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Age-Specific Reference Intervals for Plasma Free Thyroxine and Thyrotropin in Term Neonates During the First Two
Jolanda C Naafs1, Charlotte A Heinen1, Nitash Zwaveling-Soonawala1
1Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Insights
New reference intervals for neonatal screening help diagnose congenital hypothyroidism (CH). Establishing age-specific ranges for free thyroxine (fT4) and thyrotropin (TSH) improves detection of CH, a preventable cause of developmental delay.
Area of Science:
- Neonatal endocrinology
- Clinical diagnostics
- Pediatric screening
Background:
- Congenital hypothyroidism (CH) is a key preventable cause of mental retardation.
- Accurate diagnosis of CH, particularly central CH (CH-C), relies on plasma free thyroxine (fT4) and thyrotropin (TSH) levels.
- Current neonatal reference intervals (RIs) for fT4 and TSH are insufficient, hindering effective CH diagnosis.
Purpose of the Study:
- To establish age-specific neonatal reference intervals (RIs) for plasma fT4 and TSH.
- To provide a reliable lower limit for fT4 RIs to aid in diagnosing CH-C.
- To support improved diagnostic accuracy in neonatal screening programs for CH.
Main Methods:
- Blood samples were collected from 146 healthy neonates at two time points: days 3-7 and days 13-15.
- Plasma fT4 and TSH concentrations were measured using an immunoassay (Cobas; Roche Diagnostics).
- Ninety-five percent RIs were calculated using standard statistical methods based on data distribution.
Main Results:
- Established 95% RIs for fT4: 20.5-37.1 pmol/L (days 3-7) and 15.3-26.5 pmol/L (days 13-15).
- Established 95% RIs for TSH: 1.0-8.4 mU/L (days 3-7) and 1.4-8.6 mU/L (days 13-15).
- The lower limit of the fT4 RI was found to be significantly higher than adult RIs.
Conclusions:
- The established neonatal RIs for fT4 and TSH are crucial for accurate CH diagnosis.
- The lower fT4 limit of 20.5 pmol/L (3-7 days) and 15.3 pmol/L (13-15 days) is vital for identifying CH-C.
- Recommendations include using assays with established neonatal RIs and considering the neonate's age in days for CH screening.
Abstract:
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. 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. 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). 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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