Newborn screening

Newborn screening is the process by which infants are screened shortly after birth for a list of disorders that are treatable, but difficult or impossible to detect clinically. Screening programs are often run by state or national governing bodies with the goal of screening all infants born in the jurisdiction. Newborn screening originated when Robert Guthrie developed a method to screen for phenylketonuria, a disorder which could be managed by dietary adjustment if diagnosed early. Whole blood samples are collected from the infant's heel on specially designed filter paper, and then tested for a panel of disorders. The disorders tested can vary from region to region, based on funding and the prevalence of a condition in the population.

Goals

Universal newborn screening (NBS) aims to identify infants that appear healthy at birth, but are afflicted with conditions that can cause severe illness or death.^[1] With early detection, these conditions can be managed to prevent complications.

History

Robert Guthrie is given much of the credit for pioneering the earliest screening for phenylketonuria in the late 1960s using blood samples on filter paper obtained by pricking a newborn baby's heel on the second day of life to get a few drops of blood.^[2] Congenital hypothyroidism was the second disease widely added in the 1970s.^[3] The development of tandem mass spectrometry screening by Edwin Naylor and others in the early 1990s led to a large expansion of potentially detectable congenital metabolic diseases that affect blood levels of organic acids.^[4] In 2006, the American College of Medical Genetics recommended a larger list of diseases be added for newborn screening across the country. The implementation of this panel across the United States meant all babies born would be screened for the same number of conditions. 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.

Disease qualification

Screening criteria used in newborn screening programs are based largely on criteria initially established by JMG Wilson and F. Jungner in 1968.^[5] 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. The four criteria that are relied upon when making decisions for newborn screening programs are^[5]:

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

The HRSA [3] Secretary's Advisory Committee on Heritable Disorders in Newborns and Children is a national focal point for standardizing the newborn screen panel across states. The current list of tests by state can be found at the National Newborn Screening and Genetics Resource Center^[6].

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.^[5][7] 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.^[5]

Techniques

Sample collection

Heel blood on a filter paper card for the newborn screening

Newborn screening tests are most commonly done from whole blood samples collected on specially designed filter paper. The filter paper is often attached to a form containing required information about the infant and parents. This includes date and time of birth, date and time of sample collection, the infant's weight and gestational age. The form will also have information about whether the baby has had a blood transfusion and any additional nutrition the baby may have received (total parenteral nutrition). Most newborn screening cards also include contact information for the infant's physician in cases where follow up screening or treatment is needed.

Ideally, newborn screening samples are collected from the infant between 24 hours and 7 days after birth. Samples can be collected at the hospital, or by midwives. If a sample is collected from an infant who is less than 24 hours old, the laboratory will often request a repeat specimen be taken after 24 hours. Samples are mailed daily to the laboratory responsible for testing. Most jurisdictions require samples to be collected for screening from all newborns, unless the parent or guardian opts out of the process in writing. In addition to the blood test, many regions also test newborns for hearing loss^[8] and congenital heart failure using pulse oximetry.^[9]

Reporting results

The goal is to report the results within a short period of time. If screens are normal, a paper report is sent to the submitting hospital and parents rarely hear about it. If an abnormality is detected, employees of the agency, usually nurses, begin to try to reach the physician, hospital, and/or nursery by telephone. They are persistent until they can arrange an evaluation of the infant by an appropriate specialist physician (depending on the disease). The specialist will attempt to confirm the diagnosis by repeating the tests by a different method or laboratory, or by performing other corroboratory or disproving tests. The confirmatory test varies depending on the positive results on the initial screen. Confirmatory testing will include analyte specific assays to confirm any elevations detected, functional studies to determine enzyme activity, and genetic testing to identify disease-causing mutations. Depending on the likelihood of the diagnosis and the risk of delay, the specialist will initiate treatment and provide information to the family. Performance of the program is reviewed regularly and strenuous efforts are made to maintain a system that catches every infant with these diagnoses. Guidelines for newborn screening and follow up have been published by the American Academy of Pediatrics.^[10]

Targeted disorders

The following list includes most of the disorders detected by the expanded or supplemental newborn screening by mass spectrometry. This expanded screening is not yet universally mandated by most states, but may be privately purchased by parents or hospitals at a cost of approximately US$80. The same can also be purchased from other countries like Germany, Austria, Spain, Japan and India where more than 100 disorders are being tested based on a urine sample of the newborn. Perhaps one in 5,000 infants will be positive for one of the metabolic tests below (excluding the congenital infections).

Core panel

The following conditions and disorders were recommended as "core panel" by the 2005 report of the American College of Medical Genetics (ACMG).^[11] The incidences reported below are from their report, pages 143-307, though the rates may vary in different populations. (WARNING: The file is a very large PDF.)

Blood cell disorders

• Sickle cell anemia (Hb SS) > 1 in 5,000; among African-Americans 1 in 400
• Sickle-cell disease (Hb S/C) > 1 in 25,000
• Hb S/Beta-Thalassemia (Hb S/Th) > 1 in 50,000

Inborn errors of amino acid metabolism

• Tyrosinemia I (TYR I) < 1 in 100,000
• Argininosuccinic aciduria (ASA) < 1 in 100,000
• Citrullinemia (CIT) < 1 in 100,000
• Phenylketonuria (PKU) > 1 in 25,000
• Maple syrup urine disease (MSUD) < 1 in 100,000
• Homocystinuria (HCY) < 1 in 100,000

Inborn errors of organic acid metabolism

• Glutaric acidemia type I (GA I) > 1 in 75,000
• Hydroxymethylglutaryl lyase deficiency (HMG) < 1 in 100,000
• Isovaleric acidemia (IVA) < 1 in 100,000
• 3-Methylcrotonyl-CoA carboxylase deficiency (3MCC) > 1 in 75,000
• Methylmalonyl-CoA mutase deficiency (MUT) > 1 in 75,000
• Methylmalonic aciduria, cblA and cblB forms (MMA, Cbl A,B) < 1 in 100,000
• Beta-ketothiolase deficiency (BKT) < 1 in 100,000
• Propionic acidemia (PROP) > 1 in 75,000
• Multiple-CoA carboxylase deficiency (MCD) < 1 in 100,000

Inborn errors of fatty acid metabolism

• Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) > 1 in 75,000
• Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) > 1 in 25,000
• Very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD) > 1 in 75,000
• Trifunctional protein deficiency (TFP) < 1 in 100,000
• Carnitine uptake defect (CUD) < 1 in 100,000

Miscellaneous multisystem diseases

• Cystic fibrosis (CF) > 1 in 5,000
• Congenital hypothyroidism (CH) > 1 in 5,000
• Biotinidase deficiency (BIOT) > 1 in 75,000
• Congenital adrenal hyperplasia (CAH) > 1 in 25,000
• Classical galactosemia (GALT) > 1 in 50,000

Newborn screening by other methods than blood testing

• Congenital deafness (HEAR) > 1 in 5,000

Secondary targets

The following disorders are additional conditions that may be detected by screening. Many^[11] are listed as "secondary targets" by the 2006 ACMG report. Some states are now screening for more than 50 congenital conditions. Many of these are rare and unfamiliar to pediatricians and other primary health care professionals.^[11]

Blood cell disorders

• Variant hemoglobinopathies (including Hb E)^[11]
• Glucose-6-phosphate dehydrogenase deficiency (G6PD)

Inborn errors of amino acid metabolism

• Tyrosinemia II^[11]
• Argininemia^[11]
• Benign hyperphenylalaninemia
• Defects of biopterin cofactor biosynthesis^[11]
• Defects of biopterin cofactor regeneration^[11]
• Tyrosinemia III^[11]
• Hypermethioninemia^[11]
• Citrullinemia type II^[11]

Inborn errors of organic acid metabolism

• Methylmalonic acidemia (Cbl C,D)^[11]
• Malonic acidemia^[11]
• 2-Methyl 3-hydroxy butyric aciduria^[11]
• Isobutyryl-CoA dehydrogenase deficiency^[11]
• 2-Methylbutyryl-CoA dehydrogenase deficiency^[11]
• 3-Methylglutaconyl-CoA hydratase deficiency^[11]
• Glutaric acidemia type II
• HHH syndrome (Hyperammonemia, hyperornithinemia, homocitrullinuria syndrome)
• Beta-methyl crotonyl carboxylase deficiency
• Adenosylcobalamin synthesis defects

Inborn errors of fatty acid metabolism

• Medium/short-chain L-3-hydroxy acyl-CoA dehydrogenase deficiency^[11]
• Medium-chain ketoacyl-CoA thiolase deficiency^[11]
• Dienoyl-CoA reductase deficiency^[11]
• Glutaric acidemia type II^[11]
• Carnitine palmityl transferase deficiency type 1^[11]
• Carnitine palmityl transferase deficiency type 2^[11]
• Short-chain acyl-CoA dehydrogenase deficiency (SCAD)^[11]
• Carnitine/acylcarnitine Translocase Deficiency (Translocase)^[11]
• Short-chain hydroxy Acyl-CoA dehydrogenase deficiency (SCHAD)
• Long-chain acyl-CoA dehydrogenase deficiency (LCAD)
• Multiple acyl-CoA dehydrogenase deficiency (MADD)

Congenital infections

• TORCH complex (Toxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex, Syphilis etc.), if there are indicative symptoms or mothers who may have been exposed^[12]
• HIV

Miscellaneous multisystem diseases

• Galactokinase deficiency^[11]
• Galactose epimerase deficiency^[11]
• Maternal vitamin B12 deficiency

Projects

Currently, National Institutes of Health (NIH) awarded a five-year, $4.5 million grant in April 2011 to fund the "Inborn Errors of Metabolism Collaborative" (IBEMC) project through NIH's R01 program, the agency's oldest grant mechanism. Newborn blood spot screening is a critical public health responsibility, but for most newborn-screened disorders there is no comprehensive, long-term assessment of outcomes. MPHI will serve as lead of the IBEMC. Thirteen clinic and university partners in ten states will collect longitudinal data to capture the clinical progress of persons affected with conditions identified by newborn screening (NBS), focusing on inborn errors of metabolism. Data will be used to explore survival rates, medical status, and long-term outcomes, and permit development of evidence-based treatment and management. The database will allow for investigation of:

• The relationship between NBS values, genotype and early manifestations, and complications of inborn errors of metabolism

• Current interventions for treating children with metabolic disorders

• The effectiveness of current interventions for specific metabolic disorders identified through newborn screening

The IBEMC will build on the work of the Health Resources and Services Administration-funded Region 4 Genetics Collaborative (www.region4genetics.org), housed in MPHI's Systems Reform program. The project will be developed in collaboration with other national efforts; work began in April 2012.^[13]

Expanded newborn screening

The increasing availability and decreasing cost of tandem mass spectrometry (MS/MS) equipment greatly increased the number of diseases that could be detected from the standard newborn screening blood spot card. MS/MS screening to determine concentrations of amino acids and acylcarnitines can be used to screen for a large number of inherited metabolic disorders.^[13]

Expanded newborn screening allowed a large number of disorders to be detected in a single test, previously newborn screening labs would have a single test for a single disease.

Controversies

Newborn screening tests have become a subject of political controversy in the last decade. Two California babies, Zachary Wyvill and Zachary Black, were both born with Glutaric acidemia type I. Wyvill's birth hospital only tested for the four diseases mandated by state law, while Black was born at a hospital that was participating in an expanded testing pilot program. Black's disease was treated with diet and vitamins; Wyvill's disease went undetected for over six months, and during that time the damage from the enzyme deficiency became irreversible. Birth-defects lobbyists pushing for broader and more universal standards for newborn testing cite this as an example of how much of an impact testing can have.^{[citation needed]}

Instituting MS/MS screening often requires a sizable up front expenditure. When states choose to run their own programs the initial costs for equipment, training and new staff can be significant. Moreover, MS/MS gives only the screening result and not the confirmatory result. The same has to be further done by higher technologies or procedure like GC/MS, Enzyme Assays or DNA Tests. This in effect adds more cost burden and makes physicians lose precious time. To avoid at least a portion of the up front costs, some states such as Mississippi have chosen to contract with private labs for expanded screening. Others have chosen to form Regional Partnerships sharing both costs and resources. But for many states, screening is an integrated part of the department of health which can not or will not be easily replaced. Thus the initial expenditures can be difficult for states with tight budgets to justify. Screening fees have also increased in recent years as health care costs rise and more states add MS/MS screening to their programs. (See Report of Summation of Fees Charged for Newborn Screening, 2001–2005) Dollars spent for these programs may reduce resources available to other potentially lifesaving programs. It has been recommended that one disorder, Short Chain Acyl-coenzyme A Dehydrogenase Deficiency, or SCAD, be eliminated from screening programs, due to a "spurious association between SCAD and symptoms.^[14] However, recent studies suggest that expanded screening is cost effective (see ACMG report page 94-95 and articles published in Pediatrics^[15]'.^[16] Advocates are quick to point out studies such as these when trying to convince state legislatures to mandate expanded screening.

Expanded newborn screening is also opposed by among some health care providers who are concerned that effective follow-up and treatment may not be available, that false positive screening tests may cause harm, and issues of informed consent.^[17] A recent study by Genetic Alliance and partners suggests that communication between health care providers and parents may be key in minimizing the potential harm when a false positive test occurs. The results from this study also reveal that parents found newborn screening to be a beneficial and necessary tool to prevent treatable diseases.^[18] To address the false positive issue, researchers from the University of Maryland, Baltimore and Genetic Alliance established a check-list to assist health care providers communicate with parents about a screen-positive result.^[19]

Controversy has also erupted in some countries over collection and storage of blood or DNA samples by government agencies during the routine newborn blood screen. It was revealed that in Texas the state had collected and stored blood and DNA samples on millions of newborns without the parents knowledge or consent. These samples were then used by the state for genetic experiments and to set up a database to catalog all of the samples/newborns. Samples obtained without parent's consent were destroyed.^[20]

See also

• Inborn error of metabolism
• Genetic disorder
• Newborn Screening Saves Lives Act of 2007

References

External links

• U.S. National Newborn Screening and Genetics Resource Center
  • Current list of tests by state
• The History of Newborn Screening - Flash Cast by Harvey Levy, MD: In this 40-minute talk and slide presentation, offered here in ten short video sections, Dr. Levy covers the history of newborn screening, starting with the origin of the concept of errors of inborn metabolism in the early 1900s, covering Dr. Robert Guthrie's development of newborn screening for PKU, and moving through current screening methods and public health approaches.
• Newborn Screening Information & Resources Homepage of the Save Babies Through Screening Foundation, a grass-roots advocacy group devoted solely to expanding, and promoting awareness of, Newborn Screening.
• About Newborn Screening
• Baily, M.A. and Murray, T.H. (2009).Ethics and Newborn Genetic Screening. Johns Hopkins University Press. ISBN 978-0-8018-9151-9
• PerkinElmer Genetics, Inc. (Commercial company that pioneered some of the screening procedures and offers testing directly to parents. Excellent set of links to other sites about metabolic diseases and screening.)
• Waldholz, Michael, "A Drop of Blood Saves One Baby; Another Falls Ill," Wall Street Journal, 17 June 2001, p. A1 (52k PDF)
• [4]
• Novogenia DNA Plus Genetic Testing can save newborn
• Newborn Screening Program for Mumbai, Navi-Mumbai and Thane
• Baby's First Test (Educational site produced by the non-profit organization Genetic Alliance.)
• [5] Henry Morgan Anderson obituary
• [6] Adventures of Henry, LLC publishing