What's New in Newborn Screening?

Bradford L. Therrell; Colleen Buechner; Michele A. Lloyd-Puryear; Peter C. van Dyck; Marie Y. Mann


Pediatr Health. 2008;2(4):411-429. 

In This Article

Screening Policies & Screened Conditions

We have previously noted that NBS in the USA has evolved in the absence of a national policy. Hence, state policy makers have struggled with defining which conditions to include in screening mandates and how screening-system components should be implemented and financed. In many cases, public opinion/advocacy and litigation have impacted policy decisions, and many medical practice issues have not been clearly addressed. There continues to be variation nationally in the screening requirements in each state program;[12] however, recent actions by federal agencies and the Secretary of Health and Human Services' Advisory Committee on Heritable Diseases and Genetic Disorders in Newborns and Children (ACHDGDNC) have provided some encouragement for improved harmonization.[103]

Historically, NBS policy decisions have been guided by the 1960s criteria developed as part of a WHO initiative on population screening.[3] Responding to advances in science, medicine, technology and research, and recognizing the need for a centralized focal point for NBS information, HRSA/Maternal and Child Health Bureau (MCHB) initiated two national NBS projects in 1999. One project established the NNSGRC through a cooperative agreement with the University of Texas Health Science Center at San Antonio, TX, USA. The other (through a contract with the AAP) initiated a review of the status of NBS in the USA with recommendations for improvement. Presently, the NNSGRC initiative continues as a focal point for national NBS information and assistance, including national data collection and expert review/advice for state program improvement.[16] The AAP contract resulted in a published national NBS 'blueprint for the future' that more clearly defined the activities, needs and government (federal and state) responsibilities.[33]

Responding to suggestions in the AAP report, HRSA/MCHB subsequently contracted with the American College of Medical Genetics (ACMG) to address the specific issues of:

  • Developing a decision-making matrix that could be used by state programs to systematically expand (or contract) screening mandates;

  • Recommending a core panel of NBS conditions that should be included in all state mandates.[34]

As a result, the ACMG-convened NBS expert group developed a comparative scoring system for evaluating conditions that might be candidates for inclusion in state program mandates. Based on the scoring system, the group recommended a core panel of screening conditions.[35] A total of 84 conditions were evaluated. Of these, 29 core conditions (including 28 NDBS conditions and NHS) and 25 secondary targets (conditions that might be identified incidental to detecting the core conditions, but lacking a score high enough to rank them as a core condition), were recommended as a uniform NBS panel that should be required in all state NBS programs ( Table 2 ).[36,37] Even though screening for certain infectious diseases (toxoplasmosis and HIV) occurs in some programs, infectious diseases were not evaluated, owing to a lack of expertise in the working group and a lack of appropriate comparative information. Conditions not included in the 'core 29' were generally conditions for which additional research was felt necessary either to develop a satisfactory NBS test or to develop better clinical outcomes information. Thus, studies of conditions outside of the core 29 constitute a de facto research agenda.

Publication of the final ACMG report and its acceptance by the ACHDGDNC has provided national guidance for state NBS programs. While controversial regarding the methods used,[37,38,39] the ACMG report, coupled with the actions of parent advocacy organizations, individual parents and private-sector screening companies, has impacted NBS programs across the country. As a result, all state programs have expanded their required screening panels to some degree, and most have expanded significantly to require the core 29 conditions.[40] Many programs require screening for some or all of the 25 secondary targets, and some programs include conditions not yet classified as secondary or core ( Table 1 ).[5] Since the analytical markers for the core conditions may also be markers for secondary target conditions, some secondary targets may be identified and reported even though screening for them is not required. The ACHDGDNC has recently adopted a process for nominating conditions to be included in the core panel. A description of the nomination process and the appropriate nominating forms are electronically available on the HRSA's website.[104] Once a condition is nominated, the scientific information submitted must undergo a rigorous impartial review prior to its consideration by the ACHDGDNC.[41]

Among the conditions into which extensive NDBS research is ongoing are the lysosomal storage diseases (LSDs). Development of enzyme-replacement therapy and stem cell transplantation has led to demonstrated health benefits for patients, and earlier detection offers the opportunity for even better outcomes. Research into NDBS laboratory methodologies and consumer advocacy led to the addition of Krabbe disease to the required New York screening panel at the end of 2006.[5] The Illinois Legislature passed legislation in 2007 that adds screening for five LSDs (Krabbe, Pompe, Gaucher, Fabry and Niemann-Pick) within 6 months after four conditions are met:

  • Registration of the necessary screening reagents with the US FDA;

  • Availability of the necessary reagents from the CDC;

  • The availability of a quality-assurance testing methodology for the screening processes;

  • Acquisition and installment of the equipment necessary to implement the expanded screening tests (legislation available at[105]).

Research into NDBS for additional LSDs and associated NDBS reagent production is ongoing.[42,43,44,45]

Studies of possible NDBS methodologies for screening for other congenital conditions, such as severe combined immune deficiency (SCID),[46,47,48,49,50] Duchenne muscular dystrophy,[51,52] fragile X syndrome,[53] Type 1 diabetes[54,55] and others,[56] are also currently being performed, although not without controversy (particularly concerning ethical considerations of such full population screening). Of these, NDBS for SCID is perhaps the least controversial. SCID has been successfully treated with stem cells and treatment works best if initiated within a few months of birth. Therefore, early detection is critical. Recent research has shown that the measurement of T-cell receptor excision circles from excised DNA samples is successful in screening for affected individuals.[40] However, developing a cost-effective, high-throughput screen has proven difficult.[43] Other screening methods, including immunoassays for T-cell-specific proteins and measurements of lymphocyte number, are being studied, and it is likely that a reliable NBS test will be developed soon.[44] Screening for SCID began in WI, USA, in January of 2008 and the results will be continually assessed in order to refine and evaluate the success of the program. SCID has also been proposed to the ACHDGDNC to be added to the core panel of recommended tests and the application is currently under evaluation.

Barriers to population-based screening for some of the conditions under consideration include limited treatment options or inadequate treatment/management infrastructure, ambiguous screening test results and lack of reliable information on disease severity when detected in newborns. As there are risks involved in some disease treatments, such as bone marrow transplantation for Krabbe disease, parents and clinicians may face difficult decisions if the potential severity of the disorder is unclear from the screening results.[57] Some of the candidate NBS conditions currently have few treatment options. Even so, parents of affected children note that detecting these conditions through NBS can provide early diagnostic information that would help avoid the diagnostic odyssey or repeated medical visits and tests in search of a diagnosis that may take months or years to obtain. In addition, early diagnosis as a result of NBS could provide useful information for future pregnancy considerations.


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