INTRODUCTION — The goal of newborn screening is to detect disorders that are threatening to life or long-term health before they become symptomatic. These conditions include inborn errors of metabolism, endocrine disorders, hemoglobinopathies, immunodeficiency, cystic fibrosis, and critical congenital heart defects. Early treatment of these rare disorders may significantly reduce mortality and morbidity in affected patients.
The principles of newborn screening, screening policies, testing, and follow-up are reviewed here. Specific disorders and screening for hearing loss and critical congenital heart defects are discussed separately. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Newborn screening' and "Screening the newborn for hearing loss" and "Newborn screening for critical congenital heart disease using pulse oximetry".)
TECHNOLOGY — Tandem mass spectrometry (also referred to as MS-MS) and other techniques have expanded the possibilities for mass screening of multiple disorders [1-4]. Tandem mass spectrometry detects molecules by measuring their weight and is a series of two mass spectrometers, which sort samples and identify and weigh the molecules of interest. It is best used when screening for inborn errors of organic acid, fatty acid, and amino acid metabolism. The availability and cost-effectiveness of tandem mass spectrometry has allowed expansion of newborn screening and currently is the method used to detect most of the conditions included in newborn screening.
PRINCIPLES AND CRITERIA OF SCREENING — Newborn screening tests are administered to all newborns to detect infants who have a serious but potentially treatable problem. Rather than providing definitive results, they identify which newborns require further testing [5,6]. (See "Screening tests in children and adolescents", section on 'Overview'.)
Mass screening for a specific disease ideally should meet the following requirements :
●The disorder should be serious, so that lack of treatment would result in significant morbidity or death.
●Effective treatment should be readily accessible.
●Treatment in the presymptomatic or early symptomatic period should lead to better outcomes compared with usual clinical care.
●A reliable screening test with a low false-negative rate must be available.
●The screening test must be able to be adapted for high output for the general neonatal population, and the cost of the test must be acceptable relative to the potential benefit.
●The results of the test must be available and communicated to the responsible clinician and birth hospital on a timely basis so that intervention can be provided. (See 'Communication of results' below.)
●A definitive follow-up test should be readily available so that true positives can be identified and false-positives eliminated.
●Following diagnosis, monitoring and treatment should be readily available.
PROGRAMS THROUGHOUT THE WORLD — Newborn screening is incorporated into the healthcare system in all developed countries. Several resources are available regarding newborn screening programs worldwide :
●Asia Pacific region 
IMPLEMENTATION OF SCREENING
United States implementation — This topic will focus on newborn screening policy and process in the United States to illustrate how screening is implemented. (See 'Programs throughout the world' above.)
State and regional policy — In the United States, all 50 states, the District of Columbia, Puerto Rico, the United States Virgin Islands, and Guam provide universal screening for the approximately four million infants born each year [10,11]. Newborn screening is operated at the state level and integrates screening policy, follow-up, diagnosis, treatment of identified disease, and tracking of outcomes [10,12-17]. For most conditions included in newborn screening, sample collection and laboratory testing are also centralized at the state level. However, newborn screening for congenital hearing loss and critical congenital heart defects are conducted at the birth center prior to discharge home.
Information regarding each state's newborn screening program and detailed descriptions of the selected conditions are available at the Baby's First Test website, a resource for information and education for healthcare providers and families about newborn screening.
To minimize variability across states, the United States Secretary of Health and Human Services has established the Recommended Uniform Screening Panel (RUSP), which is a list of conditions that all newborn screening programs should include. These recommendations are informed by the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children. The committee also welcomes nomination of additional conditions to be included in RUSP at the Advisory Committee's nomination webpage.
Some conditions included in this panel are:
●Primary congenital hypothyroidism (see "Clinical features and detection of congenital hypothyroidism", section on 'Newborn screening')
●Congenital adrenal hyperplasia (see "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Newborn screening')
●Hemoglobinopathies including sickle cell disease and sickle C disease (see "Diagnosis of sickle cell disorders", section on 'Newborn screening')
●Critical congenital heart disease (see "Newborn screening for critical congenital heart disease using pulse oximetry")
●Cystic fibrosis (see "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Newborn screening')
●Classical galactosemia (see "Galactosemia: Clinical features and diagnosis", section on 'Newborn screening')
●Hearing loss (see "Screening the newborn for hearing loss")
●Severe combined immunodeficiencies (see "Newborn screening for primary immunodeficiencies")
●Phenylketonuria (PKU) (see "Overview of phenylketonuria")
●Maple syrup urine disease (see "Overview of maple syrup urine disease")
●Pompe disease (see "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)", section on 'Newborn screening')
●Mucopolysaccharidosis type 1 (see "Mucopolysaccharidoses: Clinical features and diagnosis", section on 'Prenatal diagnosis and newborn screening')
●Spinal muscular atrophy (see "Spinal muscular atrophy")
●X-linked adrenoleukodystrophy (see "X-linked adrenoleukodystrophy and adrenomyeloneuropathy", section on 'Newborn screening')
American Academy guidelines — In 2008, the American Academy of Pediatrics (AAP) released a clinical report that provided guidance to primary care pediatricians and other healthcare professionals on how to most effectively provide screening for newborn infants, which included the following recommendations :
●Preparing the practice – In each practice setting, proactive steps are recommended to ensure that the clinician can successfully communicate the results of the newborn screening tests to the family/caregivers and provide appropriate follow-up in a timely fashion. These include having clinicians familiarize themselves with their state screening program, collecting state-specific contact information for regional medical subspecialists, and setting up a process to confirm that all newborns have been screened and that screening results have been received.
●Collaboration among healthcare professionals – The report also outlines the roles of other healthcare professionals that are necessary to the successful operation of a newborn screening system and provision of optimal care to infants and their families/caregivers.
•Prenatal healthcare clinicians (eg, obstetricians) should educate expectant parents on the importance of newborn screening and identifying the medical home for their newborn infant.
•Birthing facilities are responsible for obtaining, processing, and delivering a high-quality specimen to the designated screening laboratory. Identification of the medical home should be established as a condition for discharge. Discharge documents should clearly indicate whether or not screening was performed. They should identify the name of the clinician responsible for the birth hospitalization and the name of the PCP providing clinical care after discharge, who are contacts for any abnormal result.
•Pediatric medical subspecialists provide coordinated care with the primary care clinician when a child is diagnosed with a specific disorder . Genetic counseling, testing of other family members, and family/caregiver support services should be facilitated [16,18,19]. Subspecialists should also provide guidance to the states in the development of screening programs, including educational material.
•Children with PKU, congenital hypothyroidism, congenital adrenal hyperplasia, and other conditions identified by newborn screening programs may have behavioral changes resulting from these disorders, although intellectual disability, learning difficulties, and some behavior problems are reduced by early intervention . Thus, long-term follow-up, including neuropsychological testing, should be provided.
•The role of the state is to design, coordinate, and manage an effective newborn screening system. However, the effectiveness of state newborn screening programs in the follow-up of infants varies . Clinicians need to be aware of the level of services provided by the screening program in their area of practice.
Clinical laboratory quality assurance — In the United States, laboratories that perform biochemical genetic testing and public health newborn screening are required to meet the general quality systems and personnel requirements for testing of the 1988 Clinical Laboratory Improvement Amendments (CLIA) regulations. As the number of tests and their complexity increases, it has become increasingly challenging to meet the CLIA requirements. As a result, guidelines have been published to help laboratories meet the CLIA requirements by a collaboration among the Centers for Disease Control and Prevention (CDC), Centers for Medicare and Medicaid Services (CMS), United States Food and Drug Administration (FDA), Health Resources and Service Administration (HRSA), and the National Institutes of Health (NIH) . These guidelines are intended to improve the quality of laboratory services and address the following:
●Benefits of a quality management system approach
●Factors to consider before introducing a new test
●Establishment and verification of test performance specifications
●Total laboratory testing process that consists of preanalytic, analytic, and postanalytic phase
●Confidentiality of patient information and test results
●Personnel qualification, responsibilities, and competency
The CDC Newborn Screening Quality Assurance Program provides help to state health departments and their laboratories to maintain and enhance the quality of test results.
NEONATAL SCREENING PROCEDURE
When to obtain testing
Normal nursery — For healthy newborns delivered in birthing centers and cared for in the normal nursery, the blood spot specimen should be obtained during birth hospitalization as close to hospital discharge as possible. This timing permits the maximum accumulation of abnormal compounds in the infant's blood and the best chance of obtaining a positive result if disease is present. Blood samples are obtained by puncture of the newborn's warmed heel. The blood is collected on filter paper provided for this purpose, completely filling the designated circles. Samples are sent to a central laboratory for analysis. Appropriate documentation is completed, including the patient's name, birth date and time, date and time of the specimen, and contact information for the clinician who will provide follow-up. (See 'Follow-up' below and 'Clinical laboratory quality assurance' above.)
As noted above, newborn screening for hearing loss and critical congenital heart disorder are performed at birth centers prior to discharge. (See "Screening the newborn for hearing loss" and "Newborn screening for critical congenital heart disease using pulse oximetry".)
Neonatal intensive care unit — Newborn screening programs have individualized recommendations regarding screening (eg, timing and number of studies) of premature or sick neonates cared for in neonatal intensive care units (NICUs). Delayed screening for these infants places them at high risk for developing identifiable conditions that may be amenable to treatment. However, this must be balanced with the increased risk of false-positive findings in premature and ill infants, particularly for screening that includes testing of amino acid and acylcarnitine profiles . In one report, the false-positive rate for amino acids was higher in preterm infants who were receiving parenteral nutrition (PN) . Although the authors of the study suggest that holding PN for three hours before obtaining the blood sample for newborn screening would reduce the rate of false-positive tests, this may not be practical in the NICU setting.
Out-of-hospital births — It is critical to make sure that all newborns have been screened. If it cannot be confirmed that a baby born out of the hospital was screened, then offer screening at the first clinic visit. Primary care clinics should contact their state newborn screening program to determine how best to obtain and send specimen to the appropriate laboratory.
Repeat screening — Some newborn screening programs require repeat dried-blood spot screening for all newborns when they are two weeks old. This additional screen can help avoid initial false-negative screens related to the limited nutritional intake in the first days after birth or other normal physiologic changes .
●Positive or equivocal screening – The rapid follow-up of an infant with a positive or equivocal screening test is of the highest priority . Positive results from newborn screening should have a confirmatory test performed as quickly as possible. The pediatrician or primary care provider (PCP) is responsible for ensuring that newborn screening has been completed and that all positive screening results are followed until a diagnosis is confirmed or excluded .
The primary care provider should also provide education and support to families/caregivers with infants with a false-positive result as parents/caregivers may continue to have some anxiety, and the impact can be decreased with careful explanation of the process. The risk of a false-positive result is higher in preterm infants with gestational age <32 weeks screened for hypothyroidism and adrenal hyperplasia before 48 hours of life .
●Negative screening – The primary care provider also must remain vigilant to the development of disease, as a negative result does not rule out a disorder even if screening is performed appropriately (false-negative test). False-negative results are more likely in infants born prematurely, in those who received blood transfusions or dialysis therapy, or in those who were tested too early (less than 24 hours of age).
Communication of results
State and local public health agencies — The mechanism of communicating test results, including the role of state and local public health agencies, varies widely [13,27-31]. In some states, the testing laboratory is assigned the responsibility of communicating test results to the health professional and birth hospital. In other states, the role of locating infants and communicating test results is assigned to local health department staff.
Most state programs require that a healthcare professional be notified of results. However, this may be the clinician of record at the infant's birth hospital and not the pediatrician who will provide long-term care. In cases of positive screening results that require urgent follow-up (eg, highly abnormal screening test for a metabolic disorder), newborn screening programs will actively seek parents/caregivers to inform them in order to expedite diagnosis and treatment.
Primary care clinician's role — The primary care provider (eg, pediatrician) should be aware of the system in his or her state to ensure the appropriate and timely transfer of information and notification of parents/caregivers. Ideally, parents/caregivers should be informed when the results of screening are normal, but this is a much less time sensitive issue and therefore less of a challenge.
In many cases, the primary care clinician may not be prepared to provide the initial counseling and subspecialty referral for these infants and their families/caregivers. This was illustrated in a survey of general pediatricians and family clinicians in the United States that demonstrated many responding clinicians did not feel competent to discuss the results of a positive newborn screen . Continued efforts are required to ensure that primary care clinicians are adequately trained and supported to deliver appropriate follow-up care of these infants and their families/caregivers . Communication of the identification of the carrier state (eg, sickle cell trait) is challenging because it does not usually have health consequences for the newborn, but is important for future reproductive planning for the newborn's parents or for the child as an adult. (See "Sickle cell trait", section on 'Screening'.)
The following section provides resources for health providers and families/caregivers about newborn screening including information about specific diseases.
●Baby's First Test is a website that provides information and education for healthcare providers and families/caregivers about newborn screening. Information is available regarding each state's newborn screening program, as are detailed descriptions of the conditions included in newborn screening. This resource also provides support for families/caregivers of children with a condition identified through newborn screening.
●The National Coordinating Center for the Regional Genetic and Newborn Screening Service Collaboratives (NCCRCG) provides links to newborn screening ACTion sheets (ACT Sheets), which provide information on the next steps of care for an infant with a positive newborn screen. The NCCRCG also provides links to seven regional newborn screening service collaboratives, which work with the states to improve the delivery of newborn screening and follow-up care.
SCREENING OUTCOME — Of the four million infants who are screened each year in the United States, approximately 12,500 are diagnosed with one of the 29 core conditions of the uniform screening panel adopted by the United States Department of Health and Human Services, resulting in a detection rate of 1:4000 live births . The five most commonly diagnosed conditions were:
●Hearing loss. (See "Screening the newborn for hearing loss".)
●Primary congenital hypothyroidism. (See "Clinical features and detection of congenital hypothyroidism", section on 'Newborn screening'.)
●Cystic fibrosis. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Newborn screening'.)
●Sickle cell disease. (See "Diagnosis of sickle cell disorders", section on 'Newborn screening'.)
●Medium-chain acyl-CoA dehydrogenase deficiency.
Early identification through newborn screening allows for earlier intervention, which reduces significant morbidity and mortality . Nevertheless, it remains challenging to provide adequate follow-up with confirmation of diagnosis and long-term care for affected individuals with a specific chronic condition [34,36].
ONGOING CHALLENGES AND CONTROVERSIES — There are many areas of challenge and debate in newborn screening, including:
●Use of the residual dried blood spot specimen – Researchers can use anonymized dried blood spots to develop new screening tests. However, some families/caregivers are concerned about the risk to privacy. The rules regarding the use of anonymized dried blood spots for research and the length of time that newborn screening programs save residual dried blood spots vary by state.
●Identification of late-onset disease – Some newborn screening tests that detect significant illness in childhood will also identify individuals who might not develop illness until adulthood. Assessing the benefit versus harm of early identification of late-onset disease is challenging.
●Identification of conditions for which treatment has not been established – Identifying newborns with serious conditions in the presymptomatic period may be important to develop new treatments. Some families/caregivers might want to know early about serious health conditions in their children, even in the absence of therapy. This can help avoid unnecessary diagnostic evaluation, and allow families/caregivers to make plans for the affected child and make informed reproductive decisions.
●Identification of carriers – Newborn screening can identify carriers for many of the targeted conditions. There is uncertainty and debate about how best and when to inform families and these children about their carrier status to inform future reproductive decisions .
●Cascade testing of family members – After diagnosis through newborn screening of certain conditions (eg, X-linked adrenoleukodystrophy), it is reasonable to test first-degree family members to see whether they are carriers or affected by the condition. A number of ethical and psychosocial issues apply to genetic testing, including the consequences for the family, issues related to testing children who are unaffected, and concerns about genetic discrimination. Clinicians must consider the benefits and risks of genetic testing, including the possibility of false-positive and false-negative results. (See "Genetic testing".)
●Provision of long-term care – Early identification of most of the conditions included in newborn screening allows modification of the condition from being associated with significant morbidity and mortality in infancy to a long-term chronic illness. Developing systems to assure that these individuals have access to chronic disease management, including medications or nonpharmacologic therapy (eg, specific diet), is challenging . The Newborn Screening Translational Research Network has developed the Longitudinal Pediatric Resource, a tool to register conditions identified by newborn screening.
●Resource allocation – Public health agencies have limited resources, and assuring comprehensive newborn screening is costly. Often the cost of the screening test is coalesced into the cost of operating the newborn screening program and does not include resources to assure appropriate follow-up care. Policy makers therefore need to consider all costs related to the adoption of newborn screening for each condition.
FUTURE DIRECTIONS — Newborn screening is expanding globally, including testing targeted to local high-risk conditions. Rapid improvements in scientific knowledge and technique continue to increase the number of disorders that can be detected. The ability to analyze residual dried blood spots from the newborn screening programs may be useful for future epidemiologic studies . In addition, prenatal screening may decrease the need for some newborn screening tests . It will be important for local, national, and international policy makers to keep pace with these changes and to address the ethical, legal, and financial challenges involved.
SUMMARY AND RECOMMENDATIONS
●Clinical importance – The goal of newborn screening is to detect disorders that are threatening to life or long-term health before they become symptomatic. Newborn screening tests are administered to general populations to identify infants who may have a serious condition and require further testing for diagnostic confirmation. These conditions include inborn errors of metabolism, endocrine disorders, hemoglobinopathies, severe combined immunodeficiency, congenital hearing loss, and critical congenital heart defects. (See 'Introduction' above and 'Principles and criteria of screening' above.)
●Criteria for screening – An effective newborn screening program selects conditions based on the severity of untreated disease; the availability of a reliable, timely, cost-effective screening test; and the accessibility of effective treatment, which improves patient outcome. Because of differences in how these decisions are made, there is variation among newborn screening programs worldwide. (See 'Principles and criteria of screening' above.)
●United States implementation – In the United States, each state has its own newborn screening program. In order to minimize variability among states, the United States Department of Health and Human Services has established a Recommended Uniform Screening Panel (RUSP). A list of disorders screened in each state is available from the Baby's First Test website, a resource for information and education for healthcare providers and families/caregivers about newborn screening. Similar information is available for other countries. (See 'United States implementation' above and 'Programs throughout the world' above.)
●Timing of testing – Testing typically occurs during the birth hospitalization. Blood samples are collected on filter paper from puncture of the newborn's warmed heel, which are sent to a central laboratory for analysis. Testing at individual birth centers includes screening for congenital hearing loss and critical congenital heart defects. (See 'When to obtain testing' above.)
●Follow-up of test results – (See 'Follow-up' above.)
•Positive results from newborn screening should have a confirmatory test performed as quickly as possible. The pediatrician or primary care provider (PCP) is responsible for ensuring that newborn screening has been completed and that all positive screening results are followed until a diagnosis is confirmed or excluded. In addition, the primary care provider needs to provide guidance counseling and support to families/caregivers with infants with a false-positive result as well as remain vigilant for development of disease despite a negative screening test (false-negative).
•Negative results do not rule out a disorder even if screening is performed appropriately (false-negative test). False-negative results are more likely in infants born prematurely, in those who received blood transfusions or dialysis therapy, or in those who were tested too early (less than 24 hours of age). The PCP must remain vigilant to the development of disease during follow-up.
●Outcome of screening programs – In the United States, newborn screening detects one of 29 core conditions in 12,500 of the four million infants born each year, which results in a detection rate of 1:4000 live births. (See 'Screening outcome' above.)
●Challenges – Although newborn screening is incorporated into the healthcare system in many countries and in all high-resource countries, there remain ongoing challenges and controversies such as resource allocation, identification of conditions that are late-onset or have no established treatment, and identification of carriers. (See 'Ongoing challenges and controversies' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lori Sielski, MD, who contributed to an earlier version of this topic review.
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