Neonatal screening: 9% of children with filter paper thyroid-stimulating hormone levels between 5 and 10μIU/mL have congenital hypothyroidism

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Christensen‐Adad, Carolina T. Mendes‐dos‐Santos, Maura M.F. Goto, Letícia E. Sewaybricker, Lília F.R. D'Souza‐Li, Gil Guerra‐Junior, André M. Morcillo, Sofia Helena V. Lemos‐Marini" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Flávia C." "apellidos" => "Christensen‐Adad" ] 1 => array:2 [ "nombre" => "Carolina T." "apellidos" => "Mendes‐dos‐Santos" ] 2 => array:2 [ "nombre" => "Maura M.F." "apellidos" => "Goto" ] 3 => array:2 [ "nombre" => "Letícia E." "apellidos" => "Sewaybricker" ] 4 => array:2 [ "nombre" => "Lília F.R." "apellidos" => "D'Souza‐Li" ] 5 => array:2 [ "nombre" => "Gil" "apellidos" => "Guerra‐Junior" ] 6 => array:2 [ "nombre" => "André M." "apellidos" => "Morcillo" ] 7 => array:2 [ "nombre" => "Sofia Helena V." 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(A) Association between forced expiratory volume in 1s (FEV1) of forced vital capacity (FVC) and rs4073, dominant model and two identified mutations in the CFTR gene (cystic fibrosis transmembrane regulator) belonging to classes I, II, and/or III (CFTR-B group) (p=0.028; pc=0.112). (AA+AT) n=39; mean of 4.77±8.95; median of 4 (ranging from −9 to 48). (TT) n=21; mean of −0.86±5.42; median of −1 (ranging from −6 to 15). (B) Association of FEV1/FVC ratio with rs4073, over-dominant model and CFTR-B group (p=0.029; pc=0.116). (AA+TT) n=30; mean of 1.17±7.36; median of 0 (ranging from −12 to 23). (AT) n=29; mean of 4.76±7.58; median of 4 (ranging from −9 to 32). (C) Association of forced expiratory flow of 50% (FEF50%) of FVC with rs4073, dominant model, and CFTR-B group (p=0.046; pc=0.184). (AA+AT) n=37; mean of 17.38±24.18; median of 16 (ranging from −20 to 89). (TT) n=21; mean of 4.95±20.8; median of −2 (ranging from −19 to 55). (D) Association of FEF50% with rs2227306, dominant model, and CFTR-B group (p=0.05; pc=0.083). (CC) n=15; mean of 1.47±17.22; median of 0 (ranging from −20 to 29). (CT+TT) n=44; mean of 15.84±25.04; median of 10.5 (ranging from −28 to 89). (E) Association of FEF50% with rs2227306, over-dominant model, and CFTR-B group (p=0.033; pc=0.083). (CC+TT) n=33; mean of 6.06±20.27; median of 4 (ranging from −20 to 55). (CT) n=23; mean of 19.96±26.43; median of 19 (ranging from −28 to 89). (F) Association of forced expiratory flow of 75% (FEF75%) of FVC with rs4073, co-dominant model regardless of identified mutations in the CFTR gene (CFTR-A group) (p=0.044; pc=0.058). 1≠3. (AA) n=28; mean of 29.93±39.98; median of 30 (ranging from −47 to 142). (AT) n=42; mean of 24.81±53.57; median of 14 (ranging from −58 to 235). (TT) n=28; mean of 9.14±36.95; median of 2.5 (ranging from −35 to 119). (G) Association of FEF75% with rs4073, dominant model, and CFTR-B group (p=0.024; pc=0.096). (AA+AT) n=38; mean of 33±55.23; median of 16 (ranging from −27 to 235). (TT) n=21; mean of 5.43±35.93; median of 2 (ranging from −35 to 119). (H) Association of FEF75% with rs4073, dominant model, and CFTR-A group (p=0.034; pc=0.058). (AA+AT) n=70; mean of 26.86±48.34; median of 18 (ranging from −58 to 235). (TT) n=28; mean of 9.14±36.95; median of 2.5 (ranging from −35 to 119). (I) Association of FEF75% with rs4073, recessive model, and CFTR-A group (p=0.04; pc=0.058). (AA) n=28; mean of 29.93±39.98; median of 30 (ranging from −47 to 142). (AT+TT) n=70; mean of 18.54±47.95; median of 10 (ranging from −58 to 235). (J) Association of FEF between 25% and 75% (FEF25–75%) of FVC with rs4073, co-dominant model and CFTR-B group (p=0.012; pc=0.024). TT≠AA and AT. (AA) n=9; mean of 25.78±23.14; median of 30 (ranging from −21 to 57). (AT) n=29; mean of 18.38±29.04; median of 14 (ranging from −33 to 117). (TT) n=21; mean of 2.14±23.74; median of 0 (ranging from −51 to 65). (K) Association of FEF25–75% with rs4073, dominant model, and CFTR-B group (p=0.007; pc=0.024). (AA+ATT) n=38; mean of 20.13±27.64; median of 18.5 (ranging from −33 to 117). (TT) n=23; mean of 2.14±23.74; median of 0 (ranging from −51 to 65). (L) Association of FEF25–75% with rs4073, dominant model, and CFTR-A group (p=0.029; pc=0.1). (AA+AT) n=82; mean of 15.48±27.2; median of 15 (ranging from −40 to 117). (TT) n=33; mean of 5.94±27.33; median of 0 (ranging from −51 to 76). (M) Association of FEF25–75% with rs4073, recessive model, and CFTR-B group (p=0.047; pc=0.063). (AA) n=9; mean of 25.78±23.14; median of 30 (ranging from −21 to 57). (AT+TT) n=50; mean of 11.56±27.89; median of 8 (ranging from −51 to 117). The dot corresponds to median values and the bar corresponds to the 95% confidence interval." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Larissa Lazzarini Furlan, José Dirceu Ribeiro, Carmen Sílvia Bertuzzo, João Batista Salomão Junior, Dorotéia Rossi Silva Souza, Fernando Augusto Lima Marson" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Larissa Lazzarini" "apellidos" => "Furlan" ] 1 => array:2 [ "nombre" => "José Dirceu" "apellidos" => "Ribeiro" ] 2 => array:2 [ "nombre" => "Carmen Sílvia" "apellidos" => "Bertuzzo" ] 3 => array:2 [ "nombre" => "João Batista" "apellidos" => "Salomão Junior" ] 4 => array:2 [ "nombre" => "Dorotéia Rossi Silva" "apellidos" => "Souza" ] 5 => array:2 [ "nombre" => "Fernando Augusto Lima" "apellidos" => "Marson" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "pt" => array:9 [ "pii" => "S2255553617300794" "doi" => "10.1016/j.jpedp.2017.07.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "pt" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2255553617300794?idApp=UINPBA000049" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0021755717306344?idApp=UINPBA000049" "url" => "/00217557/0000009300000006/v1_201711050042/S0021755717306344/v1_201711050042/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Neonatal screening: 9% of children with filter paper thyroid-stimulating hormone levels between 5 and 10μIU/mL have congenital hypothyroidism" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "649" "paginaFinal" => "654" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Flávia C. Christensen-Adad, Carolina T. Mendes-dos-Santos, Maura M.F. Goto, Letícia E. Sewaybricker, Lília F.R. D'Souza-Li, Gil Guerra-Junior, André M. Morcillo, Sofia Helena V. Lemos-Marini" "autores" => array:8 [ 0 => array:4 [ "nombre" => "Flávia C." "apellidos" => "Christensen-Adad" "email" => array:1 [ 0 => "flachristensen@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Carolina T." "apellidos" => "Mendes-dos-Santos" ] 2 => array:2 [ "nombre" => "Maura M.F." "apellidos" => "Goto" ] 3 => array:2 [ "nombre" => "Letícia E." "apellidos" => "Sewaybricker" ] 4 => array:2 [ "nombre" => "Lília F.R." "apellidos" => "D'Souza-Li" ] 5 => array:2 [ "nombre" => "Gil" "apellidos" => "Guerra-Junior" ] 6 => array:2 [ "nombre" => "André M." "apellidos" => "Morcillo" ] 7 => array:2 [ "nombre" => "Sofia Helena V." "apellidos" => "Lemos-Marini" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas, Departamento de Pediatria, Campinas, SP, Brazil" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Triagem neonatal: 9% das crianças com TSH em papel filtro entre 5 e 10 μUI/mL têm hipotireoidismo congênito" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1162 "Ancho" => 1628 "Tamanyo" => 89204 ] ] "descripcion" => array:1 [ "en" => "Flowchart of the screening for congenital hypothyroidism from April 2003 to September 2009." ] ] ] "textoCompleto" => "IntroductionCongenital hypothyroidism (CH), the most frequent congenital endocrine disorder and one of the main causes of preventable intellectual disability with early diagnosis and adequate treatment, was one of the first diseases screened in neonatal screening (NS) programs.<a class="elsevierStyleCrossRefs" href="#bib0150">1–4</a>The incidence of CH before the creation of NS programs was estimated at 1:6500,<a class="elsevierStyleCrossRef" href="#bib0170">5</a> but soon after the start of NS programs, it increased to approximately 1:3000 to 1:4000 live births (LB).<a class="elsevierStyleCrossRef" href="#bib0175">6</a> In recent years, there has been a further increase in CH incidence in several parts of the world, ranging from 1:1030 to 1:2679 LB.<a class="elsevierStyleCrossRefs" href="#bib0180">7–10</a> This fact is probably associated with an increase in the survival of preterm newborns,<a class="elsevierStyleCrossRefs" href="#bib0165">4,7</a> environmental<a class="elsevierStyleCrossRef" href="#bib0200">11</a> and ethnic factors,<a class="elsevierStyleCrossRef" href="#bib0180">7</a> as well as the reduction in the cutoff values of thyroid-stimulating hormone (TSH) on filter-paper blood-spot (b-TSH) in NS programs.<a class="elsevierStyleCrossRefs" href="#bib0165">4,12</a>Initially, higher b-TSH cutoff values were adopted to avoid recalls and excessive costs, with the justification that mild forms of CH would have no consequences for the neurological development.<a class="elsevierStyleCrossRef" href="#bib0165">4</a> However, some authors suggested that there were insufficient studies to support this hypothesis,<a class="elsevierStyleCrossRef" href="#bib0165">4</a> and the European Consensus on Congenital Hypothyroidism of 2014 highlighted, as the primary objective of NS, the detection of all cases of primary CH.<a class="elsevierStyleCrossRef" href="#bib0150">1</a>In recent years, several screening services have chosen to lower the cutoff value of b-TSH to reduce the number of cases of undiagnosed CH.<a class="elsevierStyleCrossRefs" href="#bib0165">4,13–17</a>With this reduction, several programs reported an increase in the number of children diagnosed with CH through NS programs,<a class="elsevierStyleCrossRefs" href="#bib0165">4,13–17</a> although there has also been an increase in the number of children with suspected CH and, therefore, a higher rate of recall.<a class="elsevierStyleCrossRefs" href="#bib0165">4,15,16,18</a>Since 2001, the Neonatal Screening Program of Universidade Estadual de Campinas (UNICAMP) has used a cutoff of 5μIU/mL for b-TSH and has performed clinical and laboratory follow-up for at least the first two years of life of all children whose serum TSH levels do not normalize.Considering this context, the aim of the present study was to determine the prevalence of CH in children with b-TSH levels between 5 and 10μIU/mL in the NS.MethodsNeonatal screening strategy for congenital hypothyroidismUNICAMP'S Neonatal Screening Reference Service (Serviço de Referência em Triagem Neonatal [SRTN]) is currently responsible for neonatal screening, diagnosis, and comprehensive care of children in the VII (Campinas) and XIV (São João da Boa Vista) Regional Health Departments, regions that have approximately 5000 LB per month.Since its creation, UNICAMP SRTN has worked with the same team for the treatment and follow-up of the cases, and the laboratory and imaging investigations have always been performed at the services of UNICAMP hospital complex.UNICAMP SRTN uses the cutoff value for b-TSH of 5μIU/mL in a dried whole-blood sample on filter paper, equivalent to 11μIU/mL in serum, and the analyses are performed by time-resolved fluorometry (AutoDELFIA–Perkin Elmer Life Sciences, MA, USA).UNICAMP SRTN uses the following protocol for the diagnosis and treatment of CH: children with b-TSH >5μIU/mL or ≤0.01μIU/mL are called in for serum TSH and free thyroxine (T4L) measurement. If serum TSH and T4L levels are normal, the children are discharged from the service. Children with serum TSH values higher than the reference values for age, but lower than 10μIU/mL, are monitored through clinical and laboratory examinations in UNICAMP SRTN for the first two years of life or until test normalization.Those with serum TSH ≥10μIU/mL are referred for follow-up at the Congenital Hypothyroidism Outpatient Clinic of Hospital de Clínicas of UNICAMP, where they are evaluated individually; and those who persist with TSH >10μIU/mL or have T4L levels <0.9ng/dL are diagnosed as having CH and start treatment with sodium levothyroxine (L-T4).Serum TSH and T4L collections are performed according to the technical standards of the Clinical Pathology Laboratory of UNICAMP; the analyses are performed by electrochemiluminescence, using TSH and T4L reference values of 0.41–4.5μIU/mL and 0.9–1.8ng/dL, respectively.Study designA retrospective study was carried out using the UNICAMP SRTN database to obtain the number of LB screened from April 2003 to September 2009. Children with b-TSH values between 5 and 10μIU/mL in samples collected in the first month of life were selected.Primary CH was considered when the child had serum TSH ≥10μIU/mL at any time during the first two years of life, regardless of T4L concentration, and received treatment with L-T4.The following information was obtained from the medical files of children with CH and b-TSH levels between 5 and 10μIU/mL: b-TSH value; age at NS collection; gender; initial, confirmatory TSH and T4L levels, as well as levels at the start of treatment; and age at the start of treatment.The following definitions of serum TSH and T4L values were considered for the study: initial test (the first test collected after b-TSH); confirmatory test (the first test for which serum TSH was ≥10μIU/mL for each child); and test at the start of treatment (the last test collected prior to medication introduction).Statistical analysisData were processed using the software SPSS, (SPSS Inc. version 16.0, Chicago, IL, USA). The results of the qualitative variables are shown as absolute and relative frequencies.For the TSH and T4L measurements, the median, minimum, and maximum values, range (total range), and interquartile range (IQR) were determined. When assessing TSH concentrations, the use of medians was chosen to avoid upper limit problems (>100μIU/mL) for some results.The results of the quantitative variables were expressed as mean±standard deviation or median (IQR).The prevalence of CH was determined based on the data of the study group with the respective 95% confidence interval (CI). The Mann–Whitney test was used for comparisons in relation to gender. A p-value <0.05 was considered significant in all analyses.Ethical aspectsThis project was approved by the Research Ethics Committee of Faculdade de Ciências Médicas of UNICAMP.ResultsIn the period from April 2003 to September 2009, 380,741 LB were screened for CH through UNICAMP SRTN. A total of 3,961 newborns were enrolled to complement the investigation, resulting in a recall frequency of 1.04% (95% CI: 1.01–1.07). Of these, 248 (6.26%) had b-TSH ≥10μIU/mL and 3,713 (93.74%) had b-TSH between 5 and 10μIU/mL (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Using the cutoff value of 10μIU/mL, the recall rate would have been 0.07% (95% CI: 0.06–0.08).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>After clinical and laboratory follow-up of the 3713 children with b-TSH levels between 5 and 10μIU/mL, 339 (206 males and 133 females) were diagnosed with CH and started hormone replacement therapy with L-T4, which corresponds to a CH prevalence of 9.13% (95% CI: 8.2–10.1; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).The mean and median ages at b-TSH collection were 5±4 days of life and 3 (4) days of life, respectively, and at the initial serum collection, 24±14 days of life and 20 (13) days of life. The confirmatory examination was collected at a mean age of 77±121 days of life and a median of 28 (48) days of life.As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, despite borderline values of b-TSH in the NS (5.01–9.90μUI/mL), TSH values at baseline showed a large variation in the studied group (3.02 to >100μIU/mL). The initial TSH of 113 children was <10μIU/mL, with a median of 7.00 (2.75) μIU/mL. Confirmatory TSH in this group ranged from 10.00 to >100.00μIU/mL, with a median of 11.50 (2.14) μIU/mL. The remaining 226 cases had an initial TSH≥10μIU/mL, of which 190 initiated treatment immediately; the remaining 36 patients, all with initial TSH<30μIU/mL and normal or high T4L levels, were maintained without medication at the first moment, with later introduction of hormonal replacement due to the persistence of TSH elevation.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Confirmatory serum TSH levels and levels at the start of treatment also showed significant variation (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), and 63 (18.58%) of the children had TSH levels>20μIU/mL at the start of the treatment.No differences were observed in relation to gender regarding the values of b-TSH (p=0.073) and initial (p=0.777) and confirmatory (p=0.376) TSH levels, as well as levels at the start of treatment (p=0.843).It is noteworthy that 15 of the 339 children presented T4L levels below the reference values in the first evaluation, with 14 of them showing TSH values >15μIU/mL and only one, with a TSH value of 6.06μIU/mL at the first collection, showed elevation of TSH levels above 10μIU/mL in subsequent collections. Regarding the last laboratory evaluation performed prior to the start of treatment, 17 of the 339 had T4L levels below the reference value, whereas TSH ranged from 10μIU/mL to >100μIU/mL; in 13 of these 17 patients, the values were >20μIU/mL (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>No differences were observed regarding gender in the initial (p=0.318) and confirmatory (p=0.706) T4L values, as well as in values at the start of treatment (p=0.542).Diagnosis was confirmed between 2 and 695 days of life, with a mean of 94±143 days of life and a median of 32 (68), and 76.11% of the children with CH had the diagnosis confirmed before the age of three months. However, 23.89% of the cases that would later receive the diagnosis of CH had TSH values above the upper limit of normal, but with no indication of treatment, and remained on follow-up with periodic measurements of TSH and T4L, being defined as having hypothyroidism between 3 and 24 months of age. Among these children with CH, 7.96% had a diagnosis confirmed between 1 and 2 years of age (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>DiscussionThis is a study with a significant sample, based on the experience of a service, among few in Brazil,<a class="elsevierStyleCrossRefs" href="#bib0215">14,19,20</a> which uses a lower b-TSH cutoff value than most NS programs.The use of a lower b-TSH cutoff value in the analyzed sample resulted in a 14.8-fold increase in the recall rate, which would be of 0.07% using the cutoff of 10μIU/mL, whereas it was 1.04% with a cutoff of 5μIU/mL. Another SRTN from Brazil showed a similar recall rate of 1.08%, using a cutoff value of 4.5μIU/mL,<a class="elsevierStyleCrossRef" href="#bib0215">14</a> while Korada et al.,<a class="elsevierStyleCrossRef" href="#bib0210">13</a> using a cutoff value of 6mIU/L, reported a recall rate of 0.23%. These data suggest that there is no direct association between the cutoff values used in NS for CH and recall rates, as concluded by Loeber<a class="elsevierStyleCrossRef" href="#bib0250">21</a> in the analysis of 37 European countries’ NS in 2004.The use of lower cutoff points, with a consequent increase in the number of recalled children, leads to higher costs with NS, in addition to generating anxiety for parents and relatives of healthy children.<a class="elsevierStyleCrossRef" href="#bib0235">18</a> During the study period, children with b-TSH between 5 and 10μIU/mL were submitted to at least one venous blood collection to evaluate thyroid function and, after follow-up, approximately 90% of them were defined as false-positive cases.However, during the evaluation of these six years of NS with an b-TSH cutoff value of 5μIU/mL, 339 children who would not have been detected with a cutoff point of 10μIU/mL were diagnosed with CH.Other NS programs also detected additional cases of CH with a lower cutoff value, as observed in the study by Barone et al.,<a class="elsevierStyleCrossRef" href="#bib0215">14</a> in which 63% of the 475 identified cases of CH had b-TSH between 4.5 and 9.5mIU/L, and in the study by Korada et al.,<a class="elsevierStyleCrossRef" href="#bib0210">13</a> which confirmed two cases of CH among the 67 full-term infants with b-TSH between 6 and 10mIU/L. One of the SRTNs in the state of São Paulo, which reduced the cutoff value for b-TSH between 2005 and 2008, also detected six cases of CH among 1181 children with initial b-TSH levels between 5 and 10μIU/mL.<a class="elsevierStyleCrossRef" href="#bib0245">20</a> Recently, Jones et al.<a class="elsevierStyleCrossRef" href="#bib0230">17</a> observed, among the 304 diagnosed CH cases, 26 children with b-TSH between 8 and 10mIU/L.Therefore, in this study, as well as in others,<a class="elsevierStyleCrossRefs" href="#bib0165">4,13–17</a> it has been demonstrated that children with CH might not be detected with the higher cutoff points that are usually used, and these additional diagnosed cases justify, in the present authors’ opinion and in that of other authors, the reduction in the cutoff value of b-TSH.<a class="elsevierStyleCrossRefs" href="#bib0165">4,13</a>Analysis of the thyroid function in this group detected children with serum TSH levels >20μIU/mL or T4L levels below the reference value, for whom immediate treatment is recommended.<a class="elsevierStyleCrossRef" href="#bib0150">1</a>It is not yet clear in the literature whether patients with mild elevations in TSH levels are at risk for cognitive impairment.<a class="elsevierStyleCrossRefs" href="#bib0165">4,5,8,22</a> It has been suggested that cases of neurological disorders that result in decreased school performance are related to mild forms of CH, not detected by NS due to elevated b-TSH cutoff values.<a class="elsevierStyleCrossRefs" href="#bib0165">4,23</a> A recent study showed that children with b-TSH between the 75th and 99.95th percentiles are more likely to have poor school performance, when compared to those with b-TSH below the 75th percentile.<a class="elsevierStyleCrossRef" href="#bib0265">24</a> Thus, many have argued that until there is evidence of absence of risk of intellectual disability without the use of L-T4, the treatment of these cases is preferable.<a class="elsevierStyleCrossRefs" href="#bib0165">4,25</a>Although most of the group was diagnosed with CH and started treatment early, many children who remained on follow-up due to non-normalization of TSH values developed hypothyroidism between 3 months and 2 years of age.One factor possibly involved in the late confirmation of CH is breastfeeding, since breast milk may be an exogenous source of T4, sometimes even masking clinical signs of CH.<a class="elsevierStyleCrossRefs" href="#bib0275">26,27</a> There is a chance that, given the usual recommendation of exclusive breastfeeding until the sixth month, some children with mild CH may have shown a more marked elevation in TSH levels after weaning or reduced breastfeeding. Another possibility is that they are due to thyroid hormone synthesis defect that often take some time for hypothyroidism to be established, as previously reported.<a class="elsevierStyleCrossRef" href="#bib0285">28</a>In brief, the results of this study demonstrated that the use of the b-TSH cutoff value of 5μIU/mL in NS allowed the detection of additional CH cases and many of these children only had the diagnosis confirmed later. Considering that among the different countries and even within the same country there is no homogeneity in diagnostic and follow-up criteria, more studies are needed to provide evidence for an ideal cutoff value for b-TSH and to establish more specific diagnostic and treatment protocols.<a class="elsevierStyleCrossRefs" href="#bib0150">1,4,29</a> Based on the findings of the present study, the authors suggest the use of a cutoff value of 5μIU/mL and long-term follow-up for these children, aiming to detect all CH cases.Conflicts of interestThe authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres935735" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec909681" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres935736" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec909680" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Neonatal screening strategy for congenital hypothyroidism" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Study design" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Ethical aspects" ] ] ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflicts of interest" ] 9 => array:2 [ "identificador" => "xack315965" "titulo" => "Acknowledgements" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-10-10" "fechaAceptado" => "2017-01-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec909681" "palabras" => array:5 [ 0 => "Congenital hypothyroidism" 1 => "Neonatal screening" 2 => "Infant" 3 => "Newborn" 4 => "Thyroid diseases" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec909680" "palabras" => array:5 [ 0 => "Hipotireoidismo congênito" 1 => "Triagem neonatal" 2 => "Lactente" 3 => "Recém-nascido" 4 => "Doenças da glândula tireoide" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectivesTo determine the prevalence of congenital hypothyroidism in children with filter-paper blood-spot TSH (b-TSH) between 5 and 10μIU/mL in the neonatal screening. MethodsThis was a retrospective study including children screened from 2003 to 2010, with b-TSH levels between 5 and 10μIU/mL, who were followed-up during the first two years of life when there was no serum TSH normalization. The diagnosis of congenital hypothyroidism was defined as serum TSH ≥10μIU/mL and start of levothyroxine treatment up to 2 years of age. ResultsOf the 380,741 live births, 3713 (1.04%) had filter paper TSH levels between 5 and 10μIU/mL and, of these, 339 (9.13%) had congenital hypothyroidism. Of these, 76.11% of the cases were diagnosed in the first three months of life and 7.96% between 1 and 2 years of age. ConclusionThe study showed that 9.13% of the children with b-TSH levels between 5 and 10μIU/mL developed hypothyroidism and that in approximately one-quarter of them, the diagnosis was confirmed only after the third month of life. Based on these findings, the authors suggest the use of a 5μIU/mL cutoff for b-TSH levels and long-term follow-up of infants whose serum TSH has not normalized to rule out congenital hypothyroidism." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "ObjetivosDeterminar a prevalência de hipotireoidismo congênito em crianças com TSH em papel filtro (TSH-f) entre 5 e 10μUI/mL na triagem neonatal. MétodosEstudo retrospectivo incluindo crianças triadas de 2003 a 2010, com TSH-f entre 5 e 10μUI/mL, que foram acompanhadas nos dois primeiros anos de vida quando não houve normalização do TSH sérico. O diagnóstico de hipotireoidismo congênito foi definido como TSH sérico igual ou superior a 10μUI/mL e início de tratamento com levotiroxina até os dois anos de idade. ResultadosDos 380.741 nascidos vivos triados, 3.713 (1,04%) apresentaram TSH-f entre 5 e 10μUI/mL e, destes, 339 (9,13%) tinham hipotireoidismo congênito. Destes, 76,11% dos casos foram diagnosticados nos primeiros três meses de vida e 7,96% entre um e dois anos de idade. ConclusãoO estudo mostra que 9,13% das crianças com TSH-f entre 5 e 10μUI/mL desenvolveram hipotireoidismo e que em cerca de um quarto delas o diagnóstico só se confirmou após o terceiro mês de vida. Com base nestes achados, sugere-se a utilização do ponto de corte de TSH-f de 5μUI/mL e o acompanhamento em longo prazo dos lactentes cujo TSH sérico não tenha se normalizado para descartar o hipotireoidismo congênito." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Christensen-Adad FC, Mendes-dos-Santos CT, Goto MM, Sewaybricker LE, D'Souza-Li LF, Guerra-Junior G, et al. Neonatal screening: 9% of children with filter paper thyroid-stimulating hormone levels between 5 and 10μIU/mL have congenital hypothyroidism. J Pediatr (Rio J). 2017;93:649–54." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1162 "Ancho" => 1628 "Tamanyo" => 89204 ] ] "descripcion" => array:1 [ "en" => "Flowchart of the screening for congenital hypothyroidism from April 2003 to September 2009." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "n, number of cases; IQR, interquartile range." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Median \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">IQR \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Minimum \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Maximum \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Screening \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">339 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.78 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.01 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.90 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Initial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">339 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">>100.00 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Confirmatory \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">339 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.89 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">>100.00 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">339 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">>100.00 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1581581.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "μIU/mL." ] ] ] "descripcion" => array:1 [ "en" => "TSH<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> in neonatal screening and initial, confirmatory, and after start of treatment exams." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "n, number of cases; IQR, interquartile range." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Median \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">IQR \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Minimum \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Maximum \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Initial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">338 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.39 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Confirmatory \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">338 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.35 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">338 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.12 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1581579.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "ng/dL." ] ] ] "descripcion" => array:1 [ "en" => "T4L<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> in the initial, confirmatory, and after start of treatment exams." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "n, number of cases; NS, neonatal screening; % Cum, cumulative relative frequency." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col">Age at diagnosis<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Cases</th><th class="td" title="table-head " align="left" valign="top" scope="col">NS<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Initial<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a></th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a></th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">% \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">%Cum \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">b-TSH<a class="elsevierStyleCrossRef" href="#tblfn0025">c</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TSH<a class="elsevierStyleCrossRef" href="#tblfn0025">c</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">T4L<a class="elsevierStyleCrossRef" href="#tblfn0030">d</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TSH<a class="elsevierStyleCrossRef" href="#tblfn0025">c</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">T4L<a class="elsevierStyleCrossRef" href="#tblfn0030">d</a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">0–1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">168 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49.56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49.56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.36 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">1–2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">66.67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.26 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">2–3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">3–4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78.47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.94 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.66 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.37 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">4–5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81.42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8.21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.17 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">5–6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">84.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.85 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.21 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">6–12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">92.04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.26 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">12–24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.96 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.24 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1581580.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" 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Triagem neonatal: 9% das crianças com TSH em papel filtro entre 5 e 10 μUI/mL têm hipotireoidismo congênito

Flávia C. Christensen-Adad

Corresponding author

flachristensen@hotmail.com

Corresponding author.

, Carolina T. Mendes-dos-Santos, Maura M.F. Goto, Letícia E. Sewaybricker, Lília F.R. D'Souza-Li, Gil Guerra-Junior, André M. Morcillo, Sofia Helena V. Lemos-Marini

Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Médicas, Departamento de Pediatria, Campinas, SP, Brazil

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            "nombre" => "Sofia Helena V&#46;"
            "apellidos" => "Lemos-Marini"
          ]
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            "entidad" => "Universidade Estadual de Campinas &#40;UNICAMP&#41;&#44; Faculdade de Ci&#234;ncias M&#233;dicas&#44; Departamento de Pediatria&#44; Campinas&#44; SP&#44; Brazil"
            "identificador" => "aff0005"
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            "etiqueta" => "&#8270;"
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      "pt" => array:1 [
        "titulo" => "Triagem neonatal&#58; 9&#37; das crian&#231;as com TSH em papel filtro entre 5 e 10 &#956;UI&#47;mL t&#234;m hipotireoidismo cong&#234;nito"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flowchart of the screening for congenital hypothyroidism from April 2003 to September 2009&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Congenital hypothyroidism &#40;CH&#41;&#44; the most frequent congenital endocrine disorder and one of the main causes of preventable intellectual disability with early diagnosis and adequate treatment&#44; was one of the first diseases screened in neonatal screening &#40;NS&#41; programs&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">1&#8211;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The incidence of CH before the creation of NS programs was estimated at 1&#58;6500&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a> but soon after the start of NS programs&#44; it increased to approximately 1&#58;3000 to 1&#58;4000 live births &#40;LB&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">6</span></a> In recent years&#44; there has been a further increase in CH incidence in several parts of the world&#44; ranging from 1&#58;1030 to 1&#58;2679 LB&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">7&#8211;10</span></a> This fact is probably associated with an increase in the survival of preterm newborns&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;7</span></a> environmental<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> and ethnic factors&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a> as well as the reduction in the cutoff values of thyroid-stimulating hormone &#40;TSH&#41; on filter-paper blood-spot &#40;b-TSH&#41; in NS programs&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Initially&#44; higher b-TSH cutoff values were adopted to avoid recalls and excessive costs&#44; with the justification that mild forms of CH would have no consequences for the neurological development&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> However&#44; some authors suggested that there were insufficient studies to support this hypothesis&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> and the European Consensus on Congenital Hypothyroidism of 2014 highlighted&#44; as the primary objective of NS&#44; the detection of all cases of primary CH&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In recent years&#44; several screening services have chosen to lower the cutoff value of b-TSH to reduce the number of cases of undiagnosed CH&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;13&#8211;17</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">With this reduction&#44; several programs reported an increase in the number of children diagnosed with CH through NS programs&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;13&#8211;17</span></a> although there has also been an increase in the number of children with suspected CH and&#44; therefore&#44; a higher rate of recall&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;15&#44;16&#44;18</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Since 2001&#44; the Neonatal Screening Program of Universidade Estadual de Campinas &#40;UNICAMP&#41; has used a cutoff of 5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL for b-TSH and has performed clinical and laboratory follow-up for at least the first two years of life of all children whose serum TSH levels do not normalize&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Considering this context&#44; the aim of the present study was to determine the prevalence of CH in children with b-TSH levels between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL in the NS&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Neonatal screening strategy for congenital hypothyroidism</span><p id="par0040" class="elsevierStylePara elsevierViewall">UNICAMP&#39;S Neonatal Screening Reference Service &#40;Servi&#231;o de Refer&#234;ncia em Triagem Neonatal &#91;SRTN&#93;&#41; is currently responsible for neonatal screening&#44; diagnosis&#44; and comprehensive care of children in the VII &#40;Campinas&#41; and XIV &#40;S&#227;o Jo&#227;o da Boa Vista&#41; Regional Health Departments&#44; regions that have approximately 5000 LB per month&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Since its creation&#44; UNICAMP SRTN has worked with the same team for the treatment and follow-up of the cases&#44; and the laboratory and imaging investigations have always been performed at the services of UNICAMP hospital complex&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">UNICAMP SRTN uses the cutoff value for b-TSH of 5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL in a dried whole-blood sample on filter paper&#44; equivalent to 11<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL in serum&#44; and the analyses are performed by time-resolved fluorometry &#40;AutoDELFIA&#8211;Perkin Elmer Life Sciences&#44; MA&#44; USA&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">UNICAMP SRTN uses the following protocol for the diagnosis and treatment of CH&#58; children with b-TSH &#62;5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL or &#8804;0&#46;01<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL are called in for serum TSH and free thyroxine &#40;T4L&#41; measurement&#46; If serum TSH and T4L levels are normal&#44; the children are discharged from the service&#46; Children with serum TSH values higher than the reference values for age&#44; but lower than 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44; are monitored through clinical and laboratory examinations in UNICAMP SRTN for the first two years of life or until test normalization&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Those with serum TSH &#8805;10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL are referred for follow-up at the Congenital Hypothyroidism Outpatient Clinic of Hospital de Cl&#237;nicas of UNICAMP&#44; where they are evaluated individually&#59; and those who persist with TSH &#62;10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL or have T4L levels &#60;0&#46;9<span class="elsevierStyleHsp" style=""></span>ng&#47;dL are diagnosed as having CH and start treatment with sodium levothyroxine &#40;L-T4&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Serum TSH and T4L collections are performed according to the technical standards of the Clinical Pathology Laboratory of UNICAMP&#59; the analyses are performed by electrochemiluminescence&#44; using TSH and T4L reference values of 0&#46;41&#8211;4&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL and 0&#46;9&#8211;1&#46;8<span class="elsevierStyleHsp" style=""></span>ng&#47;dL&#44; respectively&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study design</span><p id="par0070" class="elsevierStylePara elsevierViewall">A retrospective study was carried out using the UNICAMP SRTN database to obtain the number of LB screened from April 2003 to September 2009&#46; Children with b-TSH values between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL in samples collected in the first month of life were selected&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Primary CH was considered when the child had serum TSH &#8805;10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL at any time during the first two years of life&#44; regardless of T4L concentration&#44; and received treatment with L-T4&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The following information was obtained from the medical files of children with CH and b-TSH levels between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#58; b-TSH value&#59; age at NS collection&#59; gender&#59; initial&#44; confirmatory TSH and T4L levels&#44; as well as levels at the start of treatment&#59; and age at the start of treatment&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The following definitions of serum TSH and T4L values were considered for the study&#58; initial test &#40;the first test collected after b-TSH&#41;&#59; confirmatory test &#40;the first test for which serum TSH was &#8805;10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL for each child&#41;&#59; and test at the start of treatment &#40;the last test collected prior to medication introduction&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">Data were processed using the software SPSS&#44; &#40;SPSS Inc&#46; version 16&#46;0&#44; Chicago&#44; IL&#44; USA&#41;&#46; The results of the qualitative variables are shown as absolute and relative frequencies&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">For the TSH and T4L measurements&#44; the median&#44; minimum&#44; and maximum values&#44; range &#40;total range&#41;&#44; and interquartile range &#40;IQR&#41; were determined&#46; When assessing TSH concentrations&#44; the use of medians was chosen to avoid upper limit problems &#40;&#62;100<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#41; for some results&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The results of the quantitative variables were expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation or median &#40;IQR&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The prevalence of CH was determined based on the data of the study group with the respective 95&#37; confidence interval &#40;CI&#41;&#46; The Mann&#8211;Whitney test was used for comparisons in relation to gender&#46; A <span class="elsevierStyleItalic">p</span>-value &#60;0&#46;05 was considered significant in all analyses&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ethical aspects</span><p id="par0110" class="elsevierStylePara elsevierViewall">This project was approved by the Research Ethics Committee of Faculdade de Ci&#234;ncias M&#233;dicas of UNICAMP&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0115" class="elsevierStylePara elsevierViewall">In the period from April 2003 to September 2009&#44; 380&#44;741 LB were screened for CH through UNICAMP SRTN&#46; A total of 3&#44;961 newborns were enrolled to complement the investigation&#44; resulting in a recall frequency of 1&#46;04&#37; &#40;95&#37; CI&#58; 1&#46;01&#8211;1&#46;07&#41;&#46; Of these&#44; 248 &#40;6&#46;26&#37;&#41; had b-TSH &#8805;10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL and 3&#44;713 &#40;93&#46;74&#37;&#41; had b-TSH between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Using the cutoff value of 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44; the recall rate would have been 0&#46;07&#37; &#40;95&#37; CI&#58; 0&#46;06&#8211;0&#46;08&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">After clinical and laboratory follow-up of the 3713 children with b-TSH levels between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44; 339 &#40;206 males and 133 females&#41; were diagnosed with CH and started hormone replacement therapy with L-T4&#44; which corresponds to a CH prevalence of 9&#46;13&#37; &#40;95&#37; CI&#58; 8&#46;2&#8211;10&#46;1&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The mean and median ages at b-TSH collection were 5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4 days of life and 3 &#40;4&#41; days of life&#44; respectively&#44; and at the initial serum collection&#44; 24<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14 days of life and 20 &#40;13&#41; days of life&#46; The confirmatory examination was collected at a mean age of 77<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>121 days of life and a median of 28 &#40;48&#41; days of life&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; despite borderline values of b-TSH in the NS &#40;5&#46;01&#8211;9&#46;90<span class="elsevierStyleHsp" style=""></span>&#956;UI&#47;mL&#41;&#44; TSH values at baseline showed a large variation in the studied group &#40;3&#46;02 to &#62;100<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#41;&#46; The initial TSH of 113 children was &#60;10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44; with a median of 7&#46;00 &#40;2&#46;75&#41; &#956;IU&#47;mL&#46; Confirmatory TSH in this group ranged from 10&#46;00 to &#62;100&#46;00<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44; with a median of 11&#46;50 &#40;2&#46;14&#41; &#956;IU&#47;mL&#46; The remaining 226 cases had an initial TSH<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44; of which 190 initiated treatment immediately&#59; the remaining 36 patients&#44; all with initial TSH<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL and normal or high T4L levels&#44; were maintained without medication at the first moment&#44; with later introduction of hormonal replacement due to the persistence of TSH elevation&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">Confirmatory serum TSH levels and levels at the start of treatment also showed significant variation &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; and 63 &#40;18&#46;58&#37;&#41; of the children had TSH levels<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL at the start of the treatment&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">No differences were observed in relation to gender regarding the values of b-TSH &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;073&#41; and initial &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;777&#41; and confirmatory &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;376&#41; TSH levels&#44; as well as levels at the start of treatment &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;843&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">It is noteworthy that 15 of the 339 children presented T4L levels below the reference values in the first evaluation&#44; with 14 of them showing TSH values &#62;15<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL and only one&#44; with a TSH value of 6&#46;06<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL at the first collection&#44; showed elevation of TSH levels above 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL in subsequent collections&#46; Regarding the last laboratory evaluation performed prior to the start of treatment&#44; 17 of the 339 had T4L levels below the reference value&#44; whereas TSH ranged from 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL to &#62;100<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#59; in 13 of these 17 patients&#44; the values were &#62;20<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">No differences were observed regarding gender in the initial &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;318&#41; and confirmatory &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;706&#41; T4L values&#44; as well as in values at the start of treatment &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;542&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Diagnosis was confirmed between 2 and 695 days of life&#44; with a mean of 94<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>143 days of life and a median of 32 &#40;68&#41;&#44; and 76&#46;11&#37; of the children with CH had the diagnosis confirmed before the age of three months&#46; However&#44; 23&#46;89&#37; of the cases that would later receive the diagnosis of CH had TSH values above the upper limit of normal&#44; but with no indication of treatment&#44; and remained on follow-up with periodic measurements of TSH and T4L&#44; being defined as having hypothyroidism between 3 and 24 months of age&#46; Among these children with CH&#44; 7&#46;96&#37; had a diagnosis confirmed between 1 and 2 years of age &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0160" class="elsevierStylePara elsevierViewall">This is a study with a significant sample&#44; based on the experience of a service&#44; among few in Brazil&#44;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">14&#44;19&#44;20</span></a> which uses a lower b-TSH cutoff value than most NS programs&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">The use of a lower b-TSH cutoff value in the analyzed sample resulted in a 14&#46;8-fold increase in the recall rate&#44; which would be of 0&#46;07&#37; using the cutoff of 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44; whereas it was 1&#46;04&#37; with a cutoff of 5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#46; Another SRTN from Brazil showed a similar recall rate of 1&#46;08&#37;&#44; using a cutoff value of 4&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a> while Korada et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> using a cutoff value of 6<span class="elsevierStyleHsp" style=""></span>mIU&#47;L&#44; reported a recall rate of 0&#46;23&#37;&#46; These data suggest that there is no direct association between the cutoff values used in NS for CH and recall rates&#44; as concluded by Loeber<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> in the analysis of 37 European countries&#8217; NS in 2004&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">The use of lower cutoff points&#44; with a consequent increase in the number of recalled children&#44; leads to higher costs with NS&#44; in addition to generating anxiety for parents and relatives of healthy children&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a> During the study period&#44; children with b-TSH between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL were submitted to at least one venous blood collection to evaluate thyroid function and&#44; after follow-up&#44; approximately 90&#37; of them were defined as false-positive cases&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">However&#44; during the evaluation of these six years of NS with an b-TSH cutoff value of 5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44; 339 children who would not have been detected with a cutoff point of 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL were diagnosed with CH&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Other NS programs also detected additional cases of CH with a lower cutoff value&#44; as observed in the study by Barone et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a> in which 63&#37; of the 475 identified cases of CH had b-TSH between 4&#46;5 and 9&#46;5<span class="elsevierStyleHsp" style=""></span>mIU&#47;L&#44; and in the study by Korada et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> which confirmed two cases of CH among the 67 full-term infants with b-TSH between 6 and 10<span class="elsevierStyleHsp" style=""></span>mIU&#47;L&#46; One of the SRTNs in the state of S&#227;o Paulo&#44; which reduced the cutoff value for b-TSH between 2005 and 2008&#44; also detected six cases of CH among 1181 children with initial b-TSH levels between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a> Recently&#44; Jones et al&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> observed&#44; among the 304 diagnosed CH cases&#44; 26 children with b-TSH between 8 and 10<span class="elsevierStyleHsp" style=""></span>mIU&#47;L&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Therefore&#44; in this study&#44; as well as in others&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;13&#8211;17</span></a> it has been demonstrated that children with CH might not be detected with the higher cutoff points that are usually used&#44; and these additional diagnosed cases justify&#44; in the present authors&#8217; opinion and in that of other authors&#44; the reduction in the cutoff value of b-TSH&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;13</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Analysis of the thyroid function in this group detected children with serum TSH levels &#62;20<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL or T4L levels below the reference value&#44; for whom immediate treatment is recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">It is not yet clear in the literature whether patients with mild elevations in TSH levels are at risk for cognitive impairment&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;5&#44;8&#44;22</span></a> It has been suggested that cases of neurological disorders that result in decreased school performance are related to mild forms of CH&#44; not detected by NS due to elevated b-TSH cutoff values&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;23</span></a> A recent study showed that children with b-TSH between the 75th and 99&#46;95th percentiles are more likely to have poor school performance&#44; when compared to those with b-TSH below the 75th percentile&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">24</span></a> Thus&#44; many have argued that until there is evidence of absence of risk of intellectual disability without the use of L-T4&#44; the treatment of these cases is preferable&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;25</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Although most of the group was diagnosed with CH and started treatment early&#44; many children who remained on follow-up due to non-normalization of TSH values developed hypothyroidism between 3 months and 2 years of age&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">One factor possibly involved in the late confirmation of CH is breastfeeding&#44; since breast milk may be an exogenous source of T4&#44; sometimes even masking clinical signs of CH&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">26&#44;27</span></a> There is a chance that&#44; given the usual recommendation of exclusive breastfeeding until the sixth month&#44; some children with mild CH may have shown a more marked elevation in TSH levels after weaning or reduced breastfeeding&#46; Another possibility is that they are due to thyroid hormone synthesis defect that often take some time for hypothyroidism to be established&#44; as previously reported&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">28</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">In brief&#44; the results of this study demonstrated that the use of the b-TSH cutoff value of 5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL in NS allowed the detection of additional CH cases and many of these children only had the diagnosis confirmed later&#46; Considering that among the different countries and even within the same country there is no homogeneity in diagnostic and follow-up criteria&#44; more studies are needed to provide evidence for an ideal cutoff value for b-TSH and to establish more specific diagnostic and treatment protocols&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">1&#44;4&#44;29</span></a> Based on the findings of the present study&#44; the authors suggest the use of a cutoff value of 5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL and long-term follow-up for these children&#44; aiming to detect all CH cases&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of interest</span><p id="par0215" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
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              "titulo" => "Neonatal screening strategy for congenital hypothyroidism"
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              "titulo" => "Study design"
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    "fechaRecibido" => "2016-10-10"
    "fechaAceptado" => "2017-01-10"
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          "clase" => "keyword"
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            0 => "Congenital hypothyroidism"
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            0 => "Hipotireoidismo cong&#234;nito"
            1 => "Triagem neonatal"
            2 => "Lactente"
            3 => "Rec&#233;m-nascido"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To determine the prevalence of congenital hypothyroidism in children with filter-paper blood-spot TSH &#40;b-TSH&#41; between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL in the neonatal screening&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This was a retrospective study including children screened from 2003 to 2010&#44; with b-TSH levels between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44; who were followed-up during the first two years of life when there was no serum TSH normalization&#46; The diagnosis of congenital hypothyroidism was defined as serum TSH &#8805;10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL and start of levothyroxine treatment up to 2 years of age&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Of the 380&#44;741 live births&#44; 3713 &#40;1&#46;04&#37;&#41; had filter paper TSH levels between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL and&#44; of these&#44; 339 &#40;9&#46;13&#37;&#41; had congenital hypothyroidism&#46; Of these&#44; 76&#46;11&#37; of the cases were diagnosed in the first three months of life and 7&#46;96&#37; between 1 and 2 years of age&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The study showed that 9&#46;13&#37; of the children with b-TSH levels between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL developed hypothyroidism and that in approximately one-quarter of them&#44; the diagnosis was confirmed only after the third month of life&#46; Based on these findings&#44; the authors suggest the use of a 5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL cutoff for b-TSH levels and long-term follow-up of infants whose serum TSH has not normalized to rule out congenital hypothyroidism&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Determinar a preval&#234;ncia de hipotireoidismo cong&#234;nito em crian&#231;as com TSH em papel filtro &#40;TSH-f&#41; entre 5 e 10<span class="elsevierStyleHsp" style=""></span>&#956;UI&#47;mL na triagem neonatal&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudo retrospectivo incluindo crian&#231;as triadas de 2003 a 2010&#44; com TSH-f entre 5 e 10<span class="elsevierStyleHsp" style=""></span>&#956;UI&#47;mL&#44; que foram acompanhadas nos dois primeiros anos de vida quando n&#227;o houve normaliza&#231;&#227;o do TSH s&#233;rico&#46; O diagn&#243;stico de hipotireoidismo cong&#234;nito foi definido como TSH s&#233;rico igual ou superior a 10<span class="elsevierStyleHsp" style=""></span>&#956;UI&#47;mL e in&#237;cio de tratamento com levotiroxina at&#233; os dois anos de idade&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Dos 380&#46;741 nascidos vivos triados&#44; 3&#46;713 &#40;1&#44;04&#37;&#41; apresentaram TSH-f entre 5 e 10<span class="elsevierStyleHsp" style=""></span>&#956;UI&#47;mL e&#44; destes&#44; 339 &#40;9&#44;13&#37;&#41; tinham hipotireoidismo cong&#234;nito&#46; Destes&#44; 76&#44;11&#37; dos casos foram diagnosticados nos primeiros tr&#234;s meses de vida e 7&#44;96&#37; entre um e dois anos de idade&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#227;o</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">O estudo mostra que 9&#44;13&#37; das crian&#231;as com TSH-f entre 5 e 10<span class="elsevierStyleHsp" style=""></span>&#956;UI&#47;mL desenvolveram hipotireoidismo e que em cerca de um quarto delas o diagn&#243;stico s&#243; se confirmou ap&#243;s o terceiro m&#234;s de vida&#46; Com base nestes achados&#44; sugere-se a utiliza&#231;&#227;o do ponto de corte de TSH-f de 5<span class="elsevierStyleHsp" style=""></span>&#956;UI&#47;mL e o acompanhamento em longo prazo dos lactentes cujo TSH s&#233;rico n&#227;o tenha se normalizado para descartar o hipotireoidismo cong&#234;nito&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Please cite this article as&#58; Christensen-Adad FC&#44; Mendes-dos-Santos CT&#44; Goto MM&#44; Sewaybricker LE&#44; D&#39;Souza-Li LF&#44; Guerra-Junior G&#44; et al&#46; Neonatal screening&#58; 9&#37; of children with filter paper thyroid-stimulating hormone levels between 5 and 10<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL have congenital hypothyroidism&#46; J Pediatr &#40;Rio J&#41;&#46; 2017&#59;93&#58;649&#8211;54&#46;</p>"
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#46;90&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">339&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&#46;50&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;02&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Maximum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Initial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">338&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Confirmatory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">338&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">338&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;40&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;30&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">1&#8211;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#46;80&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">2&#8211;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">3&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&#46;66&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Thyroid function according to age range at diagnosis&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:29 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "European Society for Paediatric Endocrinology consensus guidelines on screening&#44; diagnosis&#44; and management of congenital hypothyroidism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; L&#233;ger"
                            1 => "A&#46; Olivieri"
                            2 => "M&#46; Donaldson"
                            3 => "T&#46; Torresani"
                            4 => "H&#46; Krude"
                            5 => "G&#46; van Vliet"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2013-1891"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2014"
                        "volumen" => "99"
                        "paginaInicial" => "363"
                        "paginaFinal" => "384"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24446653"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0155"
              "etiqueta" => "2"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Update of newborn screening and therapy for congenital hypothyroidism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;R&#46; Rose"
                            1 => "R&#46;S&#46; Brown"
                            2 => "T&#46; Foley"
                            3 => "P&#46;B&#46; Kaplowitz"
                            4 => "C&#46;I&#46; Kaye"
                            5 => "S&#46; Sundararajan"
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        "texto" => "<p id="par0220" class="elsevierStylePara elsevierViewall">To patients and their families who were part of the study&#46; To the employees of the Outpatient Clinic of Pediatrics of Hospital das Cl&#237;nicas da UNICAMP and the Neonatal Screening Reference Service of UNICAMP&#44; especially to biologist Carmen S&#237;lvia Gabetta&#44; Head of the Laboratory of the Neonatal Screening Reference Service of UNICAMP&#46;</p>"
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Article information

ISSN: 00217557
Original language: English

DOI:10.1016/j.jped.2017.05.003

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	4	2	6
2024 October	26	30	56
2024 September	31	33	64
2024 August	50	19	69
2024 July	36	38	74
2024 June	31	23	54
2024 May	21	20	41
2024 April	31	19	50
2024 March	45	15	60
2024 February	28	21	49
2024 January	30	28	58
2023 December	20	26	46
2023 November	26	26	52
2023 October	22	35	57
2023 September	31	38	69
2023 August	21	20	41
2023 July	14	19	33
2023 June	23	12	35
2023 May	14	16	30
2023 April	22	12	34
2023 March	29	26	55
2023 February	22	15	37
2023 January	18	14	32
2022 December	45	26	71
2022 November	23	24	47
2022 October	40	36	76
2022 September	21	28	49
2022 August	22	33	55
2022 July	26	32	58
2022 June	45	34	79
2022 May	27	25	52
2022 April	47	27	74
2022 March	40	40	80
2022 February	27	26	53
2022 January	21	16	37
2021 December	15	22	37
2021 November	11	14	25
2021 October	14	20	34
2021 September	11	13	24
2021 August	8	13	21
2021 July	11	5	16
2021 June	8	10	18
2021 May	10	11	21
2021 April	27	12	39
2021 March	13	11	24
2021 February	12	6	18
2021 January	10	8	18
2020 December	18	9	27
2020 November	19	10	29
2020 October	11	10	21
2020 September	11	9	20
2020 August	6	3	9
2020 July	7	2	9
2020 June	9	8	17
2020 May	15	10	25
2020 April	11	9	20
2020 March	5	5	10
2020 February	18	10	28
2020 January	10	23	33
2019 December	12	8	20
2019 November	10	2	12
2019 October	8	13	21
2019 September	5	9	14
2019 August	8	13	21
2019 July	17	5	22
2019 June	10	11	21
2019 May	9	5	14
2019 April	12	6	18
2019 March	16	9	25
2019 February	10	4	14
2019 January	3	7	10
2018 December	11	8	19
2018 November	52	17	69
2018 October	169	18	187
2018 September	67	7	74
2018 August	63	12	75
2018 July	16	1	17
2018 June	38	20	58
2018 May	17	32	49
2018 April	90	3	93
2018 March	18	5	23
2018 February	7	4	11
2018 January	21	10	31
2017 December	29	17	46
2017 November	18	20	38
2017 October	2	6	8
2017 September	0	5	5
2017 August	0	6	6

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