Permanent Congenital Hypothyroidism Research Articles

A practical gestational age-based algorithm for timely detection of hypothyroidism in premature infants.

To assess utility and accuracy of a gestational age-based screening targeting premature infants to detect congenital hypothyroidism. A prospective cohort study was conducted in infants <35 weeks' gestational age with clinical outcomes at 2-3 years of age. Patients received newborn screenings at 24 hours and 10-14 days of life. Free T4 (FT4) and thyroid-stimulating hormone (TSH) levels were measured at one month of life and repeated based on algorithm by corrected gestational age. Among infants <35 weeks gestation (n = 938), the incidence of hypothyroidism requiring treatment was 1:58. TSH levels at one month of age was predictive of treatment (AUC 0.96, 95% CI 0.88-1). The optimal TSH threshold of 8 mIU/L (8 µU/ml) increased the specificity to 0.97 and sensitivity to 0.88. Following initiation of treatment forhypothyroidism during NICU hospitalization,43.8% (n = 7) were diagnosed with permanent congenital hypothyroidism. Our study supports a gestational age-based screening algorithm for early detection of hypothyroidism in premature infants.

High frequency of transient congenital hypothyroidism among infants referred for suspected congenital hypothyroidism from the Turkish National screening program: thyroxine dose may guide the prediction of transients.

We aimed to determine the frequency of transient congenital hypothyroidism (TCH) in 17 participating centers inTürkiye, evaluate the etiological distribution in permanent congenital hypothyroidism (PCH) cases, and investigate the role of laboratory and clinical findings in predicting TCH. This retrospective observational multicenter study included patients from 17 pediatric endocrinology centers identified by "National Newborn Screening Program" (NNSP) who were born in 2015 and followed for 6years. Demographic, clinical, and laboratory information of the cases were compiled through the database http://cedd.saglik-network.org (CEDD-NET). Of the 239 cases initially treated for CH, 128 (53.6%) were determined as transient in whom a trial of levothyroxine (LT4) withdrawal was performed at a median age of 36 (34-38) months. Among the patients with PCH (n = 111), thyroid dysgenesis was diagnosed in 39.6% (n = 44). The predictive factors for TCH were: LT4 dose at the withdrawal of treatment, and initial newborn blood screening (NBS)-TSH level. Based on the receiver operating characteristic (ROC) curve analysis to predict optimal cut-offs for TCH predictors, LT4 dose < 2.0µg/kg/day at treatment discontinuation was predictive for TCH and was associated with 94.5% specificity and 55.7% sensitivity, with an area under the curve (AUC) of 0.802. The initial NBS-TSH level value <45µIU/mL was predictive for TCH with 93.1% specificity and 45.5% sensitivity, with an AUC of 0.641. In patients with eutopic thyroid gland only LT4 dose < 1.1µg/kg/day at withdrawal time was predictive for TCH with 84.7% sensitivity and 40.4% specificity, with an AUC of 0.750. According to our national follow-up data, the frequency of TCH was 53.6%. We determined the LT4 dose < 2.0µg/kg/day at discontinuation of treatment and the initial NBS-TSH level < 45µIU/mL as the best cut-off limits to predict TCH.

Comparison between transient and permanent congenital hypothyroidism on a thyroid function test after re-evaluation.

Congenital hypothyroidism (CH) is diagnosed with neonatal screening and is treated early in the neonatal period. Among these patients, transient CH (TCH) is included and requires re-evaluation. The purpose of this study was to find the best way to discontinue levothyroxine and to find trends in thyroid function tests (TFTs) after re-evaluation. We retrospectively reviewed 388 patients diagnosed with CH. They were classified as permanent CH (PCH) and TCH. The total number of the PCH and TCH groups was 83 (51 boys and 32 girls). We compared clinical parameters to predict TCH and to identify the trends of TFT. The first thyroid-stimulating hormone (TSH) value after discontinuation and the average TSH value for 1, 2, and 3 years were all significantly higher in the PCH group (P<0.01). The first fT4 value after discontinuation and the average fT4 value for 1, 2, and 3 years were all significantly higher in the TCH group (P<0.01). The optimal cutoff value on the receiver operating characteristic curve for PCH prediction with an average of 3 years of TSH was greater than 9.05 μIU/mL, which was predicted with a sensitivity of 100% and a specificity of 100%. When the TSH value ranges from 10 μIU/mL to 20 μIU/mL, clinicians can discontinue levothyroxine if the next result is around 10 μIU/mL or shows a decreasing trend.

Permanent vs Transient Congenital Hypothyroidism in Chinese Children: Physical Growth and Predictive Nomogram

Abstract Context Few reliable markers are available to distinguish transient congenital hypothyroidism (TCH) and permanent congenital hypothyroidism (PCH). Additionally, the differences in growth between TCH and PCH remain unclear. Objective To investigate the growth of children with TCH and PCH and develop a nomogram for early differentiation of these forms. Methods This retrospective study included children with TCH or PCH. The predictive efficacy of the prognostic predictors was analyzed using receiver operating characteristic analysis. Multivariate prediction models were developed. Measurements of growth were compared between groups. Results Patients with TCH had lower initial thyroid-stimulating hormone (TSH) than those with PCH at newborn screening (NBS). The supplementary dose of levothyroxine (L-T4) gradually decreased with age in TCH but not in PCH. The area under the curve (AUC) values of the initial TSH, L-T4 dose at 1 year of age, and L-T4 dose at 2 years of age for distinguishing TCH from PCH were 0.698, 0.71, and 0.879, respectively. The predictive efficacy of the multivariate models at 1 and 2 years of age improved, with AUC values of 0.752 and 0.922, respectively. A nomogram was built based on the multivariate model at 1 year of age. The growth did not differ between children with TCH and those with PCH. However, at 1 year of age, girls with CH exhibited higher z-scores in terms of height and weight than boys with CH. Conclusion TSH at NBS and L-T4 doses during treatment can be used to distinguish between PCH and TCH early in life, and the predictive efficacy can be improved using multivariable models with a visualized nomogram. At 3 years of age, patients with TCH and PCH showed similar growth.

Increased incidence of congenital hypothyroidism in China: An analysis of 119 million screened newborns.

Despite the lack of nationwide epidemiological studies, congenital hypothyroidism (CH) incidence in China has increased. We aimed to evaluate the trends of CH and the possible reasons behind them. Data from screened newborns from the Chinese Newborn Screening Information System from 2012 to 2019 was collected. We applied the Bayesian hierarchical Poisson regression model and meta-analysis to estimate incidence or proportion over the years. The estimated CH incidence increased from 4.01 per 10,000 births in 2012 to 5.77 per 10,000 births in 2019. The average annual growth rate (ARG) of CH incidence for all provinces varied from 0.59 to 20.96%. The most rapid rise in incidence was observed in cases with an initial thyroid stimulating hormone (TSH) concentration of < 10 mIU/L. The meta-analysis results showed that the proportion of permanent CH increased by 0.024% (95%CI: 0.011%, 0.037%) annually. Each 1 mIU/L decrease in TSH cutoff value was associated with a 2.96% increase in CH incidence. In the same period, the proportion of premature CH cases increased from 6.60 to 9.10%, which was much higher than the increase in preterm births. A significant relationship was not found between provincial growth rates in screening coverage and provincial baseline incidences of CH. Conclusion:CH incidence has substantially increased in China. The slight adjustment of the TSH cutoff value and increasing preterm birth rate contribute to such a trend; however, the contribution is limited. What is Known: • An uptrend in congenital hypothyroidism (CH) incidence has been reported in many European and American countries in the last two decades; however, no studies have been conducted in China to explain the increased CH incidence. • We provide a detailed epidemiological report on the trends of CH during 2012-2019 in China, with an attempt to explore the reasons behind it. What is New: • This first-ever national-wide epidemiological report in China showed an uptrend in CH incidence with variations over regions and CH subtypes. The mild lowering of TSH cutoff values and the increasing preterm birth rate contributed to this uptrend.

Congenital hypothyroidism in Northern Ireland: 40years' experience of national screening programme.

The incidence of congenital hypothyroidism (CHT) has progressively increased in several regions around the world but has yet to be evaluated in Northern Ireland (NI). CHT screening programme was introduced in NI in 1980 and has had a relatively unchanged protocol since its inception. The purpose of the study was to evaluate the incidence of CHT in NI from 1981 to 2020 and to explore possible contributing factors to any changes seen over the 40-year period. This was a retrospective database review of children diagnosed with CHT in NI between 1981 and 2020. Data was collected from the patients' medical (paper and electronic) records, including epidemiological, clinical, laboratory, and radiological features as well as outcomes at 3 years. Of 800,404 new-borns who were screened for CHT in NI between January 1981 and March 2020, 471 were diagnosed with CHT. There was a steady and significant increase in incidence of CHT over time with an incidence of 26 cases per 100,000 livebirths in 1981 versus71 cases per 100,000 in 2019 (p < .001). Of these 471, 77 new-borns (16%) were born preterm. The incidence of CHT was observed twice as much in female compared to male new-borns. Diagnostic imaging including radioisotope uptake and thyroid ultrasound scans were performed in 143 cases (30%). Of these, 101 (70%) cases had thyroid dysgenesis and 42 (30%) cases had thyroid dyshormonogenesis. There were 293 (62%) of 471 patients had confirmed permanent CHT, and 90 patients (19%) had transient CHT. Over that period at least 95% of the population were recorded as having United Kingdom/Ireland as country of birth. Our findings demonstrate a nearly tripling of the CHT incidence observed over the last 40 years. This is against a background of a relatively stable population demographics. Future research should focus on the underlying cause(s) of this condition which may include changing environmental exposures in utero.

Physical growth and intellectual function of children with congenital hypothyroidism: An observational study

Introduction: Congenital hypothyroidism (CH) is an important preventable cause of mental retardation. Objectives: To assess growth parameters and the developmental outcome of children with permanent CH on follow up. Method: This was a hospital-based observational study done in the paediatric endocrinology clinic of a tertiary care hospital in South India. The study population included all children with permanent CH aged 5-18 years attending the clinic from March 2017 to March 2018. Weight, height and head circumference of children were measured and the body mass index (BMI) was calculated. Ultrasonography (USG) of the thyroid was done for all patients and structural abnormalities of the thyroid (aplasia, hypoplasia or ectopic gland) were taken as dysgenesis. If USG had normal thyroid it was taken as dyshormonogenesis. Intelligence quotient (IQ) assessment was done by a clinical psychologist. Results: There were 35 children with CH enrolled in the study. Of this, 17 (49%) were diagnosed on or before 6 months of age and 18 (51%) after 6 months of age; 24 (69%) had thyroid dysgenesis and 11 (31%) had dyshormonogenesis; 4 had severe stunting and 5 were obese. Among the 17 children diagnosed on or before 6 months of age, 12 (70.6%) had normal intelligence and 5 (29.4%) had IQ &lt;85 whereas among the 18 children diagnosed after 6 months of age 6 (33%) had normal intelligence and 12 (66%) had IQ &lt;85, which was statistically significant (p=0.028). There were no significant differences between early and late diagnosis groups in other parameters like developmental delay, stunting and BMI. Among 24 children with dysgenesis of thyroid gland, 14 (58%) had IQ &lt;85 whereas among 11 children with dyshormonogenesis, 3 (37.5%) had IQ &lt;85. This was not statistically significant (p=0.08). Conclusions: In this study, a statistically significantly larger proportion of children diagnosed on or before 6 months of age had normal intelligence compared to children diagnosed after 6 months of age. There were no significant differences between early and late diagnosis groups in other parameters like developmental delay, stunting and BMI. Sri Lanka Journal of Child Health, 2023: 52(2): 148-154

Epidemiological profile of congenital hypothyroidism at a southern Brazilian state.

To determine the incidence of congenital hypothyroidism (CH) over a 10-year period at the Reference Service in Neonatal Screening of the state of Rio Grande do Sul (RSNS-RS). Historical cohort study including all newborns screened for CH by the RSNS-RS from January 2008 until December 2017. Data of all newborns with neonatal TSH (neoTSH; heel prick test) values ≥ 9 mIU/L were collected. According to neoTSH values, the newborns were allocated into two groups: Group 1 (G1), comprising newborns with neoTSH ≥ 9 mIU/L and serum TSH (sTSH) < 10 mIU/L, and Group 2 (G2), comprising those with neoTSH ≥ 9 mIU/L and sTSH ≥ 10 mIU/L. Of 1,043,565 newborns screened, 829 (0.08%) had neoTSH values ≥ 9 mIU/L. Of these, 284 (39.3%) had sTSH values < 10 mIU/L and were allocated to the G1 group, while 439 (60.7%) had sTSH ≥ 10 mIU/L and were allocated to the G2 group, and 106 (12.7%) were considered missing data. The overall incidence of CH was 42.1 per 100,000 newborns screened (95% confidence interval [CI] 38.5-45.7/100,000) or 1:2377 screened newborns. The sensibility and specificity of neoTSH ≥ 9 mIU/L were 97% and 11%; of neoTSH 12.6 mUI/L, 73% and 85% respectively. In this population, the incidence of permanent and transitory CH was 1:2377 screened newborns. The neoTSH cutoff value adopted during the study period showed excellent sensibility, which matters for a screening test.

Genetic testing can change diagnosis and treatment in children with congenital hypothyroidism.

Guidelines on congenital hypothyroidism (CH) recommend that genetic testing should aim to improve diagnosis, treatment or prognosis, but it is unclear which patients would benefit most from the genetic investigation. We aimed to investigate the genetic etiology of transient CH (TCH) and permanent CH (PCH) in a well-characterized cohort, and thereby evaluate the impact of genetic testing on the management and prognosis of children with CH. A total of 48 CH patients with normal, goitrous (n 5) or hypoplastic thyroid (n 5) were studied by high-throughput sequencing using a custom-designed 23-gene panel. Patients initially categorized as TCH (n 15), PCH (n 26) and persistent hyperthyrotropinemia (PHT, n 7) were re-evaluated after genetic testing. Re-evaluation based on genetic testing changed the initial diagnoses from PCH to PHT (n 2) or TCH (n 3) and from PHT to TCH (n 5), which resulted in a final distribution of TCH (n 23), PCH (n 21) and PHT (n 4). Genetic analysis also allowed us to discontinue treatment in five patients with monoallelic TSHR or DUOX2, or no pathogenic variants. The main reasons for changes in diagnosis and treatment were the detection of monoallelic TSHR variants and the misdiagnosis of thyroid hypoplasia on neonatal ultrasound in low birthweight infants. A total of 41 (35 different, 15 novel) variants were detected in 65% (n 31) of the cohort. These variants, which most frequently affected TG, TSHR and DUOX2, explained the genetic etiology in 46% (n 22) of the patients. The molecular diagnosis rate was significantly higher in patients with PCH (57%, n 12) than TCH (26%, n 6). Genetic testing can change diagnosis and treatment decisions in a small proportion of children with CH, but the resulting benefit may outweigh the burden of lifelong follow-up and treatment.

Diagnosis and treatment of congenital hypothyroidism

Background: Congenital hypothyroidism is the most common neonatal endocrine disorder, and prompt screening and treatment initiation can prevent developmental delay and growth failure.Current Concepts: The thyroid is the first endocrine gland to develop during embryogenesis. Regulation of thyroid function requires normal development of the hypothalamic-pituitary-thyroid axis, which occurs during the embryonal and neonatal periods. Defects in any of the steps involved in development and differentiation of the gland and regulation of thyroid function lead to permanent congenital hypothyroidism. Neonatal screening test programs to detect congenital hypothyroidism, which are established in 1/3 of the countries worldwide, are cost-effective with high sensitivity and specificity. Advances in molecular testing have expanded knowledge and understanding of thyroid development and function. Prompt initiation of an accurate dose of sodium levothyroxine is recommended. Frequent follow-up, including laboratory test evaluation and dose adjustments are important to maintain thyroid hormone levels within their target ranges.Discussion and Conclusion: A well-established system of newborn screening and treatment of congenital hypothyroidism is useful for management of term infants without other risk factors for this disorder. However, increasing knowledge regarding the role of genetic causes and new criteria for screening and treatment of neonates in special conditions is emerging in clinical practice.

Congenital hypothyroidism in children with eutopic gland or thyroid hemiagenesis: prognostic factors for transient vs. permanent hypothyroidism.

More than one third of children with congenital hypothyroidism (CH) and thyroid gland in situ(or eutopic gland) have transient hypothyroidism. It remains difficult to determine early on whether hypothyroidism will be transient which may cause overtreatment and its complications in these children. Our primary aim was to determine prognostic factors for transient hypothyroidism in children with congenital hypothyroidism and eutopic gland or thyroid hemiagenesis. We retrospectively reviewed medical records of111 children, born between 1996 and 2017, diagnosed withcongenital hypothyroidism and eutopic gland or hemiagenesis and treated at the Nancy Regional and University Hospital. Fifty four infants (48.6%) had permanent congenital hypothyroidism (PCH) and 57 (51.4%) transient congenital hypothyroidism (TCH). Prognostic factors for TCH included prematurity, twin pregnancy, low birth weight and Apgar score <7, while low FT3 at diagnosis, maternal levothyroxine treatment, a family history of thyroid dysfunction and TSH≥10mUI/L while receiving treatment were associated with PCH. Knee epiphyses on X-ray at diagnosis were absent only in children with PCH. The median levothyroxine dose during follow-up was significantly lower in the TCH group compared to the PCH group. A levothyroxine dose of≤3.95,≤2.56,≤2.19 and≤2.12μg/kg/day at 6months, 1, 2 and 3years of follow-up, respectively, had the best sensitivity-to-specificity ratio for predicting TCH. Even though it remains difficult to predict thecourse of hypothyroidism at diagnosis, we were able to identify several prognostic factors for TCH including perinatal problems and lower levothyroxine requirements that can guide the physician on the evolution of hypothyroidism. Clinical Trial Registration Number: NCT04712760.

Comparison of developmental outcomes in children with permanent and transient congenital hypothyroidism.

Congenital hypothyroidism (CH) is still one of the most common causes of preventable cognitive impairment in children, and its early detection and treatment prevent irreversible neurodevelopmental delay. Depending on the underlying cause, cases with CH may be transient or permanent. This study aimed to compare the developmental evaluation results of transient and permanent CH patients and to reveal any differences. A total of 118 patients with CH, who were followed up jointly in pediatric endocrinology and developmental pediatrics clinics, were included. The patients' progress was evaluated per the International Guide for Monitoring Child Development (GMCD). Of the cases, 52 (44.1%) were female, and 66 (55.9%) were male. While 20 (16.9%) cases were diagnosed with permanent CH, 98 (83.1%) were diagnosed with transient CH. According to the results of the developmental evaluation made with GMCD, the development of 101 (85.6%) children was compatible with their age, while 17 (14.4%) children had delays in at least one developmental area. All 17 patients had a delay in expressive language. Developmental delay was detected in 13 (13.3%) of those with transient CH and 4 (20%) with permanent CH. There is difficulty in expressive language in all cases of CH with developmental delay. No significant difference was found between the developmental evaluations of permanent and transient CH cases. The results revealed the importance of developmental follow-up, early diagnosis and interventions in those children. GMCD is thought to be an important guide to help monitoring the development of patients with CH.

Prevalence of Transient Hypothyroidism in Children Diagnosed with Congenital Hypothyroidism between 2000 and 2016.

Newborn screening (NBS) for congenital hypothyroidism (CH) was introduced in Switzerland in 1977, which allowed for the preclinical, biochemical diagnosis. The aim of this study was to evaluate the prevalence of transient CH (tCH) in the canton of Zurich. In this analytical cohort study, all newborns born in the canton of Zurich, between the 1st of January 2000 and the 30st of June 2016, with a TSH value above 15 mU/L (whole blood) were included. There were 115 cases out of 247,918 babies born during the study period. However, 23 cases had to be excluded due to missing data. The definite diagnosis was made after a thyroxine withdrawal at 2 years of age. The total prevalence of confirmed CH and the female to male ratio (f/m) were 1:2695 and 2.17:1; for permanent CH (pCH), 1:3443 and 2.8:1; and for tCH, 1:12,396 and 1:1, respectively. The TSH value was significantly higher in pCH compared to tCH, at 130.3 (62.9-171.9) and 36.4 (26.5-53.3) (median and interquartile range), respectively (p < 0.001). The prevalences found for congenital hypothyroidism and its transient form are comparable to previous studies. TSH concentration at birth was predictive for the further course of the disease. Low birth weight correlated with a tCH, whereas low gestational age did not. The dominance of the female sex in congenital hypothyroidism is supported by a gender ratio of 2.17:1.

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

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. 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. 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. 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.

Hypothyroidism in First-Degree Relatives of Neonates with Congenital Hypothyroidism: Is there an Association?

Recent studies have shown an increased incidence of congenital hypothyroidism (CH), especially in the middle-east region. The exact etiology is unknown; however, it has been related to several factors, the most noticeable being the high prevalence of transient CH (TCH), parental consanguinity, and the history of hypothyroidism in relatives. We sought to determine the impact of hypothyroidism in the relatives of patients with the observed trend. We included all patients with primary CH detected through the Newborn Screening (NBS) Program from 2007 to 2016. We analyzed the impact of consanguinity relationship, parental and siblings' thyroid function, second-degree relatives' thyroid function, parental educational level, age, and maternal gestational diabetes on the development of permanent CH (PCH) and TCH. A total of 1447 consecutive eligible patients were recruited during the study period. Of this number, 1171 (81%) were diagnosed with CH: 623 (53.2%) had PCH and 548 (46.8%) had TCH. Six hundred thirty-three (54.1%) participants were men, and 814 (69.5%) had a history of relatives' hypothyroidism. Our data analysis revealed a significant difference regarding the male gender, having a history of relatives' hypothyroidism, and parental hypothyroidism compared to TCH ones (P < 0.05). Patients with a history of relatives' hypothyroidism had significantly higher PCH than TCH (P < 0.0001). However, consanguineous marriage was not comparable in patients regardless of their history of relatives' hypothyroidism (P-value >0.884). Our findings indicated the role of the history of hypothyroidism in neonates' relatives in the evolution of the PCH. Meanwhile, consanguineous marriage did not impress the development of PCH and TCH.

Knowns and unknowns about congenital hypothyroidism: 2022 update

Several excellent guidelines and expert opinions on congenital hypothyroidism (CH) are currently available. Nonetheless, these guidelines do not address several issues related to CH in detail. In this review, the authors chose the following seven clinical issues that they felt were especially deserving of closer scrutiny in the hope that drawing attention to them through discussion would help pediatric endocrinologists and promote further interest in the treatment of CH. 1. How high should the levothyroxine (L-T4) dose be for initial treatment of severe and permanent CH? 2. What is the optimal method for monitoring treatment of severe CH? 3. At what level does maternal iodine intake during pregnancy affect fetal and neonatal thyroid function? 4. Does serum thyroglobulin differ between patients with a dual oxidase 2 (DUOX2) variants and those with excess iodine? 5. Who qualifies for a genetic diagnosis? 6. What is the best index for distinguishing transient and permanent CH? 7. Is there any cancer risk associated with CH? The authors discussed these topics and jointly edited the manuscript to improve the understanding of CH and related issues.

Congenital hypothyroidism and thyroid function in a Japanese birth cohort: data from The Japan Environment and Children's Study.

The most common hormonal and metabolic disease in early childhood is congenital hypothyroidism (CH). This study aimed to describe CH in large-scale birth cohort data and summarize the results of serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels in 2-yr-old children. Data were obtained from the Japan Environment and Children's Study (JECS), and we identified 171 children with CH detected in newborn screenings or medical records (170.5 per 100,000 population). Infants with CH are at higher risk of developing congenital diseases than those without CH. Of 171 children with CH, 20 (11.7%) were diagnosed with congenital heart defects, 33 (19.3%) had chromosomal or other congenital abnormalities, and 23 (13.5%) had Down syndrome. At the age of 2 yr old, the median and 95% reference range values for TSH and fT4 were 2.13 (0.78-5.52) μIU/mL and 1.2 (1.0-1.5) ng/dL, respectively. Moreover, boys had slightly higher TSH and fT4 levels than did girls. Data on the distribution of TSH and fT4 in 2-yr-old children should be useful for decreasing the misclassification of thyroid disorders in the pediatric population. Trial-off treatment and re-evaluation of thyroid function are needed to classify permanent congenital hypothyroidism and transient congenital hypothyroidism after 3 yr of age.

Etiological Profile, Targeted Levothyroxine Dosing and Impact of Partial Newborn Screening in Congenital Hypothyroidism-A Single Centre Experience.

Congenital hypothyroidism (CH) is the most common cause of preventable intellectual disability. Newborn screening (NBS) for CH has been in vogue in many parts of the world since 1970, but despite its well-known benefits, many developing countries including India have not been able to establish universal NBS for CH till date. The aim of this study was to review the clinical aspects of congenital hypothyroidism in a tertiary care university referral teaching hospital, focusing on aetiology of CH, predictors of permanence, optimal targeted dose strategies based on aetiology and the effect of newborn screening on the time to diagnosis. The electronic medical records of 233 children with CH referred to our centre between January 2009 and December 2019 were analysed. A partial NBS was established in the state in 2012. Dyshormonogenesis (57.5%) was the most common aetiology of CH. The incidence of transient CH in children with a gland in situ (GIS) was 35%. Levothyroxine (LT-4) dose of >2.75 μg/kg/day (sensitivity 76.5, specificity 72), >2.15 μg/kg/day (sensitivity 82.4, specificity 61.9) and >1.85 μg/kg/day (sensitivity 76.5, specificity 61.9) at years 1, 2 and 3, respectively, were predictors of permanent CH. An initial LT-4 dose ≥8 μg/kg was sufficient and very seldom led to undertreatment in children with dyshormonogenesis. On the contrary, even doses ≥13 mcg/kg/day led to frequent undertreatment in children with thyroid dysgenesis. After the introduction of newborn screening, the median age at diagnosis came down from 45 days (IQR 14-180 days) to ten days (IQR 3-12 days). Targeted dosing based on aetiology of CH may be more appropriate to optimise outcomes. The time to diagnosis of CH reduced significantly after the adoption of even a partial NBS program highlighting the urgent need for implementation of the same in resource poor settings.

Prevalence of congenital hypothyroidism in North Macedonia: data from a newborn screening program conducted for twenty years.

Congenital hypothyroidism (CH) is a common endocrine disorder that can be treated if timely detected by newborn screening, optimizing the developmental outcome in affected children. In the present study, we analyze the data of the national newborn thyroid screening program in North Macedonia collected over twenty years, including the CH prevalence as well as its geographical and ethnic variations. The thyroid-stimulating hormone (TSH) was measured on a filter paper blood spot sample using the DELFIA fluoroimmunometric assay. A TSH value of 15 mIU/L whole blood was used as the cutoff point until 2010 and 10 mIU/L thereafter. Out of 377,508 screened live births, a total of 226 newborns with primary CH were detected, providing an overall prevalence of 6.0 per 10,000. Lowering the TSH cutoff led to an apparently increased prevalence of the transient CH, from 0.2 to 2.4 per 10,000 live births (p < 0.0001) with an impact on the overall prevalence of primary CH (from 4.0 to 7.1 per 10,000, p=0.0001). Taking ethnicity into account, the significantly highest primary CH prevalence of 11.3 per 10,000 live births was observed among the Roma neonates, with a predominance of permanent CH (75.5%). There were also regional differences in the prevalence of primary CH. The highest primary CH prevalence of 11.7 per 10,000 live births was observed in the Vardar region, together with the highest regional prevalence of the transient CH (3.2 per 10,000). The highest prevalence of permanent CH was observed in the Pelagonia region (6.6 per 10,000) where the largest percentage of the Roma population lives. The overall CH prevalence is high in North Macedonia, with substantial ethnic and geographical variations. Further analysis to elucidate the causes for the significant variations in the CH prevalence including environmental factors is warranted.

Physical Development at School Entry in Children with Congenital Hypothyroidism Diagnosed by the National Program of Newborn Screening in Iran.

The newborn screening program for diagnosing and treating children with congenital hypothyroidism (CH) in Iran was established in 2004. This study aimed to evaluate the national program's success in maintaining the physical development and anthropometric indexes of children with CH. This historical cohort study was carried out in five provinces located in five different geographical regions of Iran. The anthropometric indexes, including weight, height, and head circumference of 240 children diagnosed with transient congenital hypothyroidism (TCH) (n = 131) and permanent congenital hypothyroidism (PCH) (n = 109) were measured and compared with those of 240 healthy children aged six. Mean ± standard deviation (SD) of weight, height, and head circumference of children with CH aged six were 20304.8 ± 4457.9 g, 115.6 ± 5.9 cm, and 50.8 ± 1.7 cm, respectively. Mean ± SD of height (116.7 ± 6.1 cm) and head circumference (51.1 ± 1.7 cm) in the control (healthy) group were significantly higher than those of the CH children group (P < 0.05). Mean ± SD weight in the control group (20741.2 ± 4337.3 g) was higher than that in the CH group (20304.8 ± 4457.9 g). However, the difference was not statistically significant (P = 0.3). No significant difference was observed between TCH and PCH children in the subgroup analysis (P > 0.05). Although the mean of anthropometric indexes in CH patients was slightly lower than that in healthy children aged six, the difference between the two groups was insignificant. The physical development of children with CH was evaluated as good. Our results suggested that the newborn screening program for identifying and treating children with CH in Iran may have improved the growth outcomes.