Newborn screening

Newborn screening
Newborn screening
MeSH D015997

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.



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.


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] Additional tests have been added to many screening programs. Confirmatory test for various metabolic disorders have evolved over the last two decade. First-line diagnosis in the organic acidemias is urine organic acid analysis by Gas chromatography-mass spectrometry (GC-MS), utilizing a capillary column. Organic acids can be measured in any physiologic fluid. However, it is most effective to use urine to identify the organic acids that signal these disorders, as semi-quantitative methods may not identify the important compounds in plasma. The organic acids found in the urine provide a high degree of suspicion for the specific pathway involved. The urinary organic acid profile is nearly always abnormal in the face of acute illness with decompensation. However, in some disorders the diagnostic analytes may be present only in small or barely detectable amounts when the affected individual is not acutely ill.

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: 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, and a test that is reliable for both affected and unaffected patients and is acceptable to the public.[5]

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][6] 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]


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 to be take 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.

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 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. The confirmatory test varies depending on the initial screen, and can include enzyme assays, DNA testing, Gas Chromatography/Mass Spectrometry. Tandem mass spectrometry(MS/MS)is a screening step towards detection of the disorder. 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.[7]

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).[8] 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

Inborn errors of organic acid metabolism

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

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[8] 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.[8]

Blood cell disorders

Inborn errors of amino acid metabolism

Inborn errors of organic acid metabolism

Inborn errors of fatty acid metabolism

  • Medium/short-chain L-3-hydroxy acyl-CoA dehydrogenase deficiency[8]
  • Medium-chain ketoacyl-CoA thiolase deficiency[8]
  • Dienoyl-CoA reductase deficiency[8]
  • Glutaric acidemia type II[8]
  • Carnitine palmityl transferase deficiency type 1[8]
  • Carnitine palmityl transferase deficiency type 2[8]
  • Short-chain acyl-CoA dehydrogenase deficiency (SCAD)[8]
  • Carnitine/acylcarnitine Translocase Deficiency (Translocase)[8]
  • Short-chain hydroxy Acyl-CoA dehydrogenase deficiency (SCHAD)
  • Long-chain acyl-CoA dehydrogenase deficiency (LCAD)
  • Multiple acyl-CoA dehydrogenase deficiency (MADD)

Congenital infections

Miscellaneous multisystem diseases

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.[10]

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.


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. 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.[11] However, recent studies suggest that expanded screening is cost effective (see ACMG report page 94-95 and articles published in Pediatrics[12]'.[13] 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.[14]

Controversy has also erupted in some countries over collection and storge 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 setup a database to catalog all of the samples/newborns. Samples obtained without parent's consent were destroyed.[15]

See also


  1. ^ Abhyankar, S.; Lloyd-Puryear, M.; Goodwin, R.; Copeland, S.; Eichwald, J.; Therrell, B.; Zuckerman, A.; Downing, G. et al. (2010). "Standardizing newborn screening results for health information exchange". AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium 2010: 1–5. PMC 3041276. PMID 21346929.  edit
  2. ^ Clague A, Thomas A (2002). "Neonatal biochemical screening for disease". Clin. Chim. Acta 315 (1-2): 99–110. doi:10.1016/S0009-8981(01)00716-1. PMID 11728413. 
  3. ^ Klein AH, Agustin AV, Foley TP (1974). "Successful laboratory screening for congenital hypothyroidism". Lancet 2 (7872): 77–9. doi:10.1016/S0140-6736(74)91637-7. PMID 4137217. 
  4. ^ 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. doi:10.1373/clinchem.2003.022178. PMID 14578311. 
  5. ^ a b c d Ross, L. F. (2006). "Screening for conditions that do not meet the Wilson and Jungner criteria: The case of Duchenne muscular dystrophy". American Journal of Medical Genetics Part A 140A (8): 914–922. doi:10.1002/ajmg.a.31165. PMID 16528755.  edit
  6. ^ Pollitt, R. J. (2009). "Newborn blood spot screening: New opportunities, old problems". Journal of Inherited Metabolic Disease 32 (3): 395–399. doi:10.1007/s10545-009-9962-0. PMID 19412659.  edit
  7. ^ Newborn Screening Expands: Recommendations for Pediatricians and Medical Homes-Implications for the System. Pediatrics121:1 192-217 January 2008 [1]
  8. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Newborn Screening Expands: Recommendations for Pediatricians and Medical Homes Implications for the System Newborn Screening Authoring Committee. Pediatrics 2008;121;192-217 DOI:10.1542/peds.2007-3021.
  9. ^ > Screening Tests for Newborns American Association for Clinical Chemistry. This page was last reviewed on March 16, 2008. | This page was last modified on December 1, 2009.
  10. ^ "About Expanded Newborn Screening". Screening, Technology and Research in Genetics. Retrieved 2011-05-27. 
  11. ^ Newborn Screening for Metabolic Disorders. Journal of the American Medical Association 2006 PMID 16926360
  12. ^ Expanded Newborn Screening for Inborn Errors of Metabolism by Electrospray Ionization-Tandem Mass Spectrometry: Results, Outcome and Implication PMID 12777559 [2]<
  13. ^ Cost-Benefit Analysis of Universal Tandem Mass Spectrometry for Newborn Screening. Pediateics 2002 PMID 12359795 [3]
  14. ^ Financial, Ethical, Legal, and Social Issues
  15. ^ Newborn DNA samples to be destroyed

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