Transient vs Permanent Congenital Hypothyroidism in Ontario, Canada: Predictive Factors and Scoring System.

CONTEXT: The apparent increased incidence of congenital hypothyroidism (CH) is partly due to increased detection of transient disease. OBJECTIVE: This work aims to identify predictors of transient CH (T-CH) and establish a predictive tool for its earlier differentiation from permanent CH (P-CH). METHODS: A retrospective cohort study was conducted of patients diagnosed with CH from 2006 to 2015 through Newborn Screening Ontario (NSO). RESULTS: Of 469 cases, 360 (76.8%) were diagnosed with P-CH vs 109 (23.2%) with T-CH. Doses of levothyroxine predicting T-CH were less than 3.9 µg/kg at age 6 months, less than 3.0 µg/kg at ages 1 and 2 years, and less than 2.5 µg/kg at age 3 years. Descriptive statistics and multivariable logistic modeling demonstrated several diverging key measures between patients with T-CH vs P-CH, with optimal stratification at age 1 year. Thyroid imaging was the strongest predictor (P < .001). Excluding imaging, significant predictors in the first year of life included thyroxine dose/kg (P < .001-.002), increase in thyrotropin (TSH) above the reference interval during treatment (P = .002), screening TSH (P = .03), and a history of maternal thyroid disease (P = .02). Based on the 1-year model without imaging, a risk score was developed to identify children with T-CH who may benefit from an earlier trial off therapy, to reduce excess medicalization and health care costs. CONCLUSION: A levothyroxine dose of less than 3 µg/kg at ages 1 and 2 years and less than 2.5 µg/kg at age 3 years can be predictive of T-CH. A novel risk score was developed that can be clinically applied to predict the likelihood of a successful trial off therapy for a given patient at age 1 year.

Low Adrenomedullary Function Predicts Acute Illness in Infants With Classical Congenital Adrenal Hyperplasia.

CONTEXT: Youth with classical congenital adrenal hyperplasia (CAH) exhibit abnormal adrenomedullary function with decreased epinephrine levels noted in newborns and young infants. Little is known about how this relates to morbidity during the first year of life. OBJECTIVE: This work aimed to study plasma epinephrine levels in infants with classical CAH and examine the clinical significance of epinephrine deficiency in the first year of life. METHODS: This prospective cohort study comprised participants recruited from a pediatric tertiary care center: 36 infants with classical CAH due to 21-hydroxylase deficiency and 27 age-matched unaffected controls with congenital hypothyroidism. Main outcome measures included plasma epinephrine levels (N = 27), CYP21A2 genotype (N = 15), and incidence of acute illnesses from birth to age 1 year (N = 28). RESULTS: Epinephrine levels in CAH infants independently predicted illness incidence in the first year of life (ß = -0.018, R = -0.45, P = .02) and were negatively correlated with 17-hydroxyprogesterone at diagnosis (R = -0.51, P = .007). Infants with salt-wasting CAH exhibited lower epinephrine levels as newborns than simple-virilizing infants (P = .02). CAH patients had lower epinephrine as newborns than did controls (P = .007) and showed decreases in epinephrine from birth to age 1 year (P = .04). Null genotype was associated with lower newborn epinephrine and more illness in the first year of life, compared to less severe mutation categories. CONCLUSION: Lower epinephrine levels are associated with increased risk of illness among CAH infants. While not currently part of clinical standard of care, measuring epinephrine levels and assessing genotype may help predict acute illness in the first year of life.

Non-inferiority of liquid thyroxine in comparison to tablets formulation in the treatment of children with congenital hypothyroidism.

OBJECTIVES: The aim of the current prospective randomized control study was to assess efficacy, safety, and non-inferiority of a new liquid L-thyroxine formulation dissolved in glycerol and water (T4® drops, produced by a Greek pharmaceutical Company, Uni-Pharma, Athens, Greece) in comparison to the standard Tablets form (T4® tablets, Uni-Pharma, Athens, Greece) in the substitutive treatment of children with congenital hypothyroidism (CH). METHODS: Thirty-nine children with CH, aged 3-12 years old, were enrolled in the study, after parental Informed Consent has been obtained, while three patients were lost from follow-up. At baseline, all participants had normal thyroid-stimulating hormone (TSH) and Free T4 values. Patients were randomly subdivided according to the assigned treatment in Group A (n=17)-Tablet Form and Group B (n=19)-Liquid Form. TSH and Free T4 levels were evaluated at 0, 2, 4, and 6 months. RESULTS: TSH values showed a statistically significant difference (p=0.017) between groups only at six months (Group A having higher TSH levels than Group B, albeit within the normal range), while Free T4 levels had no statistical difference throughout the six month study period and were always within the normal range. Moreover, dose adjustments were more frequent in Group A (p=0.038) during the six months. Liquid L-thyroxine substitutive treatment exhibited no statistically significant adverse effects in comparison to the widely used tablets. CONCLUSIONS: Levothyroxine (LT4) as liquid solution formulation is safe and noninferior to the widely used L-thyroxine Tablets, with less need for dose adjustment, and can therefore be safely used in the treatment of children with CH.

Treatment of congenital hypothyroidism: comparison between L-thyroxine oral solution and tablet formulations up to 3 years of age.

OBJECTIVE: Oral solution and tablet formulations of levothyroxine (L-T4) are both used in the treatment of congenital hypothyroidism (CH). However, few studies and with a limited follow-up period have been published comparing these two formulations in children. DESIGN: The aim of this multicenter study was to compare the effectiveness of L-T4 oral solution (with ethanol as excipient) and tablet formulation in children with CH up to 3 years of age. METHODS: Children diagnosed with CH between 2006 and 2015 were enrolled and divided into two groups according to the L-T4 formulation used: solution in drops (group D) or tablets (group T). Auxological parameters, thyroid-stimulating hormone (TSH) and free thyroxine (FT4) values and L-T4 dose were collected at diagnosis and at 15 days, 1, 3, 6, 12, 24 and 36 months of treatment. The developmental quotient (DQ) at 1 and 3 years of age was evaluated using Griffiths' Scale. RESULTS: In this study, 254 children were enrolled among which 117 were treated with solution and 137 with tablets. Auxological parameters, dose and thyroid function values at diagnosis, 3, 6, 12, 24, 36 months were not significantly different. TSH at 15 days (P = 0.002) and 1 month (P = 0.009) was significantly reduced in group D. At 2-year follow-up, median TSH was significantly lower in group T (P = 0.03). No statistical difference was detected between the median DQ; however, group D showed lower values in the language subscale at 12 months and in eye-hand coordination at 36 months. CONCLUSIONS: Both therapeutic strategies are effective in the treatment of CH. A higher risk of overtreatment in the first months of therapy seems to be associated with oral solution L-T4; therefore, a different strategy should be considered when starting and adjusting the dose. No negative effects on cognitive development were observed. The data obtained are encouraging but long-term follow-up is needed.

Thyroid Hormone Function in Small for Gestational Age Term Newborns.

OBJECTIVE: To test the hypothesis that term-born small for gestational age (SGA) neonates have elevated thyroid-stimulating hormone (TSH) concentrations and an increased incidence of congenital hypothyroidism compared with non-SGA term neonates. STUDY DESIGN: This retrospective cohort study included all term neonates screened in Wisconsin in 2015 and 2016. The cohort was divided based on SGA status, defined as birth weight <10th percentile as calculated from the World Health Organization's sex-specific growth charts for age 0-2 years. TSH concentration on first newborn screening performed between birth and 96 hours of life and incidence of congenital hypothyroidism were compared between the SGA and non-SGA groups. RESULTS: A total of 115 466 term neonates, including 11 498 (9.96%) SGA neonates, were included in the study. TSH concentration and incidence of congenital hypothyroidism was significantly higher in the SGA group, but only TSH concentration remained significant when adjusted for potential confounding variables. CONCLUSIONS: Our data do not support a higher incidence of congenital hypothyroidism in term SGA neonates after adjusting for potential confounders. However, TSH concentrations were higher in term SGA neonates compared with term non-SGA neonates. The effects of mild thyroid hormone dysfunction on neurodevelopmental outcomes and development of chronic medical conditions merit long-term study.

Screening for Mutations in Isolated Central Hypothyroidism Reveals a Novel Mutation in Insulin Receptor Substrate 4.

Background: Central hypothyroidism (CeH) is a rare condition affecting approximately 1:16 000- 100 000 individuals. Congenital forms can harm normal development if not detected and treated promptly. Clinical and biochemical diagnosis, especially of isolated CeH, can be challenging. Cases are not usually detected in neonatal screening, which, in most countries, is focused on detection of the more prevalent primary hypothyroidism. Until now, five genetic causes for isolated CeH have been identified. Here we aimed to identify the genetic cause in two brothers with impaired growth diagnosed with CeH at the age of 5 years. We further evaluated the candidate gene variants in a large genetic database. Methods: Clinical and biochemical characterization together with targeted next-generation sequencing (NGS) was used to identify the genetic cause in a family of two brothers presenting with CeH. Screening of insulin receptor substrate 4 (IRS4) variants was carried out in the FinnGen database. Results: A novel monoallelic frameshift mutation c.1712_1713insT, p.Gly572Trp fs*32 in the X-linked IRS4 gene was identified by NGS analysis in both affected males and confirmed using Sanger sequencing. Their mother was an unaffected carrier. In addition to the declined growth at presentation, central hypothyroidism and blunted TRH test, no other phenotypic alterations were found. Diagnostic tests included head MRI, thyroid imaging, bone age, and laboratory tests for thyroid autoantibodies, glucose, insulin and glycosylated hemoglobin levels. Examination of the IRS4 locus in FinnGen (R5) database revealed the strongest associations to a rare Finnish haplotype associated with thyroid disorders (p = 1.3e-7) and hypothyroidism (p = 8.3e-7). Conclusions: Here, we identified a novel frameshift mutation in an X-linked IRS4 gene in two brothers with isolated CeH. Furthermore, we demonstrate an association of IRS4 gene locus to a general thyroid disease risk in the FinnGen database. Our findings confirm the role of IRS4 in isolated central hypothyroidism.

Neonatal thyrotropin levels and auditory neural maturation in full-term newborns.

OBJECTIVE: This study aimed to look for a possible relationship between thyrotropin (TSH) values from neonatal bloodspot screening testing and newborn lower auditory pathway myelinization evaluated using the brainstem evoked response audiometry (ABR) test. METHODS: Sixty-two healthy full-term newborns without perinatal problems were enrolled in the study. TSH results were collected from neonatal bloodspot screening data and were below the test cut-off level (15µUI/mL). The TSH test was performed between three and seven days, and the ABR test was performed in the first 28 days of life. The newborns were divided into two groups: Group 1 (n = 35), TSH between 0 and 5µUI/mL, and group 2 (n = 27), TSH between 5 and 15µUI/mL. Data are presented as mean ± SD, median, or percentage, depending on the variable. RESULTS: Wave latency and interpeak interval values for Groups 1 and 2 were as follows: Wave I: 1.8 ± 0.1 and 1.7 ± 0.1; Wave III: 4.4 ± 0.1 and 4.4 ± 0.1; Wave V: 6.9 ± 0.1 and 6.9 ± 0.1; interval I-III: 2.6 ± 0.1 and 2.6 ± 0.1; interval I-V: 5.1 ± 0.1 and 5.1 ± 0.1; interval III-V: 2.4 ± 0.1 and 2.4 ± 0.1. There were no significant differences in ABR parameters between groups 1 and 2 (p > 0.05). Multiple regression analysis showed a slight significant negative correlation between TSH and wave I values (standardized ß = -0.267; p = 0.036), without observing any relationship with the other ABR waves recorded. CONCLUSIONS: This study investigated the relationship of TSH and auditory myelinization evaluated by ABR. It did not show a significant change in lower auditory pathway myelinization according to TSH levels in newborns with TSH screening levels lower than 15 µUI/mL.

Infants Diagnosed with Athyreosis on Scintigraphy May Have a Gland Present on Ultrasound and Have Transient Congenital Hypothyroidism.

Scintigraphy using technetium-99m (99mTc) is the gold standard for imaging the thyroid gland in infants with congenital hypothyroidism (CHT) and is the most reliable method of diagnosing an ectopic thyroid gland. One of the limitations of scintigraphy is the possibility that no uptake is detected despite the presence of thyroid tissue, leading to the spurious diagnosis of athyreosis. Thyroid ultrasound is a useful adjunct to detect thyroid tissue in the absence of 99mTc uptake. AIMS: We aimed to describe the incidence of sonographically detectable in situ thyroid glands in infants scintigraphically diagnosed with athyreosis using 99mTc and to describe the clinical characteristics and natural history in these infants. METHODS: The newborn screening records of all infants diagnosed with CHT between 2007 and 2016 were reviewed. Those diagnosed with CHT and athyreosis confirmed on scintigraphy were invited to attend a thyroid ultrasound. RESULTS: Of the 488 infants diagnosed with CHT during the study period, 18/73 (24.6%) infants with absent uptake on scintigraphy had thyroid tissue visualised on ultrasound (3 hypoplastic thyroid glands and 15 eutopic glands). The median serum thyroid-stimulating hormone (TSH) concentration at diagnosis was significantly lower than that in infants with confirmed athyreosis (no gland on ultrasound and no uptake on scintigraphy) (74 vs. 270 mU/L), and median free T4 concentration at diagnosis was higher (11.9 vs. 3.9 pmol/L). Six of 10 (60%) infants with no uptake on scintigraphy but a eutopic gland on ultrasound had transient CHT. CONCLUSION: Absent uptake on scintigraphy in infants with CHT does not rule out a eutopic gland, especially in infants with less elevated TSH concentrations. Clinically, adding thyroid ultrasound to the diagnostic evaluation of infants who have athyreosis on scintigraphy may avoid committing some infants with presumed athyreosis to lifelong levothyroxine treatment.

Neonatal screening for congenital hypothyroidism in an Italian Centre: a 5-years real-life retrospective study.

INTRODUCTION: Congenital hypothyroidism is an endocrine disease with a significant incidence in the general population (1:2000-1:3000 newborns in Italy) and a different geographical distribution, partially explained by endemic iodine deficiency, genetic traits and autoimmune thyroid diseases. OBJECTIVES: Aims of this study are: to evaluate the incidence of positive neonatal blood spot screening for CH in western Sicily, identified by the screening centre of the Children Hospital "G. Di Cristina", ARNAS, Palermo; to evaluate the impact of a lower TSH cutoff in the neonatal blood spot screening for CH. MATERIALS AND METHODS: The TSH threshold of the neonatal screening was established as ≥6 mU/L of whole blood. We analysed the screening centre data in the period January 2013-April 2018, for a total number of 85.373 babies (45.7% males; 54.3% females). RESULTS: 4.082 Babies (4.8%) required a second screening. Among these, 372 (0.44%) were out of range. The diagnosis of congenital hypothyroidism (CH) was confirmed in 182 babies (0.21%). 77/372 newborns (20.7%) with confirmed high TSH levels showed whole blood TSH levels ≥6 - < 7 mU/L. In synthesis, 48.9% of the out of range re-testing had a confirmed diagnosis of CH. CONCLUSION: The reduction of TSH cutoff to 6 mU/L allowed to identify 77/372 neonates (20.7%) with confirmed out of range TSH, otherwise not recruited by the previously employed TSH cutoff.

Postnatal Serum Total Thyroxine of Very Preterm Infants and Long-Term Neurodevelopmental Outcome.

Primary congenital hypothyroidism is a disease associated with low serum thyroxine and elevated thyroid-stimulating hormone (TSH) levels. The processes of screening and treating congenital hypothyroidism, in order to prevent neurodevelopmental impairment (NDI) in newborns, have been well investigated. Unlike term infants, very preterm infants (VPIs) may experience low thyroxine with normal TSH levels (<10.0 µIU/mL) during long-stay hospitalization. In the current literature, thyroxine treatment has been evaluated only for TSH-elevated VPIs. However, the long-term impact of low thyroxine levels in certain VPIs with normal TSH levels deserves more research. Since July 2007, VPIs of this study unit received screenings at 1 month postnatal age (PNA) for serum TSH levels and total thyroxine (TT4), in addition to two national TSH screenings scheduled at 3-5 days PNA and at term equivalent age. This study aimed to establish the correlation between postnatal 1-month-old TT4 concentration and long-term NDI at 24 months corrected age among VPIs with serial normal TSH levels. VPIs born in August 2007-July 2016 were enrolled. Perinatal demography, hospitalization morbidities, and thyroid function profiles were analyzed, and we excluded those with congenital anomalies, brain injuries, elevated TSH levels, or a history of thyroxine treatments. In total, 334 VPIs were analyzed and 302 (90.4%) VPIs were followed-up. The postnatal TT4 concentration was not associated with NDI after multivariate adjustment (odd ratios 1.131, 95% confidence interval 0.969-1.32). To attribute the NDI of TSH-normal VPIs to a single postnatal TT4 concentration measurement may require more research.

Lateral flow immunogold assay as a rapid detection tool for screening of congenital hypothyroidism.

Congenital hypothyroidism (CH) is one of the most common preventable causes of mental retardation. The majority of infants are diagnosed after detection through newborn screening programs using thyroid-stimulating hormone (TSH) test. A rapid immunochromatographic lateral flow assay based on monoclonal antibodies (MAbs) colloidal gold nanoparticles was developed in a sandwich format for the detection of TSH. Two MAbs binding distinct TSH epitopes are used; one is conjugated to the detection reagent while the other is immobilized at the test line on the membrane. The colloidal gold was prepared by the reduction of gold salt coupled with MAbs and this optimal concentration was determined by spectrophotometry method. The sensitivity of our developed lateral flow immunoassay was determined using 5, 10, 15, 25 and 50 µUI/mL of TSH. The color intensity of the test line was directly proportional to the TSH concentration and the visual limit of detection was 10 µUI/mL. Twenty samples of umbilical cord serum were analyzed by the developed strips and the intensity of the signal was in agreement with the results obtained by the conventional radioimmunoassay method. The results suggest that this rapid test can be used in initial screening for congenital hypothyroidism especially in rural areas.

The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth

Our objective was to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males. These characteristic include almost universal congenital central hypothyroidism (CeH) with disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index (BMI), and decreased attentional control. In addition, a subset of patients show prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood. We present a family in which the proband was diagnosed with CeH and low serum prolactin. Severe weight gain started at two years old, with a BMI of 42.3 at 13.9 years. Testicular enlargement (5-6 mL, 3.8-4.3 standard deviation score) started aged three years. A pathogenic variant was found in the IGSF1 gene: c.3411_3412del, p.(Tyr1137*). His brother was referred for short stature at age 13 years and was diagnosed with CeH, normal serum prolactin and IGF-1, and disharmonious puberty. In four male relatives (the proband's brother and three cousins) with the variant (one adult), free thyroxine (fT4) was below the lower limit of the reference range in two, and just above this limit in the other two. Three were overweight or obese, adolescents had disharmonious pubertal development and the adult had profound macroorchidism. In conclusion, male hemizygous carriers of a pathogenic IGSF1 variant can present with fT4 concentration above the lower limit of the reference range while severe early onset obesity or premature testicular growth are part of the phenotypic spectrum.

Thyroid scintigraphy differentiates subtypes of congenital hypothyroidism.

INTRODUCTION: UK screening for congenital hypothyroidism (CH) is based on dried blood spot Thyroid Stimulating Hormone (TSH). Scintigraphy may identify CH subtypes classified as dysplasia, gland in situ (GIS) and ectopia, but is not performed in all centres. We retrospectively investigated the role of scintigraphy to identify CH subtypes in a single tertiary centre cohort. METHODS: Babies who screened positive for CH between 2007 and 2017 were studied (n=418 of 534 783). Scintigraphy outcomes were correlated with TSH and levothyroxine dose. GIS patients were analysed for 3-year outcomes. RESULTS: 303 patients started levothyroxine. Scintigraphy demonstrated three subtypes: GIS (n=139, 46%) ectopia (n=84, 28%) and dysplasia (n=80, 26%). Three-year follow up demonstrated permanence in 54% of 37 GIS cases. DISCUSSION: Thyroid scintigraphy differentiates subtypes of CH and suggests a higher than expected proportion of patients with GIS and ectopia. CH is permanent in half of those with GIS.

Basal Serum Thyroxine Level should Guide Initial Thyroxine Replacement Dose in Neonates with Congenital Hypothyroidism

Objective: Initial high-dose sodium levothyroxine (Na-LT4) (10-15 µg/kg/day) replacement for primary congenital hypothyroidism (CH) is recommended in guidelines. However, high-dose Na-LT4 risks iatrogenic hyperthyroidism. The aim of this study was to investigate the normalizing effect of varying initial doses of Na-LT4 on serum thyroid hormone levels. Methods: Fifty-two patients were analyzed retrospectively. The patients were classified into mild (27/51.9%), moderate (11/21.1%) and severe (14/26.9%) CH, based on initial free thyroxine (fT4) levels. Time taken to achieve target hormone levels was compared within groups. Results: Initial mean Na-LT4 doses for mild, moderate and severe disease were 6.9±3.3, 9.4±2.2 and 10.2±2 µg/kg/day. Serum fT4 levels reached the upper half of normal range (>1.32 ng/dL) in a median of 16, 13 and 16 days in patients with mild, moderate and severe CH with the mean time from initial treatment to first control visit of 14.8±6 days (range 1-36). There was no significant difference in terms of time to achieve target fT4 hormone levels according to disease severity (p=0.478). Seven (25.9%), eight (72.7%) and eight (57.1%) patients experienced hyperthyroxinemia (serum fT4 >1.94 ng/dL) in the mild, moderate, and severe CH groups at the first visit, respectively (p=0.016). Conclusion: Not all patients diagnosed with CH require high-dose Na-LT4. Initial dose of Na-LT4 may be selected on the basis of pre-treatment thyroid hormone levels. Some patients with moderate and severe CH, experienced iatrogenic hyperthyroxinemia even though the dose was close to the lower limit of the recommended range in guidelines. We suggest that lower initial doses may be appropriate with closer follow-up within the first week.

Newborn Screening for Congenital Hypothyroidism: the Benefit of Using Differential TSH Cutoffs in a 2-Screen Program.

CONTEXT: Analysis of a 2-screen program for congenital hypothyroidism (CH) was performed using differential dried-blood spot thyrotropin (bTSH) cutoffs of 10 mU/L at first screening (all infants) and 5 mU/L at second screening (selected infants). OBJECTIVES: This work aimed to characterize CH infants identified by the second screening and compare infants with bTSH of 5.0 to 9.9 and 10 mU/L or greater on second screening. DESIGN AND PATIENTS: Maternal and neonatal clinical features were retrospectively analyzed for 119 CH babies detected on the second screen in the Lombardy region of Italy, 2007 to 2014. RESULTS: Fifty-two (43.7%) of the 119 CH neonates showed bTSH values ranging from 5.0 to 9.9 mU/L at the second screening (low bTSH group) and 67 (56.3%) bTSH of 10.0 mU/L or greater (high bTSH group). The frequency of thyroid dysgenesis and eutopic gland was similar in both groups, as was the frequency of permanent and transient CH. Moreover, a high frequency of extrathyroidal malformations was found in both groups. The percentage of preterm infants (57.7% vs 23.9%, P < .001) and infants admitted to the neonatal intensive care unit (50.0% vs 17.9%, P < .001) was significantly higher in the low vs the high bTSH group. In addition, maternal treatment with glucocorticoids in pregnancy was significantly more frequent in the low bTSH group than in the high bTSH group (11.5% vs 1.5%, P = .042), as well as maternal hypothyroidism and/or goiter (26.9% vs 10.4%, P = .036). CONCLUSIONS: This study has demonstrated that a lower TSH cutoff at the second screening can detect additional cases of CH and that a second bTSH cutoff of 5.0 mU/L is appropriate for identifying preterm newborns and babies with associated risk factors.

Characterization of patients diagnosed with congenital hypothyroidism at the Hospital Universitario San Ignacio between 2001 and 2017 / Caracterización de pacientes con hipotiroidismo congénito en el Hospital Universitario San Ignacio entre 2001 y 2017.

Introduction: Congenital hypothyroidism is a preventable cause of cognitive disability. Due to the absence of symptoms and signs in the newborn, it is necessary to perform screening tests. Its incidence ranges between 1:2,500 and 1:6,000. Objective: To describe the anthropometric and demographic characteristics, as well as the cord TSH levels, serum TSH, and serum T4L levels of the positive patients during screening and patients with confirmed congenital hypothyroidism. Materials and methods: We conducted a retrospective observational study for 17 years based on the review of clinical laboratory and medical records to describe the demographic and anthropometric characteristics of the patients at the time of diagnosis. Results: We analyzed 41,494 newborns in the 17 years of follow-up; 217 (0.52%) were positive in the screening test and the diagnosis was confirmed by serum tests (TSH and free T4) in 19 cases (8.76%) for an incidence of one for every 2,183 live births; 78.95% of the children with congenital hypothyroidism were born full-term and the average gestational age was 37.3 weeks, similar to that of those with no congenital hypothyroidism. There was no difference in the average weight and height at birth between the children with the condition and those who did not have it. TSH in the cord in the cases of congenital hypothyroidism was significantly higher than in the discarded cases. Conclusions: The incidence of congenital hypothyroidism was similar to that found in the literature. There were no relevant clinical differences between confirmed and ruled out cases reflecting the relevance of neonatal screening.

Introducción. El hipotiroidismo congénito es una causa prevenible de discapacidad cognitiva. Dada la ausencia de signos y síntomas al nacer, es necesario hacer pruebas de tamización para detectarlo. Su incidencia oscila entre uno de cada 2.500 y uno de cada 6.000 nacidos vivos. Objetivo. Describir las características antropométricas y demográficas de los participantes, así como medir la concentración de tirotropina (TSH) en sangre de cordón umbilical y de TSH y tiroxina libre (T4 libre) en el suero de los recién nacidos positivos en la prueba de tamización y de aquellos con hipotiroidismo congénito confirmado. Materiales y métodos. Se hizo un estudio observacional retrospectivo de un periodo de 17 años mediante la revisión de los registros de laboratorio clínico y las historias para establecer las características demográficas y antropométricas en el momento del nacimiento. Resultados. Se analizaron 41.494 recién nacidos. Se encontraron 217 (0,52 %) recién nacidos con prueba positiva de tamización, 19 (8,76 %) de ellos con diagnóstico confirmado mediante pruebas séricas (TSH y T4 libre), para una incidencia de uno por cada 2.183 nacidos vivos. El 78,95 % de los casos de hipotiroidismo congénito correspondió a nacidos a término, el promedio de la edad gestacional fue de 37,3 semanas, similar al de quienes no lo presentaban. No hubo diferencia en el promedio de peso ni en la talla al nacer entre los afectados y los no afectados. La concentración de TSH en sangre de cordón umbilical fue significativamente mayor en los casos de hipotiroidismo congénito que en los recién nacidos sanos. Conclusiones. La incidencia de hipotiroidismo congénito fue similar a la encontrada en los estudios consultados. No hubo diferencias clínicas relevantes entre los casos confirmados y los descartados, lo que resalta la pertinencia de la tamización neonatal para el diagnóstico temprano y el tratamiento oportuno.

A Detailed Analysis of the Factors Influencing Neonatal TSH: Results From a 6-Year Congenital Hypothyroidism Screening Program.

Background: Neonatal thyrotropin (TSH) on dried blood spot (DBS), the most common screening strategy for primary congenital hypothyroidism (CH), is influenced by numerous factors that may hinder a true CH diagnosis. A second test can thus be performed to clarify the initial findings, although its application varies among screening programs. Objectives: The aim of this study was to evaluate the effect of maternal and neonatal factors on neonatal TSH levels and offer practical screening recommendations. Methods: We retrospectively analyzed screening data of 62,132 neonates born in Abruzzo, an Italian region considered mildly iodine deficient, between 2011 and 2016. We then performed a multiple linear regression to model the relationship between TSH (the dependent variable) and 13 independent variables extracted from blood collection cards. Results: Most neonates (53,551 of 62,132, 86%) had normal TSH and no clinical indications for a second screening. A minority (1,423, 2.3%) had elevated TSH in the initial DBS, which was confirmed in 97 cases (7%) on a second screen. The remaining neonates (6,594, 10.6%) had a normal initial TSH but underwent a second test in accordance with screening protocols, and were found to have delayed TSH elevation in 23 cases (0.4%). Those 120 newborns (97 + 23), considered highly suspicious for primary CH, were referred to a pediatrician for confirmatory testing and excluded from subsequent analysis of factors influencing TSH levels. Sex (ß regression coefficient, ß = 1.11 female to male, 95% CI 1.09, 1.12) and age at collection (ß = 0.78 day 5 to days 2-3, 95% CI 0.74, 0.83) affected neonatal TSH, suggesting the utility of specific nomograms. In addition, prematurity (ß = 0.85 term to preterm, 95% CI 0.80, 0.91), dopamine use (ß = 0.71, 95% CI 0.62, 0.81), and birth weight (ß = 1.40 normal vs. very low, 95% CI 1.05, 1.89) strongly influenced neonatal TSH. Conclusions: Neonatal TSH is influenced by several factors supporting the delineation of local sex- and age-adjusted TSH cutoffs, and the universal adoption of a second TSH test in neonates at risk of missed primary CH diagnosis.

Newborn Iodine Status Is Not Related to Congenital Hypothyroidism.

BACKGROUND: Severe iodine deficiency or excess during pregnancy can cause congenital hypothyroidism (CH). Iodine deficiency is common in pregnant women in the United States. OBJECTIVES: We conducted a nested case-control study in a cohort of ∼2.5 million births in California to determine whether iodine status is related to CH in a US population. METHODS: Dried blood spots from 907 newborns with CH identified by newborn screening and 909 unaffected controls matched by month of birth were obtained from the California Newborn Screening Program to measure whole-blood iodine concentration. Iodine status was compared between cases and controls, and logistic regression was used to assess the association between CH status and blood iodine concentrations. Iodine status was also compared between cases and controls among infants treated in a neonatal intensive care unit (NICU) because CH has been reported in infants exposed to high levels of iodine in the NICU. RESULTS: Blood iodine concentrations did not differ significantly between cases (median: 20.0 ng/mL; IQR: 12.1-29.8 ng/mL) and controls (median: 20.3 ng/mL; IQR: 12.5-30.9 ng/mL; P = 0.59). Neither extremely high nor extremely low blood iodine concentrations (1st, 5th, 95th, and 99th percentiles of the distribution) were more common in cases. Among infants treated in NICUs, however, cases had significantly (P = 0.01) higher iodine (median: 22.7 ng/mL; IQR: 16.4-32.1 ng/mL) compared with controls (median: 17.3 ng/mL; IQR: 8.3-26.6 ng/mL). CONCLUSIONS: CH cases did not have significantly higher or lower iodine in this population, which is reassuring given that maternal iodine deficiency is common in the United States. Among newborns in the NICU, CH cases had higher blood iodine concentrations compared with controls, suggesting that excess iodine exposure in the NICU could be causing CH. It may be beneficial to monitor iodine exposure from surgical procedures, imaging, and iodine-containing disinfectants and to consider non-iodine alternatives.

Cribado neonatal de hipotiroidismo congénito: estudio observacional de 13 años / Newborn screening for congenital hypothyroidism: A 13-year observational study

No disponible

Newborn Screening TSH Values Less Than 15 mIU/L Are Not Associated With Long-term Hypothyroidism or Cognitive Impairment.

BACKGROUND: It is unclear whether newborns with mild thyrotropin elevation (mTSHe) are at risk of neurocognitive impairment. We assessed whether mTSHe at birth persists during childhood and compared neurocognitive functioning to siblings. METHODS: This study encompassed children born in the Auckland region (New Zealand) with a newborn screen TSH level of 8 to 14 mIU/L blood, age 6.9 to 12.6 years at assessment, and their siblings. Thyroid function tests (serum TSH and free thyroxine) and neurocognitive assessments were performed, including IQ via the Wechsler Intelligence Scale for Children, fourth edition. RESULTS: Ninety-six mTSHe individuals were studied, including 67 children recruited with 75 sibling controls. Mean mTSHe newborn TSH level was 10.1 mIU/L blood and 2.4 mIU/L at assessment (range, 0.8-7.0 mIU/L, serum). Although higher newborn TSH levels in the mTSHe group correlated with lower full-scale IQ scores (r = 0.25; P = .040), they were not associated with the magnitude of the IQ difference within sibling pairs (P = .56). Cognitive scores were similar for mTSHe and controls (full-scale IQ 107 vs 109; P = .36), with a minor isolated difference in motor coordination scores. CONCLUSIONS: Our data do not suggest long-term negative effects of neonatal mild TSH elevation. TSH elevation below the screen threshold appears largely transient, and midchildhood neurocognitive performance of these children was similar to their siblings. We propose that associations between neonatal mild TSH elevation and IQ are due to familial confounders. We caution against the practice of reducing screening CH cutoffs to levels at which the diagnosis may not offer long-term benefit for those detected.