BACKGROUND: Congenital hypothyroidism (CH) comprises disorders of either the thyroid gland (CH-T) or the regulatory system stimulating the thyroid gland consisting of the hypothalamus and the pituitary gland (central CH, CH-C). CH results in a shortage of thyroid hormone, which is essential for brain development. For this reason, a neonatal screening program for CH was established in the Netherlands in 1981. The Dutch screening for CH is primarily based on thyroxine (T4) determination in filter paper blood spots, where for the lowest 20% of T4 concentrations, TSH is measured additionally to detect CH-T. Thyroxine binding globulin (TBG) is measured in the lowest 5% of T4 values. A calculated T4/TBG ratio serves as an indirect measure for free T4. A T4/TBG ratio ≤17 in the 2nd heelprick is indicative of CH-C. Having T4 as a primary marker enables us to identify a large portion of neonates with potential CH-C. However, reports of an increasing number of referrals due to the T4/TBG ratio require a critical evaluation and exploration of possible improvements of this screening parameter.
METHODS: We estimated the performance of the T4/TBG ratio as a screening marker for CH-C, in 1752 cases referred for CH in the period 2012-2017.
RESULTS: Of 903 referrals, CH-C was established in 28 neonates (true positive rate 3.1%) with a high number of false positives (875). The false positive rate increased between 2012-2015, and decreased again by 2017. Lowering the T4/TBG ratio cut-off value (COV) in the second heel prick to 16, 15, 14 and 13 respectively results in a reduction of 214, 440, 605 and 727 false positives, at the cost of an increase in false negatives of 2, 3, 6 and 7.
CONCLUSION: Screening for CH-C is mainly based on determination of the T4/TBG ratio. With this study we show that with this ratio cases of CH-C are detected, at the cost of a high number of false positive referrals. Lowering the T4/TBG ratio COV reduces the amount of referrals tremendously, with a limited increase of missed cases of CH-C and could thus improve the specificity of neonatal screening for CH.