Correct neonatal free thyroxine reference intervals are crucial to detect central congenital hypothyroidism

Objective: In the Netherlands, after an abnormal newborn screening (NBS) result suggestive of central congenital hypothyroidism (CH), children are referred for confirmatory plasma-free thyroxine (fT4) measurement. Correct interpretation of these results relies on appropriate age- and assay-specific reference intervals (RI), which are often not available. The current study was performed to check whether the use of adult or other incorrect fT4 RIs during the post-screening work-up of neonates with an abnormal NBS had led to missed diagnoses of central CH. Design: Retrospective cohort study with prospective re-evaluation. Methods: Children born between 1 March 2018 and 1 April 2021 with an abnormal NBS result suggesting central CH were identified through the Dutch national screening registry (NEORAH). Children classified as having a “false positive” screening result based on post-screening confirmatory fT4 concentrations in the neonatal period were included if those fT4 concentrations were ≤ 3 pmol/L above the assay-specific lower limit of the adult RI. After obtaining informed consent, re-evaluation of thyroid function was performed. Results: Six children were identified and informed consent was obtained from four participants. Two out of four participants received a new diagnosis of central CH, including one case of multiple pituitary hormone deficiencies (MPHD). Conclusions: This study highlights the critical need for age- and assay-specific RIs for plasma fT4 to accurately diagnose central CH in the neonatal period.