Highlights
· Levothyroxine dose ≤3.03 μg/kg/day at 18 months predicts eligibility for early drug discontinuation. These findings may help identify candidates for early discontinuation of levothyroxine therapy in children with congenital hypothyroidism.
Introduction
Congenital hypothyroidism is one of the most common endocrine diseases, occurring in approximately 1:4,000 to 1:2,000 individual [1,2]. Congenital hypothyroidism is a generic term for thyroid hormone deficiency due to abnormal thyroid gland development, such as aplastic and ectopic glands, or thyroid hormone synthesis defects, also known as dyshormonogenesis [3]. It is a major disease in infants and young children and causes permanent neurodevelopmental sequelae [4-6]. Since this disease can be prevented if treated in early infancy, early diagnosis is important. The need for early diagnosis has led to the introduction of neonatal screening programs worldwide [7], with South Korea introducing its neonatal screening test (NST) in the early 1990s [8]. The sensitivity of thyroid-stimulating hormone (TSH) assays has improved, and the cutoff value of TSH by NST has been decreased [9,10]. These changes may allow screening programs to detect milder forms of congenital hypothyroidism, resulting in an increase in the detected incidence. Previous studies have suggested that gestational age (GA), birth weight, and 'small for gestational age' are also associated with congenital hypothyroidism [11,12].
Compared to permanent congenital hypothyroidism (PCH), transient congenital hypothyroidism (TCH) does not require lifelong medication. Current guidelines recommend that treatment be initiated immediately after confirmatory diagnosis, and that the hypopituitary-thalamic-thyroid (HPT) axis be reevaluated after 3 years of age, as neuronal development is almost complete by 34 months of age [13]. Generally, investigation of the etiology of congenital hypothyroidism is not performed at initial diagnosis; thus, children with TCH might be maintained on levothyroxine longer than necessary. Another problem is the difficulty of medication compliance for the entire 3 years.
Recently, the European Society for Pediatric Endocrinology (ESPE), the American Academy of Pediatrics (AAP), and the Japanese Society for Pediatric Endocrinology revised guidelines for congenital hypothyroidism [13-15] and proposed that a child with gland in situ (GIS) who requires<3 μg/kg levothyroxine per day at the age of 6 months be reassessed at that time [15].
Based on these novel findings and the updated guidelines, further research is needed to determine whether a consensus can be reached in Korea. For convenience and safety in children with congenital hypothyroidism, it is necessary to differentiate between TCH and PCH as early as possible to determine candidates for early medication cessation. We aimed to investigate the factors associated with TCH and to identify the criteria that might allow early treatment discontinuation.
Materials and methods
1. Participants
We collected medical records of children visiting the Pediatric Endocrinology Clinic at Korea University Hospital between January 2013 and June 2023. A total of 438 patients with congenital hypothyroidism was selected using the 10th revision of the International Classification of Diseases diagnosis code E20.3. The clinical, laboratory, and auxological data were retrospectively reviewed. All registered children underwent thyroid ultrasonography or scanning. As most children initiate levothyroxine therapy after initial diagnosis without thyroid imaging, we included patients with both normal glands and gland dysplasia. A total of 160 patients was excluded owing to insufficient medical data, and another 107 patients were excluded owing to loss to follow-up. Patients with confirmed syndromes other than Down's syndrome (n=3) and 1 with central congenital hypothyroidism (n=1) were also excluded. A total of 167 patients with confirmed primary congenital hypothyroidism was enrolled in the final analysis (Fig. 1).
2. Study design and definition
The NST was performed within 2 or 3 days after birth, and those with a TSH level above the cutoff value (>20 μIU/mL) underwent repeated NST. Blood samples were obtained from newborns with abnormal NST results or suspected congenital hypothyroidism (e.g., prolonged jaundice or bradycardia) for confirmatory testing of TSH and free T4 (fT4). Infants born prematurely (<32 weeks gestation) or with very low birth weight underwent repeated NST at least twice at the ages of 7 days and 36 weeks GA because of their higher frequency of delayed TSH increase [13,16].
According to ESPE and AAP guidelines, congenital hypothyroidism was diagnosed if TSH levels were >20 μIU/mL or persistently >10 μIU/mL after 4 weeks of age or with low fT4 values (0.9 ng/dL). After diagnosis, treatment was immediately initiated at a dose of 10–15 μg/kg of levothyroxine. Thyroid function tests were performed every 3 months, and those with results within normal limits during treatment discontinued the medication before or at 3 years of age, and their HPT axis was reevaluated. Children who were not removed from medication remained on treatment for 3 years according to the guidelines. Thyroid imaging and functional tests were performed after levothyroxine treatment was stopped for 1 month. If there were no drug cessation attempts among patients with PCH, data at 3 years of age were used instead of data at the time of discontinuation.
PCH was defined as a TSH level > 10 μIU/mL within 6 months of discontinuing and resuming levothyroxine treatment [17]. A TSH level > 10 μIU/mL during ongoing continuous treatment or evidence of ectopic gland or aplastic gland on imaging was also classified as PCH. In contrast, TCH was defined as TSH levels remaining<10 μIU/mL without levothyroxine treatment. Among TCH, patients who could discontinue treatment at 2 years of age were categorized as the "early-off " group, whereas patients who stopped taking medication at 3 years of age were categorized as the "on-time off " group.
Clinical characteristics, including GA, birth weight, thyroid function test results at each visit, and levothyroxine doses during follow-up, were compared between the TCH and PCH groups. We analyzed the predictors of TCH and early levothyroxine withdrawal using a multivariate adjusted analysis.
3. Laboratory measurements
Serum TSH and fT4 levels were measured using radioimmunoassays (Beckman Coulter, Brea, CA, USA). Our laboratory reference ranges were 0.89–1.79 ng/dl for fT4 and 0.17–4.05 μIU/mL for TSH. Analytical sensitivities were 0.03 ng/dL for fT4 and 0.04 μIU/mL for TSH. The intra-assay coefficients of variation (CVs) were 3.06%–10.29% for fT4 and 2.5%–3.7% for TSH, while the inter-assay CVs were 2.54%–7.58% for fT4 and 2.8%–8.6% for TSH.
4. Statistical analysis
Quantitative data are presented as mean±standard deviation or median (range), while qualitative data are presented as frequency (%). Student t-test and chi-square test were used to compare clinical characteristics between the TCH and PCH groups. As this was a longitudinal study and TCH was a time-dependent variable, we used multivariate Cox proportional hazards survival analysis with backward selection to identify the predictive factors associated with TCH and "early-off " success. Receiver operating characteristic (ROC) curve analyses were used to evaluate the optimum cutoff levothyroxine level, with early discontinuation as the dependent variable. Statistical significance was defined as P<0.05. All statistical analyses were performed using IBM SPSS Statistics ver. 27.0 (IBM Co.).
Results
1. Analysis of clinical and biochemical characteristics of children with congenital hypothyroidism
Of the 167 participants (99 boys and 68 girls), 96 (57.5%) were classified as having TCH and 71 (42.5%) as having PCH. The sex ratio was similar in the 2 groups (P=0.772). Preterm infants (<37 weeks) were more prevalent in the TCH group (33.3%) than in the PCH group (12.7%, P=0.002). In TCH, low birth weight infants (<2,500 g) accounted for 30.2%, which was higher than the 15.5% in PCH (P=0.034). The mean birth weight in the TCH group was lower than that of the PCH group (2.72±0.93 kg vs. 3.01±0.70 kg, P=0.028). Maternal hypothyroidism was more frequent in the TCH group (26.0%) than in the PCH group (5.6%, P=0.001). All patients with TCH had eutopic glands. On the contrary, of the 71 patients with PCH, 9 (12.7%) had thyroid agenesis and 8 (11.2%) had ectopic gland. PCH participants exhibited significantly higher TSH levels by NST (35.6, 4.9–100 μIU/mL) compared to TCH members (19.8, 0.7–100 μIU/mL, P<0.001), but initial serum TSH and fT4 levels were not significantly different between the 2 groups. Although the levothyroxine dose (per kilogram of body weight) at the start of therapy was similar in the groups, subsequent levothyroxine doses during the treatment period were significantly lower in the TCH group. Furthermore, TSH levels at the time of drug discontinuation were higher in PCH than in TCH (3.11±3.46 μIU/mL vs. 2.24±1.51 μIU/mL, P=0.030) (Table 1).
2. Predictive factors associated with TCH
Univariate Cox analysis showed that premature birth, low birth weight, maternal hypothyroidism, lower TSH levels, and levothyroxine dose during treatment were all statistically associated with TCH. In the multivariate analysis, preterm birth and levothyroxine dose at the age of 24 months remained significant predictors of TCH diagnosis (Table 2).
3. Comparison of clinical characteristics between early-off and on-time off groups in TCH
Of the 96 patients diagnosed with TCH, 26 (27.1%) attempted to discontinue treatment before 2 years of age. The mean GA was lower in the "early-off " group than in the "on-time off " group (35.0±4.7 weeks vs. 37.1±4.0 weeks, P=0.029). TSH concentration as determined by NST was lower in the "early-off " group than in the "on-time off " group, but the difference was not significant (13.35 μIU/mL vs. 22.21 μIU/mL, P=0.076). Additionally, there were no differences in the serum TSH and fT4 levels at diagnosis or at the time of drug discontinuation between the 2 groups. The "early-off " group required lower levothyroxine doses than the "on-time off " group, except at the time of treatment initiation (Table 3). Fifteen children (57.7%) in the "early-off " group required no increase of levothyroxine doses over time, 5 children (19.2%) who required reduction of medication at least once, and only 6 subjects (23.1%) who needed to increase the daily dose as they aged, but none of them required more than 50 mcg/kg/day of levothyroxine.
4. Identification of factors associated with successful early discontinuation of treatment in TCH
In the multivariate Cox analysis, the levothyroxine dose at 18 months of age was a significant predictor of early discontinuation success (adjusted hazard ratio, 0.357; 95% confidence interval [CI], 0.216–0.590; P<0.001) (Table 4). We plotted an ROC curve to identify the levothyroxine cutoff value at 18 months, which was suggestive of successful early discontinuation. A levothyroxine dose of 3.03 μg/kg/day could suggest discontinuation success and demonstrated a 75.0% sensitivity and 72.9% specificity, with an area under the ROC curve of 0.778 (95% CI, 0.685–0.926; P<0.001) (Fig. 2).
Discussion
In this study, the TCH group showed lower GA and TSH levels by NST compared to the PCH group and required lower doses of levothyroxine during the entire treatment period. Furthermore, a lower levothyroxine dose at 18 months of age could be a significant predictor of early treatment discontinuation.
Previous studies reported a TCH prevalence ranging from 33% to 54.9% [18-22]. This wide range of prevalence can be explained by different inclusion criteria across studies. Sample size, proportion of premature infants, ethnicity, and excessive screening tests also contributed to these variations. In the present study, the proportion of patients with TCH among all congenital hypothyroidism was 58.1%. The reason for this relatively high prevalence was that many premature infants were included, and elevated TSH levels are more likely to be detected in premature babies who underwent regular examinations than in full-term infants who are not examined as often.
Many studies have been conducted to identify the predictors of TCH. In previously reported studies, the mean weight and GA were significantly lower in TCH cases than in PCH cases [18,23]. Our study results are consistent with these results. Some studies have reported that TSH levels measured by the NST are significantly lower in patients with TCH than in patients with PCH [18,22], and our results demonstrated the same trend.
However, the value of serum TSH levels in predicting TCH remains controversial. Some authors have demonstrated that initial TSH concentrations might allow a distinction between TCH and PCH groups [21,23-25]. In contrast, other studies have reported that TSH levels at diagnosis do not seem to be helpful in predicting TCH [19,26]. This was probably because our study included children with high TSH concentrations despite having been diagnosed with TCH. Nonetheless, there was no significant difference in clinical characteristics among the TCH group with high TSH levels. These results suggest that TSH levels in confirmatory tests did not seem to be able to accurately distinguish between PCH and TCH. Therefore, additional research with a larger study group is needed.
Previous studies have reported that participants with TCH need lower levothyroxine doses at 3 years of age than participants with PCH [24]. Studies have also reported that children with TCH are likely to require lower levothyroxine to maintain normal thyroid function tests during treatment [20,23]. Messina et al. [19] demonstrated no increase in levothyroxine dose per kilogram of body weight from the start of treatment over time in TCH cases and reported that levothyroxine requirements<2.70 μg/kg/day at 12 months or at 24 months are highly suggestive of TCH. However, in the present study, there was no case in which medication was discontinued before 2 years of age. Furthermore, clinically, considering discontinuation of levothyroxine before 1 year of age is a large burden to endocrinologists. Therefore, we included those who stopped medication before 2 years of age as the early discontinuation group. Our results showed that need for lower doses of levothyroxine during treatment was likely to be indicative of TCH. In univariate analysis, levothyroxine doses for all periods were significant. On the other hand, multivariate analysis showed a significant P-value only for levothyroxine at 2 years of age. This suggested lower dose of levothyroxine at 2 years of age was highly associated with TCH.
As previously mentioned, the prevalence of TCH is approximately 33%. This means that at least 1 in 3 children with congenital hypothyroidism is receiving treatment for longer than necessary, and reliable markers are needed to detect TCH earlier. The number of patients with congenital hypothyroidism who do not require lifelong treatment is expected to increase gradually due to increased TCH incidence as a result of increasing detection of patients with mild TSH elevation or delayed TSH surge, particularly in premature infants [27]. With increasing interest in early drug discontinuation, many authors have suggested that treatment be discontinued before 3 years of age in children with suspected TCH [23]. The newly revised guidelines even recommend early discontinuation in children requiring<3 μg/kg per day at the age of 6 months in cases where GIS was confirmed radiologically [15]. In clinical practice, it is difficult for most patients to undergo prospective imaging studies before starting medication. Therefore, efforts have been made to identify clinical factors that can predict early discontinuation when imaging results cannot be obtained early. In a previous study conducted in Korea, the early-off group had lower serum TSH levels at diagnosis than the on-time discontinuation group [28]. However, in our study, there was no difference in fT4 and TSH levels at diagnosis between the early discontinuation and on-time discontinuation groups. In 96 participants with eutopic glands, we found a strong association between possibility of early drug withdrawal and levothyroxine dose at 18 months of age.
Our study has certain limitations. First, this study was retrospectively analyzed, so missing information and selection bias might have affected the results. Second, the participants did not represent all Korean children, and the sample size was relatively small. Third, the sensitivity and specificity of the cutoff value for levothyroxine dosage in the ROC curve were relatively low.
In conclusion, our study showed that lower GA and need for lower levothyroxine doses during treatment are highly suggestive of TCH. Those who require<3.03 μg/kg per day of levothyroxine at 18 months could undergo reevaluation of the hypothalamic-pituitary-thyroid axis at that time rather than waiting until 3 years of age.
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