Congenital Hypothyroidism Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
Neonatal Screening for Congenital Hypothyroidism Toni Torresani Swiss Newborn Screening Laboratory, University Children’s Hospital, Zurich, Switzerland
Abstract The possibility of measuring thyroid hormones from blood dried on filter paper opened the way to identifying neonates with congenital hypothyroidism (CH) already in the first days of life. Consequently the early initiation of adequate replacement therapy opened the way to an effective prevention of mental retardation. Timely and complete specimen collection, transport logistics, rapid analysis and communication of results are key points for the organization of a CH newborn screening program. Close collaboration between laboratory and treating specialists is necessary to ensure an adequate treatment and follow-up of babies identified by CH screening programs. Topics for further investigations remain in the fields of which forms of CH should be identified by screening (only severe or also very mild forms) and on the long-term outcome of the individuals identified by CH © 2014 S. Karger AG, Basel screening.
Congenital hypothyroidism (CH) is one of the most frequent preventable causes of mental retardation. It was therefore only a matter of time until an adequate neonatal screening (NS) test for the early diagnosis of CH was developed and introduced. 2014 will mark the 40th anniversary of the establishment of the first screening program for CH in 1974 in Quebec (Canada) [1]. Since then NS for CH has been established both in the developed world and more and more in developing countries. The American Office of Technology Assessment [2] concludes that screening for CH is one of the few programs in preventive medicine that has an impact on public health with a positive cost-to-benefit ratio (10:1).
In the early 70s, reports were published outlining the effectiveness of early intervention in the treatment of CH [3]. Almost simultaneously reports appeared describing the possibility of measuring thyroid hormones from cord blood [4] or from dried
Downloaded by: UCSF Library & CKM 169.230.243.252 - 12/20/2014 9:44:24 PM
History of Neonatal Screening for Congenital Hypothyroidism
blood spots (DBS) [5]. DBS were already being used for collecting specimens for the NS for phenylketonuria and became immediately the sample material of choice for CH screening. While the choice of sampling device (the filter paper card for DBS) was widely accepted, the choice of which thyroid hormone should be measured, i.e. thyroid-stimulating hormone (TSH) or thyroxine (T4), was the subject of lengthy arguments. The controversy was at that time focused mainly on specificity compared to sensitivity. TSH was thought to be the optimal analyte to detect primary hypothyroidism, but there were limitations in the TSH assays in those days, due to a relatively poor sensitivity. In contrast T4 assays were somewhat more sensitive but lacked the specificity and resulted in frequent false-positive results particularly in premature babies. In the early days NS using T4 as the detection marker was common in North America [6], while TSH was the analyte of choice in Europe [7] and Japan. Today screening for CH is in operation in most parts of the world and is, together with the screening for phenylketonuria, the first program that is implemented in the countries just starting an NS program. With few exceptions TSH is the analyte of choice. Few jurisdictions are using T4 followed by one or more secondary parameters. Almost everywhere DBS specimens are generally used. There are exceptions where cord blood specimens are used instead of DBS (generally very small jurisdictions where births occur at few or only a single location) [8].
NS in general is a public health initiative. Therefore most programs are organized and financed by the respective health departments. In some jurisdictions the participation to the screening is mandatory and regulated by law, in others is it usually based on informed dissent. This means that parents have the possibility to opt out from NS. Screening is unique in that it is not performed as part of the investigation or treatment of symptomatic individuals, but it is usually offered to all individuals in a community not known to be at risk of having the condition. This implies that NS is not a diagnostic test and results from it should not be treated as such and therefore be confirmed before intervention. NS is usually performed at large laboratory units, processing several thousands of samples per year. Such a laboratory should ideally be located at an academic facility, preferably a pediatric one. A minimal size for an NS laboratory has been put in the range of around 50,000–100,000 samples per year [9]. The rationale behind such a recommendation is derived from the fact that with less than about 50,000 samples the screening process may become inefficient. A low sample number can lead to a poor cost-benefit ratio and provide an insufficient base for statistical analysis. An NS laboratory must also participate in external quality control programs, ideally in an international one like the Newborn Screening Quality Assurance Program run by the Centers for Disease Control in Atlanta (USA). External quality control programs allow a
Neonatal Screening for Congenital Hypothyroidism Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
45
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Screening Organization
laboratory to test and meet the requirements of all aspects of an NS like training of personnel and sample processing organization. In order for an NS laboratory to perform adequately, a continuous communication with the specialists involved in taking care of the neonates with positive screening results is of the outmost importance and is also part of the process of quality control. The shorter the communication lines between laboratory and treating specialist, the better the outcome of the screening process. Ideally the pathological results of the screening and the corresponding case outcome should be registered in a centralized national register, in order to allow epidemiological studies.
Screening Strategy
Screening for primary CH has been introduced in most countries worldwide. It is essential that, when starting a new program, a decision is taken on the scope of the screening, defining the strategy for selecting the test to be used. The goal of screening for CH should be to detect all forms of primary CH – mild, moderate and severe, with particular efforts to detect those patients with severe CH, where morbidity is high if the disease is not detected and treated until several months after birth [10]. The most sensitive test for detecting primary CH is the assay of TSH. Because iodine deficiency is one of the most common preventable causes of mental retardation, developmental disabilities and CH worldwide [11], NS for CH using TSH is also an excellent tool to monitor the iodine nutritional status in both the neonatal and maternal populations [12].
Screening for CH is effective for the testing of cord blood as well as for blood collected on filter paper after 24 h of age. The ideal time for sample collection is 48–72 h of age. Blood is applied directly to the filter paper, and the card is sent immediately after drying to the laboratory for analysis. The TSH method detects primary CH more effectively than T4 screening. Analysis of T4 followed by a confirmatory TSH testing has the drawback of missing cases of mild forms of primary CH. On the other hand, if the screening program strategy defines it, this approach can detect cases of central CH (CCH). To be effective the protocols for the detection of CCH are based on one of two approaches: either a simultaneous determination of T4 and TSH in DBS or a combination of T4 followed by a secondary TSH testing and in a third step an assay of T4binding globulin (TBG). The inclusion of TBG determinations decreases the number of false-positive results [13]. Because screening for CH is usually embedded in comprehensive NS programs, some compromise has to be made with respect to the timing of sample collection.
46
Torresani Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
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Screening Protocols
Neonatal Screening for Congenital Hypothyroidism Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
47
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Home deliveries, early discharge and the increasing economic pressures on the health care systems worldwide have resulted in the timing of specimen collection being put as much forward as to less than 24 h after birth. It is therefore important that in the screening laboratory the results of the TSH assay are interpreted in relation to time of sampling, i.e. by using cutoff values accordingly stratified. Furthermore the CH screening results obtained in some groups of neonates at risk of transient and permanent CH must be evaluated separately. It is customary that in preterm neonates (gestational age less than 37 weeks), those with birth weight less than 2,000 g and all neonates admitted to an intensive-care unit have more than 1 NS specimen taken: 1 within the first 48 h and another around 14 days of age or at discharge [14]. Similarly, in the case of a specimen being collected in the first 24 h or in the case of multiple births (particularly same sex twins), there should be at least a second specimen collected. In all these instances the interpretation of the TSH values must be made taking into account all specimens collected from the same neonate. Several publications have dealt with this issue [15]. The underlying idea is that in these infants the TSH could be low-normal even in a case of CH. TSH suppression following drug administration in the intensive-care unit, hypothalamic immaturity or fetal blood mixing in multiple births are quoted as the most likely causes. Whether the possible cases of CH detected after a second specimen represent true permanent hypothyroidism or whether these are mostly transient cases is still a debated issue that needs further studies. Usually the strategy of a screening for CH is aimed at detecting all the severe forms of CH and this as early as possible. For this purpose TSH screening is the most sensitive test in detecting primary CH. This approach is nowadays being used in most CH screening programs with good success. The detection rate of cases of CH, both permanent and transient, is around 1:2,500–1:3,500 at screening. This corresponds to the cases needing at least a temporary replacement therapy, and it does not represent the ‘real’ incidence of CH. In recent years the scope, and accordingly the strategies, of several CH screening programs has been revised, and their aim is not only the detection of the severe forms of CH but more and more it is focusing on the detection of possibly ‘all’ forms of CH. The screening cutoff levels have been gradually decreased, and as a consequence an increase in the screening incidence of CH cases has been reported [16]. Studies on longterm outcome are now under way to try to determine whether there is a risk of permanent disability in these milder cases with only moderate TSH elevation and usually normal T4 levels and whether these individuals present with a permanent or a transient thyroid dysfunction. A further shift in the scope of CH screening is aiming at a possible use of the neonatal test to detect cases of CCH. The rationale behind these initiatives is that in some populations CCH is a relatively frequent disease with prevalence similar to that of phenylketonuria and that the possibility of an unfavorable outcome in cases of delayed diagnosis is documented [17]. On the downside the lack of a DBS-based free-T4 assay, the ideal analyte for the diagnosis of CCH, represents a severe obstacle.
Confirmation of Congenital Hypothyroidism
Confirmation of a positive screening result is necessary before an infant is declared a CH case. Screening is not a diagnostic test and the possibility of mislabeling samples in the nursery should not be dismissed. Particularly in multiple births mislabeling of specimens happens relatively frequently. The confirmation of the pathological screening result must be made rapidly by measuring at least TSH and free T4 in a new venous blood sample. Replacement therapy may be started immediately after drawing the blood sample and without waiting for the analytical result. In many programs a sample is drawn also from the mother of the neonate and analyzed for thyroid hormones and for thyroid antibodies. Positive antibodies in the mother can be the cause of a transient form of CH in the baby. It is good practice that the diagnosis of CH is reevaluated at about 2 years of age, in order to avoid unnecessary treatment in cases of transient CH.
Follow-Up
The neurodevelopmental outcome in children with CH detected by NS and started on thyroid hormone treatment early is normal or near-normal [18]. Importantly initial early high-dose therapy must constitute the first component of an adequate substitution therapy. Regular therapy monitoring taking care of maintaining appropriate thyroid hormone levels remains of the utmost importance.
Conclusion
48
Torresani Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
Downloaded by: UCSF Library & CKM 169.230.243.252 - 12/20/2014 9:44:24 PM
NS for CH is a great success story, and it is very likely that it will continue to be and to expand worldwide. Very recently new guidelines have been published defining recommendations for NS [19, 20]. As it has been the experience with all new disorders added to existing NS programs, the results obtained when a large birth population undergoes a comprehensive NS for CH will show some new and previously not known forms of thyroid dysfunction. CH has been shown to be a heterogeneous group of disorders with a spectrum going from severe, permanent hypothyroidism to mild, transient hypothyroidism. The significance of thyroid dysfunction characterized by delayed elevation of serum TSH in preterm infants and acutely ill term infants needs further evaluation. Even 40 years after the start of NS for CH, many of the questions concerning the etiology remain unexplained.
References 13 Lanting CI, van Tijn DA, Loeber JG, Vulsma T, de Vijlder JJ, Verkerk PH: Clinical effectiveness and cost-effectiveness of the use of the thyroxine/thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program. Pediatrics 2005; 116: 168–173. 14 Clinical and Laboratory Standards Institute: Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns: Approved Guideline, ed 1. CLSI Document NBS03-A. Wayne, Clinical and Laboratory Standards Institute, 2009. 15 Rapaport R: Evaluation of thyroid status of infants in intensive care settings recommended an extension of newborn screening. J Pediatr 2003;143:556–558. 16 Corbetta C, Weber G, Cortinovis F, Calebiro D, Passoni A, Vigone MC, Beck-Peccoz P, Chiumello G, Persani L: A 7-year experience with low blood TSH cutoff levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism (CH). Clin Endocrinol (Oxf) 2009;71:739–745. 17 Fisher D: Next generation newborn screening for congenital hypothyroidism? J Clin Endocrinol Metab 2005;90:3797–3799. 18 Dimitropoulos A, Molinari L, Etter K, Torresani T, Lang-Muritano R, Jenni O, Largo R, Latal B: Children with congenital hypothyroidism: long-term intellectual outcome after early high-dose treatment. Pediatr Res 2009;65:242–248. 19 Léger J, Olivieri A, Donaldson M, Torresani T, Krude H, van Vliet G, Polak M, Butler G; ESPEPES-SLEP-JSPE-APEG-APPES-ISPAE; Congenital Hypothyroidism Consensus Conference Group: European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab 2014; 99: 363–384. 20 Léger J, Olivieri A, Donaldson M, Torresani T, Krude H, van Vliet G, Polak M, Butler G: European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Horm Res Paed 2014; 81:80–103.
Dr. Toni Torresani Büelstrasse 84 CH–8132 Hinteregg (Switzerland) E-Mail [email protected]
Neonatal Screening for Congenital Hypothyroidism Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
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1 Dussault JH, Coulombe P, Laberge C, Letarte J, Guyda H, Khoury K: Preliminary report on a mass screening program for neonatal hypothyroidism. J Pediatr 1975;86:670–674. 2 Leutwyler K: The price of prevention. Sci Am 1995; 10:122–129. 3 Klein AH, Meltzer S, Kenney FH: Improved prognosis in congenital hypothyroidism treated before age 3 months. J Pediatr 1972;89:912–915. 4 Klein AH, Agustin AV, Foley TP: Successful laboratory screening for congenital hypothyroidism. Lancet 1974;2:77–79. 5 Dussault JH, Laberge C: Thyroxine (T4) determination in dried blood by radioimmunoassay: a screening method for neonatal hypothyroidism. Union Med Can 1973;102:2062–2064. 6 Dussault JH, Mitchell ML, LaFranchi S: Regional screening for congenital hypothyroidism: results of screening one million North American infants with filter paper spot T4-TSH; in Burrow GN, Dussault JH (eds): Neonatal Thyroid Screening. New York, Raven Press, 1980, pp 155–165. 7 Illig R, Torresani T: TSH determination in dried blood: a reliable, efficient, and inexpensive method for neonatal thyroid screening; in Burrow GN, Dussault JH (eds): Neonatal Thyroid Screening. New York, Raven Press, 1980, pp 87–94. 8 Loeber JG: Newborn screening programmes in Europe: arguments and efforts regarding harmonization. 1. From blood spot to screening result. J Inherit Metab Dis 2012;35:603–611. 9 Working Group for Neonatal Screening in Paediatric Endocrinology of the European Society for Paediatric Endocrinology: Revised guidelines for neonatal screening programs for congenital hypothyroidism. Horm Res 1999;52:49–52. 10 Grüters A, Krude H: Detection and treatment of congenital hypothyroidism. Nat Rev Endocrinol 2011;8:104–113. 11 Gilbert ME, Rovet J, Chen Z, Koibuchi N: Developmental thyroid hormone disruption: prevalence, environmental contaminants and neurodevelopmental consequences. Neurotoxicology 2011;33:842–852. 12 Zimmermann MB, Aeberli I, Torresani T, Burgi H: Increasing the iodine concentration in the Swiss iodized salt program markedly improved iodine status in pregnant women and children: a 5-year prospective national study. Am J Clin Nutr 2005;82:388–392.
Neonatal Screening for Congenital Hypothyroidism Toni Torresani Swiss Newborn Screening Laboratory, University Children’s Hospital, Zurich, Switzerland
Abstract The possibility of measuring thyroid hormones from blood dried on filter paper opened the way to identifying neonates with congenital hypothyroidism (CH) already in the first days of life. Consequently the early initiation of adequate replacement therapy opened the way to an effective prevention of mental retardation. Timely and complete specimen collection, transport logistics, rapid analysis and communication of results are key points for the organization of a CH newborn screening program. Close collaboration between laboratory and treating specialists is necessary to ensure an adequate treatment and follow-up of babies identified by CH screening programs. Topics for further investigations remain in the fields of which forms of CH should be identified by screening (only severe or also very mild forms) and on the long-term outcome of the individuals identified by CH © 2014 S. Karger AG, Basel screening.
Congenital hypothyroidism (CH) is one of the most frequent preventable causes of mental retardation. It was therefore only a matter of time until an adequate neonatal screening (NS) test for the early diagnosis of CH was developed and introduced. 2014 will mark the 40th anniversary of the establishment of the first screening program for CH in 1974 in Quebec (Canada) [1]. Since then NS for CH has been established both in the developed world and more and more in developing countries. The American Office of Technology Assessment [2] concludes that screening for CH is one of the few programs in preventive medicine that has an impact on public health with a positive cost-to-benefit ratio (10:1).
In the early 70s, reports were published outlining the effectiveness of early intervention in the treatment of CH [3]. Almost simultaneously reports appeared describing the possibility of measuring thyroid hormones from cord blood [4] or from dried
Downloaded by: UCSF Library & CKM 169.230.243.252 - 12/20/2014 9:44:24 PM
History of Neonatal Screening for Congenital Hypothyroidism
blood spots (DBS) [5]. DBS were already being used for collecting specimens for the NS for phenylketonuria and became immediately the sample material of choice for CH screening. While the choice of sampling device (the filter paper card for DBS) was widely accepted, the choice of which thyroid hormone should be measured, i.e. thyroid-stimulating hormone (TSH) or thyroxine (T4), was the subject of lengthy arguments. The controversy was at that time focused mainly on specificity compared to sensitivity. TSH was thought to be the optimal analyte to detect primary hypothyroidism, but there were limitations in the TSH assays in those days, due to a relatively poor sensitivity. In contrast T4 assays were somewhat more sensitive but lacked the specificity and resulted in frequent false-positive results particularly in premature babies. In the early days NS using T4 as the detection marker was common in North America [6], while TSH was the analyte of choice in Europe [7] and Japan. Today screening for CH is in operation in most parts of the world and is, together with the screening for phenylketonuria, the first program that is implemented in the countries just starting an NS program. With few exceptions TSH is the analyte of choice. Few jurisdictions are using T4 followed by one or more secondary parameters. Almost everywhere DBS specimens are generally used. There are exceptions where cord blood specimens are used instead of DBS (generally very small jurisdictions where births occur at few or only a single location) [8].
NS in general is a public health initiative. Therefore most programs are organized and financed by the respective health departments. In some jurisdictions the participation to the screening is mandatory and regulated by law, in others is it usually based on informed dissent. This means that parents have the possibility to opt out from NS. Screening is unique in that it is not performed as part of the investigation or treatment of symptomatic individuals, but it is usually offered to all individuals in a community not known to be at risk of having the condition. This implies that NS is not a diagnostic test and results from it should not be treated as such and therefore be confirmed before intervention. NS is usually performed at large laboratory units, processing several thousands of samples per year. Such a laboratory should ideally be located at an academic facility, preferably a pediatric one. A minimal size for an NS laboratory has been put in the range of around 50,000–100,000 samples per year [9]. The rationale behind such a recommendation is derived from the fact that with less than about 50,000 samples the screening process may become inefficient. A low sample number can lead to a poor cost-benefit ratio and provide an insufficient base for statistical analysis. An NS laboratory must also participate in external quality control programs, ideally in an international one like the Newborn Screening Quality Assurance Program run by the Centers for Disease Control in Atlanta (USA). External quality control programs allow a
Neonatal Screening for Congenital Hypothyroidism Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
45
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Screening Organization
laboratory to test and meet the requirements of all aspects of an NS like training of personnel and sample processing organization. In order for an NS laboratory to perform adequately, a continuous communication with the specialists involved in taking care of the neonates with positive screening results is of the outmost importance and is also part of the process of quality control. The shorter the communication lines between laboratory and treating specialist, the better the outcome of the screening process. Ideally the pathological results of the screening and the corresponding case outcome should be registered in a centralized national register, in order to allow epidemiological studies.
Screening Strategy
Screening for primary CH has been introduced in most countries worldwide. It is essential that, when starting a new program, a decision is taken on the scope of the screening, defining the strategy for selecting the test to be used. The goal of screening for CH should be to detect all forms of primary CH – mild, moderate and severe, with particular efforts to detect those patients with severe CH, where morbidity is high if the disease is not detected and treated until several months after birth [10]. The most sensitive test for detecting primary CH is the assay of TSH. Because iodine deficiency is one of the most common preventable causes of mental retardation, developmental disabilities and CH worldwide [11], NS for CH using TSH is also an excellent tool to monitor the iodine nutritional status in both the neonatal and maternal populations [12].
Screening for CH is effective for the testing of cord blood as well as for blood collected on filter paper after 24 h of age. The ideal time for sample collection is 48–72 h of age. Blood is applied directly to the filter paper, and the card is sent immediately after drying to the laboratory for analysis. The TSH method detects primary CH more effectively than T4 screening. Analysis of T4 followed by a confirmatory TSH testing has the drawback of missing cases of mild forms of primary CH. On the other hand, if the screening program strategy defines it, this approach can detect cases of central CH (CCH). To be effective the protocols for the detection of CCH are based on one of two approaches: either a simultaneous determination of T4 and TSH in DBS or a combination of T4 followed by a secondary TSH testing and in a third step an assay of T4binding globulin (TBG). The inclusion of TBG determinations decreases the number of false-positive results [13]. Because screening for CH is usually embedded in comprehensive NS programs, some compromise has to be made with respect to the timing of sample collection.
46
Torresani Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
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Screening Protocols
Neonatal Screening for Congenital Hypothyroidism Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
47
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Home deliveries, early discharge and the increasing economic pressures on the health care systems worldwide have resulted in the timing of specimen collection being put as much forward as to less than 24 h after birth. It is therefore important that in the screening laboratory the results of the TSH assay are interpreted in relation to time of sampling, i.e. by using cutoff values accordingly stratified. Furthermore the CH screening results obtained in some groups of neonates at risk of transient and permanent CH must be evaluated separately. It is customary that in preterm neonates (gestational age less than 37 weeks), those with birth weight less than 2,000 g and all neonates admitted to an intensive-care unit have more than 1 NS specimen taken: 1 within the first 48 h and another around 14 days of age or at discharge [14]. Similarly, in the case of a specimen being collected in the first 24 h or in the case of multiple births (particularly same sex twins), there should be at least a second specimen collected. In all these instances the interpretation of the TSH values must be made taking into account all specimens collected from the same neonate. Several publications have dealt with this issue [15]. The underlying idea is that in these infants the TSH could be low-normal even in a case of CH. TSH suppression following drug administration in the intensive-care unit, hypothalamic immaturity or fetal blood mixing in multiple births are quoted as the most likely causes. Whether the possible cases of CH detected after a second specimen represent true permanent hypothyroidism or whether these are mostly transient cases is still a debated issue that needs further studies. Usually the strategy of a screening for CH is aimed at detecting all the severe forms of CH and this as early as possible. For this purpose TSH screening is the most sensitive test in detecting primary CH. This approach is nowadays being used in most CH screening programs with good success. The detection rate of cases of CH, both permanent and transient, is around 1:2,500–1:3,500 at screening. This corresponds to the cases needing at least a temporary replacement therapy, and it does not represent the ‘real’ incidence of CH. In recent years the scope, and accordingly the strategies, of several CH screening programs has been revised, and their aim is not only the detection of the severe forms of CH but more and more it is focusing on the detection of possibly ‘all’ forms of CH. The screening cutoff levels have been gradually decreased, and as a consequence an increase in the screening incidence of CH cases has been reported [16]. Studies on longterm outcome are now under way to try to determine whether there is a risk of permanent disability in these milder cases with only moderate TSH elevation and usually normal T4 levels and whether these individuals present with a permanent or a transient thyroid dysfunction. A further shift in the scope of CH screening is aiming at a possible use of the neonatal test to detect cases of CCH. The rationale behind these initiatives is that in some populations CCH is a relatively frequent disease with prevalence similar to that of phenylketonuria and that the possibility of an unfavorable outcome in cases of delayed diagnosis is documented [17]. On the downside the lack of a DBS-based free-T4 assay, the ideal analyte for the diagnosis of CCH, represents a severe obstacle.
Confirmation of Congenital Hypothyroidism
Confirmation of a positive screening result is necessary before an infant is declared a CH case. Screening is not a diagnostic test and the possibility of mislabeling samples in the nursery should not be dismissed. Particularly in multiple births mislabeling of specimens happens relatively frequently. The confirmation of the pathological screening result must be made rapidly by measuring at least TSH and free T4 in a new venous blood sample. Replacement therapy may be started immediately after drawing the blood sample and without waiting for the analytical result. In many programs a sample is drawn also from the mother of the neonate and analyzed for thyroid hormones and for thyroid antibodies. Positive antibodies in the mother can be the cause of a transient form of CH in the baby. It is good practice that the diagnosis of CH is reevaluated at about 2 years of age, in order to avoid unnecessary treatment in cases of transient CH.
Follow-Up
The neurodevelopmental outcome in children with CH detected by NS and started on thyroid hormone treatment early is normal or near-normal [18]. Importantly initial early high-dose therapy must constitute the first component of an adequate substitution therapy. Regular therapy monitoring taking care of maintaining appropriate thyroid hormone levels remains of the utmost importance.
Conclusion
48
Torresani Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
Downloaded by: UCSF Library & CKM 169.230.243.252 - 12/20/2014 9:44:24 PM
NS for CH is a great success story, and it is very likely that it will continue to be and to expand worldwide. Very recently new guidelines have been published defining recommendations for NS [19, 20]. As it has been the experience with all new disorders added to existing NS programs, the results obtained when a large birth population undergoes a comprehensive NS for CH will show some new and previously not known forms of thyroid dysfunction. CH has been shown to be a heterogeneous group of disorders with a spectrum going from severe, permanent hypothyroidism to mild, transient hypothyroidism. The significance of thyroid dysfunction characterized by delayed elevation of serum TSH in preterm infants and acutely ill term infants needs further evaluation. Even 40 years after the start of NS for CH, many of the questions concerning the etiology remain unexplained.
References 13 Lanting CI, van Tijn DA, Loeber JG, Vulsma T, de Vijlder JJ, Verkerk PH: Clinical effectiveness and cost-effectiveness of the use of the thyroxine/thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program. Pediatrics 2005; 116: 168–173. 14 Clinical and Laboratory Standards Institute: Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns: Approved Guideline, ed 1. CLSI Document NBS03-A. Wayne, Clinical and Laboratory Standards Institute, 2009. 15 Rapaport R: Evaluation of thyroid status of infants in intensive care settings recommended an extension of newborn screening. J Pediatr 2003;143:556–558. 16 Corbetta C, Weber G, Cortinovis F, Calebiro D, Passoni A, Vigone MC, Beck-Peccoz P, Chiumello G, Persani L: A 7-year experience with low blood TSH cutoff levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism (CH). Clin Endocrinol (Oxf) 2009;71:739–745. 17 Fisher D: Next generation newborn screening for congenital hypothyroidism? J Clin Endocrinol Metab 2005;90:3797–3799. 18 Dimitropoulos A, Molinari L, Etter K, Torresani T, Lang-Muritano R, Jenni O, Largo R, Latal B: Children with congenital hypothyroidism: long-term intellectual outcome after early high-dose treatment. Pediatr Res 2009;65:242–248. 19 Léger J, Olivieri A, Donaldson M, Torresani T, Krude H, van Vliet G, Polak M, Butler G; ESPEPES-SLEP-JSPE-APEG-APPES-ISPAE; Congenital Hypothyroidism Consensus Conference Group: European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab 2014; 99: 363–384. 20 Léger J, Olivieri A, Donaldson M, Torresani T, Krude H, van Vliet G, Polak M, Butler G: European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Horm Res Paed 2014; 81:80–103.
Dr. Toni Torresani Büelstrasse 84 CH–8132 Hinteregg (Switzerland) E-Mail [email protected]
Neonatal Screening for Congenital Hypothyroidism Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
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