Newborn Screening Advisory Panel Report

I. Background

Each year, four million infants born in the United States are screened shortly after birth to detect a variety of congenital conditions. These public health screening programs have become models for population-based screening. Newborn screening programs in this country began with the work of Dr. Robert Guthrie in the 1960s with the development of a screening test for phenylketonuria (PKU). Today, all states screen for a wide range of conditions. However, the array of screening tests performed by each state varies and changes periodically. This variability reflects differences in population needs, in state political and economic environments and in technical capabilities.

Newborn screening programs are a public health activity aimed at the early identification of infants who are affected by certain genetic, metabolic, hematologic and infectious disorders. Early identification of these conditions is particularly crucial, as timely intervention can lead to a significant reduction of morbidity, mortality and associated disabilities in affected infants.

The Advisory Panel's recommendations were developed with recognition that the environmental context within which these programs were established has changed dramatically over the past 10 years. New technologies such as tandem mass spectrometry and DNA-based tests offer the possibility of screening for additional disorders. The growing impact of consumer advocacy has resulted in a congressional directive to federal agencies to expand and evaluate newborn screening programs. Not to be forgotten will be those essential ethical, legal and social questions that must be addressed as well as the challenge in balancing the need to both protect a population's health and to respect individual rights. Further, with the advent of new technologies and new knowledge, it is critical that newborn screening programs continue to operate under sound public health principles and are connected to medical homes to provide care that is accessible, family- centered, continuous, comprehensive, coordinated, compassionate and culturally competent.

These and other challenges will affect not only the specific newborn screening tests but also the entire newborn screening system. The newborn screening system has five components all of which are vitally and equally important to the efficient functioning and evaluation of a newborn screening program. These five components include:

1. Initial screen of all newborn infants

2. Retrieval of the screen positive infant for follow-up testing

3. Confirmatory diagnosis

4. Access and initiation into long-term treatment and management

5. Evaluation of the entire system

The consideration of all five components of the system have been incorporated into this report.

II. Setting the Framework for State Newborn Screening Systems

Guidance for newborn screening systems have been in place for two decades. These guidelines are linked to ethical, legal and social considerations and based on the premise that screening should be conducted only when science and technology can serve both the individual and public good. The following is a brief summary of these landmark reports:

A. National Academy of Science (1975): Set forth rigorous guidelines about the criteria for newborn screening. These include: 1) acceptance by healthcare professionals, 2) previous feasibility studies, 3) satisfactory test methodology, 4) appropriate laboratory facilities and quality control, 5) resources for counseling, treatment and follow-up, 6) acceptable costs, 7) effective education, 8) informed consent and 9) the means to evaluate the effectiveness and success of each step.

B. Institute of Medicine Report (1994): Newborn screening only takes place: 1) for conditions for which there are indications of clear benefit to the newborn, 2) when a system is in place for confirmatory diagnosis and 3) when treatment and follow-up are available for affected newborns.

C. Task Force on Genetic Testing (1997): This report further emphasized: 1) that newborn screening should be of primary benefit to the identified infant, 2) that the test should have analytical and clinical validity/utility and 3) interventions to improve the outcomes for an infant must be safe and effective.

The Advisory Panel extrapolated the following specific "criteria for adding disorders:"

1. There must be a significant life-challenging risk of morbidity if the disorder is untreated in newborns.

2. Positive health benefits must outweigh risks and burdens of screening and treatments on newborns (primarily) and relatives (secondarily).

3. The disorder must be treatable and require early treatment.

4. There must be an accurate screening test.

5. There must be resources for and access to appropriate confirmatory testing, treatment and counseling.

6. There must be a mechanism for regular review of the scientific and medical rationale for the screening procedure.

7. The total costs of the system including diagnosis, treatment and follow-up must be reasonably priced.

8. The prevalence of the disorder must be "significant."

9. There must be consumer involvement, physician and public health acceptance.

The selection of these criteria in this particular order is justified on the grounds that the burden of proof rests with the proposed newborn screening. That is, there has to be a good reason for subjecting newborns to any screenings so that the presumption is that in the absence of such a reason screening is not justified. Considered individually, not one of these criteria is sufficient to provide the necessary justification. However, taken as a whole they are able to sustain the burden of proof for the following reasons. First, they recognize the physical and the moral integrity of the newborn which ought not to be compromised. In the case of mandatory screening, there is the presumption that the proposed screening is something newborns, were they able to speak for themselves, would find acceptable. Since it is the newborns who will actually undergo screening and will be the subject of the consequences of the screening, there must be reasonable grounds for the general acceptability of the proposed screening. Secondly, the criteria recognize the need for the presumption that the proposed screening will not only be good for newborns but at the same time will not do them harm. And where there is some risk of harm, it is not so great that it nullifies the good. Were that the case, then the screening would not be justified. In other words, where benefits and burdens are in play for newborns because of screening there has to be a proportionate reason for running the risk of the burdens in order to secure the benefits. This again underscores the basic presumption that the interests of newborns must take reasonable precedence in any decisions about screening. Thirdly, the criteria address the important issue of justice as it relates to newborn screening. Simply put, justice requires that persons in similar situations, all other things being equal, should be treated similarly. If that is so, then the cost and accessibility, for example, of screening become central considerations. It would be unjust to require newborn screening whose cost or accessibility were such that either or both would not prevent some newborns from being screened but would prevent others in the same medical condition, and with no other relevant differences present, from being screened. Fourthly, the criteria require the technical integrity of the screening procedure itself, so that it has the resources to deal with the consequences of its own operation. Since screening, for example, entails the possibility of false negative or false positive results, the procedure also needs the resources to counteract these with subsequent confirmatory screening in order to ascertain the true medical condition of the newborn. And since screening can provide, for example, critical genetic information about newborns, parents will need counseling to understand and act on the information in the best interests of their children. Moreover, since screening is time-sensitive, the procedure needs resources such as a sufficient number of laboratories and technicians strategically placed within the state to provide prompt analysis and reporting within what can be very tight time lines. Without this kind of comprehensive operational integrity, the initial screening intervention would be highly questionable. Finally, the criteria recognize implicitly that the notion of required newborn screening raises a number of ethical considerations for the physical and psychological integrity of the newborn, as well as the integrity of parental rights to act in the interests of children. The presumption justifying the requirement of a particular screening is that it is a necessary condition of the newborn's well-being because of the urgency of early detection and immediate treatment, or the serious, possibly fatal, consequences of neglect over time. Under those circumstances, the state, exercising its right of parens patriae, can impose such requirements. It is, as a consequence, important for the common good to secure the involvement of citizens in deciding what screening is to be instituted so that there is public acceptance for and cooperation in its execution. The public hearings conducted during the work of the Advisory Panel were designed with this in mind. It is clear from this discussion of the criteria used by the Advisory Panel in arriving at its recommendations that the scope of the Panel's deliberations, reinforced by its composition, was able to embrace a range of considerations in recognition of the variety of issues, technical, clinical, ethical, and social, involved. Anything less would have done a disservice to those who are the primary focus of these recommendations, namely newborn infants.

III. Issues in Newborn Screening

The introduction of additional tests to the current newborn screening panel is only the initial step in a newborn screening program. In some respects, it may be the easiest to accomplish. It will require additional laboratory technology (e.g., enzyme assays, tandem MS/MS, DNA technology). Accordingly, the Panel has outlined a number of issues which need to be addressed and will be reflected in the section on recommendations. It is axiomatic that an effective and efficient newborn screening program requires the infrastructure necessary to meet the needs of an expanded program.

A. Reliability & Reproducibility of the Newer Technologies: While information is available from commercial laboratories on the internal control and reproducibility of the additional technologies, introduction of these methodologies to the state laboratory would require practice and in-house reproducibility before they are offered for general screening purposes. Time and consultations would be needed prior to an actual start date with both internal and external monitoring for quality control purposes. Additional staff resources with expertise in these new technologies will be needed.

B. Timeliness of Initial Test Sample: Optimal time to obtain the initial blood sample may vary with the disorder. For example, testing can be done at anytime for hemoglobin and galactosemia screening; other tests are time-dependent related to protein intake and others (e.g., homocystinuria) are optimally screened at 7-10 days after birth or with a second screen at two weeks of age.

C. False Positive Test Results: The addition of each new test carries with it an inherent false positive and false negative biologic factor. Data from newborn screening reports (e.g., 1995 CORN data) indicates false positive rates obtained by standard technologies (e.g., PKU and maple syrup urine disease data from bacterial inhibition assays). This may not reflect the false positive rate (presumably lower) when using tandem MS/MS. For some disorders, the false positive rate may still be unclear and would require additional data from commercial laboratories performing such testing. In any event, the following is clear: More tests, more false positive results. For example, if the aggregate false positive rate for all added tests performed in New Jersey is 1%, with an annual birth rate of 115,000, 1,150 infants per year would require retrieval and retesting in addition to those infants with true positive initial screening results. Accordingly, systems will be required to rapidly retrieve all screen positive infants for repeat confirmatory testing (true positive versus false positive). This will require additional resources for the newborn screening follow-up program, enhanced communication with the birth hospital, primary care physician and metabolic, hematologic and endocrinologic specialists. Such costs for expanded newborn screening must be taken into account as well. Additionally, these costs do not take in account the emotional cost to the family in being notified of an initial false positive screen result and the additional costs for confirmatory and "rule-out" testing .

D. Metabolic Laboratories: As noted, all initial screen positive results require confirmation. It is axiomatic that a positive screen result does not equate to diagnosis confirmation. The proposed addition of other metabolic disorders requires access to metabolic laboratories familiar with newborn screening and which can perform the appropriate confirmatory testing with a rapid turn-around time. This can be a function of the state laboratory, contracted university metabolic laboratory either in-state or out-of-state, or a commercial laboratory. It has been the Panel's experience that commercial laboratories have little experience with metabolic disorders and their reliability in performing such testing and easy communication with the metabolic specialist has been generally lacking. The Panel felt that this important component requires implementation in order to assure the smooth functioning of the newborn screening program.

E. Metabolic, Endocrinologic and Hematologic Centers: Designated specialists are required for initial evaluation, diagnosis and ongoing immediate and long- term care. The earlier recognition of these disorders will require rapid access to specialist centers for long-term care. In addition to initial and long term management, such centers will need to provide information back to the state regarding health and developmental outcomes of children identified through the newborn screening program.

F. Involvement of the Primary Care Physician: All infants including those with special needs require a "medical home." This may be the primary care physician, the specialty center or a combination of primary care/specialty center interaction and agreement. Accordingly, systems will need to be developed to enhance this interaction. The primary care physician needs to be in the "communication loop" and is a valuable resource in the retrieval of the initial screen positive infant, communication and education of the family and assuring appropriate referral to specialty centers.

G. Education: The introduction of additional testing requires a massive educational initiative for the public, obstetric and primary care physicians, birthing facilities and other healthcare agencies. The Panel feels strongly that educational efforts need to be designed (a video for pregnant women entitled "Bring Your Baby Back" is currently available but would also need to address these additional tests) and be in place prior to the introduction of new tests. Additionally, specific protocols for appropriate testing of the initial screen positive newborn need to be developed as well as protocols for ongoing monitoring and evaluation of the infant with a diagnosed disorder. Such expenses need to be included when attempting to calculate the total costs for an enhanced newborn screening program.

H. Costs: The following issues need to be addressed in addition to the initial costs for the expanded screening technologies:

1. Expanded state newborn screening follow-up personnel and infrastructure

2. Payment for confirmatory testing

3. Support of metabolic reference laboratory/laboratories that ensure appropriate, reliable and timely confirmatory testing

4. Support for pediatric metabolic, endocrinologic, pulmonary and hematologic centers to provide access and care for all infants diagnosed with a disorder through the newborn screening program. The Panel feels strongly that all diagnostic and follow-up testing, metabolic foods/therapies and specialty care need to be a part of all health insurance programs. In this regard, the State Department of Health and Senior Services should work with the appropriate agencies (e.g., Department of Banking and Insurance) to assure such coverage.

5. Educational needs (see Item G)

6. Costs for process and outcomes evaluation of the expanded system

I. Equity: The Panel is aware that several hospital systems in New Jersey are utilizing supplemental newborn screening programs. The Panel has expressed concern that this will lead to perceived inequities among the population-some babies being screened and others not even within the same community. The Panel recognizes the political and psycho-social implications and understands that this may impact on any attempt at rational incorporation of additional tests to the newborn screening profile in the state.

J. Newer Technologies: Underscoring the ability to screen for a number of additional disorders is the availability of sophisticated technology which allows for the rapid testing of a large number of metabolic disorders. This comes with both a positive and negative impact. The introduction of tandem mass spectrometry (MS/MS) allows for screening for serious metabolic disorders involving the intermediate metabolic pathways of amino acids and fatty acids. This can be achieved by "one run" of the tandem MS/MS system. However, this can also provide test result information on an additional number of disorders which may not meet the criteria for inclusion into state- authorized expanded screening programs. Other technologies may include the use of DNA-based testing. In this regard, it is currently possible to design and incorporate a metabolic newborn screening DNA panel (involving all the known genetic mutations for the designated newborn screening panel) onto a DNA microchip array; such technology would theoretically eliminate the problems related to false positive screening test results.

The Panel has heard presentations and reviewed the implications of the tandem MS/MS technology. In the utilization of tandem MS/MS technology, current testing (e.g., PKU) could be incorporated as well thereby reducing the number of false positive screen results. The Panel has no specific recommendation as to whether this technology should be incorporated into the state newborn screening laboratory or contracted out to the laboratories currently performing and experienced in this methodology. Out-sourcing newborn screening will require additional protocols for follow-up testing and a communications system through the state newborn screening follow-up team to assure rapid retrieval, follow-up testing and evaluate process outcomes.

K. Evaluation of the System: It is imperative that the initiation of an expanded newborn screening program requires ongoing evaluation. These evaluations should be programmed before the implementation of screening so that meaningful evaluation outcomes can be obtained. We believe this falls into two general evaluation categories:

1. Process evaluations-e.g., turn-around times, false positive rates, time to initial treatment, access to specialty laboratories, access to specialty centers, etc.

2. Outcomes evaluation-e.g., long-term outcomes of children, by specific disorder, diagnosed through the expanded newborn screening program. As noted above, resources and monies should be provided to accomplish these important outcomes measures.

IV. Newborn Screening Environment:

As noted, recent federal initiatives have asked for a reevaluation of state newborn screening based on evolving technologies (e.g., tandem mass spectrometry, DNA-based testing) and improved treatment modalities. Still to be answered are long term health benefits for a number of these rare disorders identified by newborn screening programs. Additionally, our neighboring states have expanded their newborn screening panel in the past few years. The following is a brief summary of the screening profile in our neighboring states (all screen for PKU, hypothyroidism and hemoglobinopathies).

.

	NY	CT	MA	DE	MD	DC	RI	PA*
Galactosemia
Maple Syrup Urine
Homocystinemia
Biotinidase
Congenital Adrenal Hyperplasia
MCAD
Organic Acidemias			pilot
Tyrosinemia
Citrullinemia
Cystic Fibrosis			pilot
G-6PD
HIV

*Some 80% of Pennsylvania hospitals utilize supplemental newborn screening through NeoGen in addition to the mandated newborn screening cited in the table.

V. Overview of Specific Disorders

The following disorders (presented in alphabetical order) were reviewed in detail for possible inclusion into an expanded panel of tests to be included as part of the New Jersey state- mandated newborn screening program. Each of these disorders were critically reviewed following a formal and academic presentation by specific experts in the field. A brief overview is presented in this section; a more detailed review of each disorder is appended.

A. Biotinidase Deficiency:

1. Overview: An autosomal recessive disorder of biotin recycling that leads to multiple carboxylase deficiency. Many affected infants and children show combinations of neurologic and cutaneous findings including myoclonic seizures, hypotonia, dermatitis, ataxia, hearing loss, optic atrophy and developmental abnormalities. Acute metabolic decompensation may result in neurologic disabilities and death.

2. Prevalence: Profound deficiency 1:137,000; partial deficiency 1:110,000; Maryland 1:105,000

• Currently screened in 20 state programs
• Expected cases in New Jersey: one/year

3. Screen Test: Quantitative colorometric assay

• 20-40 false positives: one true positive
• Mild variants may have initial negative test.
• Enzyme deficiency noted in cord blood; any specimen after birth is adequate.

4. Anticipated Benefit with Screening and Early Treatment:

• Oral biotin therapy effective
• Neonatal decompensation not a factor in this disorder; age of onset of symptoms in untreated infants 7 weeks to 3 years.
• Long-term outcome not well documented; Maryland follow-up of 10 children treated before symptoms show normal development and no neurologic features.

5. Limitations to Screening:

• Mild variants may be missed but have minimal symptoms.
• The potential for an unacceptable rate of false positive tests need further clarification.

6. Special Requirements if Included in Nb Screening Panel:

• Metabolic laboratory to perform quantitative radioimmune assay of biotinidase and organic acids for confirmation. Expected 20 to 30 false positive cases or approximately two assays/month in New Jersey.
• Requires treatment and long-term management and follow-up in a metabolic center.

B. Congenital Adrenal Hyperplasia:

1. Overview: Autosomal recessive disorder of deficient enzyme activity (21-hydroxylase) essential for cortisol biosynthesis resulting in virilization of the female infant at birth, and salt-wasting (adrenal crises) in both males and females (75%). Affected boys have no clinical findings at birth and will not be detected until they present in adrenal crises.

2. Prevalence: 1:15,000 - 16,000

• Anticipated cases in New Jersey: 6 - 8 cases/year
• Currently screened in 25 states

3. Screen Test: Immunofluorescent assay for 17- hydroxyprogesterone

• False positive rate 0.2 - 0.5%.
• Expected 30 false positive to one true positive
• Test is designed to identify cases at risk for adrenal decompensation and not for milder or nonclassical variants.
• Valid test results at 48 hours. Three percent of salt- wasters may be missed with testing within the first 24 hours of birth.

4. Anticipated Benefit with Screening and Early Treatment:

• Excellent therapy available for treatment
• Should prevent adrenal crises, persistent virilization and adult short stature due to androgen effect on premature skeletal maturation.

5. Limitations to Screening:

• Essentially no limitations

6. Special Requirements if Included in Nb Screening Panel:

• Rapid turnaround time - ideally by 7 days
• Endocrine specialist network currently available (as per thyroid screening)

C. Cystic Fibrosis:

1. Overview: Common autosomal recessive disorder of a chloride channel resulting in pancreatic insufficiency, chronic pulmonary disease and multi- organ system involvement in adolescents and young adults. Mean age of survival is about 32 years. Current treatment is supportive and aimed at reduction in pulmonary infections, progressive lung fibrosis and bronchiectasis and enhanced nutritional support.

2. Prevalence: (Approximately 25 - 30 new cases/year in New Jersey) Caucasian 1:3,000; African-American 1:15,000; Hispanics 1:9,500; Asian-American 1:32,000. Screened in three states and selected populations in three other states.

3. Screen Test: Immunoreactive trypsinogen

• Three percent false positive rate (approximately 3,000 cases/year in New Jersey)
• Five percent false negative rate in pancreatic insufficient infants who do not have meconium ileus. Will miss pancreatic sufficient children.
• Addition of DNA testing (_F508 mutation analysis) on newborn filter paper blood may improve specificity.
• Timing of initial specimen not important.

4. Anticipated Benefit with Screening and Early Treatment:

• Somewhat controversial but evidence seems to be mounting that early treatment improves nutritional status and slows pulmonary decompensation.
• No specific therapy is available although pharmacologic and antibiotic therapies aimed at reducing viscosity of lung fluids and control of superimposed infection as well as the potential for gene therapy and pharmacogenetic clinical trials are being assessed.

5. Limitations to Screening:

• Concern regarding false positive and false negative rates with current screening modalities.
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• Large number of positive tests will require follow-up confirmatory testing including repeat IRT, DNA full panel analysis and sweat testing.
• No national consensus as to long-term health benefit of newborn screening.

6. Special Requirements for Inclusion:

• Need for confirmatory testing accessibility and costs (e.g., repeat IRT, full mutation panel DNA, sweat testing).
• Regional CF centers are currently in place in New Jersey.
• Long-term outcomes measures will be required to evaluate anticipated changes in health outcome for those detected through newborn screening programs.

D. Fatty Acid Disorders: MCAD

1. Overview: Group of inherited metabolic disorders leading to accumulation of fatty acids or decrease in cell energy metabolism leading to either acute or chronic disorders resulting in encephalopathy, failure to thrive, hepatocellular disease, neurologic impairment and mental retardation. Most common disorder is medium chain acyl-CoA dehydrogenase deficiency (MCAD) but other disorders can be assessed by tandem mass spectrometry. Approximately 5 - 15% of infants with MCAD may die of Sudden Infant Death Syndrome (SIDS) during the first clinical episode.

2. Prevalence: MCAD 1:10,000. Prevalence of other fatty acid oxidation disorders are rare individually ranging over 1:100,000. Anticipated 8-10 cases/year in New Jersey. Currently screened in four states.

3. Screen Test:

• Tandem mass spectrometry to measure octanoylcarnitine
• Limited data available for false positive and false negative rates. It should presumably be extremely low but accumulated data from commercial laboratories and states currently doing screening is lacking.
• Confirmatory testing may include DNA testing for specificity.
• Timing not important as infants are asymptomatic in the neonatal period.

4. Anticipated Benefits with Screening and Early Treatment:

• Symptoms may be averted by relatively simple dietary management and avoidance of prolonged fasting.
• Requires assessment of long-term outcomes of infants detected by newborn screening.

5. Limitations to Screening:

• Requires more exact data regarding false positive and false negative rates.
• Screening requires tandem mass spectrometry.

6. Special Requirements:

• Tandem mass spectrometry
• Molecular laboratory for DNA confirmation and specificity
• Metabolic laboratory for ongoing management
• Metabolic centers for long-term management and outcomes assessment

E. Glucose-6 Dehydrogenase Deficiency:

1. Overview: A common X-linked disorder of primarily Mediterranean, Asian and African populations resulting in red cell hemolysis. Severe enzyme deficiency results in chronic anemia although most individuals only become symptomatic with exposure to infection or oxidant drugs. Neonatal hyperbilirubinemia may occur in 33% of affected neonates with severe deficiency of which 5% may develop kernicterus.

2. Prevalence: African-American 10% (mild form); Northern European 0.1%

3. Screening Test:

• Dye decoloration (NADPH formation) or fluorescent spot test

• False positive and false negative rates are not known.

• Only available as part of supplemental screening by commercial laboratory.
• Confirmation requires specific enzyme activity assay and electrophoretic mobility pattern.
• Requires rapid turnaround time as hyperbilirubinemia may occur by 5 to 7 days after birth.

4. Anticipated Benefits with Screening and Treatment:

• Anticipate and prevent hyperbilirubinemia and kernicterus (bilirubin encephalopathy). Concern that with early discharge, increasing neonatal jaundice may not be detected.
• Avoid oxidant drugs

5. Limitations to Screening: Testing methodologies require further evaluation.

6. Special Requirements for Inclusion:

• False positive and false negative rates are not clear.
• New Jersey population with low prevalence rates for severe mutation. African-American mutations produce some enzyme activity and kernicterus is not observed in this group.
• Requires rapid turnaround time - ideally 3 to 5 days
• Other clinical methods are available for monitoring neonatal hyperbilirubinemia.

F. Homocystinuria:

1. Overview: An autosomal recessive defect in the catabolism of sulfur-containing amino acids resulting in elevated levels of homocystine and methionine. Asymptomatic in the first few months of life. The most common enzymatic defect (cystathionine beta-synthase) results in predisposition to thromboembolism, optic lens displacement, developmental and mental retardation and psychiatric disturbances.

2. Prevalence: Maryland 1:110,000 with second screen at two weeks of age; U.S. 1:>200,000

3. Screen Test:

• Historical - bacterial inhibition assay for methionine
• Tandem mass spectrometry with amino acid profile
• False positive rate 0.2%. Anticipate 230 false positive cases to detect one true positive case. These rates are based on bacterial inhibition studies and may be lower with tandem mass spectrometry.
• False negative rate is of concern as methionine rises slowly after birth and is dependent on protein (milk) intake. Best time to screen is probably between 7-14 days.

4. Anticipated Benefit with Screening and Treatment:

• Fifty percent are pyridoxine responsive. Treatment requires methionine-restricted, cystine-supplemented diet, folic acid and B12 to prevent/reduce mental retardation and lens abnormalities; aspirin to prevent/reduce incidence of thromboembolic complications.
• Long-term outcomes with treatment not clear as only a few cases have been followed.

5. Limitations to Screening:

• Cases may be missed by early screening.
• Methionine levels are elevated in preterm infants and newborns with liver disease accounting for many of the "false positive" cases.
• Screening best done with tandem mass spectrometry.

6. Special Requirements for Inclusion:

• Requires diagnostic metabolic laboratory for confirmation (quantitative amino and organic acids)
• Requires metabolic center with metabolic nutritionist for long-term evaluation and outcomes data

G. Maple Syrup Urine Disease: Branched Chain Ketoacidosis

1. Overview: An autosomal recessive disorder of branched chain amino acids resulting in neonatal lethargy, irritability and metabolic decompensation progressing to coma and death in affected individuals if untreated.

2. Prevalence: U.S. mixed populations 1:278,000; Maryland 1:103,000; Pennsylvania supplemental program 1:170,000; Mennonite Amish population 1:760; milder African-American and Asian genetic variants may be more common than classical neonatal form. We would anticipate one case per year in New Jersey.

3. Screen Test:

• Historical bacterial inhibition assay
• Fluorometric testing and tandem mass spectrometry should reduce false positive rates. Previous false positive rates of 110 false positives to one true positive is based on bacterial inhibition assays. False positive rates by tandem mass spectrometry not currently available.
• Time of testing (24 to 48 hours) is satisfactory as leucine levels rise after 12 hours even in the absence of protein intake.
• Currently screened in 20 states

4. Anticipated Benefits with Screening and Treatment:

• Treatment is complex and classic neonatal form may be symptomatic within the first week of life.
• Outcome is variable but best outcome is achieved with initiation of therapy before 12 to 14 days of age or before the infant is symptomatic.
• Milder variants with greater than 5% enzyme activity should have better outcomes with early identification.
• Mortality and severe neurodevelopmental disabilities should be reduced but probably can not be eliminated.

5. Limitations to Screening:

• Requires rapid turnaround time-ideally by 5-7 days

• False positive rate needs to be clarified using newer screening technologies (fluorometric assay, tandem mass spectrometry).

6. Special Requirements for Inclusion:

• Rapid turnaround time required
• Metabolic laboratory for rapid confirmatory testing (true positive versus false positive) and ongoing monitoring
• Metabolic center with metabolic nutritionist

H. Organic Acidemias:

1. Overview: This group of individually rare inherited metabolic disorders are associated with a primary enzyme deficiency in the breakdown of organic acids leading to metabolic decompensation with neurologic and mental disabilities.

2. Prevalence: The more common* of these disorders include:

a) Methylmalonic acidemia-1:100,000

b) Propionic acidemia-1:100,000

c) Isovaleric acidemia-1:250,000

d) Type I glutaric acidemia-1:75,000

e) 3-hydroxy-3-methyl-glutaryl-CoA carboxylase deficiency- 1:300,000

*Prevalence rates from NeoGen (Naylor, et al: J Child Neurol 14:4- 8, 1999)

f) 3-methyl crontonyl-CoA carboxylase deficiency-1:75,000

Combined frequency estimated 1:20,000 to 1:50,000 with anticipated 4 to 6 cases per year in New Jersey.

3. Screen Test:

• Requires tandem mass spectrometry assessing various carnitine esters. False positive rate while unknown should be extremely low as these esters should not normally be present.
• False negative rate for milder variants is not known.

4. Anticipated Benefits with Screening and Treatment:

• Treatment is complex and poor outcomes in severe neonatal forms may not be preventable.
• Normal development and neurologic outcomes have been observed in infants begun on treatment prior to symptoms.
• Screening for these disorders requires careful outcomes evaluation. Optimal therapy for many of these individual conditions have not been well studied because of their individual rarity and marked differences in clinical findings related to variability in enzyme activities.

5. Limitations to Screening:

• Rapid turnaround time is needed for the severe neonatal presentations of these disorders.
• Confirmatory testing is complex and treatment outcomes quite variable.
• No long-term outcomes data are available.

6. Special Requirements for Inclusion:

• Rapid turnaround time
• Designated metabolic laboratory for confirmation and ongoing management
• Metabolic center with metabolic nutritionist

I. Toxoplasmosis:

1. Overview: A congenital infection caused by transplacental transfer of a maternal protozoan infection to the fetus. Most infants are asymptomatic but by age 20, as many as 85% of affected individuals have chorioretinitis (blindness) and developmental disabilities.

2. Prevalence: New England regional program 1:10,000

3. Screen Test:

• Toxoplasmosis IgM serologic testing
• Sensitivity of test is only 75%; accordingly 25% of cases may not be detected by the newborn screening assay with many inconclusive results.
• False positive to true positive ratio is 1:2
• Confirmation testing may be inconclusive.
• Timing is not important.

4. Anticipated Benefits from Screening and Treatment: Marked reduction in neurologic impairment and visual loss (New England Regional Follow-up Study).

5. Limitations to Screening: Inconclusive screening test with significant false negative tests.

6. Special Requirements for Inclusion:

• Specialty diagnostic infectious disease laboratory for confirmatory testing

• Management by infectious disease specialist

• Some current therapeutic agents not readily available in the United States

J. Tyrosinemia: (Type I - Hepatorenal Form)

1. Overview: An autosomal recessive disorder due to an enzyme deficiency leading to elevated levels of tyrosine and succinylacetone which inhibit a variety of transport systems and enzymatic activities leading to liver failure, renal impairment and neurodevelopmental disabilities.

2. Prevalence: Mixed U.S. population 1:200,000; Quebec/French Canadian 1:12,500

3. Screen Test:

• Bacterial inhibition assay
• Tyrosine can be measured by tandem mass spectrometry although the confirmatory elevation of succinylacetone is not measured by this technology.
• Reliable measurements are present in 48 to 72 hours after introduction of milk feeds.
• Confirmatory testing is quite complex and requires a specialty metabolic laboratory.
• False positive rates are unclear and might be quite high as transient tyrosinemia is rather common and resolves spontaneously. CORN data showed a false positive to true positive ratio of 330 to 1.
• Currently screened in two states.

4. Anticipated Benefits from Screening and Treatment:

• Reduction in developmental disability, progression of liver and renal disease.
• Not all morbidities can be prevented. Liver transplantation may be required for liver failure and hepatocellular carcinoma.
• Treatment is complex and disorder is highly variable.

5. Limitations to Screening:

• Many false positive screens using tyrosine measurements alone. The ability to measure succinylacetone by mass spectrometry (currently not available) would markedly increase specificity.
• Confirmatory testing is complex and requires specialty metabolic laboratory.
• Rapid turnaround time will be required.

6. Special Requirements for Inclusion:

• Better initial screening modality

• Metabolic laboratory for confirmatory testing and ongoing monitoring

• Metabolic center
• Access to liver and renal specialists; liver transplantation

K. Urea Cycle Disorders: Citrullinemia and Arginosuccinic Aciduria

1. Overview: Recessive disorders of enzymes involved in the urea cycle which prevent the accumulation of toxic nitrogen-containing compounds (e.g., NH3) and synthesize arginine. Accumulation of NH3 may result in neonatal coma, death and/or profound neurodevelopmental disabilities.

2. Prevalence: Overall prevalence 1:25,000 (all urea cycle defects); citrullinemia 1:86,000; arginosuccinic acidemia 1:70,000

3. Screen Test:

• Bacterial inhibition assay for citrulline, arginosuccinic acid and arginine
• Tandem mass spectrometry will detect these amino acids through an amino acid profile.
• False positive and false negative rates are not clear.
• Confirmatory testing requires a metabolic laboratory.

4. Anticipated Benefits from Screening and Treatment:

• All morbidity cannot be prevented. Severe neonatal onset form may develop clinical symptoms by 48 to 72 hours.
• However, late onset forms which may present only with stress (infection; protein load). Thus, best outcomes would be anticipated in such patients or those detected presymptomatically. Therapy is complex and requires both acute metabolic stress management protocols and long-term chronic dietary and therapeutic interventions. Long-term outcomes data is not available.
• Prognosis appears to depend upon the duration of the initial hyperammonemic episode or nature of recurrent episodes.

5. Limitations to Screening:

• Even with rapid turnaround times, infants with the severe neonatal form may already be symptomatic.
• Best outcomes achieved in late onset disorders.
• False positive, false negative rates are not known-particularly for the milder late onset disorders in which the screened amino acids are not elevated or only elevated when the infant is metabolically stressed.

6. Special Requirements for Inclusion:

• Tandem mass spectrometry
• Metabolic laboratory
• Metabolic center
• Availability of inpatient critical care/metabolic units and specialists

VI. Recommendations of the Panel

The following recommendations are divided into two major categories: a) general recommendations reflecting the need for enhanced infrastructure and resources required to implement, sustain and evaluate an expanded state newborn screening program and b) specific disorders recommended for testing.

A. General Recommendations: (see Section on Issues in Newborn Screening - Pages 7-15)

The Panel strongly recommends that the following infrastructure is required and needs to be implemented and functioning (i.e., in place) prior to screening for additional disorders. The Panel recommends that:

1. The State Newborn Screening Program incorporates the following newborn screening methodologies: a) tandem mass spectrometry, b) fluorometric and immunofluorescent techniques and c) molecular (DNA- based) testing.

Annotation: Such testing is required for the screening of most of the recommended disorders. Current data indicates that these technologies will reduce false positive rates, add specificity to the screening process and allow for test results to be available within 48 hours of receipt of the specimen. The Panel has no specific recommendation as to whether the newer methodologies (i.e., tandem mass spectrometry, DNA- based testing) should be performed "in-house" or out-sourced to an experienced commercial or other state laboratory, such as that contracted with other states for newborn screening. The incorporation of these newer methodologies by the State Laboratory requires time for "start-up" and internal quality control. Such measures must be in place prior to the beginning of testing. Alternate possibilities include consultation and out-sourcing during this start-up phase. The Panel notes their strong concerns with out- sourcing related to short term follow-up, confirmatory testing, process evaluations and overall control of the entire newborn screening system.

2. The State Department of Health and Senior Services should designate and contract with a metabolic laboratory (or laboratories) capable of performing appropriate confirmatory testing, testing for acute illness management and long term monitoring as per stated guidelines and protocols in a timely fashion.

Annotation: Such a designated laboratory is crucial for coordination of care and should be a partner with the state newborn screening program and the clinical metabolic centers. The Panel feels strongly that such a laboratory resource be available without regard to the ability of patients or their insurance carriers to pay for the additional costs of such testing. This would require recognition of such a laboratory by insurance carriers for "medical necessity" of specialized testing required for the care of infants identified through the state-mandated newborn screening program. This laboratory could be the state laboratory, in-state university-based specialty metabolic laboratory or out-of-state university-based or commercial laboratory.

3. The State Department of Health and Senior Services should develop designation criteria and contract to form a network of experienced metabolic, endocrinologic, cystic fibrosis and hematologic pediatric consultants/centers to serve as integral partners with the state for the state- mandated newborn screening program.

Annotation: The Panel notes and recommends that current expertise in New Jersey allows this to be accomplished on a regional basis throughout the state. These consultants/centers of expertise should serve on an advisory panel to oversee the performance of the enhanced newborn screening profile in their respective area of expertise (i.e., metabolic, endocrinologic, hematologic, cystic fibrosis pulmonologists).

4. A comprehensive communication system be implemented for rapid retrieval of the screen positive newborn, to facilitate confirmatory testing and to assure access for appropriate specialty care. The Panel recommends:

a) A comprehensive electronic communication system to involve the primary care physicians.

b) A notification system to include the consultant specialist center as well as the birth hospital and the physician of record of the infant at birth (in many instances that physician is different from the primary care physician-particularly in urban hospitals). Immediate notification of the specialist center will enhance appropriate follow-up testing and initiation of immediate therapy protocols as needed as well as providing information to the primary care physician and educational information and materials for the family.

c) Communication and linkage through the Electronic Birth Certificate system to New Jersey birthing hospitals.

5. A system for the analysis of the costs involved in adding disorders to the state newborn screening profile be developed.

Annotation: This recognizes the need for an analysis for all the components of the newborn screening system in addition to the direct laboratory costs required to perform the initial screening tests. This cost analysis should include:

a) Costs for confirmatory testing (e.g., designated laboratories) understanding that there will be an increased number of false positive tests requiring confirmation.

b) Costs for support of metabolic, endocrinologic, hematologic and cystic fibrosis centers of expertise necessary for the comprehensive management of identified patients including repeat laboratory testing as per established management protocols.

c) Costs for medical foods, special therapies, access to specialist evaluations

d) Costs for educational brochures, videos, etc for physicians, laboratories, hospitals and healthcare facilities, agencies and lay public in regard to an enhanced newborn screening program.

e) Costs for ongoing process and outcomes evaluations.

6. All costs associated with the screening and treatment of newborns be considered as medically necessary and paid as a separate and distinct benefit governed by health plans operating in the State of New Jersey. Absent the availability of such reimbursement, funds should be appropriated by the state for Fiscal Year 2002 and beyond.

7. An enhanced delivery system (outside the current mail system) is necessary and needs to be developed

Annotation: An enhanced delivery system is required so that all specimen test results are complete within 5-7 days after actual collection of the specimen with notification of the screen positive result by the seventh day after collection of the specimen. This will require a courier service or overnight express mail and should be noted as an added expense to the system. Personnel will also need to be available to perform lab tests, respond to physician and patient inquiries seven days a week.

8. Educational information regarding the expanded newborn screening program is required and be developed and disseminated for:

a) Obstetricians and primary care physicians

b) Other healthcare practitioners

c) Specialty healthcare providers participating in newborn screening

d) Hospital and healthcare facilities

e) Hospital chaplins

f) Lay public

9. The State Inborn Errors of Metabolism Laboratory and newborn biochemical screening and follow-up programs expand their current excellent "Guidelines for Practitioners" (April 2000) to include information and protocols for the expanded panel of newborn screening disorders.

10. Procedures be instituted at the onset of the expanded program to ensure the performance of process and outcomes evaluations.

Annotation: Such measures will need to be determined and programmed. A registry and surveillance system would be ideal. The Panel again stresses that these costs are inherent to the newborn screening program.

11. The Newborn Screening Advisory Panel be a standing committee of the State Department of Health and Senior Services for continuous oversight and partnership in assuring that New Jersey has a model program and retains its leadership in assuring the best outcomes for all its citizens.

B. Specific Recommendations:

The following disorders met the Panel's criteria (see Pages 3 through 5) for immediate inclusion into an expanded mandatory newborn screening program for the State of New Jersey.

A. Disorders Recommended for Immediate Inclusion:

1. Biotinidase Deficiency

Rationale for inclusion:

a) Meets national acceptance standards; currently screened in 20 states.

b) Satisfactory test methodology (quantitative colorometric assay) and manageable false positive rate.

c) Clear benefit to the infant as newborn screening will detect affected infants prior to symptoms. Evidentiary data is available indicating that early recognition and treatment significantly prevents and/or reduces neurodevelopmental disabilities.

d) Effective therapy (biotin replacement) is available. Requires a metabolic center.

e) Prevalence of 1:110,000 meets guidelines with an anticipated one identified case per year in New Jersey.

2. Congenital Adrenal Hyperplasia

Rationale for inclusion:

a) Meets national acceptance standards; currently screened in 25 states.

b) Test methodology (immunofluorescent assay) in place; acceptable false positive rate.

c) Clear benefit to infant; early recognition and treatment will prevent significant morbidity from adrenal crisis. Requires pediatric endocrine expertise.

d) Therapy is effective and standardized.

e) Prevalence (1:15,000) is significant.

3. Fatty Acid Oxidative Disorders

• MCAD (medium chain acyl-CoA dehydrogenase deficiency)
• Rationale for inclusion:

  a) Recently added to several state newborn screening programs including Massachusetts, Washington DC, Wisconsin, North Carolina and Pennsylvania (supplemental screening).

  b) Test methodology requires tandem mass spectrometry utilizing acylcarnitine profiles. This methodology would be new to the NJ State Newborn Screening Laboratory. DNA mutation analysis, also new to the state, would enhance specificity.

  c) Infants are not symptomatic in the newborn period; early recognition may prevent morbidity and mortality from acute metabolic decompensation (e.g., sudden infant death syndrome).

  d) Treatment including diet and anticipatory guidance for families is easily manageable; requires a metabolic center.

  e) Prevalence (1:10,000) is significant.

Additional disorders to be screened in this category:

• Short Chain Acyl-CoA Dehydrogenase Deficiency (SCAD)
• Long Chain Acyl-CoA Dehydrogenase Deficiency (LCAD)
• Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD)

The Panel recognizes that the prevalence of MCAD, its easy manageability and potential for reduction of acute metabolic decompensation makes this the priority disorder to be screened in this category. Additionally, as SCAD, LCAD and VLCAD have similar presentations, have effective management interventions and can be screened with the same tandem mass spectrometry methodology, the Panel recommends that these disorders be included for screening along with MCAD. The inclusion criteria cited above for MCAD would be similar although the combined prevalence rate for these disorders approaches 1:100,000. (Naylor EW, Chase DH: J Child Neurol 1999;14:S4-S8)

4. Maple Syrup Urine Disease

Rationale for inclusion:

a) Meets national acceptance criteria; screened in 20 states.

b) Test methodology currently in place using fluorometric assay. The Panel noted that with the incorporation of the tandem mass spectrometry system, that the screening specificity would be enhanced with the significant potential for a reduction in false positive rates.

c) This is a life-threatening illness in which early recognition and presymptomatic management will reduce morbidity and mortality.

d) Treatment protocols have been established and long term health outcomes data are available; requires a metabolic center.

e) Prevalence data in Maryland is 1:103,000; Pennsylvania supplemental screening 1:83,000. One to two cases per year expected in New Jersey.

5. Citrullinemia and Arginosuccinic Acidemia (urea cycle disorder)

Rationale for inclusion:

a) Screened in states utilizing tandem mass spectrometry (Washington DC, Pennsylvania)

b) Test methodology requires tandem mass spectrometry utilizing an amino acid profile. Minimal false positive rates.

c) Life-threatening disorder with significant neurodevelopmental sequelae in undiagnosed infants. Early recognition and treatment of presymptomatic infants has the potential to eliminate/reduce neurodevelopmental disabilities.

d) Treatment is available but complex and requires a metabolic center.

e) Combined prevalence 1:25,000

6. Cystic Fibrosis

Rationale for inclusion:

a) Screened in two states (Wisconsin and Colorado) and pilot program in Massachusetts (97% of Massachusetts' parents opt for screening in their pilot program).

b) Test methodology (immune reactive trypsinogen) is available; specificity increased with incorporation of DNA testing will require implementation of this testing modality into the state laboratory.

c) Outcomes data from newborn screening programs now available from the United States (Wisconsin), Australia, France and United Kingdom showing reduction in cystic fibrosis associated infancy and early childhood morbidity and complications.

d) Cystic Fibrosis Center Network in place in New Jersey.

e) Common disorder 1:3,000 Caucasians, 1:9,500 Hispanics; 1:19,000 African-Americans

B. Disorders Recommended for Ongoing Review:

The following disorders were judged to be potential candidates for inclusion into a newborn screening system but require additional clarification regarding test methodologies, detection rates and/or impact on health outcomes. Accordingly, the Panel recommends continuing review of evolving information which would address the unresolved issues related to each of these specific disorders. When information becomes available with respect to the conditions listed below, these disorders will be reviewed to determine if the criteria for inclusion previously cited (Pages 4 & 5) are met.

1. LCHAD: (Fatty acid oxidative disorder - long chain 3- hydroxyl acyl-CoA dehydrogenase deficiency) This disorder has a similar clinical onset and presentation as the other fatty acid oxidative disorders cited above. However, it is not detected by current mass spectrometry methodology but by DNA mutation analysis; one mutation accounting for approximately 95% of cases. The Panel notes that DNA methodology as it applies to newborn screening is evolving rapidly. Almost certainly, this methodology will be added in the near future and the Panel recommends continued observation of the trends in this area.

2. Organic Acidemias: (see Page 32 for listing of these disorders) These disorders require screening by acylcarnitine profiles utilizing tandem mass spectrometry and specific standards for each of these disorders. While the Panel was generally disposed to testing, it was noted that the infantile form of many of these disorders present quite quickly after birth and involve complex therapies. Outcomes in these disorders with neonatal onset have been quite variable with little evidence of reduction in morbidity or mortality. Although the overall prevalence of 1:25,000 would meet "significant prevalence" criteria; the lack of good therapeutic interventions at this time compelled the Panel to revisit testing for this disorder in the near future when issues of benefit to the infant may become available. The Panel also noted that a clinical research question can be explored by comparing health outcome of infants identified by newborn screening (i.e., Pennsylvania supplemental screening program) with those infants clinically identified in New Jersey and similarly managed.

3. Tyrosinemia: Specific research questions include the need to incorporate succinylacetone in the initial screen along with tyrosine so as to reduce the unacceptable large number of false positive screen results and to establish the prevalence of this disorder in New Jersey.

4. Homocystinuria: This disorder would be best screened by a second screening methodology at two weeks of age because of the slow neonatal rise in methionine and absence of clinical features in the neonatal period. Many cases may be missed by screening at 48 hours of age. Programs are currently looking at reducing the cut-off range in order to enable detection by 48 hours but such studies remain inconclusive at this time.

5. Arginase Deficiency: Not currently identified by tandem mass spectrometry in the neonate. When appropriate test methodology becomes available and/or second screens are routinely obtained at two weeks of life, this disorder should be considered for screening.

C. Disorders Not Recommended for Inclusion at This Time:

1. G-6PD Deficiency. Specific rationale for noninclusion include variable screen test results and the current availability of good clinical assessments and treatments which would prevent kernicterus. Treatment for this disorder is essentially educational and anticipatory; no specific therapy is available.

2. Toxoplasmosis. This condition might best be addressed by prenatal screening, testing and treatment of the mother and subsequent clinical evaluation of the infant.

Summary:

An expert multi-disciplinary panel consisting of pediatric specialists in genetics, metabolic disorders, endocrinology, pulmonology, hematology, neonatology, medical ethics, nursing, nutrition and social services as well as representatives from the state newborn screening program and laboratory as well as representatives from the NJ Chapter of the American Academy of Pediatrics and American College of Obstetrics and Gynecology and consumer representatives undertook an extensive and intensive review of newborn screening programs and the current status of screening programs in other states. The panel is cognizant of recent national and federal recommendations for consideration for review of current state programs and recommendations for inclusion of screening for additional disorders under state guidelines. The Advisory Panel recommended that the following disorders be added to the newborn screening profile:

1. Biotinidase deficiency

2. Congenital adrenal hyperplasia

3. Fatty acid oxidation disorders (MCAD)-highest priority; SCAD; LCAD and VLCAD)

4. Maple syrup urine disease

5. Citrullinemia and arginosuccinic acidemia (urea cycle disorders)

6. Cystic fibrosis

The Advisory Panel also recommended that 1) LCHAD, 2) organic acidemias, 3) tyrosinemia, 4) homocystinemia and 5) arginase deficiency be considered as possible candidates for newborn screening in the future while assessing best testing modalities, prevalence rates, treatment availability and health outcomes of those infants identified through newborn screening. Following additional information regarding unresolved issues for each of these specific disorders, optional testing with outcomes measures could be the next step. The Panel will be revisiting these disorders on a continuing basis.

The Advisory Panel also strongly emphasizes that the initial screen is only the first step in a state-mandated newborn screening program and that successful programs require resources and funding to: a) retrieve screen positive infants for confirmatory testing, b) perform confirmatory testing, c) initiate appropriate immediate treatment and plan for long term management of the affected infant and d) establish programs for evaluation of the entire system including process and healthcare outcomes. Therefore, additional resources and funding need to be committed to:

• Establishing the newer technologies involved in initial screening and follow-up (tandem mass spectrometry, DNA-based methodologies, immune assays, etc) including quality assurance measures and internal controls with state oversight.
• Expansion of the state's newborn screening follow-up program including the development of electronic communication systems.
• Designation of reference metabolic and DNA laboratories for confirmation and long term laboratory monitoring required to attain optimal outcomes for these relatively uncommon disorders. Such designation and support would allow for optimum management strategies for these complex disorders.
• Designation and support of metabolic centers in New Jersey to provide initial assessment, assure confirmatory diagnostic testing and maintain long term care and surveillance of the affected child. This would also apply to specialty endocrine, hematologic and cystic fibrosis centers of expertise.
• Development and distribution of appropriate educational materials for physicians, hospitals, agencies and the lay public regarding the expanded newborn screening program.
• Development of protocols for the initial retrieval of screen positive infants, designation of appropriate confirmatory testing and initial and long term treatment plans.
• Reduction in turnaround times that are not dependent upon the mail system.
• Establishment of outcomes measures to evaluate the performance of the entire newborn screening program.
• Continuation of the Advisory Panel for oversight and expert guidance of the newborn screening program.

The Advisory Panel believes that with the significant resource commitment required for full implementation of all the components of an expanded newborn screening program that these recommendations will place New Jersey in a public health leadership role and as a model for other state programs.