Abstract

Objective

This study was conducted to assess the perspectives of pediatric endocrinologists in Türkiye about the management of congenital hypothyroidism (CH) and to analyze the potential impact of work environment and professional experience on different attitudes.

Methods

The members of the Turkish Society for Pediatric Endocrinology and Diabetes were invited to participate in an online survey. An evaluation was made after obtaining survey responses from 95 (19%) of 502 members.

Results

Participants’ mean age was 42.0±9.6 years, 46.3% of them were working in a university hospital, and 48.6% had >7 years of work experience. When the participants were asked about their approach to a 1-3-week-old neonate whose serum thyroid stimulating hormone (TSH) concentration was 6-20 mU/L with a serum-free thyroxine (FT4) concentration within the age-specific reference interval, 97.7% of the participants preferred to monitor without medication. Only 24% of physicians consider starting treatment immediately if the serum TSH concentration is 20-40 mU/L with a normal FT4 level. While 5.3% of participants preferred dual imaging (ultrasound and scintigraphy), 90.5% requested only thyroid ultrasound for etiological investigation. When considering the discontinuation of levothyroxine (LT4) in patients with a normal thyroid gland and a low LT4 dose, 28.4% of the participants stated that treatment should be stopped at the earliest at the age of 3 years, 16.8% at 2 years, 5.3% at 1 year, 16.8% at 6 months, and 32.6% at any time if the TSH levels remain low despite the low dosage. Physicians with over 7 years of experience may discontinue medication if TSH is low, even with a lower dose, more frequently than those with less experience (p=0.011). There were no significant differences in the approach of the physicians between employees at university hospitals and other health institutions.

Conclusion

Although the attitudes of pediatric endocrinologists working in Türkiye towards the management of CH are generally consistent with the recommendations of international guidelines, their approaches to the treatment for isolated neonatal TSH elevation, thyroid imaging preferences and time to discontinue treatment differ significantly. These different attitudes, which are similar between all subgroups by experience and work setting, reflect the differences in local conditions in Türkiye and underline the need for a national consensus on the management of CH.

Introduction

Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency present at birth (1). Newborn screening programs (NSP) enabled early diagnosis before the onset of clinical symptoms, based on biochemical measurement of thyroid stimulating hormone (TSH) and thyroxine (T4). Since CH is one of the most common preventable causes  of intellectual disability worldwide but treatment largely mitigates this, prompt diagnosis and treatment are vital to optimize long-term outcomes (2). In 2021, an international consensus guideline on CH was published by the European Society for Pediatric Endocrinology and the European Society for Endocrinology, to update the practice guidelines for the diagnosis and management of CH (3). The consensus guideline provided strong evidence-based recommendations for diagnosis and treatment. However, in situations with insufficient evidence, it makes weak recommendations based on expert opinion. For this reason, there may be differences in attitudes among physicians. In addition, alternative approaches may be needed in countries such as Türkiye, where transient neonatal hyperthyrotropinemia (NHT) and hypothyroidism are more common due to perinatal iodine deficiency or overload (4, 5, 6, 7).

The aim of this national study was to determine the attitudes of pediatric endocrinologists in Türkiye regarding the management of CH and to examine the effects of work environment and professional experience on differences in attitudes. To the best of our knowledge, this is the first study to investigate Turkish physicians’ attitudes toward CH management. We believe that the results obtained from this study may contribute to the development of a national consensus on the management of CH.

Methods

The survey was devised by six members of the Thyroid Working Group of the Turkish Society for Pediatric Endocrinology and Diabetes (TSPED). It was created in Google Forms based on the updated consensus guideline recommendations. The survey link, consisting of 24 questions, was sent to 502 members of TSPED via e-mail. While the initial four questions inquired about personal data, the subsequent questions assessed the practices of pediatric endocrinologists in diagnosing, treating, and monitoring CH. The entire survey is available as an online supplement (Supplementary File 1).

The study protocol was approved by the Local Ethics Committee of the University of Health Sciences Türkiye, Şişli Hamidiye Etfal Training and Research Hospital, Health Application and Research Center (approval no: 4459, date: 09/07/2024).

Statistical Analysis

Descriptive statistics of the data included mean, standard deviation, median and range, frequency, and rate values. The chi-square test was used to compare qualitative independent data between subgroups based on professional experience (less than or more than 7 years of work experience) or place of work (university hospital or other). When test conditions were not met, the Fisher’s exact test was used. Statistical analyses were performed using the SPSS, version 28.0 (IBM Inc., Armonk, NY, USA).

Results

Out of the 502 members questioned, 95 (19%) submitted valid surveys. Participants’ characteristics are shown in Table 1.

Table 2 shows the responses regarding treatment approaches for newborns with elevated TSH and normal serum free T4 (FT4) levels. When the participants were asked about their approach to a 1-3 week-old neonate whose serum TSH concentration is 6-20 mU/L with FT4 concentration within the age-specific reference interval, most of the participants (94.7%) preferred monitoring without medication and retesting 1 to 2 weeks later to re-evaluate the need for treatment. When the serum TSH concentration is between 20-40 mU/L, only 24% of physicians consider starting treatment immediately. In addition, 42% reported that they decided on treatment according to the FT4 level, while the remaining 28% stated that they followed these babies without any intervention. In the survey, when asked about the approach to a baby with TSH between 6-20 mU/L for 3-4 weeks, the responses regarding treatment and monitoring were similar, but the frequency of decisions based on thyroid imaging increased significantly from around 2% to more than 20% (Table 2).

When asked about their approach to initiating levothyroxine (LT4) dose, 18% of physicians preferred to start treatment with 10-15 µg/kg per day for each case, while 25% favored starting treatment with 5-15 µg/kg per day based on FT4 level. In addition, 57% preferred starting treatment with 5-15 µg/kg based on FT4 level and etiology. While 52.6% of physicians always prefer branded LT4, 47.4% do not care whether it is brand or generic. When asked about the approach to LT4-liothyronine (LT3)  combination therapy, 20% of the participants reported that they never used it; 80% reported that they could use it in cases with persistent TSH elevation. A 10% subgroup stated that LT4-LT3 treatment could also be used in cases of thyroid agenesis. When evaluating treatment response, 57% of the participants stated that the appropriate sample collection time for FT4 measurement was before taking LT4, while for 43% of the participants, at least 4 hours after taking LT4 was sufficient.

Attitudes towards determining the etiology of CH and possible associated problems are given in Table 3. In the etiological investigation of CH, 90.5% (n=86) of the participants preferred thyroid ultrasound (US) alone, 5.3% (n=5) preferred dual imaging (the combination of US and scintigraphy), while 4.2% (n=4) stated that they did not want routine imaging. No one requested scintigraphy alone for thyroid imaging. When the radioactive element used in scintigraphy was investigated, technetium-99m and iodine-123 were reported as 45% and 18%, respectively. However, 37% of physicians were not aware of which isotope was used. Lack of knowledge about the substance used in scintigraphy was higher in those with less than 7 years of experience (51.7%) than in those with more experience (14.3%) (p<0.05). This was one of the rare differences between the two subgroups (Figure 1). The most frequently requested tests (always/often) for the etiological evaluation of CH after thyroid US (96%) were thyroglobulin (71%), thyroid antibodies (42%), and urinary iodine levels (33%). In addition, 42% of physicians occasionally want to take knee X-rays to evaluate possible developmental effects of CH, while 58% never request it (Table 3). Only 4.2% of physicians request both echocardiography (ECHO) and abdominal US for all cases of CH, while 60-63% prefer these imaging studies only in the presence of dysmorphic findings on physical examination. Moreover, 22-29% of physicians state that abdominal US and ECHO are needed only in cases with thyroid dysgenesis (Table 3).

While 55% of the participants want genetic testing for patients with CH, 45% do not. Participants most commonly request genetic tests for patients with common accompanying anomalies or syndromic features (42%), those confirmed to have permanent CH (23.2%), and those found to have persistently high TSH (21%).

Fifty-three percent of physicians believe that the screening program should also cover central hypothyroidism cases, while 38% are undecided. The question “In which patient group would you consider a post-screening strategy?” was mostly answered as in premature babies (91%) by participants. Other respondents suggested, in order of frequency, sick babies (87.4%), infants with clinical suspicion of hypothyroidism (76.8%), low birthweight infants (72.6%), Down syndrome (48.4%), babies with congenital anomalies (40%) and twins (37.9%).

When asked about physicians’ approach to the timing of trial off therapy in patients with a normal thyroid gland and a low LT4 dose (<3 μg/kg/day), 28.4% of the participants stated that treatment should be stopped at the earliest at the age of 3 years, 16.8% at 2 years, 5.3% at 1 year, 16.8% at 6 months, and 32.6% at any time if the TSH levels remain low despite the low dosage. Physicians with over 7 years of experience were more likely to discontinue medication if the TSH was low, even with a lower LT4 dose, more frequently than those with less experience (p<0.05) (Figure 2). No significant difference was found when comparing other survey responses between groups with experience of ≤7 years and >7 years. Moreover, no significant difference was found between the survey responses of participants working in university hospitals and other healthcare institutions.

Discussion

The field of CH currently has a wealth of excellent guidelines and expert opinions. While these guidelines encompass various aspects of CH, clinicians may face challenges in evaluating the quality of evidence for specific situations related to CH (8). Thus, physicians may have different attitudes toward the management of CH. Working conditions and professional experience will affect these attitudes. Approaches may even vary between countries, depending on differences in local conditions. Therefore, there is a need to establish a national consensus for a common approach to CH in many countries, including Türkiye. The data obtained from this survey may stimulate the creation of such a consensus that could serve for Türkiye and as a model for similar countries.

Current consensus guidelines recommend starting treatment if venous TSH is above 20 mU/L even if the FT4 level is normal (3, 9, 10). This is an arbitrary threshold for treatment decisions and is based on expert opinion due to the lack of sufficient evidence. Despite the consensus recommendation, when the survey questions asked about TSH elevations of 20-40 mU/L in the first 3 weeks of life, only 24% of responding physicians stated that they would immediately start treatment in this case. In addition, 42% of the participants reported that they would take into account the FT4 level (in the lower or upper half of the reference range) for the treatment decision, and 28% would prefer follow-up without treatment. These responses indicate that most pediatric endocrinologists in Türkiye would not start treatment when serum TSH elevation is at a moderate level (20-40 mU/L). Likewise, if serum TSH is mildly elevated (6-20 mU/L), almost no one starts treatment.

The definition and management of NHT is unclear (11, 12, 13). NHT may be defined as an increase in serum TSH concentrations between 6 and 20 mU/L with normal FT4 concentrations in newborns (3, 10, 13). This description overlaps with the definition of subclinical (compensated) hypothyroidism (SCH) in childhood (14, 15). The term SCH implies that elevated TSH secretion occurs to compensate for insufficient hormone production due to an impairment in the hypothalamic-pituitary-thyroid (HPT) axis and that this condition must be treated. However, TSH elevation can occur outside the HPT feedback loop, for example in response to stress, such as the neonatal TSH surge after birth. This increased TSH concentration at birth usually returns to normal within 24-48 hours. However, in some newborns, recovery from elevated TSH concentrations may take longer, possibly due to delayed HPT axis maturation (16). This transient NHT state, usually accompanied by high FT4 levels, does not require treatment. Indeed, transient NHT are most commonly caused by maternal iodine deficiency and/or perinatal iodine exposure (13). Of course, iodine deficiency or excess increases TSH secretion by impairing T4 production, but it is usually a temporary condition that resolves itself within a few days or weeks. LT4 treatment is not necessary unless the serum FT4 levels fall below normal limits, indicating true hypothyroidism. In Türkiye, mild iodine deficiency is still an ongoing problem in pregnant women and nursing mothers (4, 5, 17, 18, 19, 20, 21, 22, 23). Perinatal iodine exposure is also common due to the use of iodine-containing antiseptics during delivery (5). In addition, the use of a TSH cutoff as low as 5.5 mU/L whole blood in the national NSP has led to more frequent detection of false positives and transient NHT cases (7). Therefore, pediatric endocrinologists working in Türkiye are familiar with iodine problems in their environments and frequently encounter cases of iodine-related transient NHT. It seems that this experience of physicians is reflected in the high rate of “follow-up without treatment” responses in the survey. These responses also suggest that each country should determine its own TSH threshold values ​​for treatment decisions in accordance with regional conditions. Otherwise, transferring guideline recommendations directly to daily practice may lead to unnecessary treatments, long-term follow-ups, and increased workload and costs.

Attitudes towards NHT lasting longer than 21 days varied among participants, with only 23% of participants reporting a preference for starting treatment immediately. As in the current consensus (3), physicians’ treatment decisions are based on FT4 level, TSH trend, or further investigations, especially thyroid imaging.

Although scintigraphy is the most accurate diagnostic test for determining the etiology of CH, this study showed that pediatric endocrinologists in Türkiye did not prefer scintigraphy or dual imaging. The preference for less invasive and faster-yielding tests in the diagnosis of CH may lead doctors to prefer scintigraphy less frequently. However, there may be other explanations for the 90% preference for the US alone. In Türkiye, the incidence of CH at birth is as high as 1/650 (24), and more than half of the cases consist of transient hypothyroidism (6, 7). On the other hand, in permanent CH, 40-80% of the patients have dyshormonogenesis, and this figure varies in direct proportion to the frequency of consanguineous marriage in the study area (6, 7, 25). In iodine-replete countries where the incidence of CH is relatively low and about 80% of cases are due to thyroid dysgenesis (1, 2), scintigraphy may be the first-choice imaging modality, as recommended by guidelines. Considering the high number of cases of transient NHT and CH, and permanent CH with gland in situ, scintigraphy for treatment decisions or etiological investigation would not be the first choice for Türkiye (26). Furthermore, the lack of easy access to scintigraphy in most centers may have caused this option to be chosen less. Thus, this perspective is reflected in the responses that the majority of physicians prefer US as the first choice imaging method. Moreover point of care US performed by endocrinologists can be helpful in this situations (27).

After thyroid US, the most frequently requested tests were thyroglobulin, thyroid antibodies and urinary iodine concentrations, which is consistent with the high prevalence of transient hypothyroidism in Türkiye, and possible causes, such as iodine deficiency or overload and maternal blocking antibodies. On the other hand, knee X-rays are rarely requested, indicating that the physicians focus on the etiological investigation of CH rather than its intrauterine effects. In addition, abdominal US and ECHO are occasionally requested in special cases such as dysmorphism or thyroid dysgenesis, which suggests that Turkish pediatric endocrinologists consider the cost-benefit ratio of expensive examinations.

The treatment goal is to quickly achieve euthyroidism and then maintain it consistently. Normalization of serum TSH and FT4 levels within 2 weeks after starting therapy appears to improve cognitive outcomes. Undertreatment in the first years of life is linked to adverse neurodevelopmental outcomes (28, 29). However, it is also important to avoid overtreatment, which may also be harmful (30). In the survey, only one fifth of physicians chose directly a starting LT4 dose of 10-15 µg/kg/day, while the majority preferred doses ranging from 5-15 µg/kg/day, depending on FT4 levels (very low to normal) and/or etiology (athyreosis or not). This attitude is consistent with guideline recommendations and reflects sensitivity to overtreatment and its potential deleterious effects on brain development.

The data indicating the preference for brand-name LT4 over its generic counterpart is inconclusive. However, taking personal experiences and expert opinions into account, the general agreement leans towards recommending the brand-name medication over the generic version (3). According to survey results, half of the participants indicated that it does not matter whether the molecule is original or not.

A subgroup of infants with CH displays variable degrees of thyroid hormone resistance with persistently elevated TSH levels despite high-normal or frankly elevated free T4 concentrations (31, 32). For these patients, adding LT3 to LT4 therapy can facilitate the normalization of TSH (33, 34). Indeed, 80% of the survey participants reported that they were able to use the LT4-LT3 combination in CH cases with persistent TSH elevation despite high-normal FT4 levels. Although this response does not mean that 80% of physicians routinely use LT3 treatment in cases of persistent TSH elevation, it does show that they are aware of this treatment option and may prefer it in some cases. Interestingly, 10% of physicians stated that they could also use LT3 in patients with thyroid agenesis. This response was attributed to the knowledge that central T4 resistance is more common in patients with thyroid dysgenesis (33).

Recent studies have shown that transient CH is very common among CH patients with gland in situ (7, 35). The consensus suggested that early treatment withdrawal to assess the necessity of further treatment may be considered and done from the age of 6 months onward, particularly in patients with a gland in situ, a negative first-degree family history of CH, or in those requiring a low LT4 dose (<3 μg/kg per day) (3). While 17% of physicians follow this recommendation, a larger group prefer to re-evaluate at any time if TSH is low regardless of LT4 doses. The preference for early cessation of treatment is probably based on the physicians’ observations that thyroid dysfunction due to iodine deficiency or excess resolves in a relatively short time. At this point, the difference in experience is striking, as more senior physicians are more likely to discontinue LT4 therapy whenever the possibility of overtreatment appears, regardless of guideline recommendations and therefore a time limit. In the entire survey, it was observed that professional experience did not cause any difference in attitudes towards CH management, except for the time of drug withdrawal. Similarly, work dynamics (employed in university hospitals and others) did not seem to affect the participants’ responses.

In TSH-based neonatal screening programs, some groups of children, such as preterm or low birthweight and sick babies may not be able to generate an adequate TSH response in the first weeks of life. They pass their initial screening test but are at high risk for later development of mild CH (36, 37). Therefore, consensus strongly recommends re-screening for these groups. Moreover, in patients with Down’s syndrome, measuring TSH at the end of the neonatal period is a strong recommendation (3, 10). While almost all of the survey participants stated that they re-screened preterm and sick babies, only less than half re-screened for Down’s syndrome. The reason for this might be that since individuals with Down syndrome have frequent doctor visits, there is a higher likelihood of detecting high TSH levels during routine appointments. In contrast, approximately half of the participants reported re-screening babies with congenital anomalies, even though there is no recommendation in the consensus. CH appears to be associated with an increased risk of congenital malformations. In one study of 1420 infants with CH, extrathyroidal congenital malformations had a prevalence of 8.4% (38). Thus, babies with congenital malformations can also be re-screened.

Although there are not many studies in the literature reporting physicians’ attitudes toward CH, a survey study was published in the United Kingdom in 2009. A questionnaire survey of the British Society for Pediatric Endocrinology and Diabetes membership was undertaken to examine clinical practice in CH. Results were compared with published management guidelines from Europe and the United Kingdom. There were differences in preference for tablet or liquid preparation, method of tablet administration, time of seeing infant after notification, the interval between the initial-first follow-up visit, and initial LT4 dose (39). In a survey study conducted by Cielonko et al. (40) in 2017 with 44 respondents, differences were found regarding imaging methods and the dose of LT4.

Study Limitations

This study has some limitations. The main limitation is the low response rate for the survey, which may limit the generalizability of the findings to the broader population of pediatric endocrinologists in Türkiye. Those who choose not to respond may differ significantly in the results. Another limitation is that, like all other survey studies, respondents may not accurately reflect actual behaviors, attitudes, or experiences.

Conclusion

Although the attitudes of pediatric endocrinologists working in Türkiye towards the management of CH are generally consistent with the recommendations of international guidelines, their approaches to the treatment for isolated neonatal TSH elevation, thyroid imaging preferences and time to discontinue treatment differ significantly. These different attitudes, which were similar between subgroups defined by experience or work setting, reflect the differences in local conditions in Türkiye and underline the need for a national consensus on the management of CH.