Age-Specific Reference Intervals for Plasma Free Thyroxine and Thyrotropin in Term Neonates During the First Two Weeks of Life
Abstract
Background: Congenital hypothyroidism (CH) is a common and preventable cause of mental retardation, which is detected in many neonatal screening programs. Upon suspicion of CH, plasma free thyroxine (fT4) and thyrotropin (TSH) concentrations are measured. CH can be of thyroidal or central origin (CH-T and CH-C, respectively). While CH-T diagnosis is based on an elevated TSH with a low fT4, CH-C diagnosis is based on a low fT4 without a clearly elevated TSH. Currently, reliable neonatal reference intervals (RIs) for plasma fT4 and TSH are lacking. Age-specific RIs would greatly improve the diagnostic process for CH, especially for CH-C. Our aim was to establish neonatal RIs for plasma fT4 and TSH in term neonates at day 3–7 ( t = 1) and day 13–15 ( t = 2). The study was particularly designed to provide a reliable fT4 lower limit of the RI to facilitate the diagnosis of CH-C. In the Netherlands, neonates are screened at day 3–7 of life. After a screening result suggestive for CH-C, pediatric consultation takes place on average at day 14. Thus, the time points were chosen accordingly. Methods: Venous blood was collected from 120 healthy neonates at each time point (94 participants provided blood samples at two time points; 52 participants provided a sample at t = 1 or t = 2). fT4 and TSH were measured using an immunoassay (Cobas; Roche Diagnostics). RIs were calculated using the 95% confidence interval for normally distributed data and the nonparametric percentile method if data were not normally distributed. Results: From 146 participants (49% female), ≥1 measurement was available. Ninety-five percent RIs for fT4 were 20.5–37.1 pmol/L (day 3–7) and 15.3–26.5 pmol/L (day 13–15). Ninety-five percent RIs for TSH were 1.0–8.4 mU/L (day 3–7) and 1.4–8.6 mU/L (day 13–15). Conclusions: Our results indicate an fT4 lower limit of the RI of 20.5 pmol/L at day 3–7 and 15.3 pmol/L at day 13–15. These lower limits are considerably higher than this assay's lower limit of the adult RI for fT4. In case CH is suspected, we recommend measuring fT4 and TSH using an assay with an established neonatal RI, taking into account the child's age in days.
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Serum TSH is very high in neonates.
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [9]
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References 35 · Cited by 21
- Authors
- Naafs, J. C., Heinen, C. A., Zwaveling-Soonawala, N., van der Schoor, S. R. D., van Tellingen, V., Heijboer, A. C., Fliers, E., Boelen, A., & van Trotsenburg, A. S. P.
- Affiliations
- Emma Kinderziekenhuis (NL)
- Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
- Department of Pediatrics and Neonatology, OLVG Oost, Amsterdam, the Netherlands.
- Department of Pediatrics, Catharina Hospital, Eindhoven, the Netherlands.
- Amsterdam University Medical Centers (NL)
- Venue
- Thyroid®
- Publisher
- SAGE Publications
- Published
- 2020-08
- Volume
- 30
- Issue
- 8
- Pages
- 1106-1111
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- OpenAlex
- W3009091560
- Semantic Scholar
- 980fe6f9a619375f11ae00ab3d4fa54fcdf8af6b
- Cited by
- 21
- References
- 35
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 6
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Thyroid (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- age-related reference values, thyroid-stimulating hormone, term infants, congenital hypothyroidism, newborn screening, neonatal thyroid function, percentile method, 95% confidence interval
- MeSH terms
- Adult, Age Factors, Congenital Hypothyroidism, Female, Humans, Immunoassay, Infant, Newborn, Male, Maternal Age, Netherlands, Pregnancy, Pregnancy Complications, Reference Values, Thyroid Function Tests, Thyroid Hormones, Thyrotropin, Thyroxine, Neonatal Screening, Linear Models, Term Birth
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