Newborn screening

Newborn screening is a public health program of screening in infants shortly after birth for conditions that are treatable, but not clinically evident in the newborn period. The goal is to identify infants at risk for these conditions early enough to confirm the diagnosis and provide intervention that will alter the clinical course of the disease and prevent or ameliorate the clinical manifestations. NBS started with the discovery that the amino acid disorder phenylketonuria could be treated by dietary adjustment, and that early intervention was required for the best outcome. Infants with PKU appear normal at birth, but are unable to metabolize the essential amino acid phenylalanine, resulting in irreversible intellectual disability. In the 1960s, Robert Guthrie developed a simple method using a bacterial inhibition assay that could detect high levels of phenylalanine in blood shortly after a baby was born. Guthrie also pioneered the collection of blood on filter paper which could be easily transported, recognizing the need for a simple system if the screening was going to be done on a large scale. Newborn screening around the world is still done using similar filter paper. NBS was first introduced as a public health program in the United States in the early 1960s, and has expanded to countries around the world.
Screening programs are often run by state or national governing bodies with the goal of screening all infants born in the jurisdiction for a defined panel of treatable disorders. The number of diseases screened for is set by each jurisdiction, and can vary greatly. Most NBS tests are done by measuring metabolites or enzyme activity in whole blood samples collected on filter paper. Bedside tests for hearing loss using automated auditory brainstem response and congenital heart defects using pulse oximetry are included in some NBS programs. Infants who screen positive undergo further testing to determine if they are truly affected with a disease or if the test result was a false positive. Follow-up testing is typically coordinated between geneticists and the infant's pediatrician or primary care physician.

History

is given much of the credit for pioneering the earliest screening for phenylketonuria in the late 1960s using a bacterial inhibition assay to measure phenylalanine levels in blood samples obtained by pricking a newborn baby's heel on the second day of life on filter paper. Congenital hypothyroidism was the second disease widely added in the 1970s. Guthrie and colleagues also developed bacterial inhibition assays for the detection of maple syrup urine disease and classic galactosemia. The development of tandem mass spectrometry screening in the early 1990s led to a large expansion of potentially detectable congenital metabolic diseases that can be identified by characteristic patterns of amino acids and acylcarnitines. In many regions, Guthrie's BIA has been replaced by MS/MS profiles, however the filter paper he developed is still used worldwide, and has allowed for the screening of millions of infants around the world each year.
In the United States, the American College of Medical Genetics recommended a uniform panel of diseases that all infants born in every state should be screened for. They also developed an evidence-based review process for the addition of conditions in the future. The implementation of this panel across the United States meant all babies born would be screened for the same number of conditions. This recommendation is not binding for individual states, and some states may screen for disorders that are not included on this list of recommended disorders. Prior to this, babies born in different states had received different levels of screening. On April 24, 2008, President George W. Bush signed into law the Newborn Screening Saves Lives Act of 2007. This act was enacted to increase awareness among parents, health professionals, and the public on testing newborns to identify certain disorders. It also sought to improve, expand, and enhance current newborn screening programs at the state level.

Inclusion of disorders

Newborn screening programs initially used screening criteria based largely on criteria established by JMG Wilson and F. Jungner in 1968. Although not specifically about newborn population screening programs, their publication, Principles and practice of screening for disease proposed ten criteria that screening programs should meet before being used as a public health measure. Newborn screening programs are administered in each jurisdiction, with additions and removals from the panel typically reviewed by a panel of experts. The four criteria from the publication that were relied upon when making decisions for early newborn screening programs were:

having an acceptable treatment protocol in place that changes the outcome for patients diagnosed early with the disease
an understanding of the condition's natural history
an understanding about who will be treated as a patient
a screening test that is reliable for both affected and unaffected patients and is acceptable to the public

As diagnostic techniques have progressed, debates have arisen as to how screening programs should adapt. Tandem mass spectrometry has greatly expanded the potential number of diseases that can be detected, even without satisfying all of the other criteria used for making screening decisions. Duchenne muscular dystrophy is a disease that has been added to screening programs in several jurisdictions around the world, despite the lack of evidence as to whether early detection improves the clinical outcome for a patient.

Targeted disorders

Newborn screening is intended as a public health program to identify infants with treatable conditions before they present clinically, or suffer irreversible damage. Phenylketonuria was the first disorder targeted for newborn screening, being implemented in a small number of hospitals and quickly expanding across the United States and the rest of the world. After the success of newborn screening for PKU, Guthrie and others looked for other disorders that could be identified and treated in infants, eventually developing bacterial inhibition assays to identify classic galactosemia and maple syrup urine disease.
Newborn screening has expanded since the introduction of PKU testing in the 1960s, but can vary greatly between countries. In 2011, the United States screened for 54 conditions, Germany for 12, the United Kingdom for 2, while France and Hong Kong only screened for one condition. The conditions included in newborn screening programs around the world vary greatly, based on the legal requirements for screening programs, prevalence of certain diseases within a population, political pressure, and the availability of resources for both testing and follow-up of identified patients.

Congenital Disorders of Amino Acid Metabolism

Newborn screening originated with an amino acid disorder, phenylketonuria, which can be easily treated by dietary modifications, but causes severe Intellectual disability if not identified and treated early. Robert Guthrie introduced the newborn screening test for PKU in the early 1960s. With the knowledge that PKU could be detected before symptoms were evident, and treatment initiated, screening was quickly adopted around the world. Ireland was the first country in the world to introduce a nationwide screening programme in February 1966, Austria started screening the same year and England in 1968.
Other congenital disorders of amino acid metabolism tested for on the newborn screening include Tyrosinemia and Maple Syrup Urine Disorder.

Fatty acid oxidation disorders

With the advent of tandem mass spectrometry as a screening tool, several fatty acid oxidation disorders were targeted for inclusion in newborn screening programs. Medium chain acyl-CoA dehydrogenase deficiency, which had been implicated in several cases of sudden infant death syndrome was one of the first conditions targeted for inclusion. MCADD was the first condition added when the United Kingdom expanded their screening program from PKU only. Population based studies in Germany, the United States and Australia put the combined incidence of fatty acid oxidation disorders at 1:9300 among Caucasians. The United States screens for all known fatty acid oxidation disorders, either as primary or secondary targets, while other countries screen for a subset of these.
The introduction of screening for fatty acid oxidation disorders has been shown to have reduced morbidity and mortality associated with the conditions, particularly MCADD. An Australian study found a 74% reduction in episodes of severe metabolic decompensation or death among individuals identified by newborn screening as having MCADD versus those who presented clinically prior to screening. Studies in the Netherlands and United Kingdom found improvements in outcome at a reduced cost when infants were identified before presenting clinically.
Newborn screening programs have also expanded the information base available about some rare conditions. Prior to its inclusion in newborn screening, short-chain acyl-CoA dehydrogenase deficiency was thought to be life-threatening. Most patients identified via newborn screening as having this enzyme deficiency were asymptomatic, to the extent that SCADD was removed from screening panels in a number of regions. Without the cohort of patients identified by newborn screening, this clinical phenotype would likely not have been identified.

Endocrinopathies

The most commonly included disorders of the endocrine system are congenital hypothyroidism and congenital adrenal hyperplasia. Testing for both disorders can be done using blood samples collected on the standard newborn screening card. Screening for CH is done by measuring thyroxin, thyrotropin or a combination of both analytes. Elevated 17α-hydroxyprogesterone is the primary marker used when screening for CAH, most commonly done using enzyme-linked immunosorbant assays, with many programs using a second tier tandem mass spectrometry test to reduce the number of false positive results. Careful analysis of screening results for CAH may also identify cases of congenital adrenal hypoplasia, which presents with extremely low levels of 17α-OHP. When the immunoassay method is utilized as a screening method for quantifying 17α-OHP in dried blood spots, it exhibits a significant rate of false positive results. As per the clinical practice guideline issued by the Endocrine Society in 2018, employing LC-MS/MS to measure 17α-OHP and other adrenal steroid hormones is recommended as a supplementary screening approach to enhance the accuracy of positive predictions.
CH was added to many newborn screening programs in the 1970s, often as the second condition included after PKU. The most common cause of CH is dysgenesis of the thyroid gland After many years of newborn screening, the incidence of CH worldwide had been estimated at 1:3600 births, with no obvious increases in specific ethnic groups. Recent data from certain regions have shown an increase, with New York reporting an incidence of 1:1700. Reasons for the apparent increase in incidence have been studied, but no explanation has been found.
Classic CAH, the disorder targeted by newborn screening programs, is caused by a deficiency of the enzyme steroid 21-hydroxylase and comes in two forms – simple virilizing and a salt-wasting form. The incidence of CAH can vary greatly between populations. The highest reported incidence rates are among the Yupic Eskimos of Alaska and on the French island of Réunion.