Introduction to the Newborn Screening Fact Sheets

Newborn screening fact sheets were last revised in 1996 by the Committee on Genetics of the American Academy of Pediatrics (AAP). Publication of these revised newborn screening fact sheets was prompted by advances in the field, including technologic innovations, as well as greater appreciation of ethical issues such as those surrounding informed consent.

Every infant born in the United States is screened shortly after birth using heel-stick blood spots to detect a variety of congenital conditions. Many infants are also screened for congenital hearing loss. Newborn screening programs have been developed and managed within states, the District of Columbia, Puerto Rico, the US Virgin Islands, and Guam (Table 1). As public health programs, they require a coordinated system of follow-up, diagnosis, and treatment. Periodic program evaluation is also necessary. Thus, newborn screening is not simply a test to identify whether a metabolite is found in unusually high or low concentration in a particular blood spot. Newborn screening is also more than a state-run program that ensures that each abnormal screening result is linked to a particular infant who subsequently receives a diagnostic test and, if indicated, referral for appropriate treatment. Newborn screening is a 5-part system¹  in which the pediatrician plays a vital role.

Along with the obstetrician, the pediatrician is involved in the education of parents regarding the availability of newborn screening tests, the benefits of early detection of disorders for which screening is performed, the risks that exist for newborn infants who do not receive screening, the process of screening and follow-up, and government requirements that may exist.²  The pediatrician is also involved in obtaining informed consent in states where this is applicable. Although the timing of specimen collection is straightforward in term, healthy newborn infants, the pediatrician should be aware of factors that may influence the results of a particular screening test, including gestational and postnatal age, early discharge, diet, transfusions, and total parenteral nutrition (Table 2). Results must be documented for all patients in a timely fashion, which may be a challenge in geographic regions with large numbers of neonates, understaffed nurseries and physician offices, and poor technologic support.

Proper follow-up of a “not-normal” screening result is crucial if mortality, morbidity, and disabilities are to be avoided. The primary function of the follow-up program is to locate infants with abnormal screening results and facilitate timely diagnostic testing and management. The time frame for follow-up will vary by disorder and by the degree of abnormality of the screening result. Maple syrup urine disease, congenital adrenal hyperplasia, and galactosemia are 3 disorders that can be fatal rapidly unless treatment is instituted very quickly. The pediatrician may be the provider of first contact for screen-positive infants; hence, he or she must be familiar with initial management, including referral management and subsequent diagnostic testing of such infants. The pediatrician also must be prepared to explain to the family the meaning of a positive screening result, the possibility of a false-positive test result, and the steps that must be taken next.

Many of the disorders identified by newborn screening programs are heterogeneous. This variability requires specialized laboratory testing, interpretation, and treatment. The pediatrician works with specialized laboratories and providers in obtaining appropriate specimens, initiating treatment, diagnosis when appropriate, and coordinating care once the diagnosis is confirmed.

Infants affected with disorders detected by newborn screening usually require lifelong management. Every child should have a medical home to coordinate care; that care should be accessible, family centered, continuous, comprehensive, coordinated, compassionate, and culturally competent.³  The pediatrician plays a central role in the development of the medical home, which includes experts who understand the etiology, pathophysiology, clinical heterogeneity, and psychosocial issues associated with the disorder. Genetic counseling, including discussion of carrier testing of family members and prenatal diagnosis of future pregnancies, may be indicated.

The newborn screening system can function optimally only when its components are coordinated, which means that there must be regular and timely communication between nurseries, screening laboratories, state health departments, pediatricians, and subspecialists. To ensure that this is happening, the effectiveness of each component of the system must be assessed continuously through the collection and analysis of data, including outcomes data. Although an adequate evaluation program has not been developed for most newborn screening systems, the pediatrician will be central to the implementation of such a program, particularly through the provision of outcomes data.

Several factors have contributed to the need for review of the newborn screening system, including enhanced public interest in newborn screening as a universal genetic screening program; the introduction of new technologies such as tandem mass spectrometry (MS/MS) and DNA-based tests; and changing demographics, which emphasize the importance of human variation and cultural competence. In response to this need, the AAP, with support from the Health Resources and Services Administration and the National Institutes of Health, convened a task force to review the role and operation of newborn screening as a public health system.⁴  The Newborn Screening Task Force outlined a national agenda to strengthen state newborn screening systems through the development of model regulations for disease and test selection; minimum standards for sample collection and other activities; model guidelines for follow-up, diagnosis, and treatment; strategies to inform families and the public more effectively; and demonstration projects to evaluate technology, quality assurance, and health outcomes. The task force report emphasized the need for a sixth component of the 5-part newborn screening system: education of professionals and the public.

With the introduction of DNA-based testing as a component of newborn screening panels, consumers, health care professionals, and policy makers have become increasingly aware of issues of informed consent for both the performance of the screening tests and retention and use of residual test samples. Although all states require newborn screening, most newborn screening laws or regulations provide exemptions in some situations.⁵  Expert panels have not reached consensus, but in general, they have recognized the benefit of informed consent before testing as a tool for educating parents.⁶  When the validity and utility of the test have been established, experts have usually concluded that informed consent for newborn screening could be waived.⁷  The Newborn Screening Task Force emphasized the need for education and concluded that, “Before newborn screening, parents (on behalf of their children) have a right to be informed about screening, and have the right to refuse screening. They also have a right to confidentiality and privacy protection for information contained in all newborn screening results.”⁴  The consent process in each state is governed by state law.

Among the benefits, newborn screening may:

• detect a serious, treatable disorder before symptoms are present;

• lead to treatment that can prevent serious problems including mental retardation and death; or

• detect carriers of certain genetic disorders.

Among the risks, newborn screening may:

• fail to identify some children who actually have the condition;require repeat testing;

• cause parental anxiety after false-positive results;

• reveal (through genetic tests) misattributed paternity; or

• detect disorders for which treatment is not effective.

There is agreement that policy guidelines for residual sample retention and use are needed, but to date, there has been no consensus on the content of such guidelines.

Population screening for phenylketonuria (PKU) began in the 1960s using a relatively simple analytic method. New disorders were added as methods to use blood spots were developed and were applicable to large populations at low cost. By the 1990s, scientific advances and technologic innovations led to the possibility of adding numerous new metabolic disorders to the screening panel using MS/MS (Table 3). Consumers throughout the nation acted quickly through their state legislatures to mandate the addition of medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency and other disorders of fatty acid oxidation (FAO) to the list of disorders for which newborn screening is mandated. Several states now require screening for MCAD deficiency and other disorders of FAO⁸  (Table 4), and a cost/benefit analysis of MS/MS has been published.⁹  MS/MS technology can also be used to screen for PKU and some other amino acid disorders and has a rate of false-positive results that is lower than other screening methods. Therefore, states that adopt MS/MS technology to screen for FAO disorders may also revise their panels of amino acid disorders for which they screen (Table 5). In addition, certain screening methods for particular disorders permit the diagnosis of other conditions that were not originally designated on the list of disorders for newborn screening. These have been called “secondary-target conditions” (Table 6). Pediatricians, who are central to the newborn screening system as discussed earlier, will need to be familiar with these new disorders as they are added to screening panels or are diagnosed because the technology for newborn screening identifies them (secondary-target conditions).

Analysis of DNA for mutations is not a primary screening method for any of the disorders for which newborn screening is performed today. However, secondary DNA analysis may be used in conjunction with other tests to decrease the rate of false-positive results. It may also be used as a diagnostic test for certain disorders.

Because the initial test in the newborn screening process is a screening test, there is a significant risk of false-positive (abnormal test, normal infant) and false-negative (normal test, affected infant) results. False-positive results lead to additional testing and parental anxiety, and long-term consequences such as the vulnerable-child syndrome may occur. False-negative results may lead to a delay in diagnosis, because the health care professional may be falsely reassured by a normal newborn screening result. These possibilities raise clinical and ethical issues, which should be discussed with parents before testing.

There is a lack of uniformity between states regarding the diseases screened and the technology used. Such lack of uniformity results in the place of birth determining the likelihood of early diagnosis of these serious but treatable conditions. Newborn screening rules and statutes require that a newborn infant be screened using the panel in the state in which he or she was born, not necessarily the state in which the mother is a resident. There is also controversy regarding whether newborn screening should incorporate conditions for which highly effective interventions that reduce morbidity for the child are unavailable. Numerous state and national organizations have convened groups to discuss these issues and propose policies, but no national consensus has been developed.¹⁰  Finally, it must be emphasized that “normal” results of newborn screenings do not rule out the presence of these disorders, because some variants of these conditions may have onset later in life, and false-negative results may occur. The clinical judgment of the pediatrician remains the most important tool in the diagnosis of all of these conditions.

The following newborn screening fact sheets are available at www.pediatrics.org/cgi/content/full/118/3/e934:

• Biotinidase deficiency

• Congenital adrenal hyperplasia

• Congenital hearing loss

• Congenital hypothyroidism

• Cystic fibrosis

• Galactosemia

• Homocystinuria

• Maple syrup urine disease (branched-chain ketoaciduria)

• MCAD deficiency

• PKU

• Sickle cell disease and other hemoglobinopathies

• Tyrosinemia

G. Bradley Schaefer, MD, Chairperson

Marilyn J. Bull, MD

Gregory M. Enns, MD

Jeffrey R. Gruen, MD

Joseph H. Hersh, MD

Nancy J. Mendelsohn, MD

Howard M. Saal, MD

James D. Goldberg, MD

American College of Obstetricians and Gynecologists

James W. Hanson, MD

American College of Medical Genetics

National Institute of Child Health and Human Development

Michele A. Lloyd-Puryear, MD, PhD

Health Resources and Services Administration

Sonja A. Rasmussen, MD, MS

Centers for Disease Control and Prevention

Paul Spire

Celia I. Kaye, MD, PhD, Chairperson

Past Member, AAP Committee on Genetics

Frank Accurso, MD

Past Member, AAP Section on Pulmonology

Stephen La Franchi, MD

AAP Section on Endocrinology

Peter A. Lane, MD

AAP Section on Hematology/Oncology

Hope Northrup, MD

AAP Section on Genetics and Birth Defects

Sonya Pang, MD

Past Member, AAP Section on Endocrinology

G. Bradley Schaefer, MD

AAP Committee on Genetics

Michele A. Lloyd-Puryear, MD, PhD

Health Resources and Services Administration

Michael Watson, MD

American College of Medical Genetics