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Childhood Thyroid Function Reference Ranges and Determinants: A Literature Overview and a Prospective Cohort Study
Ibrahim Önsesveren1,2,3, Mirjana Barjaktarovic1,2,3, Layal Chaker2,3
11 The Generation R Study Group, Erasmus Medical Center-Sophia Children's Hospital , Rotterdam, The Netherlands .
Insights
Childhood thyroid reference ranges for thyrotropin (TSH) and free thyroxine (fT4) vary widely. This study identified key determinants like weight, sex, and ethnicity influencing these ranges in children.
Area of Science:
- Pediatric endocrinology
- Clinical chemistry
- Reference range establishment
Background:
- Reported reference ranges for childhood thyroid-stimulating hormone (TSH) and free thyroxine (fT4) exhibit significant variability.
- Existing knowledge on factors influencing thyroid function in children is limited.
Purpose of the Study:
- To systematically review existing literature on childhood TSH and fT4 reference ranges.
- To identify determinants of TSH and fT4 concentrations in a pediatric cohort.
- To assess the impact of these determinants on reference range calculations.
Main Methods:
- Systematic literature search of major scientific databases (PubMed, Embase, etc.) for thyroid function reference ranges in children.
- Analysis of a prospective cohort of 4273 children (median age 6.0 years) to examine associations between TSH/fT4 levels and factors like age, sex, anthropometrics, ethnicity, maternal education, and venipuncture timing.
- Investigation into how individual variations in determinants affect reference range calculations.
Main Results:
- Published TSH and fT4 reference ranges show substantial differences across and within age groups.
- In the study cohort, weight, sex, and ethnicity were significant determinants for both TSH and fT4.
- Height and time of venipuncture influenced TSH levels, while minimal association was observed between TSH and fT4.
- Determinants accounted for considerable variation in reference range cutoffs for TSH and fT4.
Conclusions:
- Significant discrepancies exist in established childhood TSH and fT4 reference ranges.
- Factors such as weight, sex, and ethnicity are crucial determinants of thyroid function in children.
- These identified determinants explain a substantial portion of the variability observed in pediatric thyroid reference ranges.
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.
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