Iodine status and supplementation in pregnancy: an overview of the evidence provided by meta-analyses.

Iodine supplementation during pregnancy in areas with mild-moderate deficiency is still a matter of debate. The present study aimed at systematically reviewing currently available evidences provided by meta-analyses with the aim to further clarify controversial aspects regarding the need of iodine supplementation in pregnancy as well as to provide guidance on clinical decision-making, even in areas with mild-moderate deficiency. Medline, Embase and Cochrane search from 1969 to 2022 were performed. For the purpose of this review, only studies containing meta-analytic data were selected. A total of 7 meta-analyses were retrieved. Four meta-analyses evaluated the relationship between iodine status during pregnancy and neonatal and maternal outcomes suggesting the existence of a U-shaped correlation between iodine status and several maternal and neonatal consequences, especially if iodine status is evaluated at the beginning of pregnancy. Three meta-analyses evaluating the results of intervention trials failed to provide straightforward conclusions on the benefits of iodine supplementation in pregnant women in areas with mild-moderate iodine deficiency. Although evidence coming from meta-analyses suggests a role of iodine status during pregnancy in determining maternal and child outcomes, results of meta-analyses of intervention trials are still controversial. Several factors including, degree of iodine deficiency, and pooling studies conducted in areas with different iodine intake, may account for the lack of benefits reported by meta-analyses of intervention trials. More high-quality, randomized, controlled trials including information on timing, dose and regimen of iodine supplementation are needed to further elucidate this issue.

Iodine nutritional status and thyroid effects of exposure to ethylenebisdithiocarbamates.

INTRODUCTION: Italy is still characterized by a mild iodine deficiency and is among the most intensive users of chemical products for agriculture in Europe. The aim of this study was i) to evaluate thyroid effects of exposure to mancozeb, a fungicide widely used in agriculture, in a sample of Italian grapevine workers, and ii) to verify whether the iodine intake may modulate the risk of thyroid disruption due to the mancozeb metabolite ethylenthiourea (ETU). METHODS: One hundred seventy-seven occupationally exposed male workers (29 from Chianti, a mild iodine deficient area, and 148 from Bolzano an iodine sufficient province) and 74 non-occupationally exposed male controls (34 from Chianti and 40 from Bolzano) were enrolled in the study. Serum biomarkers of thyroid function, as well as urinary iodine and ETU concentrations were assessed. Moreover all the recruited subjects underwent clinical examination and thyroid ultrasound. RESULTS: Multivariate comparisons showed lower mean serum levels of FT4 in Chianti-workers as compared to Bolzano-workers. Moreover, an increased urinary iodine excretion (>250µg/L) was more frequently found among more exposed workers (ETU>20µg/L) than among less exposed ones and this effect was more pronounced in Chianti- than in Bolzano-workers. Chianti-workers also showed a significantly higher frequency of very low thyroid volume (≤6.0ml) as compared to controls. CONCLUSIONS: These findings showed a mild thyroid disrupting effect due to occupational exposure to mancozeb, more pronounced in workers residing in an area characterized by a mild to moderate iodine deficiency as compared to workers residing in an area covered by a long-lasting iodine prophylaxis program.

Nutritional iodine status and obesity.

Iodine is an essential component of the thyroid hormones, thyroxine and triiodothyronine. Its availability strictly depends on iodine content of foods, which may vary from very low to very high. Inadequate iodine intake (deficiency or excess) may affect thyroid function resulting in hypothyroidism or hyperthyroidism. Based on median urinary iodine concentrations, epidemiological criteria have been established for the categorization and monitoring of nutritional iodine status of a population (or subgroups of populations). Additional methods for iodine intake assessment include measurement of thyroid size (by thyroid palpation or ultrasonography) and of biochemical parameters, such as neonatal thyroid stimulating hormone, thyroglobulin and thyroid hormones.Recent studies carried out in overweight/obese children and adults provide evidence that body mass index (BMI) may significantly influence the above indicators, thus theoretically affecting the epidemiological evaluation of nutritional iodine status in populations.In this short review, we analyze current knowledge on the effects of overweight and obesity on indicators of adequacy and monitoring of iodine status, namely urinary iodine excretion and thyroid volume and echogenicity.Data on urinary iodine excretion in overweight/obese children are divergent, as both increased and reduced levels have been reported in overweight/obese children compared to normal-weight controls.Whether gastrointestinal surgery may affect iodine absorption and lead to iodine deficiency in patients undergoing bariatric surgery has been evaluated in a limited number of studies, which excluded iodine deficiency, thus suggesting that supplements usually recommended after bariatric surgery do not need to include iodine.Albeit limited, evidence on thyroid volume and obesity is consistent with a direct relationship between thyroid volume and BMI, irrespective of nutritional iodine status. Finally, a higher frequency of thyroid hypoechoic pattern has been described in overweight/obese children. This finding has been recently related to an increased adipocyte infiltration and thyroid parenchyma imbibition mediated by inflammatory cytokines and should be considered when the frequency of thyroid hypoechoic pattern is used as non-invasive marker to indirectly assess thyroid autoimmunity in monitoring Universal Salt Iodization programs. Further studies, specifically addressing the role of schoolchildren body mass index as a factor potentially influencing iodine intake indicators are needed.

Iodoprophylaxis and thyroid autoimmunity: an update.

Adequate iodine intake is necessary for normal thyroid function. Iodine deficiency is associated with serious complications, but also iodine excess can lead to thyroid dysfunction, and iodine supplementation aimed to prevent iodine deficiency disorders has been associated with development of thyroid autoimmunity. The epidemiology of thyroid diseases has undergone profound changes since the implementation of iodoprophylaxis, notably by means of iodine-enriched salt, specifically resulting in decreased prevalence of goiter and neonatal hypothyroidism, improved cognitive function development in infancy, and reduced incidence of more aggressive forms of thyroid cancer. The main question we address with this review is the clinical relevance of the possible effect on autoimmunity exerted by the use of iodine-enriched salt to correct iodine deficiency. In animal models, exogenous iodine is able to trigger or exacerbate thyroid autoimmunity, but it is still not clear whether the observed immunological changes are due to a direct effect of iodine on immune response, or whether they represent a secondary response to a toxic effect of iodine on thyroid tissue. Previous iodine status of a population seems to influence the functional thyroid response to increased iodine intake and possibly the development of thyroid autoimmunity. Moreover, the prevalence of thyroid antibodies, regarded as hallmark of autoimmune thyroid disease, varies between populations under the influence of genetic and environmental factors, and the presence of thyroid antibodies does not always coincide with the presence of thyroid disease or its future development. In addition, the incidence of autoimmune diseases shows a general increasing trend in the last decades. For all these reasons, available data are quite heterogeneous and difficult to analyze and compare. In conclusion, available data from long-term population surveys show that a higher than adequate population iodine intake due to a poorly controlled program of iodine prophylaxis could induce thyroid dysfunction, including thyroid autoimmunity mostly represented by euthyroid or subclinical hypothyroid autoimmune thyroiditis. Close monitoring iodine prophylaxis is therefore advised to ensure that effects of both iodine deficiency and iodine excess are avoided.

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.

Obesity and Monitoring Iodine Nutritional Status in Schoolchildren: is Body Mass Index a Factor to Consider?

Background: The frequency of overweight (OW) and obese (OB) children has increased worldwide, particularly in economically developed countries. No studies have been conducted to verify whether the increasing frequency of OW and obesity in schoolchildren may affect the evaluation of iodine nutritional status in populations. The aim of this study was to verify whether urinary iodine concentration (UIC), thyroid volume (TV), and thyroid hypoechoic pattern may be affected by body mass index (BMI) in schoolchildren. Methods: The children included in this study (aged 11-13 years) were a part of the schoolchildren recruited in the second nationwide survey (period 2015-2019) conducted in Italy to monitor by law (Atto di Intesa Stato-Regioni February 26, 2009) the nationwide iodine prophylaxis program. Specifically, 1281 schoolchildren residing in iodine-sufficient areas (IS group) and 384 children residing in a still mildly iodine-deficient area (ID group) were recruited between January and March 2015 in the first-degree secondary state schools. In all the children, spot UIC was measured, thyroid ultrasound was performed to evaluate TV, and hypoechogenicity was assessed to indirectly evaluate iodine-associated thyroid autoimmunity. Results: The frequency of OW, OB, and adequate weight (AW) children was similar in the IS and ID groups at any age. After adjusting for sex and age, the regression analysis showed lower UIC values in OB children than in AW children of the IS group (beta coefficient = -34.09 [95% confidence interval -65.3 to -2.8]), whereas no significant differences were observed in the ID group. In both the IS and ID groups, the distribution of TV in AW children was significantly shifted toward lower values in comparison to the distribution of OB children (p < 0.001 in the IS group; p = 0.012 in the ID group). Furthermore, the frequency of thyroid hypoechogenicity was higher in the ID group than in the IS group (10.9% vs. 6.6%, p = 0.005); however, in both groups, it was significantly lower in AW children than in OB children (p < 0.01). Conclusions: This study for the first time demonstrates that BMI may be a confounding factor in monitoring iodine nutritional status in schoolchildren. Since in Italy as in other Western countries the number of OW and OB children is high, BMI is a factor to consider in monitoring salt iodization programs worldwide.

Neonatal Screening for Congenital Hypothyroidism: What Can We Learn From Discordant Twins?

CONTEXT: Newborn screening program for congenital hypothyroidism (CH) adopting rescreening in at-risk neonates. OBJECTIVES: To estimate the concordance rate for CH in twin pairs discordant at the first screening; to verify whether long-term follow-up of healthy cotwins belonging to CH discordant pairs may be useful to diagnose thyroid hypofunction during development; to evaluate the importance of genetic and environmental influences on liability to permanent and transient CH. DESIGN AND PATIENTS: Forty-seven screening discordant twin pairs were investigated. Proband was defined as the twin in the pair with a positive test at the first screening and a confirmed diagnosis of CH. RESULTS: Seven screening discordant twin pairs became concordant for CH within the first month of life (pairwise concordance of 14.9%) because seven screening negative cotwins showed high TSH values when retested. During long-term follow-up (range, 3 to 21 years), hypothyroidism was diagnosed in two monozygotic screening negative cotwins at the age of 9 months and 12 years, respectively. Furthermore, the twin analysis showed that 95% of liability to transient CH was explained by genetic factors and 5% by environmental (unshared) factors, whereas 64% of phenotypic variance of permanent CH was explained by common environmental factors (shared during the fetal life) and 36% by unshared environmental factors. CONCLUSIONS: This study showed that the introduction of rescreening permits the diagnosis of CH in a greater number of twins. It also showed the importance of long-term follow-up in both twins in the pair, and the role of nongenetic factors in the etiology of permanent CH.

High risk of congenital hypothyroidism in multiple pregnancies.

CONTEXT: In Italy, the surveillance of congenital hypothyroidism (CH) is performed by the Italian National Registry of Infants with CH (INRICH). Up to now, about 3600 infants with CH are recorded in the INRICH, and a high number of twins are included. OBJECTIVE: Our objective was to estimate the risk of CH in multiple and single deliveries and to compare neonatal features of CH twins with twins from the general population. DESIGN: The Italian population of CH infants recorded in the INRICH from 1989-2000 was investigated. RESULTS: A more than 3-fold higher frequency of twins was found in the CH population than in the general population, and for the first time, it was possible to estimate the CH incidence in multiple (10.1 in 10,000) and single deliveries (3.2 in 10,000 live births). Significantly higher frequencies of in situ gland as well as lower TSH mean level at screening were found in twin than in singleton CH babies. The concordance rate for permanent CH was very low (4.3%) and due to only three concordant couples. However, a high recurrence risk for CH was estimated in siblings of affected babies recorded in the INRICH, including twins considered as siblings. CONCLUSIONS: The high CH incidence observed in twins is worthy of interest for the high number of induced pregnancies in Italy as well as in other Western countries. Moreover, the low concordance rate for CH among twins together with a high recurrence risk for the disease among siblings indicates that environmental risk factors may act as a trigger on a susceptible genetic background in the etiology of the disease.

Are lower TSH cutoffs in neonatal screening for congenital hypothyroidism warranted?

When newborn screening (NBS) for congenital hypothyroidism (CH) using thyroid-stimulating hormone (TSH) as a primary screening test was introduced, typical TSH screening cutoffs were 20-50 U/L of whole blood. Over the years, lowering of TSH cutoffs has contributed to an increased prevalence of detected CH. However, a consensus on the benefit deriving from lowering TSH cutoffs at screening is lacking. The present paper outlines arguments both for and against the lowering of TSH cutoffs at NBS. It includes a review of recently published evidence from Australia, Belgium and Italy. A section focused on economic implications of lowering TSH cutoffs is also provided. One issue that bears further examination is the extent to which mild iodine deficiency at the population level might affect the association of neonatal TSH values with cognitive and developmental outcomes. A debate on TSH cutoffs provides the opportunity to reflect on how to make NBS for CH more effective and to guarantee optimum neurocognitive development and a good quality of life to babies with mild as well as with severe CH. All authors of this debate article agree on the need to establish optimal TSH cutoffs for screening programs in various settings and to ensure the benefits of screening and access to care for newborns worldwide.

The way forward in Italy for iodine.

Italy is dealing with iodine deficiency since ancient times. In 1848 an ad hoc committee appointed by the king of Sardinia, identified extensive areas afflicted by endemic goiter and endemic cretinism in Piedmont, Liguria and Sardinia. Since then many epidemiological studies have been conducted in our country. These showed that iodine deficiency was present not only in mountain areas but also in coastal areas. In 1972 the iodization of salt at 15 mg/kg was allowed by law and iodized salt was distributed on request to selected endemic areas. Five years later the distribution was extended to the whole country. However the sale of iodized salt was not mandatory at that time and only a small fraction of the Italian population started using iodized salt. In 1991 the content of iodine in the salt was raised to 30 mg/kg and in 2005 a nationwide salt iodization program was finally implemented. Some years later a nationwide monitoring program of iodine prophylaxis was also implemented. Since 2005 the sale of iodized salt in Italian supermarkets has increased (34% in 2006, 55% in 2012), although it has been observed that the use of iodized salt is still low in the communal eating areas and in the food industry. These data are coherent with recent epidemiological studies showing that some regions in our country are still characterized by mild iodine deficiency and a high frequency of goiter and other iodine deficiency disorders. This implies that further efforts should be made to successfully correct iodine deficiency in Italy.

Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis.

CONTEXT: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000-4000 at birth. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland [thyroid dysgenesis (TD)]. Mutations in genes controlling thyroid development have demonstrated that in a few cases, TD is a Mendelian trait. However, accumulating evidence supports the view that the genetics of TD are complex, possibly with a polygenic/multifactorial basis. A higher prevalence of congenital heart disease has been documented in children with CH than in the general population. Such an association suggests a possible pathogenic role of genes involved in both heart and thyroid development. NKX2-5 encodes a homeodomain-containing transcription factor with a major role in heart development, and mutations affecting this gene have been reported in individuals with congenital heart disease. OBJECTIVE: In the present work we investigated the possible involvement of NKX2-5 mutations in TD. RESULTS: Our results indicate that Nkx2-5(-/-) embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2-5 plays a role in thyroid organogenesis and that NKX2-5 mutations contribute to TD. NKX2-5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties, with a dominant-negative effect on wild-type NKX2-5. CONCLUSION: Our results suggest a previously unknown role of NKX2-5 in the pathogenesis of TD.

Risk factors for congenital hypothyroidism: results of a population case-control study (1997-2003).

OBJECTIVE: To identify risk factors for permanent and transient congenital hypothyroidism (CH). DESIGN: A population-based case-control study was carried out by using the network created in Italy for the National Register of Infants with CH. METHODS: Four controls were enrolled for each new CH infant; 173 cases and 690 controls were enrolled in 4 years. In order to distinguish among risk factors for permanent and transient CH, diagnosis was re-evaluated 3 years after enrollment when there was a suspicion of transient CH being present. Familial, maternal, neonatal and environmental influences were investigated. RESULTS: An increased risk for permanent CH was detected in twins by a multivariate analysis (odds ratio (OR) = 12.2, 95% confidence interval (CI): 2.4-62.3). A statistically significant association with additional birth defects, female gender and gestational age >40 weeks was also confirmed. Although not significant, an increased risk of CH was observed among infants with a family history of thyroid diseases among parents (OR = 1.9, 95% CI: 0.7-5.2). Maternal diabetes was also found to be slightly associated with permanent CH (OR = 15.7, 95% CI: 0.9-523) in infants who were large for gestational age. With regard to transient CH, intrauterine growth retardation and preterm delivery were independent risk factors for this form of CH. CONCLUSION: This study showed that many risk factors contribute to the aetiology of CH. In particular, our results suggested a multifactorial origin of CH in which genetic and environmental factors play a role in the development of the disease.

Galectin-3/AGE-receptor 3 knockout mice show accelerated AGE-induced glomerular injury: evidence for a protective role of galectin-3 as an AGE receptor.

We previously showed that mice lacking galectin-3/AGE-receptor 3 develop accelerated diabetic glomerulopathy. To further investigate the role of galectin-3/AGE-receptor function in the pathogenesis of diabetic renal disease, galectin-3 knockout (KO) and coeval wild-type (WT) mice were injected for 3 months with 30 microg/day of N(epsilon)-carboxymethyllysine (CML)-modified or unmodified mouse serum albumin (MSA). Despite receiving equal doses of CML, KO had higher circulating and renal AGE levels and showed more marked renal functional and structural changes than WT mice, with significantly higher proteinuria, albuminuria, glomerular, and mesangial area and glomerular sclerosis index. Renal 4-hydroxy-2-nonenal content and NFkappaB activation were also more pronounced in KO-CML vs. WT-CML. Kidney mRNA levels of fibronectin, laminin, collagen IV, and TGF-beta were up-regulated, whereas those of matrix metalloproteinase-2 and -14 were down-regulated, again more markedly in KO-CML than WT-CML mice. Basal and CML-induced RAGE and 80K-H mRNA levels were higher in KO vs. WT mice. MSA injection did not produce any significant effect in both genotypes. The association of galectin-3 ablation with enhanced susceptibility to AGE-induced renal disease, increased AGE levels and signaling, and altered AGE-receptor pattern indicates that galectin-3 is operating in vivo as an AGE receptor to afford protection toward AGE-dependent tissue injury.

Multiple factors influencing the incidence of congenital hypothyroidism detected by neonatal screening.

BACKGROUND/AIMS: Over the years a rise in the incidence of congenital hypothyroidism (CH) has been described worldwide. The aim of our study was to investigate trends in the incidence of CH in Italy over the period 1987-2008, and to investigate which factors may have influenced the CH incidence in our country. METHODS: Data were derived from the Italian National Registry of Infants with Congenital Hypothyroidism. Since 1998 the laboratory procedures related to neonatal screening for CH have changed drastically. Accordingly, we estimated the CH incidence during the period 1987-1998 (period 1) and the period 1999-2008 (period 2). RESULTS: The incidence of CH confirmed at birth (including transient hypothyroidism) has increased from 1:3,000 liveborn infants in period 1 to 1:1,940 in period 2 (+54%), whereas the incidence of purely permanent CH increased from 1:3,200 to 1:2,320 (+38%). Lowering of the TSH cutoff was the most important factor contributing to the increase of CH incidence in Italy. Moreover, an increment of 58% of preterm babies with permanent CH was found in period 2 compared with period 1. CONCLUSION: Our results suggest that more than one cause is responsible for the rise in the increasing CH incidence, with lowering of the screening TSH cutoff and an increased survival rate of a growing number of preterm babies both playing an important role.

European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism.

OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). EVIDENCE: A systematic literature search was conducted to identify key articles relating to the screening, diagnosis, and management of CH. The evidence-based guidelines were developed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. CONSENSUS PROCESS: Thirty-two participants drawn from the European Society for Paediatric Endocrinology and five other major scientific societies in the field of pediatric endocrinology were allocated to working groups with assigned topics and specific questions. Each group searched the literature, evaluated the evidence, and developed a draft document. These papers were debated and finalized by each group before presentation to the full assembly for further discussion and agreement. RECOMMENDATIONS: The recommendations include: worldwide neonatal screening, approaches to assess the cause (including genotyping) and the severity of the disorder, the immediate initiation of appropriate L-T4 supplementation and frequent monitoring to ensure dose adjustments to keep thyroid hormone levels in the target ranges, a trial of treatment in patients suspected of transient CH, regular assessments of developmental and neurosensory functions, consulting health professionals as appropriate, and education about CH. The harmonization of diagnosis, management, and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder. Individuals with CH require monitoring throughout their lives, particularly during early childhood and pregnancy.

European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism.

OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). EVIDENCE: A systematic literature search was conducted to identify key articles relating to the screening, diagnosis, and management of CH. The evidence-based guidelines were developed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. CONSENSUS PROCESS: Thirty-two participants drawn from the European Society for Paediatric Endocrinology and five other major scientific societies in the field of pediatric endocrinology were allocated to working groups with assigned topics and specific questions. Each group searched the literature, evaluated the evidence, and developed a draft document. These papers were debated and finalized by each group before presentation to the full assembly for further discussion and agreement. RECOMMENDATIONS: The recommendations include: worldwide neonatal screening, approaches to assess the cause (including genotyping) and the severity of the disorder, the immediate initiation of appropriate L-T4 supplementation and frequent monitoring to ensure dose adjustments to keep thyroid hormone levels in the target ranges, a trial of treatment in patients suspected of transient CH, regular assessments of developmental and neurosensory functions, consulting health professionals as appropriate, and education about CH. The harmonization of diagnosis, management, and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder. Individuals with CH require monitoring throughout their lives, particularly during early childhood and pregnancy.

The geographical pattern of thyroid cancer mortality between 1980 and 2009 in Italy.

BACKGROUND: Mortality for thyroid cancer (TC) is low and has been decreasing worldwide; yet few population studies based on mortality have been conducted. Several nonradiation risk factors have been associated with TC, including residence in goiter-endemic areas (as an indicator of iodine deficiency). We used mortality data to perform a spatial-temporal analysis regarding TC in Italy and investigated the association between mortality and socioeconomic status and geographical features (residing in a mountainous area is a proxy for iodine deficiency). METHODS: We analyzed data from Italy's National Mortality Database (1980-2009). To evaluate temporal trends in mortality the age-standardized death rate (ASR) was used; to identify geographic areas with excess deaths due to TC standardized mortality rates (SMR) were calculated. We also calculated the rate ratios (RR) of the ASR and the 95% CI by sex. We performed a cluster analysis to identify municipalities with major departures from expected mortality, both in the entire study period and in two separate periods to evaluate the spatial-temporal variability. Finally, we evaluated the association between mortality and index of deprivation and altitude. RESULTS: There were 16,473 deaths due to TC (10,690 females, 5783 males). The mean ASR was unsurprisingly low (0.58/100.000). There was a trend of decrease in mortality throughout Italy (-42% for 2007-2009 vs. 1980-1984), more pronounced among women. The decrease was greater in the north. Four geographic clusters were identified when considering the entire study period, two in the north and two in the south; however, the clusters in northern Italy refer to the earlier period (1980-1994) and those in southern Italy to the later period (1995-2009). Mortality was associated with residing in a mountainous area. A slight association with high socioeconomic status was found. CONCLUSIONS: This study reveals space-time differences in TC mortality in Italy. It shows an association between mortality and residing in mountainous areas, which is a proxy of iodine deficiency. The observed temporal north-south shift cannot be explained by socioeconomic differences, whereas the efficient prophylaxis program implemented in the 1980s in some areas of northern Italy can help to explain the disappearance of the clusters in those areas in the period 1995-2009.

Congenital hypothyroidism due to defects of thyroid development and mild increase of TSH at screening: data from the Italian National Registry of infants with congenital hypothyroidism.

CONTEXT: Over the years lower TSH cutoffs have been adopted in some screening programs for congenital hypothyroidism (CH) worldwide. This has resulted in a progressive increase in detecting additional mild forms of the disease, essentially with normally located and shaped thyroid. However, the question of whether such additional mild CH cases can benefit from detection by newborn screening and early thyroid hormone treatment is still open. OBJECTIVE: The aim of this study was to estimate the frequency of cases with mild increase of TSH at screening in the Italian population of babies with permanent CH and to characterize these babies in terms of diagnosis classification and neonatal features. METHODS: Data recorded in the Italian National Registry of infants with CH were analyzed. RESULTS: Between 2000 and 2006, 17 of the 25 Italian screening centers adopted a TSH cutoff at screening of <15.0 µU/mL. It was found that 21.6% of babies with permanent CH had TSH at screening of 15.0 µU/mL or less, whereas this percentage was 54% in infants with transient hypothyroidism. Among the babies with permanent CH and mild increase of TSH at screening (≤15 µU/mL), 19.6% had thyroid dysgenesis with serum TSH levels at confirmation of the diagnosis ranging from 9.9 to 708 µU/mL. These babies would have been missed at screening if the cutoff had been higher. CONCLUSIONS: Lowering TSH cutoff in our country has enabled us to detect additional cases of permanent CH, a number of which had defects of thyroid development and severe hypothyroidism at confirmation of the diagnosis.

Reproductive toxicity and thyroid effects in Sprague Dawley rats exposed to low doses of ethylenethiourea.

Ethylenethiourea (ETU) is the common metabolite of the widely used ethylenebisdithiocarbamate fungicides. It is identified as Endocrine Disruptor given its ability to interfere with thyroid hormone biosynthesis by inhibiting thyroid peroxidase activity. As far as we know, no studies have been performed to assess potential effects of ETU exposure at low dose levels, i.e. below the established LOAEL and NOAEL, during critical phases of development. Therefore, the aim of the present study was to verify the short- and long-term effects on thyroid function, reproduction and development of oral exposure to ETU levels comparable to and lower than LOAEL/NOAEL in rats. Sixty dams were treated daily by gavage during pregnancy and lactation with 0, 0.1, 0.3, 1.0 mg/kg bw per day of ETU. F1 generation was similarly treated from weaning to sexual maturity. Thyroid biomarkers were analyzed in dams and in offspring. Reproductive biomarkers were analyzed in F1 rats. For the first time this study has demonstrated reproductive toxicity and hypothyroidism at a lower than LOAEL dose exposure in pregnant dams and F1 generation. Our data suggest that even low doses of ETU can interfere with thyroid homeostasis and reproductive hormone profile if exposure starts in critical stages of development.