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

Current State Screening Practices

All states have specific statutes that either directly require or indirectly allow for requiring universal NDBS under a broader public health mandate, and most also require universal screening for NHS.[12] Since there is neither a national NDBS nor a national NHS policy, the numbers of NBS conditions required and the manner in which screening is implemented varies by state.[12,15] State legislatures ultimately control broad NBS administrative issues (e.g., legal requirements, program financing and oversight responsibility). State public health departments are usually given the legal responsibility for developing operational details of the screening systems, including associated public health programs. While state legislatures determine the extent to which government funds can be used for system support, state public health departments define and operationalize system financing.[58,59] Since NHS programs and systems are less uniform than NDBS programs across the country, a discussion of NHS protocols and program administrative details is best addressed on a program by program basis and will not be attempted here. Instead, we will focus on NDBS programs and systems, which are more amenable to a general descriptive discussion.

All but six public health NDBS programs use fee income to offset at least part of the expenses for maintaining the screening system.[12,58,59] Of the remaining six, at least four have been given authority to begin charging a fee in the near future. The amount of fees varies depending on the extent to which other public health funds are available for NDBS support (a current fee listing is available at[106]). In no case is a newborn refused screening because of a lack of ability to pay for screening services, although issues such as insurance may impact whether or not a routine second screen is obtained.[60]

While most private insurers cover the cost of initial NBS, payment for follow-up services is often problematic. In some states, insurers are required to pay for metabolic formulas and metabolic foods, but there is little uniformity in such insurance requirements across the country. As a result, clinicians must at times be involved in insurance reimbursement issues on behalf of their patients.[61] And, while NBS is an allowed Medicaid expense, the manner in which it is covered and the amount of reimbursement is a state-specific issue with significant variability across the country. The lack of Current Procedural Terminology (CPT®) codes for NDBS at the national level has been cited as a confounding factor in financing the program.[59]

The method for fee collection in state NDBS programs also varies widely. Some programs bill birthing facilities directly following completion of the screening laboratory tests, while others bill in advance as filter paper collection kits are ordered. Programs that require two specimens usually include the cost of both in the initial testing or kit fee, but some have a fee system that bills physicians who may be providing the second or subsequent screens. The components of NBS fees are not standardized. Some fees include nonlaboratory components, such as follow-up, education and public relations, while others are limited to laboratory costs alone. Some programs receive direct Medicaid fund transfers, while others consider Medicaid reimbursement to be a hospital/physician issue.[58,59] Few include any treatment or medical management expenses.[61]

Details of specimen collection and its subsequent transmittal to the screening laboratory are defined by state screening protocols, many of which are available in printed manuals sent to specimen submitters or on program websites (an interactive national map with program links is available at[107]). The collection of an initial NDBS specimen routinely occurs prior to hospital discharge, usually after 24 h of age. A limited number of programs require specimen collection after the age of 48 h, and one allows specimen collection after 12 h of age. Only three programs, WY, DC and MD, require consent for the required NBS panel. In most other states, there is an option to 'opt out' for religious reasons.[12] Age requirements for specimen collection historically reflect a concern that specimens collected 'too early' may result in insufficient levels of certain analytes that depend on age-related physiologic processes. Over the years, technological improvements in test kits have overcome many of the age concerns so that earlier specimen collection is now more accepted. Several state programs have a consent/dissent process where supplemental testing may be available in addition to the required screening panel.[62]

Some programs require the collection of a second NDBS specimen at 1-2 weeks of age in an attempt to improve screening efficiency.[3,12] Reports of additional case detections in these programs have generally focused on endocrinopathies.[63,64,65,66] Metabolic case reports as a result of second screen findings have been limited. Since the overall number of newborns receiving second screens is approximately 25% nationally, the Laboratory Standards and Procedures Subcommittee of the ACHDGDNC has initiated a study to more formally assess the impact of second screens. Included in the study are programs with alternative screening protocols focused on limited supplemental testing in certain defined instances, such as those newborns in neonatal intensive care units.

The idealized goal of NBS, in general, is to identify and assist all 'at-risk' newborns and their families so that early diagnosis and intervention can occur. As a result, sensitivity and specificity of NBS tests are continually under evaluation. With the exception of some of the diagnostic technologies used in the screening environment (e.g. tandem mass spectrometry [MS/MS], isoelectric focusing, HPLC and DNA), most NDBS methodologies have low positive predictive rates and require additional testing to differentiate true cases. While diagnostic capability is a consideration, other test characteristics are also important for screening, including speed of analyis and ability to detect a particular analyte in a unique specimen matrix, such as dried blood on filter paper. In NDBS, the basic nature of the screening specimens and screening laboratory protocols, and the biology of the target condition in the newborn period, precludes 100% case ascertainment without some out-of-range results that require recall for further testing. Realistically, the goal of all NBS is to identify as many at-risk newborns as possible needing additional (diagnostic) tests without excessive recall. As screening tests are by definition not diagnostic, there may be significant differences in the ability of individual screening tests to detect affected newborns. Program policies may further define the manner in which recall occurs (e.g., recall not to exceed 1% of all newborns screened). Whether screening laboratories utilize diagnostic or nondiagnostic methodologies, adjusting expected ranges of results based on case-ascertainment data is an essential part of improving the overall screening process. Screening cutoffs must be continually evaluated and adjusted to reduce unnecessary patient recall. In the case of the rarer conditions, combining case-finding data from multiple programs may assist in defining screening cutoffs; this is currently the case in an ongoing study with MS/MS case finding.[67]

Improved analytical efficiency is sometimes possible by considering additional factors, such as birth weight or age at time of specimen collection.[68] Occasionally, screening efficiency can be improved by adding a second-tier test (an additional test performed on screening specimens initially found to be out of the expected range) to the screening protocol.[32] As an example, US NDBS programs screening for congenital hypothyroidism using thyroxin (T4) as the initial screening test routinely employ thyrotropin (TSH) testing as a second tier on a certain portion of out-of-range initial screens.[22] DNA testing is sometimes used as a second-tier test for sickle cell disease[69] and is often a second-tier test for cystic fibrosis screening.[70] The current interest in second-tier testing centers around improving the screening efficiency for congenital adrenal hyperplasia with second-tier liquid chromatography-MS/MS steroid profiling[71,72] and for tyrosinemia type 1 using second-tier succinylacetone testing.[73,74] Second-tier tests have also been piloted for methylmalonic acidemia, homocystinuria and maple syrup urine disease.[75]

The goal of NBS follow-up is timely confirmatory testing, diagnosis and clinical management so that optimal long-term outcomes can be realized. Short-term NBS follow-up protocols define appropriate actions for rapid follow-up of out-of-range screens and unsatisfactory screening specimens to the point of diagnosis and initiation of appropriate clinical management. The CLSI follow-up guideline identifies the elements of efficient and effective follow-up and provides guidance for closed-loop tracking systems.[19] It loosely defines long-term follow-up as the processes occurring after diagnosis that ensure monitoring of screening effectiveness, possibly including ensuring the availability of interventions and services throughout the life cycle. The ACHDGDNC has defined long-term follow-up to include the assurance and provision of quality chronic disease management, condition-specific treatment and age-appropriate preventive care throughout the lifespan of affected individuals.[76] Clarification of the roles and responsibilities in long-term follow-up are currently being addressed by the ACHDGDNC Subcommittee on Long-Term Follow-Up and Treatment.

Birthing facilities are responsible for maintaining records that document completion of the NBS process. In particular, NDBS records should show that for every newborn: a specimen was collected, a result was obtained and appropriate follow-up actions were completed. In cases where unsatisfactory or out-of-range NDBS results occur, documentation of efforts to assist with rescreening or other confirmatory processes should exist. Specimen submitters have a responsibility to transmit accurate information about the newborn's primary healthcare provider (PCP) so that NDBS patient tracking is not delayed by inaccurate or missing information on the specimen collection card.[19] Responsibilities for providing NDBS results to PCPs vary according to the state program's rules and policies. Results may be transmitted to the PCP by the birthing facility, the state NBS program or both. In either case, PCPs should take appropriate steps to see that they receive timely NDBS reports.[77]

As development and utilization of electronic health records proceeds, efforts to facilitate the integration of NBS results are underway.[78,79] Discussions about inclusion of NBS (both NDBS and/or NHS) information currently focus on universal coding schemes for screening results. Since NDBS identifies increased risk(s) for the presence of congenital conditions, interpretations of qualitative or quantitative laboratory findings may be reported for some screening analyses instead of, or in addition to, a numeric result. As an example, qualitative isoelectric focusing screening results for sickle cell disease usually do not include percentages of the various hemoglobins observed. Or, screening laboratories sometimes may use percentile rankings for endocrine screening tests rather than using analyte concentrations. The complexity of reporting a NBS result that arises from nonstandardized screening protocols and analytic methods will require creativity and flexibility in developing useful result-transfer standards. These standards will likely not be as straightforward as in a diagnostic setting. Whether quantitative values for screening results or their interpretations are reported (or some combination of the two), standardized language (coding) will be necessary for electronic information technology to be efficiently utilized in NBS.


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