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 on CH is primarily based on thyroxine (T4) determination in filter paper blood spots. In the lowest 20% of T4 values, TSH levels are measured. 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. Two consecutive abnormal T4/TBG ratios (≤17) are indicative of CH-C whereas increased TSH indicates CH-T. Having T4 as a primary marker enables us to identify a large portion of neonates with potential CH-C. However, increasing reports of false positive cases of CH-C require a critical evaluation and exploration of possible improvements of the current program.

METHODS: We estimated the contribution of the T4/TBG ratio to the poor specificity of CH screening in 1234 cases referred for CH in the period 2012-2015.

RESULTS: Of 708 referrals, CH-C was established in 17 neonates (true positive rate 2.4%) with a high number of false positives (691). Lowering the T4/TBG ratio cut-off value in the second heel prick to 16, 15, 14, 13 and 12 respectively results in a reduction of 176, 358, 483, 578 and 646 false positives, at the cost of an increase in false negatives of 2, 3, 4, 4 and 5.

CONCLUSION: Screening on CH-C is mainly based on determination of the T4/TBG ratio. With this study we show that this ratio is a major contributor to the high number of false positive CH-C referrals and thus to the poor specificity of CH screening. Lowering the ratio COV reduces the amount of referrals tremendously, while the increase of missed cases is limited. Thus, adaptation of the COV of the T4/TBG ratio is the first step in improving the specificity of neonatal screening on CH.