SAMPLE. Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns; Approved Guideline

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1 October 2009 Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns; Approved Guideline This guideline outlines the recommended protocols for screening preterm, sick, or low birth weight infants for hearing loss and disorders detectable through dried blood spot testing. A guideline for global application developed through the Clinical and Laboratory Standards Institute consensus process.

2 Clinical and Laboratory Standards Institute Setting the standard for quality in clinical laboratory testing around the world. The Clinical and Laboratory Standards Institute (CLSI) is a not-for-profit membership organization that brings together the varied perspectives and expertise of the worldwide laboratory community for the advancement of a common cause: to foster excellence in laboratory medicine by developing and implementing clinical laboratory standards and guidelines that help laboratories fulfill their responsibilities with efficiency, effectiveness, and global applicability. Consensus Process Consensus the substantial agreement by materially affected, competent, and interested parties is core to the development of all CLSI documents. It does not always connote unanimous agreement, but does mean that the participants in the development of a consensus document have considered and resolved all relevant objections and accept the resulting agreement. Commenting on Documents CLSI documents undergo periodic evaluation and modification to keep pace with advancements in technologies, procedures, methods, and protocols affecting the laboratory or health care. CLSI s consensus process depends on experts who volunteer to serve as contributing authors and/or as participants in the reviewing and commenting process. At the end of each comment period, the committee that developed the document is obligated to review all comments, respond in writing to all substantive comments, and revise the draft document as appropriate. Comments on published CLSI documents are equally essential, and may be submitted by anyone, at any time, on any document. All comments are addressed according to the consensus process by a committee of experts. Appeals Process If it is believed that an objection has not been adequately addressed, the process for appeals is documented in the CLSI Administrative Procedures. All comments and responses submitted on draft and published documents are retained on file at CLSI and are available upon request. Get Involved Volunteer! Do you use CLSI documents in your workplace? Do you see room for improvement? Would you like to get involved in the revision process? Or maybe you see a need to develop a new document for an emerging technology? CLSI wants to hear from you. We are always looking for volunteers. By donating your time and talents to improve the standards that affect your own work, you will play an active role in improving public health across the globe. For further information on committee participation or to submit comments, contact CLSI. Clinical and Laboratory Standards Institute 950 West Valley Road, Suite 2500 Wayne, PA USA P: F: standard@clsi.org

3 ISBN Vol. 29 No. 24 Formerly I/LA31-A ISSN Vol. 29 No. 24 Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns; Approved Guideline Volume 29 Number 24 Julie Miller, BS Judith Tuerck, MS, BS, RN Khalid Awad, MD Donald H. Chace, PhD, MSFS Sara Copeland, MD Abstract Sonja A. Rasmussen, MD, MS Leanne Rien, RN, BS Christina J. Valentine, MD, MS, RD Dianne R. Webster, PhD, FHGSA Bridget Wilcken, MBChB, FRACP, FRCPA Clinical and Laboratory Standards Institute document Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns; Approved Guideline addresses newborn screening of preterm, low birth weight (LBW), and sick newborns worldwide to detect treatable conditions before physical damage can occur to the infant. In developed countries, advances in the treatment they receive have improved survival rates, making the early detection of conditions detected by newborn screening even more important. The physiological states associated with preterm, LBW, and sick newborns, and the treatments they receive, directly affect the reliability of results for many conditions screened in public health dried blood spot and newborn hearing screening systems. This guideline describes the effects of maternal and infant conditions, as well as treatments given to newborns. It also provides the rationale for the recommended intervals for screening designed to minimize the risk of missing or delaying a diagnosis in an affected newborn. It is intended for use by those involved in any aspect of newborn screening specimen collection or hearing screening testing and follow-up, including health care providers, parents, public health professionals, and others concerned with the health and welfare of newborns. Clinical and Laboratory Standards Institute (CLSI). Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns; Approved Guideline. CLSI document (ISBN ). Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania USA, The Clinical and Laboratory Standards Institute consensus process, which is the mechanism for moving a document through two or more levels of review by the health care community, is an ongoing process. Users should expect revised editions of any given document. Because rapid changes in technology may affect the procedures, methods, and protocols in a standard or guideline, users should replace outdated editions with the current editions of CLSI documents. Current editions are listed in the CLSI catalog and posted on our website at If your organization is not a member and would like to become one, and to request a copy of the catalog, contact us at: Telephone: ; Fax: ; customerservice@clsi.org; Website:

4 Number 24 Copyright 2009 Clinical and Laboratory Standards Institute. Except as stated below, any reproduction of content from a CLSI copyrighted standard, guideline, companion product, or other material requires express written consent from CLSI. All rights reserved. Interested parties may send permission requests to permissions@clsi.org. CLSI hereby grants permission to each individual member or purchaser to make a single reproduction of this publication for use in its laboratory procedure manual at a single site. To request permission to use this publication in any other manner, permissions@clsi.org. Suggested Citation CLSI. Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns; Approved Guideline. CLSI document. Wayne, PA: Clinical and Laboratory Standards Institute; Proposed Guideline December 2008 Approved Guideline October 2009 ISBN ISSN ii

5 Volume 29 Contents Abstract... i Committee Membership... iii Foreword... vii 1 Scope Introduction Standard Precautions Terminology A Note on Terminology Definitions Abbreviations and Acronyms General Considerations Maternal Conditions and Treatment and Their Effects on Newborn Screening Results Thyroid Dysfunction Steroids Maternal and Infant Conditions Detectable by Tandem Mass Spectrometry Effects of Preterm Birth and Special Care Baby Unit Interventions on Newborn Screening Routine Special Care Baby Unit Interventions Disorders on Screening Panels Cystic Fibrosis Congenital Hypothyroidism Urea Cycle Defects, Organic Acidemias, and Aminoacidopathies Fatty Acid Oxidation Defects Enzymopathies: Galactosemia and Biotinidase Deficiency Sickle Cell Disease and Hemoglobinopathies Difficulties With Current Special Care Baby Unit Protocols for Newborn Screening Pretreatment Screening General Recommendations for Blood Spot Screening of Preterm, Low Birth Weight, and Sick Infants Blood Spot Screening Primary Recommendation On Admission to the Special Care Baby Unit for Blood Spot Testing Day of Life 48 to 72 Hours Day of Life Alternative Recommendation for Blood Spot Collection Timing Admission to the Special Care Baby Unit After 24 to 48 Hours of Life or Pretransfusion, Preparenteral Nutrition Recommendations for Special Care Baby Unit Infants Not Screened as Recommended Special Considerations for Timing of Blood Specimen Collection (in the Event of Deviation From Established Protocols) v

6 Number 24 Contents (Continued) 12 Hearing Screening for Special Care Baby Unit Infants Risk Factors for Hearing Loss in the Special Care Baby Unit Special Circumstances Related to the Special Care Baby Unit Roles of the Newborn Screening Follow-up Evaluation and Quality Assurance Research Opportunities and Education References Appendix A. Summary of Factors in Preterm/Sick Infants Affecting Reliability of Newborn Screening Results Appendix B. Summary of Conditions Included on Screening Panels Summary of Delegate Comments and Subcommittee Responses The Quality Management System Approach Related CLSI Reference Materials vi

7 Volume 29 Foreword There are approximately 127 million births per year worldwide. 1 In the United States, in million infants were born, and 8.2% of those infants were low birth weight, 12.7% were preterm (< 37 weeks gestation), and 3% were born with birth defects. 2 In developed and developing countries, these infants are usually cared for in specially equipped wards or units such as special care baby units (SCBUs) sometimes referred to as neonatal intensive care units (NICUs). For the purpose of this document, SCBU is used to represent these levels of nursery care. Preterm birth is defined as a gestational age of less than 37 completed weeks and low birth weight (LBW) as less than 2500 g. In some countries, approximately 25% of infants are less than this weight and may or may not be considered candidates in need of the specialized care. Tremendous advances in the care of preterm infants have resulted in improved survivability for increasingly smaller and more preterm infants. Today in developed countries, infants of 28 weeks gestation or older have a > 96% chance of survival, with the lower limits of viability at about 22 weeks, with only 2% of these infants surviving. 2 Newborn screening (NBS) systems and laboratory technology have evolved as well, with the addition of isoelectric focusing and high-performance liquid chromatography for hemoglobinopathies, enzyme assays for biotinidase deficiency and galactosemia, DNA analysis for cystic fibrosis and hemoglobinopathy screening, and tandem mass spectrometry (MS/MS) for metabolic disorders and other multiplex screening tests. It is now possible to screen for a large number of conditions. As of 2008, more than 50 conditions are included in blood spot screening panels in some NBS programs. 3 In addition, most infants are now screened for hearing loss before discharge from the birth facility. Including hearing screening, the collective incidence of disorders for which NBS is available is 1:250 infants compared with 1:3000 only 10 years ago. 4 New tests for additional conditions are under development, undergoing pilot testing, or both in many parts of the world. With the pace of technologic and therapeutic advances, it is certain that more conditions will be added to NBS panels in the future. As more conditions are added, it becomes increasingly difficult to advise practitioners about the ideal time to collect an NBS specimen. Each condition has its own best screening window when there is the greatest chance of diagnosing and treating the disorder in question before symptoms or permanent damage occurs. Some conditions, such as maple syrup urine disease (MSUD), galactosemia, and congenital adrenal hyperplasia, have very short screening windows, with abnormal analytes present in the first day or so of life, illness beginning by the end of the first week, and death in the second week if not diagnosed. Therefore, the best time to collect specimens for those disorders that necessitate early treatment is in the first 24 to 48 hours, and specimens collected after four days may be too late to prevent death or damage. Other conditions, such as homocystinuria, are difficult to detect on a specimen collected in the first 24 to 48 hours of life because the analyte currently used in many programs, methionine, rises very slowly in affected infants and may not be elevated for several days to a week. Likewise, in some infants with congenital hypothyroidism, the decline in thyroid hormone (thyroxine T4) and rise in thyroid-stimulating hormone (thyrotropin TSH), analytes commonly used to detect the condition, may not occur for several days (or longer) if the infant has a large ectopic gland producing sufficient T4 to suppress TSH production at birth. Because maturation of the hypothalamic-pituitary axis at birth is insufficient to produce TSH in very low birth weight (VLBW) infants, these infants with hypothyroidism often have low or normal TSH levels at birth and may not be identified on a screening specimen collected at less than one week of age. 5 Specimen collection timing varies around the world; in Europe and Australia-Asia, most specimens are collected at 48 to 72 hours of age; in the United States, before 48 hours of age; and in Great Britain, infants are not screened until the fifth to eighth day of life. 6 No published data on age at collection were found for the Latin American or Middle East/South African regions. Unfortunately, SCBU infants are at greater risk for missed or incomplete NBS than normal newborns owing to the focus on the critical activities surrounding their care, their pre- and postnatal environments, vii

8 Number 24 the treatments given to them, and the unique genetic and biochemical nature of the infants themselves. These factors can negatively affect both the quality and validity of the screening results for many of the disorders included in NBS panels. As a result, SCBU infants are much more likely to have false-positive or false-negative results after NBS and thus, they account for a disproportionate follow-up effort, compared with normal newborns. Preterm, LBW, or sick term infants often have multiple NBSs and diagnostic specimens collected in an attempt to clarify the significance of an out-of-range result. At the other extreme, collection of NBS specimens can be overlooked in the complexity of activities that occur in the SCBU. These factors increase the chance that a newborn requiring SCBU care will not have a condition detectable by NBS identified in a timely manner, with potentially catastrophic results. 7-9 Although a few case reports have documented the presence of this problem, studies assessing its magnitude have not been performed. During the development of this guideline, experts in neonatology, NBS, endocrinology, metabolism, hematology, hearing loss, genetics, and cystic fibrosis worked collectively to outline factors that interfere with the reliability of NBS, review the significance and duration of the interference, and provide recommendations for NBS specimen collection, including information on timing and number of specimens. This guideline is in agreement with existing consensus guidelines, including those from CLSI (see CLSI documents I/LA27 10 and LA04 11 ) and various neonatology organizations This guideline provides reference for NBS programs and SCBUs to develop and provide screening, testing and followup protocols. The goal is to complete NBS for every SCBU infant in the shortest period of time, with the highest degree of reliability and using the fewest number of specimens. It is hoped that individual NBS programs will adopt this guideline to standardize procedures for intensive care practitioners, and most important, to improve the quality of NBS and follow-up for all infants in their jurisdictions. Key Words Best practices, congenital anomalies, low birth weight, newborn hearing screening, newborn screening, preterm birth, sick infants, special care baby unit viii

9 Volume 29 Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns; Approved Guideline 1 Scope This guideline addresses best practices for SCBU personnel, as well as primary health care providers, laboratory, and follow-up personnel to provide all preterm, LBW, and sick infants with valid newborn blood spot and hearing screening. Best practices are defined with consideration of the conditions screened for and timing of screening events. Special circumstances include the condition of the infant, treatments given, maternal conditions/therapies, and other factors. This document does not intend to dictate SCBU care practices. Goals of this guideline are to 1) Ensure rapid, consistent, and complete blood spot and hearing screening, including appropriate follow-up to ensure early diagnosis and treatment for preterm, LBW, or sick newborns affected with a screened condition. 2) Minimize the risk of a missed or delayed diagnosis and treatment for all screened conditions. 3) Optimize the timing and minimize the number of blood spot specimen collections and hearing screening events. 4) Define essential elements of quality assurance relevant to this guideline. 5) Provide education on the effects of SCBU treatments on newborn blood spot and hearing screening. 6) Identify areas needing further research. 2 Introduction This guideline is a part of a series produced by CLSI over the last several years that includes related CLSI documents LA04 11 and I/LA These documents provide more detail regarding the structure and function of specific elements of NBS systems, and this information is not duplicated here, except for a discussion of proposed reporting and follow-up algorithms. This document focuses on treatments and practices within the SCBU and neonatal conditions that are either known or suspected to interfere with valid NBS, the consequences of the interference, and recommendations for avoiding or counteracting these problems. Care and treatment of preterm, LBW, and sick infants and improvements to NBS programs have made great advancements, but little is known as to the impact of one on the other. The effects of preterm birth and its associated treatment are partially understood for certain disorders on NBS panels, for example, endocrine disorders, hemoglobinopathies, enzymopathies such as galactosemia, and cystic fibrosis (CF). However, very little is known about most metabolic disorders. Simple questions such as how long parenteral nutrition (PN) affects results on amino acid tests are unknown at this time, and this document reflects areas where no data exist. Further research is urgently needed. Because no test has been proven to produce results consistently with 100% sensitivity and specificity, including those used in NBS, practitioners should be reminded to remain vigilant for signs and symptoms associated with screened conditions, even in the presence of normal NBS results. Clinical and Laboratory Standards Institute. All rights reserved. 1

10 Number 24 Beyond individual case reports, the number of affected SCBU infants missed because of incomplete or no screening is unknown. Any missed case, however, represents a failure of the system and a double tragedy for the infant and family, who have already endured the rigors of survival for preterm birth, LBW, or other neonatal illness and now must face lifelong damage to their child usually as a result of a simple mistake or omission. The complexity and number of factors in SCBU infants and the associated treatments that can affect NBS assays are challenging; and an even larger number of factors are not currently understood. This underscores a need for more consultation between neonatologists and NBS professionals. With the addition of more conditions to NBS panels and continuous advances and new treatments in SCBUs, the problem will only grow with time. It is advisable to have formal working relationships between NBS programs and neonatologists on the local level, and for neonatologists to be involved at the national and international level in advising on NBS policy issues. All NBS and SCBU staff urgently need to be educated about all the known factors, to implement SCBU standard protocols within screening jurisdictions, and to encourage research collaboration. This guideline does not attempt to address data systems in SCBUs that might facilitate implementation of this document. However, the document does recognize that more than one SCBU may be located in different cities, which could greatly enhance the complexity of implementation of laboratory information system (LIS) codes and procedures that should be uniform for all babies. Those professionals who work in NBS programs and SCBU units are well aware of the frequency of flagged results among these infants. Even with adjusted cutoffs, many if not most LBW infants have some abnormality on NBS that must be resolved. This results in more screening specimens, confirmatory testing, or both being ordered; the vast majority eventually provided false-positive results. Unfortunately, sensitivity and specificity of non DNA-based assays are inversely related, making it impossible to calibrate NBS assays to find no false-positive results, because this would greatly increase the probability of a false-negative finding, defeating the goal of NBS to find the maximum number of affected infants. As a result, approximately 2% to 10% of all NBS specimens are flagged as abnormal or the specimen itself is rejected for collection and handling problems. Of all abnormal NBS specimens, 10% to 40% belong to infants in SCBUs. With no standard protocol for screening or follow-up in this population, neonatologists and other nursery staff must cope with different recommendations that vary from program to program. Uniform recommendations crossing jurisdictional boundaries would perhaps increase adherence to them. This guideline represents a starting point for developing harmonious consensus with NBS programs and SCBUs worldwide, but consensus requires NBS programs to adopt and evaluate the guidelines and to recommend adjustments as necessary. It is very important to ensure that guidelines improve screening for SCBU infants and prevent infants from being missed. 3 Standard Precautions Because it is often impossible to know what isolates or specimens might be infectious, all patient and laboratory specimens are treated as infectious and handled according to standard precautions. Standard precautions are guidelines that combine the major features of universal precautions and body substance isolation practices. Standard precautions cover the transmission of all infectious agents and thus are more comprehensive than universal precautions, which are intended to apply only to transmission of blood-borne pathogens. Standard and universal precaution guidelines are available from the US Centers for Disease Control and Prevention. 15 For specific precautions for preventing the laboratory transmission of all infectious agents from laboratory instruments and materials and for recommendations for the management of exposure to all infectious diseases, refer to CLSI document M Clinical and Laboratory Standards Institute. All rights reserved.

11 Number 24 The Quality Management System Approach Clinical and Laboratory Standards Institute (CLSI) subscribes to a quality management system approach in the development of standards and guidelines, which facilitates project management; defines a document structure via a template; and provides a process to identify needed documents. The approach is based on the model presented in the most current edition of CLSI/NCCLS document HS01 A Quality Management System Model for Health Care. The quality management system approach applies a core set of quality system essentials (QSEs), basic to any organization, to all operations in any health care service s path of workflow (ie, operational aspects that define how a particular product or service is provided). The QSEs provide the framework for delivery of any type of product or service, serving as a manager s guide. The QSEs are Documents and Records Equipment Information Management Process Improvement Organization Purchasing and Inventory Occurrence Management Customer Service Personnel Process Control Assessment External and Internal Facilities and Safety addresses the QSEs indicated by an X. For a description of the other documents listed in the grid, please refer to the Related CLSI Reference Materials section on the following page. Documents and Records Organization Personnel Equipment Purchasing and Inventory Process Control X I/LA27 LA04 M29 Information Management Occurrence Management Assessment External and Internal Adapted from CLSI/NCCLS document HS01 A Quality Management System Model for Health Care. Path of Workflow A path of workflow is the description of the necessary steps to deliver the particular product or service that the organization or entity provides. For example, CLSI/NCCLS document GP26 Application of a Quality Management System Model for Laboratory Services defines a clinical laboratory path of workflow, which consists of three sequential processes: preexamination, examination, and postexamination. All clinical laboratories follow these processes to deliver the laboratory s services, namely quality laboratory information. addresses the clinical laboratory path of workflow steps indicated by an X. For a description of the other documents listed in the grid, please refer to the Related CLSI Reference Materials section on the following page. Examination ordering Process Improvement Customer Service Preexamination Examination Postexamination Sample collection Facilities and Safety Sample transport Sample receipt/processing Examination Results review and follow-up Interpretation Results reporting and archiving LA04 LA04 LA04 LA04 LA04 LA04 Adapted from CLSI/NCCLS document HS01 A Quality Management System Model for Health Care. Sample management M29 68 Clinical and Laboratory Standards Institute. All rights reserved.

12 Volume 29 Related CLSI Reference Materials I/LA27-A LA04-A5 Newborn Screening Follow-up; Approved Guideline (2006). This guideline describes the basic principles, scope, and range of follow-up activities within the newborn screening system. Blood Collection on Filter Paper for Newborn Screening Programs; Approved Standard Fifth Edition (2007). This document addresses the issues associated with specimen collection, the filter paper collection device, and the application of blood to filter paper, and provides uniform techniques for collecting the best possible specimen for use in newborn screening programs. M29-A3 Protection of Laboratory Workers From Occupationally Acquired Infections; Approved Guideline Third Edition (2005). Based on US regulations, this document provides guidance on the risk of transmission of infectious agents by aerosols, droplets, blood, and body substances in a laboratory setting; specific precautions for preventing the laboratory transmission of microbial infection from laboratory instruments and materials; and recommendations for the management of exposure to infectious agents. CLSI documents are continually reviewed and revised through the CLSI consensus process; therefore, readers should refer to editions. the most current Clinical and Laboratory Standards Institute. All rights reserved. 69

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