In developed countries, the introduction of screening programs for congenital hypothyroidism (CH) has enabled effective detection of this condition in neonates. In response to screening, the prevalence of CH has increased, particularly for patients with a eutopic (normally located) thyroid gland and a mild elevation in thyroid-stimulating hormone (TSH; hyperthyrotropinemia)¹⁾. The reasons for this may be related to lower screening thresholds compared to initial values, allowing for more effective detection of CH, and an increase in the number of premature infants as a result of development of reproductive technologies^2,3,4). Thyroid hormones play an important role in early neurodevelopment, and thus the early treatment of hypothyroidism is crucial^1,5,6). Although the long-term outcomes of mild hypothyroidism or hyperthyrotropinemia are not yet fully understood, low screening thresholds and early intervention can mean unnecessary or over-treatment of hyperthyrotropinemia or transient hypothyroidism (TH). Permanent CH (PH) usually results from thyroid dysgenesis (athyreosis, ectopic thyroid), whereas the underlying aetiologies of TH are not clear; however, suggested factors include iodine deficiency or excessive iodine intake, penetration of maternal thyroid auto-antibodies, preterm delivery, or immaturity of thyroid iodine organification^7,8,9). Current guidelines recommend treatment in patients less than 2 weeks of age if their venous free thyroxine (fT4) concentration is lower than average, or if their venous TSH concentration is higher than 20 mU/L, this age threshold is lower than that of previous guidelines^1,10). Generally, further investigations on aetiology are not performed at initial diagnosis, and re-evaluation at 3 years of age is recommended; thus, it is possible that patients with TH are for treated longer than necessary^1,10). A number of studies have been conducted to determine how best to discriminate between cases of TH and PH, when treatment should be stopped, and when reevaluation can be performed^11,12,13,14). Hypothyroidism due to thyroid aplasia and/or ectopic thyroid require L-thyroxine lifelong. Therefore if the infants are documented to have thyroid dysgenesis, L-thyroxine treatment is required. However, in case of hypothyroid infants with eutopic thyroid gland, definitive criteria have not yet been suggested.

In this study, we investigate the differences between TH and PH in patients with a eutopic thyroid gland, and attempt to identify factors enabling their distinction.

In the present study, the prevalence of TH was 39.4%, which is comparable with that in other recent studies which showed values of 38%-54.9%^{11,12,15,16,17)}. Based on this information, more than one-third of CH cases do not require lifelong medication. Therefore, markers that would allow early detection of TH are required.

In this retrospective review of pediatric patients with CH with a eutopic thyroid gland, initial venous TSH concentration, 12M dose, and 24M dose were significantly higher in PH than TH cases. Among these patients, a 12M and 24M dose >3.25 µg/kg indicated a higher chance of developing PH. Current guidelines recommend the administration of 10-15 µg/kg of L-thyroxine after the initial diagnosis of CH, followed by dose titration at 1- to 3-month intervals to maintain a venous TSH concentration within the average range¹⁾. Hong et al.¹¹⁾ states that the only difference between PH and TH is the L-thyroxine dose required. They showed that required doses are significantly lower in TH than in PH at 6 months, 12 months, 24 months, and 36 months of age, with doses of 3.3±1.2 µg/kg for TH and 4.8±1.3 µg/kg for PH at 12 months of age. Unuvar et al.¹²⁾ also suggest that only L-thyroxine dose can be used to distinguish between TH and PH, with values of 2.8±1.19 µg/kg for TH and 4.07±1.88 µg/kg for PH at 12 months of age given. These doses are comparable to those described here; however, their study population contained patients with thyroid dysgenesis, and the authors did not suggest an optimum cut-off dose in predicting TH. Thus, to the best of our knowledge, our study is the first to suggest a cut-off dose of L-thyroxine that would allow discrimination between babies with TH and PH in eutopic CH.

TSH concentrations in venous blood at initial diagnosis were higher for PH than TH in this study. This has also been shown in several other studies^12,17,18,19). Lim et al.¹⁷⁾ suggest a cut-off TSH level of 34 mU/L (sensitivity, 72%; specificity, 93%) for the prediction of PH. In the present study, cut-off TSH level was 28.4 mU/L with slightly higher sensitivity and lower specificity than that of Lim et al.¹⁷⁾. On the other hand, Rabbiosi et al.¹⁶⁾ suggest there is no difference in TSH concentration between PH and TH, although initial TSH concentrations might vary depending on when the blood sample was drawn. If the sampling was carried out too early, TSH levels may not have been sufficiently elevated. Therefore, TSH concentration at initial diagnosis cannot accurately predict the severity of CH.

Several reports have suggested that preterm and low birth weight infants have a higher tendency to have TH^{20,21,22,23,24)}. Preterm, low birth weight infants are usually critically ill and vulnerable to neurodevelopmental disability. Thus, even if their thyroid dysfunction is transient, L-thyroxine treatment is necessary. In the present study, 6 of the 9 preterm or low birth weight infants had PH. However, our results were not significant in predicting TH or PH.

Otherwise, the prevalence of thyroid dyshormonogenesis was 75% (31 from 40 patients with PH). It is various from 31.3% to 76.9% in several studies^11,12,17,25). These wide variety of prevalence might be due to the various ethnicity and whether perchlorate discharge test was done or not. We did not conduct perchlorate discharge test to infants with eutopic thyroid gland.

In contrast to past standards, current guidelines recommend early treatment with L-thyroxine (where possible at less than 2 weeks of age) when the venous TSH concentration is >20 mU/L irrespective of fT4 concentration, and "playing safe" by treating with L-thyroxine during early childhood when TSH levels are low (6-20 mU/L) and fT4 levels are normal¹⁾. In addition, once treatment is started, re-evaluation is not recommended until 3 years of age or older. This is based on the fact that myelination of the brain is completed by 36-40 months of age²⁶⁾, and that the child may be more co-operative during imaging. Thyroid scans require sedation, intravenous access, and should be carried out at least 5 days after L-thyroxine administration begins, and thus cannot be easily conducted for neonates at the initial diagnosis of CH. However, ultrasonography is not invasive, and can be easily performed for neonates, although it cannot identify dyshormonogenesis. Therefore, we suggest that neonates with a high likelihood of developing CH be treated immediately, and undergo thyroid ultrasonography. If the infants have thyroid dysgenesis, re-evaluation can be delayed until 3 years of age or over. According to the present study, the patients with eutopic thyroid gland requiring L-thyroxine >5.55 µg/kg at 12 months or >5.0 µg/kg have highly suggestive of PH, they should not be decreased the dose or carefully re-evaluated at 3 years of age. Patients requiring lower L-thyroxine doses tend to have TH at the re-evaluation of 3 years of age in some studies^16,25). Furthermore, if patients requiring lower than 1.9 µg/kg at 12 months and lower than 2.8 µg/kg at 24 months can be transient hypothyroidism in the present study. These patients could be tapered the dosage of L-thyroxine at 12 months or 24 months easily. In the present study if infants have a eutopic thyroid gland, and L-thyroxine doses <3.25 µg/kg are required at 12 months and 24 months of age, re-evaluation may be performed carefully by decreasing the dose of L-thyroxine by 30% for 2-3 weeks, and rechecking by TFT¹⁾. This study has several limitations. It involved a retrospective review of medical records. Although patients from 3 different hospitals were included, the relatively small study population hindered significance in our analyses. In addition, the sensitivity and specificity for the cut-off with the highest Youden index of the 12M and 24M dose in predicting PH were not particularly high; therefore, it cannot be used as a definitive standard. Further long-term studies on the benefits of L-thyroxine treatment in TH in relation to neurodevelopment are also required.

The results of this study suggest that infants with CH who require lower L-thyroxine doses by 12 months and 24 months of age are likely to have TH. Therefore, infants with CH requiring lower L-thyroxine doses (3.25 µg/kg at 12 months and 24 months) may be re-evaluated at 12 months or 24 months rather than 3 years of age by decreasing the dose of L-thyroxine.