the cohort, the associations of age, sex, anthropometric characteristics, ethnicity, maternal education, and time and season at venipuncture were studied with TSH and fT4 concentrations. The study also investigated to what extent between-individual variations in the determinants of TSH and fT4 could influence the calculation of reference ranges. Results: Published reference ranges for TSH and fT4 differ per age range and within age ranges (cutoffs low TSH: 0.13 to >1 mIU/L; high TSH: 2.36 to >10 mIU/L; low fT4: 7.0 to >10 pmol/L; high fT4: 15.5 to >30 pmol/L). In the present cohort, weight, sex, and ethnicity were determinants of TSH (p ≤ 0.03) and fT4 concentrations (p ≤ 0.01), and height and time at venipuncture were determinants of TSH only (p < 0.0001). The between-individual variation depending on clinical determinants for TSH ranged between 0.64 and 0.96 mIU/L (total population 0.87 mIU/L) for the lower limit and 4.30 and 5.62 mIU/L (total population 5.20 mIU/L) for the upper limit, whereas for fT4, the lower limit ranged between 13.6 and 14.2 pmol/L (total population 13.8 pmol/L) and the upper limit ranged between 20.2 and 23.0 pmol/L (total population 20.8 pmol/L). Conclusions: Considerable differences exist in the reported reference ranges for childhood TSH and fT4 across and within age ranges and assays. The present cohort shows only a minimal association between TSH and fT4, suggesting that the hypothalamus–pituitary–thyroid axis remains unaffected by thyroid interfering factors. Various determinants of TSH and fT4 in children were identified, which accounted for a considerable variation of reference range cutoffs.