Childhood Thyroid Function Reference Ranges and Determinants: A Literature Overview and a Prospective Cohort Study
Open accessAbstract
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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Cross-sectional studies generally show higher TSH upper limits in younger children (<5 years) compared with older children (≥5 years), with a gradual decline in TSH concentration towards adult age (15-18 years), and lower FT3 with higher increases in FT4 concentrations from age 4 years.
“Cross-sectional studies generally show higher TSH upper limits in younger children (<5 years) compared with older children (≥5 years), with a gradual decline in TSH concentration towards adult age (15-18 years), 119-124 and lower FT3 with higher increases in FT4 concentrations from age 4 years.[125][126][127][128]”
From Hypothyroidism (2024) · cites this paper as [119]
Overall, there is considerable variation between reference ranges by the platform used and age, with weight, sex, and genetic architecture also having an effect.
“Overall, there is considerable variation between reference ranges by the platform used and age, with weight, sex, and genetic architecture also having an effect. 119”
From Hypothyroidism (2024) · cites this paper as [119]
TSH showed ethnic-related variation, being higher in Caucasian children compared to children of African descent or in Jewish versus non-Jewish children.
“showed ethnic-related variation. For example, TSH was higher in Caucasian children compared to children of African descent [36] or in Jewish versus non-Jewish children [41].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [36]
Reference range variation in children was more pronounced in younger age brackets and grew narrower with increasing age.
“In addition, reference range variation was even more pronounced in the younger age brackets and grew narrower with increasing age.”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [36]
Cross-sectional studies generally show higher TSH upper limits in younger children (<5 years) compared to older children, with a gradual decline in TSH concentration as adult age is approached.
“Cross-sectional studies generally show higher TSH upper limits in younger children (< 5 years) compared to older children, with a gradual decline in TSH concentration as the adult age is approached [33, 36–39].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [36]
A systematic review of reference range studies in children showed TSH upper limit ranges as wide as 2.36-6.45 mIU/L in 11-20-year-olds, with FT4 lower and upper limits of 7.0-14.2 and 15.5-31.5 pmol/L, respectively.
“A systematic review of reference range studies in children showed TSH upper limit ranges as wide as 2.36–6.45 mIU/L in 11–20-year-olds with free thyroxine (FT4) lower and upper limits of 7.0–14.2 and 15.5–31.5 pmol/L, respectively [36].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [36]
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- Authors
- Önsesveren, I., Barjaktarovic, M., Chaker, L., de Rijke, Y. B., Jaddoe, V. W. V., van Santen, H. M., Visser, T. J., Peeters, R. P., & Korevaar, T. I. M.
- Affiliations
- Erasmus MC (NL)
- Erasmus Medical Center—Sophia Children's Hospital
- Erasmus MC - Sophia Children’s Hospital (NL)
- University Medical Center
- Corresponding author
- Peeters, Robin P.
- Venue
- Thyroid®
- Publisher
- SAGE Publications
- Published
- 2017-11
- Volume
- 27
- Issue
- 11
- Pages
- 1360-1369
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- OpenAlex
- W2758194849
- Cited by
- 58
- References
- 58
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 8 · 2023: 8 · 2022: 12 · 2021: 10 · 2020: 6 · 2019: 6 · 2018: 3
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Locations
- Thyroid (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- anthropometric factors, sex differences, ethnicity, between-person variation, pediatric endocrinology, children aged 6-9 years, maternal education
- MeSH terms
- Adolescent, Age Factors, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Predictive Value of Tests, Prospective Studies, Reference Values, Thyroid Function Tests, Thyroid Gland, Thyrotropin, Thyroxine, Reproducibility of Results, Biomarkers, Young Adult
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