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Predictive factors for the diagnosis of permanent congenital hypothyroidism and its temporal changes in Sergipe, Brazil – A real-life retrospective study

ABSTRACT

Objectives:

Congenital hypothyroidism (CH) can be permanent (PCH) or transient (TCH). While the importance of thyroxine in myelination of the brain is undisputed, the benefits to neurodevelopmental outcomes of TCH treatment are controversial. Our objectives were to determine predictive factors for PCH and verify its prevalence changes over time.

Subjects and methods:

A total of 165 children were evaluated at 3 years of age to verify the diagnosis of PCH. 130 were submitted to a two-step cluster analysis, with the aim of grouping them into homogeneous clusters. The mean incidence of PCH and TCH was calculated from 2004 to 2010 and 2011 to 2015.

Results:

Sixty-six children were diagnosed with PCH, and 99 were diagnosed with TCH. Eighty-one percent of PCH children and all TCH children with thyroid imaging had glands in situ. Eighty children (61.5%) were in Cluster 1, 8 children (6.2%) were in Cluster 2 and 42 children (32.3%) were in Cluster 3. No children had PCH in Cluster 1, while 87.5% of children in Cluster 2 and all children in Cluster 3 had PCH. The most important predictor for PCH was the initial serum TSH, which was marginally higher in importance than the blood spot TSH, followed by the initial serum free T4. The mean incidence of PCH (odds ratio: 1.95, 95% CI 1.36 to 2.95, p < 0.0001) and TCH (odds ratio 1.33, 95%, CI 1.02 to 1.77, p = 0,038) increased over time.

Conclusions:

The most important PCH predictors are the initial serum TSH and the blood spot TSH. The mean incidence of both PCH and TCH in our series increased.

Keywords
Neonatal screening; congenital hypothyroidism; thyrotropin; thyroxine

INTRODUCTION

Congenital hypothyroidism (CH) can be permanent (PCH) due to thyroid dysgenesis or dyshormonogenesis or, in up to 35% of cases, transient (TCH) (11 Messina MF, Aversa T, Salzano G, Zirilli G, Sferlazzas C, De Luca F, et al. Early discrimination between transient and permanent congenital hypothyroidism in children with eutopic gland. Horm Res Paediatr. 2015;84:159-64.). Although gene mutations of DUOX2 and TSH-R have been described in TCH (22 De Deken X. DUOX defects and their roles in congenital hypothyroidism. Methods Mol Biol. 2019;1982:667-93.44 Peters C, Nicholas A, Schoenmakers E, Lyons G, Langham S, Serra EG, et al. DUOX2/DUOXA2 mutation frequently cause congenital hypothyroidism that evades detection on newborn screening in the united kingdom. Thyroid. 2019;29(6):790-7), most of these cases do not have a defined cause, with the iodine intake, the decrease in the cutoff levels of the neo-natal screening programs (NSP), and the time of blood spot collections being the factors initially suggested for the occurrence of nongenetic TCH cases (55 Ford GA, Denniston S, Sesser D, Skeels MR, LaFranchi SH. Transient versus Permanent Congenital Hypothyroidism after the Age of 3 Years in Infants Detected on the First versus Second Newborn Screening Test in Oregon, USA. Horm Res Paediatr. 2016;86(3):169-77.).

A neonatal screening program (NSP) for CH (CH-NSP) is one of the most notable milestones in public health. Since its inauguration by Dussault (66 Dussault JH. The anecdotal history of screening for congenital hypothyroidism. J Clin Endocrinol Metab. 1999;84:4332-4.) in Quebec-Canada in 1972, severe cases of CH with irreversible mental retardation have been abolished in countries with wide coverage CH-NSP. Currently, the focus is on ensuring the maximum neuromotor and intellectual development of those affected. To achieve this, an anticipation of the age of treatment and a reduction of cutoff points have been used worldwide. However, half a century later, some issues in the CH-NSP remain unresolved. Among these, the overtreatment of transient CH cases may have medical consequences and generate unnecessary concerns in affected families (77 Matejek N, Tittel SR, Haberland H, Rohrer T, Busemann EM, Jorch N, et al. Predictors of transient congenital primary hypothyroidism: data from the German registry for congenital hypothyroidism (AQUAPE “HypoDok”). Eur J Pediatr. 2021;180(8):2401-8.). The importance of thyroxine in myelination of the infant brain is indisputable, as has been recently shown in MRI studies (88 Rovet JF. The role of thyroid hormones for brain development and cognitive function. Endocr Dev. 2014;26:26-43.). Although the reason to detect severe CH is unequivocal, the benefit for neurodevelopmental outcomes when treating babies with modest TSH elevations and borderline free T4 (FT4) concentrations still generates discussions, with some studies showing a relationship between academic performance and neonatal TSH (99 Lain SJ, Bentley JP, Wiley V, Roberts CL, Jack M, Wilcken B, et al. Association between borderline neonatal thyroid-stimulating hormone concentrations and educational and developmental outcomes: a population-based record-linkage study. Lancet Diabetes Endocrinol. 2016;4(9):756-65.), while others do not (1010 Trumpff C, De Schepper J, Vanderfaeillie J, Vercruysse N, Van Oyen H, Moreno-Reyes R, et al. Thyroid-stimulating hormone (TSH) concentration at birth in Belgian neonates and cognitive development at preschool age. Nutrients. 2015;7:9018-32).

Another intriguing issue is the worldwide increased incidence of CH (1111 Fisher DA, Dussault JH, Foley TP Jr, Klein AH, LaFranchi S, Larsen PR, et al. Screening for congenital hypothyroidism: results of screening one million North American infants. J Pediatr. 1979;94(5):700-5.), especially with glands in situ (1212 Rabbiosi S, Vigone MC, Cortinovis F, Zamproni I, Fugazzaloa L, Persani L, et al. Congenital hypothyroidism with eutopic thyroid gland: analysis of clinical and biochemical features at diagnosis and after re-evaluation. J Clin Endocrinol Metab. 2013;98(4):1395-402). The reduction of the neonatal TSH cutoff values and the increased survival of premature and low birth weight children can contribute to this increase (1313 Deladoëy J, Ruel J, Giguère Y, Van Vliet G. Is the incidence of congenital hypothyroidism really increasing? A 20-year retrospective population-based study in Quebec. J Clin Endocrinol Metab. 2011;96(8):2422-9.). However, the reasons for this increase remain unclear, although genetic, epigenetic, and environmental factors have been proposed (1414 Corbetta C, Weber G, Cortinovis F, Calebiro D, Passoni A, Vigone MC, et al. A 7-year experience with low blood TSH cutoff levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism (CH). Clin Endocr. 2009;71:739-451818 Steinmaus CM. Perchlorate in Water Supplies: Sources, Exposures, and Health Effects. Curr Environ Health Rep. 2016;3(2):136-43.).

The Brazilian Health Ministry Policy established in 2001 the University Hospital of the Federal University of Sergipe (HU-UFS) as the unique entity to perform the NSP in the State of Sergipe, which has used the same cutoff point of neonatal bloodspot TSH (5.2 μU/mL) since its implementation. This allows an appropriate comparison of different time periods (1919 Ramalho RJR, Ramalho ARO, Oliveira CRP, Aguiar-Oliveira MH. Evolução do programa de triagem neonatal para o hipotireoidismo congênito e fenilcetonúria no Estado de Sergipe de 1995 a 2003. Arq Bras Endocrinol Metab. 2004;48(6):890-6.2121 Matos DM, Ramalho RJ, Carvalho BM, Almeida MA, Passos LF, Vasconcelos TT, et al. Evolution to permanent or transient conditions in children with positive neonatal TSH screening tests in Sergipe, Brazil. Arch Endocrinol Metab. 2016;60(5):450-6.). In a previous paper, we found that among children with serum initial TSH levels greater than 10 μU/mL (more than two-thirds of the cases had PCH), 13.5% had TCH. In children with initial serum TSH levels greater than 4.2 μU/mL and less than or equal to 10 μU/m, 13.8% had PCH, while 58.1% had TCH (2121 Matos DM, Ramalho RJ, Carvalho BM, Almeida MA, Passos LF, Vasconcelos TT, et al. Evolution to permanent or transient conditions in children with positive neonatal TSH screening tests in Sergipe, Brazil. Arch Endocrinol Metab. 2016;60(5):450-6.). The main objective of the present study was to assess predictive factors for the diagnosis of permanent congenital hypothyroidism in a newborn with abnormal neonatal blood spot TSH. An additional objective is to verify whether the incidence of permanent and transient CH has changed in the periods from 2004 to 2010 and from 2011 to 2015.

SUBJECTS AND METHODS

A descriptive, analytical, and retrospective study was carried out in children with abnormal screening tests in the CH-NSP in the state of Sergipe from 2011 to 2015 and followed at the outpatient clinics of the University Hospital of Federal University of Sergipe. According to our protocol, all children with abnormal neonatal TSH (TSH ≥ 5.2 µU/mL) were summoned for collection of TSH and total T4 and free t4 in blood: venous. If serum TSH was less than or equal to 4.2 µU/mL, with normal free T4, in two consecutive measurements, the patient was considered as normal and excluded. If serum TSH was between 4.21 and 10 µU/mL with normal free T4, the child was classified as having hyperthyrotropinemia. In those with serum TSH ≥ 10 µU/mL or between 4.21 and 10 µU/mL with low free T4, treatment was started, and children were referred to the pediatric endocrinology outpatient clinic. At the age of three years, those who had serum TSH greater than 10.0 µU/mL and who required high doses of levothyroxine were classified as PCH. In children requiring low doses and with no established etiology for CH, levothyroxine therapy was interrupted for a period of 30 days to measure TSH and free T4 to assess the permanence or transience of the condition.

The inclusion criteria were neonatal TSH (measured by the immunofluorimetric method, AutoDELFIA, Perkin-Elmer, Life-Sciences, Turku, Finland) higher than 5.2 µU/mL and confirmed serum TSH above 4.2 µU/mL (2121 Matos DM, Ramalho RJ, Carvalho BM, Almeida MA, Passos LF, Vasconcelos TT, et al. Evolution to permanent or transient conditions in children with positive neonatal TSH screening tests in Sergipe, Brazil. Arch Endocrinol Metab. 2016;60(5):450-6.). The exclusion criteria were absence of medical records in the outpatient facility of the University Hospital; loss of follow-up before the final diagnosis; and children with a final diagnosis of hyperthyrotropinaemia after the measurement of fT4. This is a permanent condition, with uncertain physiological impact, defined in children without levothyroxine replacement therapy, with serum TSH between 4.2 µU/mL and 10 µU/mL, but with normal fT4. The study variables were birth date, sex, origin, prematurity, neonatal blood spot TSH, initial serum TSH and free T4. PCH was defined by serum TSH greater than 10 µU/mL, regardless of fT4 values, or using levothyroxine, or without levothyroxine use with serum TSH between 4.2 µU/mL and 10 µU/mL, but free T4 less than 0.79 ng/dL. TCH was defined as a child initially screened as CH who normalized in the follow-up after levothyroxine withdrawal (serum TSH less than or equal to 4.2 µU/mL, free T4 greater than or equal to 0.79 ng/dL). The normal reference value for free T4 was ≥ 0.79 ng/dL.

Out of 172,547 newborns born from 2011 to 2015 (Sergipe Datasus-MS), 140,325 were screened by NSP-SE (81.32% coverage), of which 767 (0.54%) presented an abnormal neonatal bloodspot test (neonatal TSH greater than 5.2 µU/mL). Fifty-eight (7.5%) children were not located by the social service for the confirmatory serum test, and 391 (50.97%) children were excluded due to serum initial TSH lower than 4.2 µU/mL. The medical records of 315 remaining children were searched to assess follow-up and final diagnosis. Children whose medical records were missing or lost to follow-up before final diagnosis were excluded from the study. One hundred and sixty-five children (21.5% of altered neonatal bloodspot tests) were eligible for this study. In children in whom there was doubt about the permanent or temporary condition of CH, levothyroxine was suspended at age three to assess whether CH persisted after this suspension. Imaging techniques (ultrasound and/or thyroid scintigraphy) were performed in 88 children. These images were summarized in three groups: gland in situ, hyperplasia, and dysgenesis (agenesia and ectopic thyroid). The IRB Committee of the Federal University of Sergipe approved the research project under the number CAAE 43123021.0.0000.5546.

Statistical analysis

Shapiro-Wilk and Kolmogorov-Smirnov tests were used to verify the normality of the variables. The continuous variables exhibited a nonnormal distribution, and they were expressed as the median (interquartile distance). Differences between the PCH and TCH groups were analyzed by the Mann-Whitney test. Categorical variables were expressed as absolute frequencies and percentages and were compared by Fisher's exact test. The comparison of variables among the three thyroid imaging groups was performed by the independent-samples Kruskal-Wallis test, with pairwise comparisons.

In this paper, we used cluster analysis, which is a multivariate analysis that allows the identification of groups with homogeneous characteristics and can be used when there are at least three numerical variables. This technique disaggregates a set of objects into smaller subsets (clusters) according to their characteristics (variables). By using mathematical distance calculations, it is possible to assign a measure of proximity (similarity) between each object and clusters. Accordingly, the clusters formed so that the distances between the members of a cluster are minimal and the distances between the clusters are maximal.

The two-step cluster analysis method (2222 Kaufman L, Rousseeuw PJ, editors. Finding Groups in Data: An Introduction to Cluster Analysis. Hoboken, NJ: John Wiley & Sons, Inc.; 1990.) was used with categorical (PCH diagnosis) and continuous (neonatal blood spot TSH, serum initial TSH and serum initial fT4) variables. The log-likelihood method was used for distance measurements. The number of clusters to be formed was not specified in advance. We estimated the silhouette of cohesion and separation measures, a measure for the overall suitability of the found cluster structure. It ranges from -1 to 1 and is thus defined as follows: less than 0.25: no substantial structure; 0.26 to 0.50: weak structure; 0.51 to 0.70: fair structure; and 0.71 to 1.0: strong structure. Differences in characteristics between clusters were compared by the independent-samples Kruskal-Wallis test, with pairwise comparisons.

The mean incidence of each final condition was calculated by WinPepi version 4.0, dividing the number of affected children with PCH or TCH by the number of children screened during the period. The 95% confidence interval (CI): 95% CI and odds ratio (OR) were also registered. Statistical analysis was performed using IBM SPSS (Statistical Package for the Social Sciences), version 23.0, Chicago, IL, USA). The accepted level of significance was less than 0.05, and all tests were two-tailed.

RESULTS

Table 1 shows the possible predictive factors for the diagnosis of PCH in 66 children or TCH in 99 children. While the age of treatment onset and sex were similar, the levels of neonatal blood spot and serum initial TSH were higher and the levels of fT4 were lower in PCH than in TCH (p < 0.0001, in all comparisons).

Table 1
Possible predictive factors to the diagnosis of permanent (PCH) in 66 children, or transient (TCH) in 99 children, with congenital hypothyroidism

Table 2 shows the final diagnosis of PCH or TCH according to the increasing concentrations of serum initial TSH. Two-thirds of PCH and most HCT cases had an initial serum TSH between 4.2 and 20 µU/mL. Conversely, one-third of PCH and only 8% of TCH cases had initial serum TSH greater than 41 µU/mL This distribution of frequencies was highly different (p < 0.0001, Fisher's exact test).

Table 2
Final diagnosis of permanent (PCH) or transient (TCH) in according to the increasing concentrations of serum diagnosis TSH (µU/mL)

Table 3 shows the final diagnosis of PCH or transient TCH according to the decreasing concentrations of serum initial fT4. Half of the PCH and most THC cases had an initial ft4 between 0.79 and 1.16 ng/dL. Conversely, a third of PCH and a minority of TCH cases had an initial ft4 lower than 0.4 ng/dL. This distribution of frequencies was highly different (p < 0.0001, Fisher's exact test).

Table 3
Final diagnosis of permanent (PCH) or transient (TCH) in according to the decreasing concentrations of serum free T4 (ng/dL)

Out of 58 PCH cases, 54 (93.1%) were full-term, and four (6.9%) were preterm newborns. Out of 88 TCH cases, 81 (92%) were full-term, and seven (8.0%) were preterm newborns with similar frequency distributions (p = 0.541, Fisher's exact test).

Table 4 shows the thyroid morphology in 58 children with PCH and 30 with TCH. Most cases of PCH (81%) and all cases of TCH had glands in situ. This distribution of frequencies was different (p = 0.034, Fisher's exact test).

Table 4
Thyroid morphology in 58 children with permanent (PCH) and 30 with transient (TCH) congenital hypothyroidism

Table 5 shows the hormonal data according to thyroid morphology in 58 PCH and 30 TCH children. While TSH in blood spots in the serum increased from the gland in situ to hyperplasia and dysgenesis, the levels of fT4 were higher in the gland in situ in comparison to the other categories.

Table 5
Hormonal date in according to thyroid morphology in 58 children with permanent (PCH) and 30 with transient (TCH) congenital hypothyroidism

Table 6 shows the characteristics of the three discriminated clusters in 130 screened children and the number of permanent congenital hypothyroidism (PCH) cases in each cluster. Eighty (61.5%) of the newborns were located in Cluster 1, 8 (6.2%) in Cluster 2, and 42 (32.3%) in Cluster 3. No children had PCH in Cluster 1, while 87.5% of children in Cluster 2 and all children in Cluster 3 had PCH. The structure of this analysis was strong, with a medium silhouette value of 0.9. The analysis of the importance of predictors for PCH revealed that serum initial TSH was the most important (predictor importance, 1.00) and marginally more important than the neonatal blood spot TSH (predictor importance 0.97), followed by the serum initial fT4 (predictor importance 0.07).

Table 6
Characteristics of the clusters in 130 screened children and the number of permanent congenital hypothyroidism (PCH) in each cluster

From 2004 to 2010, out of 193,794 screened newborns, 46 had a diagnosis of PCH, with a mean incidence of 1:4,166. From 2011 to 2015, out of 140,325 screened newborns, 66 had a diagnosis of PCH, with a mean incidence of 1:2,126 (odds ratio: 1.95, 95% CI 1.36 to 2.95, p < 0.0001). From 2004 to 2010, out of 193,794 screened newborns, 102 had a diagnosis of TCH, with a mean incidence of 1:1,900. From 2011 to 2015, out of 140,325 screened newborns, 99 had a diagnosis of TCH, with a mean incidence of 1:1,1417 (odds ratio: 1.33, 95% CI 1.02 to 1.77, p = 0.038).

DISCUSSION

CH is a different disease after 50 years of CH-NSP. Before neonatal screening, it was a multisystem disease, with dermatologic, hematologic, cardiopulmonary, intestinal, and brain manifestations, marked hypometabolism, severe short stature, sometimes inability to maintain a standing position, pubertal delay, and marked mental retardation. Late treatment with l-thyroxine improved metabolic and systemic status, but the mental deficit was irreversible, sometimes with worsening of preexisting seizures. Currently, CH is a disease with minimal brain involvement and some intellectual and fine motor deficits, and the focus is on ensuring maximum neuromotor and intellectual development of these patients. However, even today, the functioning of a family with a patient with sequelae of CH may be compromised. Diagnosing and correctly treating CH children in a timely (1919 Ramalho RJR, Ramalho ARO, Oliveira CRP, Aguiar-Oliveira MH. Evolução do programa de triagem neonatal para o hipotireoidismo congênito e fenilcetonúria no Estado de Sergipe de 1995 a 2003. Arq Bras Endocrinol Metab. 2004;48(6):890-6.) manner represents a significant benefit for the patient, his or her family, and the community, reducing social, emotional, and financial costs, including higher-cost special schools (88 Rovet JF. The role of thyroid hormones for brain development and cognitive function. Endocr Dev. 2014;26:26-43.). Treatment should be started with a daily dose of levothyroxine of 10 to 15 mcg/kg, ideally starting prior to the 14th day after birth, but the overtreatment of TCH cases may have medical consequences and generate unnecessary concerns in affected families (77 Matejek N, Tittel SR, Haberland H, Rohrer T, Busemann EM, Jorch N, et al. Predictors of transient congenital primary hypothyroidism: data from the German registry for congenital hypothyroidism (AQUAPE “HypoDok”). Eur J Pediatr. 2021;180(8):2401-8.), and the neurodevelopmental benefits in these children remain controversial (99 Lain SJ, Bentley JP, Wiley V, Roberts CL, Jack M, Wilcken B, et al. Association between borderline neonatal thyroid-stimulating hormone concentrations and educational and developmental outcomes: a population-based record-linkage study. Lancet Diabetes Endocrinol. 2016;4(9):756-65.,1010 Trumpff C, De Schepper J, Vanderfaeillie J, Vercruysse N, Van Oyen H, Moreno-Reyes R, et al. Thyroid-stimulating hormone (TSH) concentration at birth in Belgian neonates and cognitive development at preschool age. Nutrients. 2015;7:9018-32).

Here, we found that while the age of treatment onset and sex were similar in PCH and TCH, the levels of neonatal blood spot and serum initial TSH were higher and the levels of fT4 were lower in PCH than in TCH. When we analyzed the diagnosis of PCH or transient (TCH) according to the increasing concentrations of serum initial TSH, a highly different distribution of frequencies was found. Two-thirds of PCH and most HCT cases had serum initial TSH between 4.2 and 20 µU/mL. Conversely, one-third of PCH and only 8% of TCH cases had an initial serum TSH greater than 41 µU/mL. When we analyzed the prevalence of PCH or TCH according to the decreasing concentrations of serum initial ft4, a highly different distribution of frequencies was also found. Half of the PCH and most THC cases had an initial ft4 between 0.79 and 1.16 ng/dL. Conversely, a third of PCH and a minority of TCH cases had an initial ft4 less than 0.4 ng/dL. These data agree with an Irish study, which suggested that higher neonatal blood spot and initial serum TSH concentrations and lower serum initial fT4 levels were associated with an increased likelihood of permanent CH. However, in that study, it was not possible to predict the outcome with certainty because significant variation was found. In this study, PCH was present in one-third of infants with serum TSH concentrations between 8 and 20 mU/L, and TCH was observed in one-fifth of infants with serum TSH concentrations above 100 mU/L (1717 McGrath N, Hawkes CP, McDonnell CM, Cody D, O’Connell SM, Mayne PD, et al. Incidence of Congenital Hypothyroidism Over 37 Years in Ireland. Pediatrics. 2018;142(4):e2018119)

From a practical point of view, in clinical practice, it is very important, when the physician receives a newborn with altered neonatal TSH results, to know which factors can be predictors of the diagnosis of PCH versus TCH. To this end, a two-step cluster analysis method was used, with categorical (PCH diagnosis) and continuous (neonatal blood spot TSH, serum initial TSH and serum initial fT4) variables. Three clusters were identified, and the number of PCHs in each cluster was measured. Eighty screened children (61.5%) were in Cluster 1, 8 (6.2%) were in Cluster 2, and 42 (32.3%) were in Cluster 3. No children had PCH in Cluster 1, while 87.5% of children in Cluster 2 and all children in Cluster 3 had PCH. The analysis of the importance of prediction for PCH revealed that the initial serum TSH was the most important and was marginally more important than the neonatal blood spot TSH, followed by initial serum free T4. Therefore, the serum initial TSH is the best predictor of the diagnosis of PCH.

Most cases of PCH and all cases of TCH had glands in situ. This finding agrees with several previously published reports (1212 Rabbiosi S, Vigone MC, Cortinovis F, Zamproni I, Fugazzaloa L, Persani L, et al. Congenital hypothyroidism with eutopic thyroid gland: analysis of clinical and biochemical features at diagnosis and after re-evaluation. J Clin Endocrinol Metab. 2013;98(4):1395-402,1717 McGrath N, Hawkes CP, McDonnell CM, Cody D, O’Connell SM, Mayne PD, et al. Incidence of Congenital Hypothyroidism Over 37 Years in Ireland. Pediatrics. 2018;142(4):e2018119,2323 Léger J. Épidémiologie de l’hypothyroïdie congénitale en France : données récentes [Epidemiology of congenital hypothyroidism in France: recent data]. Biol Aujourd’hui. 2019;213(1-2):1-5.). The etiology of CH with glands in situ remains unclear, and the factors that determine its clinical diversity are unknown. The possible effects of toxic environmental agents on the fetal and neonatal thyroid gland are currently being studied in several scenarios (2323 Léger J. Épidémiologie de l’hypothyroïdie congénitale en France : données récentes [Epidemiology of congenital hypothyroidism in France: recent data]. Biol Aujourd’hui. 2019;213(1-2):1-5.2525 Li ZM, Hernandez-Moreno D, Main KM, Skakkebæk NE, Kiviranta H, Toppari J, et al. Association of In Utero Persistent Organic Pollutant Exposure with Placental Thyroid Hormones. Endocrinology. 2018;159:3473-81.).

Another important finding of the current work is the significant increase of the incidence of PCH and TCH comparing the 2004-2010 and the 2011-2015 periods in the same region, without demographic changes, with the same iodine intake, the same screening procedure, and the same cutoff point in both periods (2121 Matos DM, Ramalho RJ, Carvalho BM, Almeida MA, Passos LF, Vasconcelos TT, et al. Evolution to permanent or transient conditions in children with positive neonatal TSH screening tests in Sergipe, Brazil. Arch Endocrinol Metab. 2016;60(5):450-6.). A similar increase was also demonstrated in Ireland over a period of 37 years. The authors suggest that other potential causes, such as iodine deficiency or excess, and environmental factors need to be considered (1717 McGrath N, Hawkes CP, McDonnell CM, Cody D, O’Connell SM, Mayne PD, et al. Incidence of Congenital Hypothyroidism Over 37 Years in Ireland. Pediatrics. 2018;142(4):e2018119). Several pollutants have been studied as potentially toxic to fetal and neonatal thyroid that might impact the transcription of genes involved in thyroid gland development, such as perchlorate (1818 Steinmaus CM. Perchlorate in Water Supplies: Sources, Exposures, and Health Effects. Curr Environ Health Rep. 2016;3(2):136-43.), halogenated organochlorines, pesticides, polychlorinated biphenyls and polybrominated diethyl ethers (2525 Li ZM, Hernandez-Moreno D, Main KM, Skakkebæk NE, Kiviranta H, Toppari J, et al. Association of In Utero Persistent Organic Pollutant Exposure with Placental Thyroid Hormones. Endocrinology. 2018;159:3473-81.2727 Nagayama J, Kohno H, Kunisue T, Kataoka K, Shimomura H, Tanabe S, et al. Concentrations of organochlorine pollutants in mothers who gave birth to neonates with congenital hypothyroidism. Chemosphere. 2007;68:972-6.), fungicides (2828 Medda E, Santini F, De Angelis S, Franzellin F, Fiumalbi C, Perico A, et al. Iodine nutritional status and thyroid effects of exposure to ethylenebisdithiocarbamates. Environ Res. 2017;154:152-9.), bisphenol (2929 Zhang DH, Zhou EX, Yang ZL. Waterborne exposure to BPS causes thyroid endocrine disruption in zebrafish larvae. PLoS One. 2017;12:e0176927.) and nitrogen oxide (3030 Harari-Kremer R, Calderon-Margalit R, Korevaar TIM, Nevo D, Broday D, Kloog I, et al. Associations Between Prenatal Exposure to Air Pollution and Congenital Hypothyroidism. Am J Epidemiol. 2021;190(12):2630-8.). A Scottish study using space-time clustering suggested the involvement of a spatially varying and transient environmental agent or agents. Such agents could include pollutants or pesticides, which would be expected to occur in more rural communities (2424 McNally RJQ, Jones JH, Shaikh MG, Donaldson MDC, Blakey K, Cheetham TD. Congenital Hypothyroidism: Space-Time Clustering of Thyroid Dysgenesis Indicates a Role for Environmental Factors in Disease Etiology. Thyroid. 2021;31(6):876-83.). Brazil is a great consumer of pesticides (3131 Pesticides from the perspective of the Brazilian Public Heath ISBN 978-85-334-2588-0 volumes 1 and two.), but we are not aware of any influence of these environmental factors on the incidence of CH in Sergipe. The increase in CH incidence seems widespread, as was also demonstrated in the past decade in Xiamen, China, where the incidence of CH has increased, due to an increase in the incidence of both PCH and TCH, mainly in those with glands in situ (3232 Chen J, Lin S, Zeng G, Wang W, Lin Z, Xu C, et al. Epidemiologic characteristics, and risk factors for congenital hypothyroidism from 2009 to 2018 in Xiamen, China. Endocr Pract. 2020;26(6):585-94). The authors suggested potential causes of CH, such as iodine deficiency or excess and environmental factors, and genes susceptible to CH (3232 Chen J, Lin S, Zeng G, Wang W, Lin Z, Xu C, et al. Epidemiologic characteristics, and risk factors for congenital hypothyroidism from 2009 to 2018 in Xiamen, China. Endocr Pract. 2020;26(6):585-94).

Some factors can explain the increase in the incidence of CH, such as the reduction in the cutoff point and the demographic composition of the population. In Italy, the reduction of TSH cutoff to 6 mU/L from cutoffs above or equal to 6 and lower than 7 mU/L, above or equal to 7 and lower than 10, and equal to or above 10 mU/L allowed the identification of one-fifth of newborns with confirmed out-of-range TSH, otherwise not recognized by the previously employed TSH cutoff (3333 Maggio MC, Ragusa SS, Aronica TS, Granata OM, Gucciardino E, Corsello G. Neonatal screening for congenital hypothyroidism in an Italian Centre: a 5-years real-life retrospective study. Ital J Pediatr. 2021;47(1):108.). Our CH-NSP uses the same cutoff level since February 2003 (1919 Ramalho RJR, Ramalho ARO, Oliveira CRP, Aguiar-Oliveira MH. Evolução do programa de triagem neonatal para o hipotireoidismo congênito e fenilcetonúria no Estado de Sergipe de 1995 a 2003. Arq Bras Endocrinol Metab. 2004;48(6):890-6.); therefore, this is not the factor for the increase in the incidence of CH. Another possible factor for changes in CH could be the demographic composition. Hispanics and Asians are reported to have the highest CH incidences (1:1,600 and 1:2,380, respectively) (3434 Ford G, LaFranchi SH. Screening for congenital hypothyroidism: a worldwide view of strategies. Best Pract Res Clin Endocrinol Metab. 2014;28(2):175-87.). Sixty percent of the population of northeastern Brazil is of European origin (3535 Pena SDJ, Pietro GD, Fuchshuber-Moraes M, Genro JP, Hutz MH, Kehdy FSG, et al. The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One. 2011;6(2):e17063.), and Sergipe is one of the regions where the Portuguese began the colonization of Brazil. However, the composition of the population did not change in the twelve years of this study, and therefore, demographics are not a reason for the increase in CH incidence in Sergipe.

Evidence from different screening programs indicated that the rate of CH was higher in preterm and low birth weight infants than in those born at term. Incomplete development of the hypothalamic-pituitary axis in preterm infants and low birth weight infants may result in a delayed rise in TSH. To bypass this problem, the recommended strategies are using both TSH and fT4 for screening preterm infants and a second screening at two, four, six and ten weeks of life (3636 Ford GA, Denniston S, Sesser D, Skeels MR, LaFranchi SH. Transient versus Permanent Congenital Hypothyroidism after the Age of 3 Years in Infants Detected on the First versus Second Newborn Screening Test in Oregon, USA. Horm Res Paediatr. 2016;86(3):169-77.3838 Cherella CE, Wassner AJ. Update on congenital hypothyroidism. Curr Opin Endocrinol Diabetes Obes. 2020;27(1):63-9.). Although we did not use any of these strategies in our CH-NSP, the percentage of preterm newborns was similar in PCH and TCH, which does not seem to influence the increase in the incidence of both PCH and TCH in the two periods of the study. A recent Canadian study concluded that, at the time of diagnosis, in the absence of known thyroid dysgenesis, there are no clear predictors of TCH, although thyroxine dose, an increase in serum TSH above the reference range during treatment, neonatal blood TSH and a history of maternal thyroid disease appear to predict TCH in some way (3939 Marr A, Yokubynas N, Tang K, Saleh D, Wherrett DK, Stein R, et al. Transient vs Permanent Congenital Hypothyroidism in Ontario, Canada: Predictive Factors and Scoring System. J Clin Endocrinol Metab. 2022 17;107(3):638-48.). This work differs from ours, as only one-third of the cases of PCH presented glands in situ, while glands in situ were present in our study in 81% of the cases of PCH.

The limitations of our study include the possible incomplete quality of medical records, the loss of newborns after neonatal TSH collection and the loss of follow-up before the final diagnosis, which reduced the number of children studied.

In conclusion, the two-step cluster analysis discriminated three clusters in children with an altered neonatal TSH blood spot. No children had PCH in Cluster 1, while 87.5 percent of children in Cluster 2 and all children in Cluster 3 had PCH. The most important predictor of PCH was the initial serum TSH, which was marginally higher than the blood spot TSH. The mean incidence of both PCH and TCH increased from 2004 to 2010 and from 2011 to 2015. The reason for this increase remains unclear.

Acknowledgments:

the authors thank Dr. Roberto Salvatori (The Johns Hopkins University School of Medicine) for the final revision of the manuscript.

REFERENCES

  • 1
    Messina MF, Aversa T, Salzano G, Zirilli G, Sferlazzas C, De Luca F, et al. Early discrimination between transient and permanent congenital hypothyroidism in children with eutopic gland. Horm Res Paediatr. 2015;84:159-64.
  • 2
    De Deken X. DUOX defects and their roles in congenital hypothyroidism. Methods Mol Biol. 2019;1982:667-93.
  • 3
    Fu C. Mutation screening of DUOX2 in Chinese patients with congenital hypothyroidism. J Endocrinol Invest. 2015;38(11):1219-24.
  • 4
    Peters C, Nicholas A, Schoenmakers E, Lyons G, Langham S, Serra EG, et al. DUOX2/DUOXA2 mutation frequently cause congenital hypothyroidism that evades detection on newborn screening in the united kingdom. Thyroid. 2019;29(6):790-7
  • 5
    Ford GA, Denniston S, Sesser D, Skeels MR, LaFranchi SH. Transient versus Permanent Congenital Hypothyroidism after the Age of 3 Years in Infants Detected on the First versus Second Newborn Screening Test in Oregon, USA. Horm Res Paediatr. 2016;86(3):169-77.
  • 6
    Dussault JH. The anecdotal history of screening for congenital hypothyroidism. J Clin Endocrinol Metab. 1999;84:4332-4.
  • 7
    Matejek N, Tittel SR, Haberland H, Rohrer T, Busemann EM, Jorch N, et al. Predictors of transient congenital primary hypothyroidism: data from the German registry for congenital hypothyroidism (AQUAPE “HypoDok”). Eur J Pediatr. 2021;180(8):2401-8.
  • 8
    Rovet JF. The role of thyroid hormones for brain development and cognitive function. Endocr Dev. 2014;26:26-43.
  • 9
    Lain SJ, Bentley JP, Wiley V, Roberts CL, Jack M, Wilcken B, et al. Association between borderline neonatal thyroid-stimulating hormone concentrations and educational and developmental outcomes: a population-based record-linkage study. Lancet Diabetes Endocrinol. 2016;4(9):756-65.
  • 10
    Trumpff C, De Schepper J, Vanderfaeillie J, Vercruysse N, Van Oyen H, Moreno-Reyes R, et al. Thyroid-stimulating hormone (TSH) concentration at birth in Belgian neonates and cognitive development at preschool age. Nutrients. 2015;7:9018-32
  • 11
    Fisher DA, Dussault JH, Foley TP Jr, Klein AH, LaFranchi S, Larsen PR, et al. Screening for congenital hypothyroidism: results of screening one million North American infants. J Pediatr. 1979;94(5):700-5.
  • 12
    Rabbiosi S, Vigone MC, Cortinovis F, Zamproni I, Fugazzaloa L, Persani L, et al. Congenital hypothyroidism with eutopic thyroid gland: analysis of clinical and biochemical features at diagnosis and after re-evaluation. J Clin Endocrinol Metab. 2013;98(4):1395-402
  • 13
    Deladoëy J, Ruel J, Giguère Y, Van Vliet G. Is the incidence of congenital hypothyroidism really increasing? A 20-year retrospective population-based study in Quebec. J Clin Endocrinol Metab. 2011;96(8):2422-9.
  • 14
    Corbetta C, Weber G, Cortinovis F, Calebiro D, Passoni A, Vigone MC, et al. A 7-year experience with low blood TSH cutoff levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism (CH). Clin Endocr. 2009;71:739-45
  • 15
    van Trotsenburg P, Stoupa A, Léger J, Rohrer T, Peters C, Fugazzola L, et al. Congenital Hypothyroidism: A 2020-2021 Consensus Guidelines Update-An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid. 2021;31(3):387-419.
  • 16
    Peters C, van Trotsenburg ASP, Schoenmakers N. Diagnosis of endocrine disease: Congenital hypothyroidism: update and perspectives. Eur J Endocrinol. 2018;179(6):R297-317.
  • 17
    McGrath N, Hawkes CP, McDonnell CM, Cody D, O’Connell SM, Mayne PD, et al. Incidence of Congenital Hypothyroidism Over 37 Years in Ireland. Pediatrics. 2018;142(4):e2018119
  • 18
    Steinmaus CM. Perchlorate in Water Supplies: Sources, Exposures, and Health Effects. Curr Environ Health Rep. 2016;3(2):136-43.
  • 19
    Ramalho RJR, Ramalho ARO, Oliveira CRP, Aguiar-Oliveira MH. Evolução do programa de triagem neonatal para o hipotireoidismo congênito e fenilcetonúria no Estado de Sergipe de 1995 a 2003. Arq Bras Endocrinol Metab. 2004;48(6):890-6.
  • 20
    Ramalho ARO, Ramalho RJA, Oliveira CRP, Santos EG, Oliveira MCP, Aguiar-Oliveira MF. Programa de triagem neonatal para hipotireoidismo congênito no nordeste do Brasil: critérios diagnósticos e resultados. Arq Bras Endocrinol Metab. 2008;52(4):617-27.
  • 21
    Matos DM, Ramalho RJ, Carvalho BM, Almeida MA, Passos LF, Vasconcelos TT, et al. Evolution to permanent or transient conditions in children with positive neonatal TSH screening tests in Sergipe, Brazil. Arch Endocrinol Metab. 2016;60(5):450-6.
  • 22
    Kaufman L, Rousseeuw PJ, editors. Finding Groups in Data: An Introduction to Cluster Analysis. Hoboken, NJ: John Wiley & Sons, Inc.; 1990.
  • 23
    Léger J. Épidémiologie de l’hypothyroïdie congénitale en France : données récentes [Epidemiology of congenital hypothyroidism in France: recent data]. Biol Aujourd’hui. 2019;213(1-2):1-5.
  • 24
    McNally RJQ, Jones JH, Shaikh MG, Donaldson MDC, Blakey K, Cheetham TD. Congenital Hypothyroidism: Space-Time Clustering of Thyroid Dysgenesis Indicates a Role for Environmental Factors in Disease Etiology. Thyroid. 2021;31(6):876-83.
  • 25
    Li ZM, Hernandez-Moreno D, Main KM, Skakkebæk NE, Kiviranta H, Toppari J, et al. Association of In Utero Persistent Organic Pollutant Exposure with Placental Thyroid Hormones. Endocrinology. 2018;159:3473-81.
  • 26
    Ouhoummane N, Levallois P, Gingras S. Thyroid function of newborns and exposure to chlorine dioxide by-products. ArchEnviron Health. 2004;59:582-7.
  • 27
    Nagayama J, Kohno H, Kunisue T, Kataoka K, Shimomura H, Tanabe S, et al. Concentrations of organochlorine pollutants in mothers who gave birth to neonates with congenital hypothyroidism. Chemosphere. 2007;68:972-6.
  • 28
    Medda E, Santini F, De Angelis S, Franzellin F, Fiumalbi C, Perico A, et al. Iodine nutritional status and thyroid effects of exposure to ethylenebisdithiocarbamates. Environ Res. 2017;154:152-9.
  • 29
    Zhang DH, Zhou EX, Yang ZL. Waterborne exposure to BPS causes thyroid endocrine disruption in zebrafish larvae. PLoS One. 2017;12:e0176927.
  • 30
    Harari-Kremer R, Calderon-Margalit R, Korevaar TIM, Nevo D, Broday D, Kloog I, et al. Associations Between Prenatal Exposure to Air Pollution and Congenital Hypothyroidism. Am J Epidemiol. 2021;190(12):2630-8.
  • 31
    Pesticides from the perspective of the Brazilian Public Heath ISBN 978-85-334-2588-0 volumes 1 and two.
  • 32
    Chen J, Lin S, Zeng G, Wang W, Lin Z, Xu C, et al. Epidemiologic characteristics, and risk factors for congenital hypothyroidism from 2009 to 2018 in Xiamen, China. Endocr Pract. 2020;26(6):585-94
  • 33
    Maggio MC, Ragusa SS, Aronica TS, Granata OM, Gucciardino E, Corsello G. Neonatal screening for congenital hypothyroidism in an Italian Centre: a 5-years real-life retrospective study. Ital J Pediatr. 2021;47(1):108.
  • 34
    Ford G, LaFranchi SH. Screening for congenital hypothyroidism: a worldwide view of strategies. Best Pract Res Clin Endocrinol Metab. 2014;28(2):175-87.
  • 35
    Pena SDJ, Pietro GD, Fuchshuber-Moraes M, Genro JP, Hutz MH, Kehdy FSG, et al. The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One. 2011;6(2):e17063.
  • 36
    Ford GA, Denniston S, Sesser D, Skeels MR, LaFranchi SH. Transient versus Permanent Congenital Hypothyroidism after the Age of 3 Years in Infants Detected on the First versus Second Newborn Screening Test in Oregon, USA. Horm Res Paediatr. 2016;86(3):169-77.
  • 37
    Hashemipour M, Hovsepian S, Ansari A, Keikha M, Khalighinejad P, Niknam N. Screening of congenital hypothyroidism in preterm, low birth weight and very low birth weight neonates: A systematic review. Pediatr Neonatol. 2018;59(1):3-14.
  • 38
    Cherella CE, Wassner AJ. Update on congenital hypothyroidism. Curr Opin Endocrinol Diabetes Obes. 2020;27(1):63-9.
  • 39
    Marr A, Yokubynas N, Tang K, Saleh D, Wherrett DK, Stein R, et al. Transient vs Permanent Congenital Hypothyroidism in Ontario, Canada: Predictive Factors and Scoring System. J Clin Endocrinol Metab. 2022 17;107(3):638-48.

Publication Dates

  • Publication in this collection
    27 Jan 2023
  • Date of issue
    Mar-Apr 2023

History

  • Received
    23 May 2022
  • Accepted
    03 Oct 2022
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