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Bulletin Board Received: December 24, 1999 Accepted after revision: May 28, 2001
Horm Res 2001;55:201-205
Procedure for Neonatal Screening for Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency Working Group on Neonatal Screening of the European Society for Paediatric Endocrinology 1
KeyWords Congenital adrenal hyperplasia ·Screening procedures · 21-Hydroxylase deficiency
Abstract The value of screening of neonates for congenital adrenal hyperplasia is not universal ly accepted. Procedures for screening are recommended here in order to provide a structure to the testing and ultimately bring together data that will allow the effect of screening to be judged for benefit or dismissed as no better than clinical recognition of the disease state. Copyright© 2001 S. Karger AG. Basel
J .W. Honour, Departmcnt ofChemical Pathology, University College of London Hospitals, London, UK; T. Torresani, Universitäts-Kinderklinik, Zürich, Switzerland; J.-E. Toublanc, Groupe Hospitalier Cochin/St-Vincent-dePaul, Paris, France; A. Larsson, Department of Paediatrics, Karolinska Institute, Huddinge, Sweden; A. Gruetcrs-Kieslich, Virchow-Klinikum, Kinderklinik, Charite, Berlin, Germany; G. G iovanelli, Department of Paediatrics, University of Parma, ltaly; M. Donaldson, Royal Hospital for Siek Children, Glasgow, UK; A. Ferrandez-Longas, Hospital Infantil 'Miguel Servet', Zaragoza, Spain; M. Klett, Universitäts-Kinderklin ik, Abteilung für Pädiatrische Endokrinologie, Heidelberg, Germany; 0. Hnikova, Departmcnt of Pacdiat rics, 3rd Mcdical Faculty, Prague, Czcch Republic; S.M.P.F. de Muinck Keizcr Schrama, Division of Endocrinology, Sophia Childrcn's Hospital, Rotterdam, Thc Ncthcrlands.
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The ESPE Working Group on Neonatal Screening has conducted a review of recent data for the outcome of screening for congenital adrenal hyperplasia (CAH) [ 1]. As with the screening for congenital hypothyroidism [2], the evaluation of the benefits of CAH screening requires degrees of uniformity to procedures that cover time of blood spot sampling, screening methods, follow-up of positive screening test results, confirmation tests, and repeat tests.
General Requirements
Parents should be informed of when and why any screening tests are being pcrformed. In the case of CAH, the low risks of the child being found to be affected with the disease, the benefits of early detection, and the risks of false results need to be explained. A paediatrician with endocrinc experience should be nominated tobe responsible for managing a patient when a positive screening test result is reported.
Blood Spot Sample Collection
Blood spots should if possible be taken on day 3 (4872 h after birth) and definitely not later than the end of the 1st week of life. As more tests arc addcd to the panel for neonatal Screening, it is important that all spots on the card are properly filled with blood. There may be some
John W. Honour. PhD Department ofChemical Pathology University College London Hospitals, Windeyer Building 46 Cleveland Slreet, London WIT 4JF (UK) Tel./Fax +44 20 7679 9592, E-Mail john.hono
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advantage to venous sampling over capillary blood sampling. The cards must be sent to the laboratory on the same day, as the blood spots are taken. When dexamethasone has been recently given to the child or the mother to assist lung maturation, the family should be warned that a false-negative result might be a consequence of that steroid administration. Screening for CAH should still be recommended, but the use of dexamethasone in the child should be recorded on the request form. The family should be advised that a repeat sample is necessary at a later date to exclude CAH. If a baby requires a transfusion, a blood spot sample should be obtained prior to the transfusion and at the earliest 4 days after the transfusion.
blood or if the blood spots are themselves of poor quality, a further blood spot sample must be requested, so that the neonatal screening procedures are complete.
Communication of Results
Organization of the laboratory procedures and followup of suspicious or positive results is essential, with clear team links defined between laboratory, paediatricians, paediatric endocrinologists, and general practitioners. Tue screening programme will fail, if there is no proper clinical follow-up and review of every aspect in the organization. Positive results must be actively pursued through the mechanisms appropriate to each country.
Laboratory Organization Organization of CAH Screening
Laboratories have considerable responsibilities in the execution and validation of the tests. As already stated for congenital hypothyroidism screening, the workload of laboratories for effective CAH screening should ideally be on samples from about 50,000 newborn infants per year in order that the laboratory gets experience of 3-4 positive cases each year and can accumulate normal data for preterm infants. Thorough internal and external quality assurance programmes should be in place and carefully monitored.
If infants are discharged home during the first 48 h after birth, there must be clear responsibility for the collection of blood spots and early transfer of specimens to the laboratory. lt is essential that a paediatrician be alerted of any positive screening test result within 10 days of birth at the latest. To achieve this requires: ( 1) timely sample collection, (2) rapid transport of the samples to the laboratory, and (3) good procedures to communicate the results to a paediatrician.
Screening Methods Programme Evaluation
(1) All samples should be assayed for 17-hydroxyprogesterone (17-0HP), ideally within 24 h and a maximum of 48 h of receipt in the laboratory. A screening test should, in the first instance, use a direct immunoassay method validated for use in neonates. The results are needed within 10 days of birth. (2) Cross-reactions of 17hydroxypregnenolone as free steroid and as the sulphate and glucuronide conjugates should be less than 1%, and this information must be included in the panel of steroids tested for interference in any assay development. Pregnenolone and dehydroepiandrosterone sulphate should have lcss than 0.0 l % cross-reaction. (3) Reference data for preterm infants as well as term infants are essential. (4) Results for 17-0HP by convention are expressed in nanomoles per litre of blood. (5) The laboratory must be able to follow every equivocal result by requesting further samples, until results are normalized or CAH is confirmed. (6) If the cards do not have sufficient spots with
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The screening programme must be subject to evaluation which requires setting up and maintaining a line of feedback, where there are false-negative and false-positive laboratory results detected clinically.
Procedures for Term Babies
A flow chart for term babies and for infants of more than 36 weeks' gestation and/or with a birth weight ::::: 2,500 g (fig. l) covers procedures for the follow-up of positive screening results. If 17-0HP in the blood spot exceeds the laboratory cutoff value (90 nmol/l in many laboratories, but dependent upon the laboratory and technique used), then CAH is almost certain. Confirmatory tests should be organized, then treatment should be started. A blood spot 17-0HP :s 30 nmol/l blood is a nor-
Working Group on Neonatal Screening
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Termbaby >36weeks >2,500g
17-0HP normal 30ng/ml
Normal cttild •
Suspicion ofCAH
alinost certain
In hospital
CAfl
Athome
Serum 17-0HP + electrolytes
Repeat bloodspot
Normal 17-0HP
Fig. 1. Flow chart for neonatal CAH screening of infants delivered at term. 17-0HP concentrations are typical cutoff points, but each laboratory needs to confirm the appropriate local value.
Elevated 17-0HP
Raised 17-0HP
Normal child
mal result, and no further action is required. When the 17-0HP is ~ 30 nmol/l but ::; 90 nmol/l blood, a follow-up must be arranged, preferably as a repeat blood spot. If any further abnormal results are found, either in the repeat blood spot taken at home or in hospital, a serum test for 17-0HP should be organized. If a term baby is critically ill with no signs of CAH, the l 70HP elevation is most likely not caused by CAH. In this case take blood spots every 2 weeks, until the 17-0HP level is ::; 30 nmol/l.
Procedures for Preterm lnfants
Normal child
Confirmation test; start treatment
CAH confirmed; genetics
A second blood spot is recommended in all preterm infants around day 14, partly as a precaution against the risk that dexamethasone was used in the mother and/or the preterm infant, thus falsely suppressing any 17-0HP value and increasing the chance of a false-negative result. Fluid balance problems and hyperbilirubinaemia are potentially contributing factors to false-positive results due to the effects of dehydration on blood concentration or assay interference. The result of the second screening test may not be available when the infant is discharged from hospital, so follow-up of a high 17-0HP level in the second test may require alerting the paediatrician with responsibility in the community.
Most infants ::; 36 weeks of gestation will still be in hospital when the first screening test result is available (flow chart; fig. 2). The first blood spot should be taken on days 3-5 (48-120 h after birth), before any transfusions.
Neonatal Screening for Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
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Pretern baby >36 week's gestation
