Newborn screening is the process of testing newborn babies for treatable genetic, endocrinologic, metabolic and hematologic diseases. 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.  Congenital hypothyroidism was the second disease widely added in the 1970s.
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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. Additional tests have been added to many screening programs over the last two decades. Newborn screening has been adopted by most countries around the world, though the lists of screened diseases vary widely.
Common considerations in determining whether to screen for disorders:
- A disease that can be missed clinically at birth
- A high enough frequency in the population
- A delay in diagnosis will induce irreversible damages to the baby
- A simple and reasonably reliable test exists
- A treatment or intervention that makes a difference if the disease is detected early
Newborn screening in the United States and Canada
The following tests are mandated (required to be performed on every newborn born in the state) in most of the United States and Canada. According to the U.S. Centers for Disease Control, approximately 3,000 babies with severe disorders are identified in the United States each year using newborn screening programs at current testing rates. States vary, and not all tests are required in every state, and a few states mandate more than this. The first test to be universally mandated across the U.S. was the Guthrie test for phenylketonuria (PKU), and in many areas and hospitals, the newborn blood test is still referred to as a "PKU test", even though all states now universally test for congenital hypothyroidism, galactosemia, and increasing numbers of other diseases as well.
- Endocrine disorders: Congenital adrenal hyperplasia (CAH), Congenital hypothyroidism
- Blood cell disorders: sickle-cell disease (SS)
- Inborn errors of carbohydrate metabolism: Galactosemia
- Inborn errors of amino acid metabolism: Phenylketonuria (PKU), Maple syrup urine disease (MSUD), Homocystinuria
- Inborn errors of organic acid metabolism: Biotinidase deficiency
For a recent state-by-state list, see U.S. National Newborn Screening and Genetics Resource Center. According to this resource, the only tests mandated in every state are the following:
- CH - Congenital hypothyroidism
- H-HPE - Benign hyperphenylalaninemia
- PKU -- Phenylketonuria/hyperphenylalaninemia
- HEAR - Hearing
- GALT - Transferase deficient galactosemia
Usual procedures and responses to positive results
In nearly all of the United States, the newborn screening program is a division of the state health department. State law mandates collecting a sample by pricking the heel of a newborn baby to get enough blood (typically, two to three drops) to fill a couple of circles on filter paper labeled with names of infant, parent, hospital, and primary physician. It is usually specified that the sample be obtained on the second or third day of life, after protein-containing feedings (i.e., breast milk or formula) have started, and the postnatal TSH surge subsided. Every hospital in the state as well as independent midwives supervising home deliveries are required to collect the papers and mail each batch each day to the central laboratory.
The state health department agency in charge of screening will either run a laboratory or contract with a laboratory to run the mandated screening tests on the filter paper samples. 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 occurs, 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 tests. 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.
Expanded screening and expanded controversies
With the development of tandem mass spectrometry in the early 1990s, the number of detectable diseases quickly grew, especially in the categories of fatty acid oxidation disorders and organic acidoses. Screening tests for the disorders listed below (and an increasing number of others) are now available, though not universally mandated. Laws have not kept up with this expansion, and there is considerable variability from state to state, and sometimes from hospital to hospital within a state. To make matters more confusing, some hospitals routinely obtain supplemental expanded screening (most of the tests below) on all infants even if not mandated by the state or requested by parents. In recent years in the United States, expanded newborn screening with tandem mass spectrometry has become a profitable commercial venture. For example, Pediatrix Screening, Inc offers parents a full screening test for $89 (as of 1/23/2006).
Newborn screening tests have become a subject of political controversy in the last decade. It is difficult to resist the appeal of screening when a single child injured by a treatable disease can be shown to the news media and legislature. A prime recent example is the so-called "tale of the two Zacharys." 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 are using the tale of the two Zacharys as powerful persuasion.
Why would anyone be reluctant to support the new, expanded screening programs? 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. 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 healthcare costs rise and more states add MS/MS screening to their programs. (See Report of Summation of Fees Charged for Newborn Screening, 2001 - 2005) Some argue that 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" PMID 16926360. However, recent studies suggest that expanded screening is cost effective (see ACMG report page 94-95 and articles published in Pediatrics here(p1406) and here). 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 causing controversy among some health care providers who worry about the availability of effective treatments, screening accuracy and issues of informed consent (see Financial, Ethical, Legal, and Social Issues)
The issue may ultimately be determined by juries deciding whether hospitals must routinely offer expanded newborn screening or risk multimillion dollar malpractice verdicts.
Conditions and 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 privated purchased by parents or hospitals at a cost of approximately US$80. Perhaps one in 5,000 infants will be positive for one of the metabolic tests below (excluding the congenital infections).
The 29 marked with a "@" were recommended as "core panel" by the 2005 report of the American College of Medical Genetics (ACMG). 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
- Glucose-6-phosphate dehydrogenase deficiency (G6PD)
- @ 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
- Tyrosinemia II
- @ 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
- Glutaric acidemia type II
- HHH syndrome (Hyperammonemia, hyperornithinemia, homocitrullinuria syndrome)
- @ Hydroxymethylglutaryl lyase deficiency (HMG) < 1 in 100,000
- @ Isovaleric acidemia (IVA) < 1 in 100,000
- Isobutyryl-CoA dehydrogenase deficiency
- 2-Methylbutyryl-CoA dehydrogenase deficiency
- @ 3-Methylcrotonyl-CoA carboxylase deficiency (3MCC) > 1 in 75,000
- Beta-methyl crotonyl carboxylase deficiency
- 3-Methylglutaconyl-CoA hydratase deficiency
- @ 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
- Adenosylcobalamin synthesis defects
- @ Multiple-CoA carboxylase deficiency (MCD) < 1 in 100,000
- Carnitine palmityl transferase deficiency type 2 (CPT)
- Long-chain acyl-CoA dehydrogenase deficiency (LCAD)
- @ Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) > 1 in 75,000
- Short-chain acyl-CoA dehydrogenase deficiency (SCAD)
- Short-chain hydroxy Acyl-CoA dehydrogenase deficiency (SCHAD)
- @ Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) > 1 in 25,000
- @ Very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD) > 1 in 75,000
- Carnitine/acylcarnitine Translocase Deficiency (Translocase)
- Multiple acyl-CoA dehydrogenase deficiency (MADD)
- @ 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
- Maternal vitamin B12 deficiency
- @ 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
Newborn screening programs worldwide
Newborn screening has also been adopted by most countries in Europe and around the world, though the lists of screened diseases vary widely.
- Tarini BA (2007). "The current revolution in newborn screening: new technology, old controversies". Archives of pediatrics & adolescent medicine. 161 (8): 767–72. PMID 17679658. doi:10.1001/archpedi.161.8.767.
- Kayton A (2007). "Newborn screening: a literature review". Neonatal network : NN. 26 (2): 85–95. PMID 17402600.
- Clague A, Thomas A (2002). "Neonatal biochemical screening for disease". Clin. Chim. Acta. 315 (1-2): 99–110. PMID 11728413.
- Klein AH, Agustin AV, Foley TP (1974). "Successful laboratory screening for congenital hypothyroidism". Lancet. 2 (7872): 77–9. PMID 4137217.
- Chace DH, Kalas TA, Naylor EW (2003). "Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns". Clin. Chem. 49 (11): 1797–817. PMID 14578311.
- U.S. National Newborn Screening and Genetics Resource Center
- About Newborn Screening
- Pediatrix Screening, 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)
- March of Dimes, The Difference is Black and Wyvill, 2004
- Save Babies Through Screening Foundation
- Organic Academia Association
- $Millions saved nationally by newborn screening per Delaware DPH
- The New England Consortium of Metabolic Programs