Newborn Screening and Genetic Testing Michele A. Lloyd-Puryear, MD, PhD, FAAP, Irene Forsman, RN, MS

Transcription

1 CLINICAL ISSUES Newborn Screening and Genetic Testing Michele A. Lloyd-Puryear, MD, PhD, FAAP, Irene Forsman, RN, MS Mandated newborn screening programs for genetic and other congenital conditions for the some 4 million infants born in the United States each year have seen dramatic changes over the past decade. With the mapping of the human genome and other advances in science and technology, there will be continued challenges to and changes in these programs. Nurses who care for infants and their families should be knowledgeable about those changes to correctly transmit information to families and to participate in determining policy for newborn screening practices. JOGNN, 31, ; Keywords: Genetic testing Hearing screening Newborn screening Tandem mass spectrometry Accepted: July 2001 For more than 35 years, there has been universal screening for genetic and other congenital conditions of infants born in the United States (National Research Council, Committee for the Study of Inborn Errors of Metabolism, 1975; Newborn Screening Task Force, 2000; Paul, 1997; President s Committee for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1983). Because of such screening, conditions can be diagnosed and treated in the newborn period before the onset of clinical symptoms. Early identification of many congenital conditions may be particularly crucial when early and timely intervention can lead to a significant reduction in morbidity, mortality, and associated disabilities in affected infants (Forsberg, 1997). With the mapping of the human genome and other advances in science and technology, there will be challenges to and changes in newborn screening programs. This article summarizes the current status of newborn screening programs and examines issues that are of concern to some and exciting to others. Most immediate are the challenges that new technologies bring. With new hearing screening technologies came the advent of hearing screening programs. The integration of these programs with ongoing screening and early intervention programs remains a challenge. With tandem mass spectrometry (MS-MS), and soon with the ability to examine DNA in the newborn specimen, comes the possibility of expanding newborn genetic screening programs. The use of MS-MS and mutation analysis enables the detection of many additional conditions, some for which there may be no effective clinical therapy or intervention for newborns. Overview Screening is generally considered part of the routine care for newborns. Newborn screening programs have been described as consisting of the following: (a) initial screening, (b) retrieval for follow-up testing of infants who have screened positive, (c) diagnosis confirmation for true positives, (d) short- and long-term care and management, (e) education, and (f) program evaluation (Newborn Screening Task Force, 2000). Although the initial screening test is performed within the birthing facility, newborn genetic screening programs are population based and organized within state public health agencies (National Research Council, Committee for the Study of Inborn Errors of Metabolism, 1975; Newborn Screening Task Force, 2000; Paul, 1997; President s Committee for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1983). Newborn hearing screening programs began in the last decade as hospital-based programs, but in the past few years have become increasingly state based. 200 JOGNN Volume 31, Number 2

2 Nurses who provide care to families before and after birth should be prepared to discuss the benefits and risks of screening newborns for the conditions that are routinely screened for in their states. The following cases illustrate different families encounters with these statebased newborn screening programs. Case 1 Presentation A girl age 4.5 years was brought to the emergency department because of complaints of a headache, fever, and decreased activity. On physical examination, the child looked ill and was lethargic and febrile. The results of the laboratory evaluation showed target and sickle red blood cells. Further evaluation with hemoglobin electrophoresis indicated sickle cell disease, a new diagnosis. When questioned about family history, the parents said they knew of no one with sickle cell anemia on either side of the family, but both parents acknowledged stories of American Indian blood in the family. Further investigation by the hospital staff indicated that the child was born in a state that screens for sickle cell disease but performs only targeted screening. Therefore, because the child appeared to be White, she was not screened for sickle cell disease. Case 2 Presentation A male infant was born at term after an uncomplicated pregnancy and delivery. He was discharged at 48 hours of age with reports of adequate breastfeeding and normalcolored stools. Four months after discharge, the parents sought care for the infant in the hospital emergency department, reporting that he was vomiting, was lethargic, and seemed to be having seizures. He was diagnosed with otitis media and placed on antibiotic therapy. He was doing well, although the mother noted that his appetite had decreased significantly. Several blood chemistry abnormalities were noted, and after further laboratory evaluation, a diagnosis of medium-chain acyl-coa dehydrogenase deficiency (MCADD) was made. The family history included sudden infant death syndrome in a child previously born to the couple. Case 3 Presentation A female was born at term after an uneventful pregnancy and delivery. This was the mother s first pregnancy, and the newborn was discharged to home at 36 hours old. When the newborn was 4 days old, the parents brought her to their pediatrician s office, and her physical examination was normal. Upon investigation of records from the hospital, the newborn screening result was noted to be positive for phenylketonuria (PKU). The infant was referred to the state metabolic clinic, where a diagnosis of PKU was made. Nutrition therapy was initiated, and the family enrolled in the metabolic clinic. Because the father s health insurance did not cover metabolic foods or formula, the family enrolled in the state s metabolic foods program. Case 4 Presentation A male newborn was discharged to home at 2 days of age. The hospital had just started its own screening program for newborn hearing. Routine screening tests conducted before discharge included a two-stage hearing screening examination. This newborn did not pass the two-stage screening. The primary care provider was notified immediately, and a referral for more sophisticated audiologic testing was initiated. The family was informed that their newborn son appeared to have a hearing problem that required follow-up. Educational materials about newborn hearing screening were provided to the family. The family did not appear for the scheduled audiologic examination, however, and failed to respond to repeated letters and phone calls from the hospital urging them to complete the testing. Organization of Screening Programs History State-based newborn screening began in 1962 when Robert Guthrie and Robert MacCready organized the first universal screening program for PKU in Massachusetts (Guthrie & Susi, 1963; MacCready, 1963). By the late 1960s, the practice of routine screening of newborns for PKU had spread to almost every state. Within one to two decades, all states had begun universal screening (National Research Council, Committee for the Study of Inborn Errors of Metabolism, 1975; Newborn Screening Task Force, 2000; Paul, 1997; President s Committee for Newborn screening can enable timely intervention for affected infants and a significant reduction of morbidity, mortality, and disabilities. the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1983) for additional conditions such as sickle-cell disease, hypothyroidism, and galactosemia. In 1998, a task force convened by the American Academy of Pediatrics undertook a thorough review of newborn screening programs (Newborn Screening Task Force, 2000). A Test Is Never Just a Test Newborn screening programs are organized as systems to provide a coordinated approach to screening, followup, diagnosis, treatment and management, parental edu- March/April 2002 JOGNN 201

3 TABLE 1 Newborn Genetic and Hearing Screening in the United States Maple Congenital Medium-Chain Syrup Urine Homo- Biotinidase Sickle-Cell Adrenal Acyl-CoA Dehydrogenase Hearing State a Disease cystinuria Deficiency Disease Hyperplasia Deficiency Loss b Alabama X X Alaska X X * X * Arizona X X X X X Arkansas X X California X * X Colorado X X X X Connecticut X X X X X X Delaware X District of Columbia X X X Florida X X Georgia X X X X X Hawaii X X X X * X Idaho X X Illinois X X X X Indiana X X X X X X Iowa * X X X Kansas X X Kentucky X Louisiana X X X Maine X X X X X X Maryland X X X X X Massachusetts X X X X X X X Michigan X X X X Minnesota * * X X * Mississippi X X X Missouri X X Montana * * * * Nebraska X X Nevada X X X New Hampshire X X * * New Jersey X X New Mexico X X X New York X X X X * * X North Carolina X X X North Dakota X Ohio X X X X Oklahoma X Oregon X X X * X Pennsylvania X X X * Rhode Island X X X X X X South Carolina X X X South Dakota * * * * Tennessee X X Texas X X X Utah X X Vermont X X X X Virginia X X X X X Washington X X West Virginia * X Wisconsin * * X X X X Wyoming X X X a All states routinely screen for phenylketonuria and congenital hypothyroidism. All states, except for Washington, screen for galactosemia. b Newborn hearing screening programs mandated by state legislatures. *Screening only on selected populations, pilot programs, optional, or planning under way. 202 JOGNN Volume 31, Number 2

4 cation, and program evaluation (Forsberg, 1997; Newborn Screening Task Force, 2000; Therrell, Panny, & Davidson, 1992). The primary public health objective of each state s newborn screening system is to ensure that every newborn receives appropriate services in a timely manner (Holtzman, 1991; Wilson & Jungner, 1968). Integral to this assurance are the assessment of the prevalence of conditions, the establishment of programs that universally screen all infants, the assurance of the quality and availability of testing, and the provision of follow-up services for all infants identified (Newborn Screening Task Force, 2000). The following is a brief description of some of the programmatic components of newborn screening with which nurses are most often involved and that nurses are responsible for: obtaining informed consent and educating families, performing the test, and coordinating follow-up services. What Screening Tests Are in Use? In the United States, all states and the District of Columbia screen every infant for phenylketonuria and congenital hypothyroidism. Except for these two conditions, states vary considerably in their screening for other conditions (see Table 1). Almost all states screen for galactosemia, and more than 40 states screen for sicklecell disease. Some newborn screening programs include congenital adrenal hyperplasia, homocystinuria, maple syrup urine disease, biotinidase deficiency, and tyrosinemia (see Table 1) (National Newborn Screening and Genetic Resource Center, 2001; Newborn Screening Task Force, 2000). A few states also screen for cystic fibrosis and other conditions, including congenital infections such as human immunodeficiency virus and toxoplasmosis. More than 32 states now require newborns to be screened for hearing loss (National Center for Hearing Assessment and Management, 2001; Newborn Screening Task Force, 2000), and this number is increasing rapidly. How Is Testing Done? Newborn hearing screening is accomplished through the use of a variety of computerized equipment that uses automated auditory brainstem response, distortion product otoacoustic emissions, or transient-evoked otoacoustic emissions and is performed before the newborn is discharged from the nursery (National Center for Hearing Assessment and Management, 2001). Screening for congenital hearing loss is a simple process and in some cases may be performed by specially trained volunteers under the supervision of nurses or other hospital staff. The procedure for screening for genetic conditions has been standardized and begins with a heel stick taken after birth and prior to discharge. The area of the foot lateral to the heel is lanced and blood drops are collected either directly onto a filter paper or through use of a capillary tube and transferred to filter paper. The blood spot on the filter paper is dried in air and then delivered to the testing laboratory (American Academy of Pediatrics Committee on Genetics, 1992). An adequate specimen should be obtained in the nursery; for a normal, healthy newborn the specimen should be obtained as close to discharge as possible. It is generally recommended that the initial specimen be taken as close as possible to 48 hours after birth and when the infant is more than 24 hours of age (American Academy of Pediatrics Committee on Genetics, 1992). Premature infants, infants being treated for illness, or those born outside a hospital should have newborn screening tests before the 7th day of life and prior to any blood transfusion. All states and the District of Columbia screen every infant for phenylketonuria and congenital hypothyroidism, but states vary considerably in the other conditions for which they screen. After the Screening Test It is essential that a screening program ensure careful follow-up of both positive and negative screening tests and continuity of care for individuals with positive screens. This is especially true for newborn screening because significant mortality and morbidity are associated with the conditions for which newborns are screened. The program must have protocols that delineate who is responsible for follow-up and what that follow-up should be. In hearing screening programs, children who are identified early and receive intensive early intervention perform better on school-related measures (reading, arithmetic, vocabulary, articulation, percentage of the child s communication understood by nonfamily members, social adjustment, and behavior) than children who do not receive such intervention (Yoshinaga-Itano, Sedey, Coulter, & Mehl, 1998). In areas where universal newborn hearing screening occurs, appropriate and timely diagnosis and intervention continue to be major challenges. Attrition rates as high as 60% are not unusual between initial referral and diagnostic confirmation. Linkages between hospitalbased screening programs and early intervention programs may not be well established, and data management and tracking of infants through the screening and diagnostic process may be in the developmental stage (Blake & Hall, 1990). As the state programs assume more responsibility for the tracking and follow-up of infants at risk for hearing loss, these linkages will be more firmly established. March/April 2002 JOGNN 203

5 With newborn blood sample screening, the follow-up systems also vary widely (Forsberg, 1997; Great Lakes Regional Genetics Group, 1996; Newborn Screening Task Force, 2000). In some states, the laboratory has the primary responsibility to follow up with the birthing facility or a designated health care professional. In other cases, the local health department locates the family or designated health care professional to communicate the results of the screening test. In turn, this entity is responsible for the communication of the results to the family. Other follow-up activities include collecting blood specimens for further diagnosis of infants identified with positive screening, providing nutritional education to help families establish and maintain dietary control for their children, and providing social services and other needed support to families of affected children. State agencies attempting to coordinate infant programs face a variety of challenges (Newborn Screening Task Force, 2000). Screening programs may operate with varying time frames, priorities, demands, and constraints imposed by categorical funding sources and may be administered by different agencies within state governments. Information systems that support these programs may be insufficient, redundant, or independent of one another. As a result, services may not be well integrated or coordinated, leading to the inefficient use of resources. Frustration can occur when families are asked to provide the same information on multiple forms. The Newborn Screening Task Force (2000) recommended that interagency coordination be structured to improve the efficiency and effectiveness of newborn screening systems. Informing and Educating Families An important component of the newborn screening program should be a sound educational effort to inform families and health care providers about the newborn screening efforts in their states. The success of these programs depends on the understanding of newborn screening by the public and health care providers. Medical and nursing care providers share the responsibility for such education. Educating and informing parents about and receiving permission for newborn screening are not simple processes. Generally, the nursing staff is responsible for obtaining informed consent in states that require it for screening. Education is needed to help parents not only understand the system but also deal with any anxiety associated with equivocal results, repeated tests, and false-positive results. Ideally, parent education and informed consent should include shared decision making, but most state newborn screening laws only make accommodations for parents who refuse testing. The argument or premise that predominates is that screening and potential detection are in the interest of the child, and parents objections should not hinder that screening process. Many also argue that it is too time consuming or costly to talk to parents and ask permission. The Newborn Screening Task Force (2000) recommended that a greater emphasis be placed on parental education. This approach, they argued, might improve parents understanding and increase their adherence to recommendations for further testing and follow-up. The task force also emphasized that education and shared decision making were important because of the possible addition of new DNA-based tests and other screening for conditions for which treatment is unavailable or the efficacy of the treatment intervention is unknown. The task force noted that ethical, legal, and social pressure to obtain documented permission for newborn screening may increase. Case Discussion In Case 1, the child was diagnosed with sickle-cell disease; this diagnosis had been missed at birth. A group of hematologic disorders characterized by the predominance of sickle hemoglobin is referred to as sickle-cell disease. Screening for sickle-cell disease began in the 1970s; it is one of the most common genetic diseases in the United States. Because the highest mortality occurs in the first 2 years of life, affected infants must be identified early and have access to appropriate care, which should include parent education and penicillin therapy for the infant (American Academy of Pediatrics Committee on Genetics, 1992; Gaston et al., 1986). Although recommended by a National Institutes of Health (1987) consensus conference, universal screening for sickle cell disease has not been established in every state (Newborn Screening Task Force, 2000). Rather, misperceptions about race, the benefits of screening, and the prevalence of disease among various ethnic groups have contributed to delay in universal screening (Newborn Screening Task Force, 2000). This case illustrates how those misperceptions may play out. Although sickle-cell disease affects 1 in every 375 African American live births, it is not limited to African Americans. In genetic science, superficial differences that have had profound social implications, such as categorization by race, are not meaningful. Sickle-cell disease is also seen in those of Asian, Middle-Eastern, and Mediterranean descent. Differences in appearance among people and groups of people are incidental. Rather, differences in the genetic makeup from person to person reflect the cumulative effects of human history, migrations, ancient tribal groupings, and marriages. Genetic variation is a record of that history. When screening remains targeted on the basis of race, affected infants may not be identified. It is therefore impossible to assign any genetic disorder solely to a specific ethnic group. In Case 2, the infant was eventually diagnosed with MCADD, which is one of five known acyl-coa dehydro- 204 JOGNN Volume 31, Number 2

6 genases. Medium-chain acyl-coa dehydrogenase deficiency typically presents in the 2nd year of life as hypoketotic hypoglycemia associated with fasting; it may progress to liver failure, coma, and death. Medium-chain acyl-coa dehydrogenase deficiency can cause a crisis when an infant fasts, such as during an illness. Such an episode can sometimes lead to seizures, failure to breathe, cardiac arrest, and death. The main focus of treatment is to prevent a metabolic crisis from happening by preventing long fasts from occurring. Currently, very few states screen for this disorder (see Table 1). The ability to screen for MCADD is dependent on the availability of MS-MS, and few states have acquired this new technology (Chase & Naylor, 1999; Levy, 1998; Levy & Albers, 2000). Criteria to decide whether to include a specific disorder within a state s newborn screening panel should include the availability of treatment for a newborn and the consequences for the newborn if the disorder is not treated (Holtzman, 1991; Newborn Screening Task Force, 2000; Wilson & Jungner, 1968). Many think that MCADD fits those criteria (Levy 1998; Levy & Albers, 2000). Other criteria also include the cost to the program (e.g., for follow-up, treatment, and management) and the prevalence of the disorder (Newborn Screening Task Force 2000; Wilson & Jungner, 1968), although these two considerations may be irrelevant to the affected families. Many state newborn screening programs, state legislators, hospitals, parents, and health care professionals have been targeted by marketers who want to expand state newborn screening programs to include MCADD and other disorders that can be detected through MS-MS. States may be reluctant to incorporate MS-MS because of the costs associated with the acquisition of the new technology and because the ability of MS-MS to screen for more than 25 additional disorders may lead to additional costs. Case 3 pointed to the need for establishment of an allinclusive program that includes follow-up, confirmatory testing, and the availability of treatment and long-term management. The Newborn Screening Task Force (2000) reported that it is essential for a screening program to have a provision for medical foods and formula and that states must ensure adequate financing of all parts of the system. Ultimately, the provisions for treatment and management (including medical foods and formula) should be a part of any medical benefits package. This position is further supported by the National Institutes of Health (2000) consensus conference on PKU. Finally, Case 4 highlighted a new program that many states have begun: newborn screening for congenital hearing loss. In every state, infants with significant hearing loss and their families are eligible for services through the state early intervention program (Part C of the Individuals With Educational Disabilities Act), which may be located in the state health department or in the department of education or social services. They may also be eligible for services provided through the state Maternal and Child Health (Title V) program for children with special health needs. Referral to these programs at hospital discharge helps to minimize loss to follow-up. The Newborn Screening Task Force (2000) suggested that the child health programs would avoid unnecessary duplication of effort if their infrastructures were more closely aligned with each other for oversight, follow-up and tracking, retrieval, and evaluation. There is disagreement about whether newborn screening programs should expand to include disorders detectable by tandem mass spectrometry. For some disorders, the significance to the newborn is unknown or there is no effective treatment. What Is New in Newborn Screening? As has occurred with hearing screening, new science and technology are making it possible to screen for additional conditions. The decision about which tests to include in a newborn screening panel is becoming increasingly complex (Holtzman, 1991, 1997; Levy & Albers, 2000). Although MS-MS is not a new technology, it was recently introduced into newborn screening programs. Research and development in the newborn screening applications of MS-MS were started in the early 1990s and continue today (Chase & Naylor, 1999). One clear advantage of this technology is that in a single analysis of the heel stick blood sample, more than 25 disorders of body chemistry can be detected (Chase & Naylor, 1999). There have been some objections to incorporating MS- MS into screening because its use changes the principles under which many public health screening programs operate (Levy & Albers, 2000; National Research Council, Committee for the Study of Inborn Errors of Metabolism, 1975; Newborn Screening Task Force, 2000; President s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1983; Wilson & Jungner, 1968). Tandem mass spectrometry detects relatively rare disorders that are not prevalent enough for a public health screening program. For some of these disorders, the significance to the newborn is unknown or there is no available treatment. For other disorders, there is no treatment for the newborn that can begin early enough to prevent neurologic damage. Hence, there is still disagreement about whether states should March/April 2002 JOGNN 205

7 expand their newborn screening programs to include MS- MS. Some argue that the low frequency of a specific disorder becomes less important when arguing against the use of MS-MS because the disorders detected by MS-MS have a high combined frequency (Levy, 1998; Levy & Albers, 2000). These arguments do not take into account the cost of the follow-up for individually relatively rare disorders. The use of DNA-based technology will bring many more complex issues to newborn screening programs. As with MS-MS, these can include screening for conditions for which there may be no effective treatment for the newborn. Such screening could include early detection of hypercholesterolemia or of conditions that do not affect the newborn and are considered to be adult onset diseases, such as Alzheimer s disease, Huntington s disease, and breast cancer. Some argue that there is still a potential benefit to the family of early identification even if there is no treatment. Without the use of early screening technology, diagnosis and treatment of genetic disorders may be delayed for years until clinical complications appear (Levy & Albers, 2000). Early screening, detection, and diagnosis could lead to early intervention and the avoidance of unnecessary medical procedures, inaccurate diagnoses, and continued ignorance of the associated morbidity. The use of DNA-based screening or mutation analysis as the primary method of newborn screening is probably not in the immediate future. This is not because of the limitations of technology but rather because of our limited current knowledge base. Although several disorders for which screening is available have a predominant mutation, multiple genotypes may lead to the same phenotype. Testing all newborns for the predominant mutation alone would leave a substantial number of mutations and therefore affected newborns undetected. At this time, the only exception appears to be DNA-based analysis for sickle-cell disease. However, some newborn screening programs already have seen a role for mutation analysis in the second tier of screening, as with screening for cystic fibrosis. The first tier of screening is for immunoreactive trypsinogen. Because the false-positive rate can be high as a result of increased levels of immunoreactive trypsinogen in infants without cystic fibrosis, most programs have adopted a second tier of screening using DNA analysis (Ranieri et al., 1994; Wilcken, 1993; Wilcken, Wiley, Sherry, & Bayliss, 1995). Some screening programs use mutation analysis as secondary screening for MCADD and longchain 3-hydroxyacyl-CoA dehydrogenase deficiency (Levy & Albers, 2000), whereas others recommend its use for galactosemia (Urwin, Christodoulou, Wiley, Murrell, & Wilcken, 1997) and sickle-cell disease (Zhang, McCabe, Wilborn, Therrell, & McCabe, 1994). Summary Newborn screening for genetic and other metabolic and congenital conditions is an area in which there have been dramatic changes in past decades. Advances in science and technology and clinical applications for those advances soon will significantly alter newborn screening practices. Nurses who care for infants and their families should be knowledgeable about those changes so that they can correctly transmit information to families and participate in determining newborn screening policy. REFERENCES American Academy of Pediatrics Committee on Genetics. (1992). Issues in newborn screening. Pediatrics, 89, Blake, P. E., & Hall, J. W. (1990). The status of statewide policies for neonatal hearing screening. Journal of the American Academy of Audiology, 1, Chase, D. H., & Naylor, E. W. (1999). Expansion of newborn screening programs using tandem mass spectrometry. M.R.D.D. Research Review, 5, Forsberg, S. A. (1997). Infant metabolic screening: A total quality management approach. 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8 National Newborn Screening and Genetic Resource Center. Retrieved April 2001 from National Research Council, Committee for the Study of Inborn Errors of Metabolism. (1975). Genetic screening: Programs, principles, and research. Washington, DC: National Academy of Science. Newborn Screening Task Force. (2000). Serving the family from birth to the medical home: A report from the Newborn Screening Task Force. Pediatrics, 106, S383-S427. Paul, D. B. (1997). The history of phenylketonuria screening in the US. In: N.A. Holtzman & M.S. Watson, Eds., Promoting safe and effective genetic testing in the United States: Final report of the Task Force on Genetic Testing. Bethesda, MD: National Institutes of Health. President s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. (1983). Screening and counseling for genetic conditions: A report on the ethical, social and legal implications of genetic screening and counseling, and education programs. Washington, DC: Government Printing Office. Ranieri, E., Lewis, B. D., Gerace, R. L., Ryall, R. G., Morris, C. P., Nelson, P. V., Carey, W. F. & Robertson, E. F. (1994). Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis: Four years experience. British Medical Journal, 308, Therrell, B. L., Panny, S. R., & Davidson, A. (1992). US newborn screening systems guidelines: Statement of the Council of Regional Networks for Genetic Services. Screening, 1, Urwin, R., Christodoulou, J., Wiley, V., Murrell, M., & Wilcken, B. (1997). Evaluation of a second tier newborn screening for galactosemia: Utility of N314D mutation for screening. Paper presented at the 7th International Congress on Inborn Errors of Metabolism, Vienna, Austria. Wilcken, B. (1993). Newborn screening for cystic fibrosis: Its evolution and a review of the current situation. Screening, 2, Wilcken, B., Wiley, V., Sherry, G., & Bayliss, U. (1995). Neonatal screening for cystic fibrosis: A comparison of two strategies for case detection in 1.2 million babies. Journal of Pediatrics, 127, Wilson, J., & Jungner, G. (1968). The principles and practice of screening for disease. Geneva: World Health Organization. Yoshinaga-Itano, C., Sedey, A. L., Coulter, D. K., & Mehl, A. L. (1998). Language of early- and later-identified children with hearing loss. Pediatrics, 102, Zhang, Y. H., McCabe, L. L., Wilborn, M., Therrell, B. L., & McCabe, E. R. (1994). Application of molecular genetics in public health: Improved follow-up in a neonatal hemoglobinopathy screening program. Biochemical Medicine and Metabolic Biology, 52, Michele A. Lloyd-Puryear is chief of the Genetic Services Branch, Division of Services for Children With Special Health Needs, Maternal and Child Health Bureau, Health Resources and Services Administration, U.S. Department of Health and Human Services, Rockville, MD. Irene Forsman is a nurse consultant, Integrated Services Branch, Division of Services for Children With Special Health Needs, Maternal and Child Health Bureau, Health Resources and Services Administration, U.S. Department of Health and Human Services, Rockville, MD. Address for correspondence: Michele A. Lloyd-Puryear, MD, PhD, FAAP, Genetic Services Branch, Division of Services for Children With Special Health Needs, Maternal and Child Health Bureau, Health Resources and Services Administration, U.S. Department of Health and Human Services, 5600 Fishers Lane, Room 18A19, Rockville, MD Mpuryear@ hrsa.gov. March/April 2002 JOGNN 207