Newborn screening in the United States

The following tests are mandated (required to be performed on every newborn born in the state) in most of the United States. 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 often erroneously 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

Heel blood on a filter paper card for the newborn screeningIn 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 few 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 or disproving 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. Guidelines for newborn screening and follow up have been published by the American Academy of Pediatrics.

Recommended target 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).

Core panel

The following conditions and disorders 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

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 are listed as "secondary targets" by the 2005 report ACMG. 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.

Blood cell disorders

Variant hemoglobinopathies (including Hb E)

Glucose-6-phosphate dehydrogenase deficiency (G6PD)

Inborn errors of amino acid metabolism

Tyrosinemia II

Argininemia

Benign hyperphenylalaninemia

Defects of biopterin cofactor biosynthesis

Defects of biopterin cofactor regeneration

Tyrosinemia III

Hypermethioninemia

Citrullinemia type II

Inborn errors of organic acid metabolism

Methylmalonic acidemia (Cbl C,D)

Malonic acidemia

2-Methyl 3-hydroxy butyric aciduria

Isobutyryl-CoA dehydrogenase deficiency

2-Methylbutyryl-CoA dehydrogenase deficiency

3-Methylglutaconyl-CoA hydratase deficiency

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

Medium-chain ketoacyl-CoA thiolase deficiency

Dienoyl-CoA reductase deficiency

Glutaric acidemia type II

Carnitine palmityl transferase deficiency type 1

Carnitine palmityl transferase deficiency type 2

Short-chain acyl-CoA dehydrogenase deficiency (SCAD)

Carnitine/acylcarnitine Translocase Deficiency (Translocase)

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

HIV

Miscellaneous multisystem diseases

Galactokinase deficiency

Galactose epimerase deficiency

Maternal vitamin B12 deficiency

Expanded screening and 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. There is considerable variability from state to state, and sometimes from hospital to hospital within a state, on disease that are screened. To make matters more confusing, some hospitals routinely obtain supplemental 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.

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.

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) 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. However, recent studies suggest that expanded screening is cost effective (see ACMG report page 94-95 and articles published in Pediatrics ' . 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