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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Algorithm for re-evaluation and definitive diagnosis of congenital hypothyroidism&#46;</p>"
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      <span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewextended"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Hypothyroidism is characterised by the clinical and laboratory features that result from the decreased biological activity of thyroid hormones at the tissue level&#46; In most cases&#44; it is associated with decreased serum levels of thyroid hormones with elevation of thyroid stimulating hormone &#40;TSH&#41; levels&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Congenital hypothyroidism &#40;CHT&#41; and neonatal hypothyroidism comprise a heterogeneous group of thyroid hormone abnormalities leading to reduced thyroid function that can be detected as early as the neonatal period&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Thyroid hormones are essential to achieve normal growth and brain maturation&#46; Hypothyroidism with onset in the early months of life may cause irreversible lesions in the central nervous system&#46; Congenital and neonatal hypothyroidism must be diagnosed and treated on an urgent basis&#44; as they are a frequent and preventable cause of intellectual disability&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">3&#8211;6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The symptoms are nonspecific and progress in direct correlation to the duration and the severity of hypothyroidism&#46; In the first month of life&#44; when treatment should be initiated&#44; only 5&#37; of affected individuals could be diagnosed based on symptoms alone&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The first programme for neonatal screening of CHT was implemented in Quebec in 1974&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">1</span></a> At present&#44; most developed countries offer routine screening&#44; but this is not the case in developing countries&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Screening programmes have evinced that CHT is very frequent and have prevented&#44; in most cases&#44; the brain damage and secondary permanent intellectual disability that had been observed in these children in the past&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The prevalence of primary CHT &#40;which is due to an absent or defective thyroid&#41; reported in international case series is of 1 per 2000 live births&#44; which is consistent with the figures reported for Spain&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">7&#44;8</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Objective of the neonatal screening programme for congenital hypothyroidism</span><p id="par0040" class="elsevierStylePara elsevierViewall">The Programme for the Early Detection of Congenital Hypothyroidism&#44; a public health and preventive medicine priority&#44; is part of the neonatal screening programme&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Its main goal is the detection and treatment of severe and permanent CHT&#46; Detection of mild permanent CHT or transient CHT is a secondary objective of screening&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In all of these forms of CHT&#44; early detection prevents neurologic damage and reduces the morbidity&#44; mortality and potential disabilities associated with the disease&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">It is important to emphasise that neonatal screening tests are not diagnostic procedures&#46; Patients with a positive result of screening require additional diagnostic evaluation&#44; which requires the support of clinicians specialised in the diagnosis and treatment of the disease &#40;clinical follow-up centres &#91;CFUCs&#93;&#41;&#46; Clinical follow-up centres should meet certain conditions &#40;<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>&#41;&#46; Their purpose is to confirm or rule out the diagnosis of CHT&#44; and promptly initiate treatment if applicable&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">8&#44;9</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Neonatal screening should not be understood as a mere laboratory procedure&#44; but as a multidisciplinary activity whose coordination with the health care system is essential to ensure its effectiveness and efficiency&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Procedure for neonatal screening for congenital hypothyroidism</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Measurement of TSH</span><p id="par0065" class="elsevierStylePara elsevierViewall">The collection of samples is scheduled so that coverage of 100&#37; of newborns is ensured&#44; along with treatment of 100&#37; of the detected cases&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Screening for early detection of primary congenital hypothyroidism is performed by measurement of the levels of TSH at 48<span class="elsevierStyleHsp" style=""></span>h post birth to avoid the initial physiological elevation of this hormone after birth&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">A capillary blood sample is obtained from the newborn by heel puncture and collected on standard filter paper&#59; this procedure needs to be performed by specially trained health care staff to optimise yield&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The serum levels of TSH are measured by immunofluorescence assay &#40;DELFIA<span class="elsevierStyleSup">&#174;</span>&#44; Laboratorios Perkinelmer&#41;&#46; The cut-off point above which CHT is suspected has been established at 7&#8211;10<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#46; When the TSH value exceeds the established threshold&#44; the total thyroxine level &#40;tT4&#41; is measured as well&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">At present&#44; all centres that screen for CHT in Spain measure the levels of TSH&#44; while the levels of both TSH and tT4 are only measured simultaneously in the initial test in a few autonomous communities &#40;Basque Country&#44; Navarre and Cantabria&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Central hypothyroidism &#40;secondary or tertiary&#41; is not detected by screening programmes that only measure TSH&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">10&#44;11</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Confirmation of congenital hypothyroidism</span><p id="par0095" class="elsevierStylePara elsevierViewall">In case of a positive screen result&#44; the facility that did the screening urgently contacts the patient for referral to the corresponding CFUC&#44; where testing will be performed for confirmation of hypothyroidism and to establish the aetiology of the abnormal thyroid function&#44; without delaying initiation of treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">12&#8211;17</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The aetiology of congenital hypothyroidism is multifactorial&#46; In 95&#37; of cases the patient has primary hypothyroidism &#40;abnormalities in the thyroid gland&#41;&#44; while central hypothyroidism is less frequent&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Congenital and neonatal hypothyroidism are present from birth&#46; Depending on the aetiology&#44; the hypothyroidism may be permanent and require lifelong treatment&#44; or it may be transient and resolve spontaneously when the underlying cause disappears &#40;e&#46;g&#46; excessive concentration of iodine or the presence of maternal antithyroid antibodies&#41;&#46; Notwithstanding&#44; every patient requires treatment to normalise thyroid function during the period of brain development&#44; and treatment is inefficient if it starts later &#40;existence of a &#8220;window of opportunity&#8221;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">The most frequent cause of primary CHT is thyroid dysgenesis &#40;85&#37;&#8211;90&#37;&#41;&#44; in most cases thyroid ectopia &#40;60&#37;&#8211;65&#37;&#41;&#44; followed by thyroid agenesis or athyreosis &#40;35&#37;&#8211;40&#37;&#41;&#46; Different forms of thyroid dyshormonogenesis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41; account for 10&#37; of cases&#46; Specific mutations in the transcription termination factor 2 gene &#40;<span class="elsevierStyleItalic">TTF2</span>&#41; and genes encoding other thyroid transcription factors have been identified in some patients with thyroid dysgenesis&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">In some cases&#44; the aetiology of hypothyroidism cannot be determined&#46; Numerous genes may be involved in the multifactorial aetiology of primary congenital hypothyroidism&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">17&#8211;24</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Reporting test results</span><p id="par0120" class="elsevierStylePara elsevierViewall">This is a key step in the diagnosis and treatment of CHT&#46; The purpose is to help parents understand the benefits of early diagnosis in the prevention of brain damage&#44; teach them how to correctly administer medication&#44; and promote adherence to treatment and to follow-up care for the duration of CHT &#40;months&#44; years&#44; or life&#41;&#46; The initial results should be conveyed by experienced staff&#44; ensuring that parents fully understand the information&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Management at the clinical follow-up centre for congenital hypothyroidism</span><p id="par0125" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> presents the protocol for management following a positive result of neonatal screening&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">A detailed personal and family history is taken in every case&#44; with particular emphasis on potential consumption of pharmacological agents or iodine-containing substances&#44; family history of thyroid disease &#40;especially in the mother&#41; and of symptoms of underactive thyroid&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The patient also undergoes a clinical evaluation to identify the signs and symptoms of hypothyroidism &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Diagnostic tests</span><p id="par0140" class="elsevierStylePara elsevierViewall">The results of the dried blood spot test are confirmed by venous blood tests &#40;TSH&#44; free thyroxine &#91;fT4&#93;&#41;&#46; In primary hypothyroidism&#44; elevated TSH levels are associated with reduced levels of fT4&#46; Thyroglobulin levels are measured to assess for the presence of the thyroid gland&#46; The presence of antithyroid antibodies supports the diagnosis of transient autoimmune thyroiditis due to hormone blocking&#46; Elevation of iodine levels in the urine &#40;&#62;200<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L&#41; suggests excessive exposure to iodine with blocking of thyroid receptors&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Imaging tests&#44; such as thyroid ultrasound and scintigraphy&#44; are very useful in determining the aetiology of CHT&#46; They allow the definitive diagnosis of dysgenesis&#44; while detection of an eutopic thyroid gland with normal tracer uptake may suggest transient CHT&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">A thyroid ultrasound examination</span> can verify the presence of thyroid tissue in the neck&#46; It can differentiate between thyroid dysgenesis &#40;agenesis or ectopia&#41; and dyshormonogenesis&#44; which manifests with presence of the thyroid gland in the normal location&#46; However&#44; the interpretation of thyroid ultrasound findings in the newborn requires a high degree of specialisation&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Thyroid scintigraphy</span> with sodium iodide I 131 or technetium Tc 99m can be used to determine the position and size of the thyroid gland and establish a definitive diagnosis of thyroid agenesis&#44; ectopia&#44; hemiagenesis or hypoplasia&#46; If the thyroid cannot be visualised with scintigraphy in a patient with elevated thyroglobulin levels&#44; it may be helpful to perform an ultrasound scan&#44; as this may be due to the presence of thyroid-blocking antibodies &#40;maternal autoimmune thyroid disease&#41;&#44; a defect in iodide trapping in cases of dyshormonogenesis &#40;<span class="elsevierStyleItalic">NIS</span> mutation&#41;&#44; a genetic change in the TSH-&#946; gene or inactivating mutations of the TSH receptor gene&#46; In cases of partial block of thyroid hormonogenesis&#44; the thyroid may be eutopic and of normal size&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Other tests &#40;not essential to the initial diagnosis&#41;</span><p id="par0160" class="elsevierStylePara elsevierViewall">Auditory evoked potentials&#58; the relationship between hypothyroidism and hearing loss is well established&#46; Some forms of thyroid dyshormonogenesis &#40;Pendred syndrome&#44; Hollander syndrome&#41; should be suspected if there is a family history of hearing loss&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Congenital malformations may be more frequent in patients with CHT compared to the general population&#44; especially congenital heart defects&#44; and therefore&#44; performance of a cardiologic evaluation is recommended in these patients&#46; An evaluation by a paediatric neurologist at the time of diagnosis is also very useful to detect potential comorbidities associated with psychomotor retardation&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Differential diagnosis</span><p id="par0170" class="elsevierStylePara elsevierViewall">If CHT is detected in a newborn through screening and later confirmed by the thyroid function study conducted in the CFUC&#44; differential diagnoses need not be considered and treatment must not be delayed under any circumstances to attempt to determine the exact aetiology of hypothyroidism&#46; In many cases&#44; the definitive diagnosis is established in the re-evaluation performed at 3 years of chronological age&#44; while in other cases&#44; especially those of transient CHT&#44; the aetiology may not ever be established&#46;\n
      &lt;ce:para&gt;&lt;/ce:para&gt;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Paediatricians have to evaluate newborns from countries where screening is not performed to verify normal thyroid function&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">There are special situations where performance of repeat TSH measurements at 2 and 4 weeks of life is recommended due to the potential for delayed elevation of TSH or the need to measure both T4 and TSH &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">25&#8211;28</span></a></p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Treatment of congenital hypothyroidism</span><p id="par0190" class="elsevierStylePara elsevierViewall">In congenital and neonatal hypothyroidism&#44; the degree of brain damage is directly associated with the time elapsed between onset of hypothyroidism and initiation of treatment&#46; Thus&#44; treatment should be initiated as soon as possible&#44; preferably before age 15 days&#46; Treatment should start the day the diagnosis is made&#44; and its initiation should not be delayed pending performance of additional diagnostic tests&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The first-line drug is synthetic levothyroxine via the oral route&#44; administered 30<span class="elsevierStyleHsp" style=""></span>min before a feeding once every 24<span class="elsevierStyleHsp" style=""></span>h at a dose of 10&#8211;15<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#47;day&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">29&#8211;33</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Generic formulations of levothyroxine do not exhibit the same bioavailability&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a> Liquid compounded formulations of levothyroxine are not stable&#46; The absorption of levothyroxine is hindered by ingestion of foods or products containing soy&#44; iron&#44; calcium&#44; aluminium hydroxide&#44; omeprazole&#44; fibre&#44; sucralfate or bile acid sequestrants&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Once treatment with levothyroxine starts&#44; the patient must undergo frequent clinical and laboratory follow-up evaluations to optimise treatment&#46; We recommend a second visit 2 days after diagnosis to confirm acceptance of the diagnosis and prescribed treatment&#44; a third evaluation at 15 days with measurement of TSH and fT4 levels&#44; then monthly visits in the first 6 months of life&#44; followed by visits every 2 months until age 1 year&#44; and visits every 3&#8211;4 months until the patient is re-evaluated at age 3 years&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Each follow-up visit should include a full physical examination and measurement of fT4 and TSH levels&#46; The aim of treatment is to quickly normalise fT4 and TSH levels&#46; Free thyroxine levels must remain in the upper range of normal to avoid subclinical hypo- and hyperthyroidism&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a> The levels of TSH and fT4 must be measured 4 weeks after any dosage change&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Definitive diagnosis of congenital hypothyroidism</span><p id="par0215" class="elsevierStylePara elsevierViewall">The treatment of children identified through screening programmes for early detection of CHT must be maintained without interruption through age 3 years to ensure normal thyroid function until brain growth is complete&#44; whether the hypothyroidism is transient or permanent&#46; At age 3 years&#44; patients without a definitive diagnosis may undergo re-evaluation &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0220" class="elsevierStylePara elsevierViewall">Children with an initial diagnosis of thyroid agenesis or ectopic thyroid&#44; which are both permanent&#44; do not require re-evaluation&#46; The diagnosis ought to be re-evaluated in children with CHT and a normally positioned thyroid at the time of initial diagnosis&#44; and in children with CHT of unknown aetiology&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">36&#44;37</span></a> Re-evaluation should also be contemplated in patients in whom the diagnosis was not confirmed &#40;by scintigraphy&#41; at the time treatment was initiated&#46; There are 2 possible approaches to the diagnostic re-evaluation&#44; which should always be performed after the patient reaches age 3 years&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">To determine whether the hypothyroidism is permanent or transient&#44; it is sufficient to half the current dose of levothyroxine and measure the levels of TSH and fT4 one month after&#58; if the TSH level is 10<span class="elsevierStyleHsp" style=""></span>mIU&#47;L or higher&#44; the hypothyroidism is considered permanent and the patient will resume treatment with levothyroxine at the dose that achieved normal thyroid function&#46; In patients with a very high initial level of TSH and an eutopic thyroid gland&#44; discontinuing levothyroxine for just 2 weeks should be enough to produce elevation of TSH&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">If the aim is to make a definitive diagnosis&#44; treatment with levothyroxine should be suspended for 1 month&#44; followed by measurement of levels of fT4&#44; TSH&#44; thyroglobulin and antithyroid antibodies &#40;antithyroglobulin or anti-thyroid peroxidase&#41;&#46; If it was not performed before initiation of treatment&#44; thyroid scintigraphy with technetium 99 can be used to diagnose an ectopic thyroid or possibly thyroid agenesis&#44; which would be confirmed with a thyroid ultrasound scan&#46; In patients with permanent CHT with eutopic thyroid gland&#44; thyroid scintigraphy with sodium iodide I 131 allows performance of a perchlorate discharge test for assessment of dyshormonogenesis&#46; Molecular genetic testing is very useful in the diagnosis of CHT&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">The following findings are suggestive of permanent CHT in patients with an eutopic thyroid gland&#58; history of goitre or primary congenital hypothyroidism with eutopic thyroid gland in first-degree relative&#44; thyroid hypoplasia at the time of initial diagnosis&#44; need for high doses of levothyroxine &#40;&#62;2<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#47;day&#41; during the follow-up&#44; thyroid hyperplasia at the time of re-evaluation&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> summarises the aetiological classification of CHT based on the results of the diagnostic re-evaluation&#46; If a permanent aetiology is confirmed&#44; the family needs to be informed of the need to maintain treatment with levothyroxine for life with the required dose adjustments&#46; In case of transient hypothyroidism&#44; treatment is discontinued&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Prognosis</span><p id="par0245" class="elsevierStylePara elsevierViewall">Early detection of CHT through neonatal screening prevents the intellectual disability formerly observed in these children when the diagnosis was clinical and delayed&#46; Patients with CHT that receive early and adequate treatment have normal intellectual quotients&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">17&#44;18&#44;36&#44;38&#44;39</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">In some cases&#44; mild brain impairment occurs despite early initiation of treatment&#44; resulting in behavioural problems&#44; and impairment in language comprehension&#44; fine motor skills and visual-perceptual motor skills&#44; usually with little impact on the ability to carry out a normal life&#46; These abnormalities have been associated with the age at initiation of treatment &#40;greater than 15&#8211;21 days&#41;&#44; the dose of levothyroxine &#40;usually lower than recommended&#41;&#44; the initial severity of hypothyroidism and fT4 levels below or above the recommended range during the follow-up&#46; Excessive levels of fT4 in the early months of life may be associated to inattention in subsequent years&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Discontinuation of treatment before age 3 years without medical supervision or subsequent follow-up can have dire effects on neurologic development&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Follow-up in these patients is important not only to achieve healthy maturation&#44; but also optimal growth and development&#46; In countries where there are no CFUCs for patients with CHT&#44; the reported proportion of patients that discontinue treatment prematurely ranges between 25&#37; and 30&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">37&#44;40</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Transition to adult care</span><p id="par0265" class="elsevierStylePara elsevierViewall">Children with CHT should be followed up in a CFUC through puberty and until reaching their final height&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">16&#44;17</span></a> Thereon&#44; follow-up visits should be scheduled every 6&#8211;12 months&#44; or more frequently in case of poor adherence&#46; The purpose of followup is to monitor thyroid function to prevent subclinical hypo- or hyperthyroidism and the associated cardiovascular problems&#44; excess weight and bone mineralisation defects in adulthood&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">Only 70&#37; of adults with CHT adhere to treatment correctly&#46; This is particularly alarming in the case of women who are or wish to become pregnant&#44; whose thyroid hormone requirements are greater&#46; Optimal treatment of maternal hypothyroidism is essential to achieve a normal pregnancy with healthy neurocognitive development in the child&#46; Monitoring of treatment is recommended throughout childhood and adulthood&#46; Educational strategies need to be developed and implemented to improve adherence to treatment&#44; especially during the transition to adult care&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Unresolved problems in the early detection of congenital hypothyroidism</span><p id="par0275" class="elsevierStylePara elsevierViewall">Even if the results of screening are normal&#44; if there is clinical suspicion of hypothyroidism the paediatrician should request urgent measurement of serum fT4 and TSH levels&#44; as the elevation of TSH may occur later in some patients&#46; Other infrequent causes&#44; such as consumptive hypothyroidism in the postnatal period secondary to overexpression of type 3 deiodinase in patients with large haemangiomas&#44; will not be detected in screening tests due to normal levels of TSH and T4 in the early stages&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">The screening protocol that measures TSH alone cannot identify cases of central CHT&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">10&#44;11</span></a> The incidence of central CHT&#44; whether isolated or associated with hypopituitarism&#44; is higher &#40;1 per 16&#44;000 to 20&#44;000 live births&#41; than previously reported &#40;1 per 100&#44;000&#41;&#44; so expanded screening with simultaneous measurement of TSH and tT4 levels is recommended&#46; For now&#44; we advocate for measurement of T4 levels in the newborn screening sample&#44; as this would prevent delayed diagnosis in these patients&#44; in many of whom symptoms may be either absent or nonspecific&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">Abnormalities in TSH-&#945; and TSH-&#946; may manifest with a late elevation of TSH&#46; Changes in the monocarboxylate transporter 8 &#40;<span class="elsevierStyleItalic">MCT8</span>&#41; gene should be suspected in patients with neurologic manifestations in the first year of life and initially manifest with normal thyroid function&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">16&#44;17</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclusions</span><p id="par0290" class="elsevierStylePara elsevierViewall">The Programme for the Early Detection of CHT constitutes one of the greatest advances in child health and preventive medicine of the XX century&#46; The identification of these patients prevents the suffering involved in living with permanent brain damage in both the individual and the family&#46; From an economic perspective&#44; these programmes offer a high yield to society&#44; yet only 25&#37; of the global population benefits from them&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">Further cost-benefit analyses are required to establish a consensus regarding the need to measure the levels of only TSH&#44; only T4 or both to allow detection of central hypothyroidism too&#44; and whether the cut-off point for TSH should be lowered to 5<span class="elsevierStyleHsp" style=""></span>mIU&#47;L to allow detection of milder forms of hypothyroidism while avoiding an increase in the false-positive rate&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">For all the above reasons&#44; in upcoming years the necessary infrastructure should be developed to provide these programmes with the capability to apply current scientific knowledge&#44; and their positive outcomes disseminated effectively in health care and social forums&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of interest</span><p id="par0305" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>
      """
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Objective of the neonatal screening programme for congenital hypothyroidism"
        ]
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          "identificador" => "sec0015"
          "titulo" => "Procedure for neonatal screening for congenital hypothyroidism"
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              "identificador" => "sec0020"
              "titulo" => "Measurement of TSH"
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              "identificador" => "sec0025"
              "titulo" => "Confirmation of congenital hypothyroidism"
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            2 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Reporting test results"
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              "identificador" => "sec0035"
              "titulo" => "Management at the clinical follow-up centre for congenital hypothyroidism"
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                  "identificador" => "sec0040"
                  "titulo" => "Diagnostic tests"
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                  "identificador" => "sec0045"
                  "titulo" => "Other tests &#40;not essential to the initial diagnosis&#41;"
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              "identificador" => "sec0050"
              "titulo" => "Differential diagnosis"
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              "identificador" => "sec0055"
              "titulo" => "Treatment of congenital hypothyroidism"
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            6 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Definitive diagnosis of congenital hypothyroidism"
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              "identificador" => "sec0065"
              "titulo" => "Prognosis"
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              "identificador" => "sec0070"
              "titulo" => "Transition to adult care"
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              "identificador" => "sec0075"
              "titulo" => "Unresolved problems in the early detection of congenital hypothyroidism"
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          "titulo" => "Conclusions"
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          "titulo" => "References"
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    "fechaRecibido" => "2018-09-25"
    "fechaAceptado" => "2018-11-05"
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            0 => "Congenital hypothyroidism"
            1 => "Neonatal screening"
            2 => "Early detection"
            3 => "Follow-up units for endocrine diseases"
            4 => "Free T4"
            5 => "TSH"
            6 => "L-thyroxin"
            7 => "Molecular genetics"
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            0 => "Hipotiroidismo cong&#233;nito"
            1 => "Cribado neonatal"
            2 => "Detecci&#243;n precoz"
            3 => "Unidades de seguimiento endocrinopat&#237;as"
            4 => "T4 libre"
            5 => "Hormona estimulante del tiroides"
            6 => "L-tiroxina"
            7 => "Gen&#233;tica molecular hipotirodismo"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The screening programme of congenital hypothyroidism &#40;CH&#41; is probably one of the best achievements in paediatrics&#46; Thyroid hormones are essential for brain development and brain maturation that continue through the neonatal period&#46; Hypothyroidism that begins in the first months of life causes irreversible damage to the central nervous system&#44; and is one of the most frequent and preventable causes of mental retardation&#46; As children with congenital hypothyroidism are born with a normal appearance&#44; analytical studies are required to immediately start the appropriate therapy&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This article analyses the aims&#44; diagnostic procedures&#44; tests required&#44; aetiology&#44; and differential diagnosis in this disorder&#46; Especially relevant is to perform frequent monitoring to ensure dose adjustments of L-Thyroxine therapy&#44; avoiding infra- or supra-dosing that negatively affects neurosensory functions&#46; Re-evaluation of the aetiology permanent vs transient hypothyroidism is always recommended after 3 years of chronological age&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The relevance of this screening programme should be widely discussed in paediatrics&#46; The main objective is to avoid cerebral damage in these patients&#44; and has been highly successful and economically beneficial&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Other aspects are required to optimise patient outcomes&#44; to perform all the controls according to the recommendations and to include&#44; in the near future&#44; the diagnosis of central hypothyroidism&#46; Implementation of this programme is necessary to progress in accordance with current scientific knowledge&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El Programa de cribado o detecci&#243;n precoz del hipotiroidismo cong&#233;nito &#40;HC&#41; es uno de los mayores avances logrados en Pediatr&#237;a&#46; Las hormonas tiroideas son imprescindibles para el desarrollo y la maduraci&#243;n cerebral&#44; que contin&#250;an en la etapa neonatal&#46; El hipotiroidismo de comienzo en los primeros meses de vida origina lesiones irreversibles en el sistema nervioso central y es una de las causas m&#225;s frecuentes y evitables de retraso mental&#46; El diagn&#243;stico cl&#237;nico es tard&#237;o&#44; por lo que requiere estudio anal&#237;tico para poder efectuar el tratamiento adecuado&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Este art&#237;culo actualiza los objetivos&#44; los procedimientos diagn&#243;sticos&#44; las pruebas imprescindibles y complementarias requeridas&#44; la etiolog&#237;a y los diagn&#243;sticos diferenciales en esta patolog&#237;a&#46; Con especial &#233;nfasis en los requerimientos de los centros de seguimiento para protocolizar los resultados del tratamiento con L-tiroxina administrada de forma inmediata al diagn&#243;stico y a las dosis que eviten fases de infra o supradosificaci&#243;n que pueden alterar diversos aspectos del desarrollo cognitivo&#46; La revaluaci&#243;n de etiolog&#237;a permanente vs&#46; transitoria se recomienda siempre despu&#233;s de los 3 a&#241;os de edad&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La relevancia de este programa precisa su difusi&#243;n a todas las &#225;reas de pediatr&#237;a&#46; El objetivo principal&#44; evitar el da&#241;o cerebral en estos pacientes&#44; se ha logrado y es adem&#225;s altamente beneficioso desde el punto de vista econ&#243;mico&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Otros aspectos para optimizar los resultados cognitivos con todos los controles peri&#243;dicos necesarios y lograr la inclusi&#243;n del diagn&#243;stico del HC central&#44; precisan implementar los recursos de los centros de seguimiento y continuar avanzando seg&#250;n los conocimientos actuales&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Rodr&#237;guez S&#225;nchez A&#44; Chueca Guindulain MJ&#44; Alija Merillas M&#44; Ares Segura S&#44; Moreno Navarro JC&#44; Rodr&#237;guez Arnao MD&#44; et al&#46; Diagn&#243;stico y seguimiento de los pacientes con hipotiroidismo cong&#233;nito diagnosticados por cribado neonatal&#46; An Pediatr &#40;Barc&#41;&#46; 2019&#59;90&#58;250&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Appendix 1 lists the members of the Thyroid Working Group of the Sociedad Espa&#241;ola de Endocrinolog&#237;a Pedi&#225;trica &#40;SEEP&#41;&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">To produce this work&#44; we used the Appraisal of Guidelines for Research and Evaluation &#40;AGREE&#41; Instrument&#44; Spanish version &#40;<a class="elsevierStyleInterRef" target="_blank" id="intr0010" href="http://www.agreecollaboration.org/">www&#46;agreecollaboration&#46;org</a>&#41;&#46;</p>"
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            "apendice" => "<p id="par0310" class="elsevierStylePara elsevierViewall">Caimari Jaume&#44; Mar&#237;a&#44; Hospital Universitario Son Espases&#44; Balearic Islands&#59; Casano Sancho&#44; Paula Hospital Sant Joan de D&#233;u&#44; Barcelona&#59; Grau Bolado&#44; Gema&#44; Hospital Cruces&#44; Bizkaia&#59; Mu&#241;oz Calvo&#44; M&#46; Teresa&#44; Hospital Infantil Ni&#241;o Jes&#250;s&#44; Madrid&#59; Rial Rodr&#237;guez&#44; Jos&#233; Manuel&#44; Hospital Universitario Nuestra Se&#241;ora de Candelaria&#44; Santa Cruz de Tenerife&#44; and Temboury Molina&#44; Carmen&#44; Hospital del Sureste&#44; Madrid&#46;</p>"
            "etiqueta" => "Appendix 1"
            "titulo" => "Members of the Thyroid Working Group of the Sociedad Espa&#241;ola de Endocrinolog&#237;a Pedi&#225;trica &#40;Spanish Society of Paediatric Endocrinology&#41;"
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            "etiqueta" => "Appendix C"
            "titulo" => "Supplementary data"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Sources&#58; Rodr&#237;guez-Arnao et al<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a> and Rodr&#237;guez S&#225;nchez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a>&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Confirming the CHT diagnosis through history-taking&#44; physical examination and the necessary diagnostic tests &#40;blood and imaging tests&#41; with immediate turnaround of results&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Informing and reassuring the family&#59; explaining the benefits of early detection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Urgent initiation of treatment &#40;levothyroxine&#41; with optimisation of treatment during follow-up visits until thyroid function normalises&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Achieving a normal neurologic and psychomotor development and an intellectual quotient within the normal range while preventing comorbidities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diagnosing the aetiology &#40;permanent vs transient CHT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diagnosing other potentially associated congenital anomalies&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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Establishing a direct relationship with the patient&#39;s paediatrician to coordinate care&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Fuente&#58; Rodr&#237;guez-Arnao et al<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a> and Rodr&#237;guez S&#225;nchez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a>&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Paediatric endocrinologists with experience in CHT and full-time dedication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Department of Biochemistry with rapid testing capabilities for diagnostic confirmation and follow-up evaluation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Department of Nuclear Medicine &#40;initial urgent thyroid scintigraphy&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Department of Paediatric Radiology &#40;thyroid ultrasound&#44; bone age study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Department of Psychology for evaluation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Inpatient and neonatal care services&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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Periodic communication with the Subdirectorate General of Health Promotion and Prevention of the Department of Health or the institution overseeing the programme&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Expert Committee meetings to assess and improve programme outcomes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">1&#46; Defects in iodine trapping or transport</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">2&#46; Defects in organification</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mutation in thyroid peroxidase gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Defects in hydrogen peroxide generation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Iodine acceptor abnormalities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pendred syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">3&#46; Defective iodotyrosine coupling</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hollander syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">4&#46; Iodotyrosine dehalogenase deficiency</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">5&#46; Abnormal iodoproteins</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">6&#46; Abnormalities in thyroglobulin synthesis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mutation in thyroglobulin gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Decreased thyroglobulin mRNA levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Truncated thyroglobulin protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sialic-acid-deficient thyroglobulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">7&#46; Insensitivity to TSH</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Clinical score suggestive of congenital hypothyroidism&#58; &#62;4 points&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Letarte A&#46; et al&#46;&#44; 1980&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a></p>"
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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">A&nbsp;\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&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">0&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2&#46; Gestation &#62;40 weeks&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;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3&#46; Prolonged jaundice&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;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4&#46; Weight &#62;3500<span class="elsevierStyleHsp" style=""></span>g&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;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5&#46; Umbilical hernia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6&#46; Poor sucking&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">7&#46; Hypotonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">8&#46; Constipation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">9&#46; Macroglossia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">10&#46; Inactivity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">11&#46; Mottled skin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">12&#46; Dry and rough skin&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;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">13&#46; Posterior fontanelle &#62; 0&#46;5<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span>&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;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">14&#46; Classic facies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Clinical signs and symptoms of congenital hypothyroidism&#46; Congenital hypothyroidism index&#46;</p>"
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          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Rodr&#237;guez S&#225;nchez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a></p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Newborns with gestational age &#8804;30 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Birth weight &#8804;1500<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Use of iodine antiseptic products during delivery or in the care of the newborn &#40;caesarean section&#44; major surgery&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Performance of radiologic tests with iodinated contrast media&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Silastic catheter insertion&#44; cardiac catheterization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Down syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Multiple birth&#44; especially twins of the same sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;potential for foeto-foetal transfusion syndrome&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Newborns admitted to intensive care unit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Post-transfusion samples&nbsp;\t\t\t\t\t\t\n
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          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:40 [
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              "identificador" => "bib0205"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The anecdotal history of screening for congenital hypothyroidism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46;H&#46; Dussault"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "1999"
                        "volumen" => "84"
                        "paginaInicial" => "4332"
                        "paginaFinal" => "4334"
                      ]
                    ]
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            1 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term consequences of congenital hypothyroidism in the era of screening programs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46; Gr&#252;ters"
                            1 => "A&#46; Jenner"
                            2 => "H&#46; Krude"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Best Pract Res Clin Endocrinol Metab"
                        "fecha" => "2002"
                        "volumen" => "16"
                        "paginaInicial" => "369"
                        "paginaFinal" => "382"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Ares S&#44; Quero J&#44; S&#225;enz-Rico B&#44; Morreale de Escobar G&#46; Hypothyroidism and thyroid function alterations during the neonatal period&#44; a new look at hypothyroidism&#46; Dr&#46; Drahomira Springer &#40;Ed&#46;&#41;&#44; ISBN&#58; 978-953-51-0020-1&#44; InTech&#59; 2012&#46; Available in&#58; http&#58;&#47;&#47;www&#46;intechopen&#46;com&#47;books&#47;a-new-look-at-hypothyroidism&#47;hypothyroidism-and-thyroid-functionalterations-during-the-neonatal-period"
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thyroid hormones receptors in brain development and function"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46; Bernal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ncpendmet0424"
                      "Revista" => array:7 [
                        "tituloSerie" => "Nat Clin Pract Endocrinol Metab"
                        "fecha" => "2007"
                        "volumen" => "3"
                        "paginaInicial" => "249"
                        "paginaFinal" => "259"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17315033"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0264410X15013092"
                          "estado" => "S300"
                          "issn" => "0264410X"
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              ]
            ]
            4 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neurodevelopmental and neurophysiological actions of thyroid hormone"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "G&#46;R&#46; Williams"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2826.2008.01733.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neuroendocrinol"
                        "fecha" => "2008"
                        "volumen" => "20"
                        "paginaInicial" => "784"
                        "paginaFinal" => "794"
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