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Feature

Important changes to newborn screening in Ontario

by Joe T.R. Clarke, MD, PhD
     Michael T. Geraghty, MB, MSc
     Alan P. Hudak, MD
     Pranesh Chakraborty, MD

The province of Ontario is about to embark on major changes to the newborn screening program, which are expected to enhance the efficiency and effectiveness of the program while saving lives and preventing serious disability.
The changes include plans to:

1. Substitute tandem mass spectrometry, a vastly superior analytic technology, for the now antiquated Guthrie test for PKU screening.
   
   
2. Centralize testing at the Children’s Hospital of Eastern Ontario, rather than at the Provincial Public Health Laboratories in Toronto.
   
   
3. Expand the number of conditions included in the test panel to include a number of amino acid disorders, in addition to PKU, disorders of organic acid metabolism, fatty acid oxidation disorders, such as MCAD deficiency, sickle cell disease, congenital adrenal hyperplasia, galactosemia, and biotinidase deficiency.
   
   
4. Enhance the education of health-care providers and the public regarding the purposes and operation of the program.
   
   
5. Establish an expert committee to monitor the efficiency and effectiveness of the program, to advise the Ministry of Health and Long-Term Care on newborn screening policy (including what should be added to the screening panel), and to promote research on newborn screening.
   

The expansion of the screening panel to include the other disorders will be phased in during 2006. There will be no change in current guidelines regarding the way samples are collected.

The requisition will be modified to improve communications with attending physicians. Physicians will be notified of any positive screening tests, sent specific educational material regarding the condition, and provided with telephone numbers where they can obtain further information about it.

The retrieval, follow-up diagnostic workup, and continuing care of infants with positive screening tests will continue to be supervised by subspecialists in the five regional treatment centres in the province.

Background
In the summer of 1965, the province of Ontario was one of the first jurisdictions in the world to introduce population-wide newborn screening for phenylketonuria (PKU).

The initiative was made technically feasible by Robert Guthrie’s discovery in 1961 of a simple method for measuring blood phenylalanine levels in a few drops of blood collected and dried on a piece of filter paper. Soon, every baby born in the province was being tested for PKU in the first few days of life.

In 1978, screening was expanded to include testing for congenital hypothyroidism (CH), another preventable cause of severe mental retardation. As a result, up to 1,600 people over the past 40 years in Ontario have been saved from inevitably developing severe brain damage causing profound mental retardation.

These measures are generally accepted to be among the most important public health initiatives ever to be undertaken for the prevention of severe disability or death.¹

In 2002, the province added universal newborn testing for hearing impairment to the screening panel. Over the past 10 years, technical advances in the early detection and treatment of a number of similar diseases, have prompted the expansion of newborn screening to include testing for a wide range of disorders.

Key developments included the development of tandem mass spectrometry and its application to the analysis of amino acids and acylcarnitines in dried blood spots, which made possible the early diagnosis of a large number of treatable inborn errors of amino acid metabolism, defects in fatty acid oxidation, and inherited disorders of organic acid metabolism.^2-4

The early identification of infants with sickle cell anemia and treatment with prophylactic penicillin was shown to be effective in the prevention of large numbers of deaths from pneumococcal sepsis.^5-8

Deaths and long-term morbidity from congenital adrenal hyperplasia (CAH) were shown to be preventable by early detection and intervention.^9-11
Progress in the implementation of changes in newborn screening practices as a result of these developments has been particularly rapid in the United States, where 50 states and the District of Columbia now test for up to 35 disorders in the first few days of life.

A consortium of stakeholders in that country recently produced a consensus report, accessible online (www.mchb.hrsa.gov/screening/), summarizing the new state of the art of newborn screening, and recommending the implementation of several additions to routine newborn screening.

The new Ontario initiative
The province of Ontario recently struck a new advisory committee (see Table 1, p. 34), chaired by Dr. Joe Clarke, Director of the Genetic Metabolic Diseases Program at the Hospital for Sick Children, and long-time advocate for expanded newborn screening, to provide guidance in the evaluation and implementation of additions to the provincial newborn screening program.

As a result, screening will soon be expanded to include testing for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, an easily treatable condition that has claimed the lives of five to nine infants a year in the province.

Plans are afoot to add testing for a number of amino acid disorders, in addition to PKU; disorders of organic acid metabolism; other fatty acid oxidation disorders, in addition to MCAD deficiency; sickle cell disease; congenital adrenal hyperplasia; galactosemia; and biotinidase deficiency by the end of 2006.

The committee, which reports directly to the Deputy Minister of Health and Long-Term Care, is charged with advising the Ministry on policies relating to newborn screening, monitoring the performance of existing screening procedures, and encouraging research on questions relevant to newborn screening. The Committee will:

1. Review and provide advice regarding provincial policies, standards and guidelines relating to Ontario’s newborn and childhood screening program, including but not limited to:
   
   
   • Modification or extension of the screening program in the light of advances in screening technology and the Ontario experience with newborn and childhood screening in particular.
     
     
   • Advise on the Ministry’s reimbursement policy for special dietary products and drugs required for the management of the diseases, including:
     
     
     • The types of disorders to be covered.
     • The types of products to be covered for each disease.
       
       
   • Educational programs about newborn and childhood screening for both health professionals and the public.
     
     
   • Specific newborn and childhood screening protocols and procedures.
     
     
   • Specific areas of newborn and childhood screening, including surveillance, genetic counseling issues.
     
     
   • Any other related issue at the request of the Minister of Health and Long-Term Care or her or his delegate.
     
     
2. Review requests and provide advice to determine eligibility of individuals with inborn metabolic disorders for funding for specialized drugs, medical foods and low-protein foods, which are outside the approved coverage list.
   
   
3. Review the effectiveness of the Ontario newborn and childhood screening program periodically, including assessment of:
   
   
   • The completeness and timeliness of sampling.
     
     
   • The efficiency of the transportation of samples.
     
     
   • The quality of testing and interpretation of test results.
     
     
   • The efficiency of retrieval of infants and children with positive tests.
     
     
   • The efficiency and effectiveness of the process of diagnostic testing.
     
     
   • The outcome of treatment of infants and children with disorders detected by the program.
     
     
4. Prepare advisory statements and bulletins for health-care providers to address new newborn and childhood screening developments or new screening issues of provincial significance as they arise.
   
   
5. Collaborate with appropriate academic, research and professional bodies to:
   
   
   • Develop performance indicators.
     
     
   • Develop a provincewide registry of patients with conditions identified in the course of newborn and childhood screening.
     
     
   • Maintain statistics on the incidence of conditions identified in the Ontario program.
     
     
   • Develop audit tools.
     
     
   • Identify research questions and facilitate the undertaking of research on the impact of newborn and childhood screening through studies on the Ontario experience.
     
     
   • Review any other product, tool or document at the request of the Minister of Health and Long-Term Care or her or his delegate.
     
     
6. Report annually to the Deputy Minister of Health and Long-Term Care on:
   
   
   • The efficiency and effectiveness of the newborn and childhood screening program.
     
     
   • The incidence of all disorders screened in Ontario’s newborn and childhood screening program.
     
     
   • The impact of screening and early intervention on the health outcomes of infants and children with disorders identified as a result of screening.
     

By employing an integrated, trans-disciplinary approach to this complex area of public health, the province will be setting a new international standard for the management of rare conditions causing serious disability or death in infancy.

What will NOT be changing in the newborn screening program
Some aspects of the current newborn screening program will not change with the introduction of the new, expanded screening to be phased in over several months after March 30, 2006.

As far as health-care providers are concerned, the sample collection will be done exactly as before. That is, the blood will continue to be obtained by heel-stick and applied to a specimen card, as it is at present.

While samples taken between one day (24 hours) and seven days after birth are acceptable, the best time to collect the blood sample is when the baby is between two days (48 hours) and three days (72 hours) of age. This is because abnormalities that are present between 24 and 48 hours of age become more obvious over the next day.

Newborn infants born in hospital and discharged before 24 hours of age should be tested before discharge, then re-tested within five days of discharge, at the first postnatal checkup. This has been the policy recommended by physicians advising the Ministry on newborn screening for some years, and it will continue to be the policy.

A sample collected before 24 hours of age is better than no sample at all as it reduces the risk of a baby not being screened at all. Furthermore, it also increases the chances of detecting and treating newborns who have early-onset diseases.

A second test is suggested because of the risk of missing some infants with disorders included in the screening panel when testing is done before 24 hours of age.

Physicians or midwives attending infants with positive screening tests will continue to be notified immediately by one of the regional treatment centres in the province.

Because the physician of record when a woman is admitted to hospital is often different from the physician who will be caring for the infant after discharge, mothers will be asked when they are admitted to hospital specifically which physician should be contacted if a screening test turns out to be positive. By doing this, we hope to decrease the time currently taken to find and notify the appropriate physician when a test is positive.

Families will also be contacted directly, but only after the attending physician or midwife is notified, or a reasonable attempt has been made to contact them. This is particularly necessary in the case of some of the very rapidly progressive disorders that will be part of the expanded screening panel. If the mother does not know who will be attending her baby after discharge, retrieval of those with positive screening tests will be done through the appropriate local regional public health unit.

All screening test results will be reported to the attending physician or midwife and to the hospital where the infant was born. The test results will be identified as screen positive or screen negative, as before.

In the case of screen positive results, the physician or midwife will be contacted by the regional treatment centre, generally long before a hard copy of the report arrives.

What WILL be different
Several important changes occurred as of mid-March. First, testing has been shifted from the Central Public Health Laboratory in Toronto to a newly developed newborn screening centre located at the Children’s Hospital of Eastern Ontario (CHEO).

All initial newborn testing, except for the hearing tests, are now done in the laboratory at CHEO. Hearing tests will continue to be done, as before, in the hospitals where the infants are born.

The requisition used to collect the blood spots from newborn infants will look different, though the amount of additional information being requested is being kept to a minimum.

The most important addition is the explicit identification of the physician who will be attending the baby after discharge from hospital.

The Ministry of Health and Long-Term Care will communicate with physicians and hospitals once the new forms are available and ready to be sent directly to CHEO.

The Guthrie test for PKU has been replaced by tandem mass spectrometry, a much more sensitive and reliable test for hyperphenylalaninemia. As well as reporting a phenylalanine concentration, the test result is now tagged as positive or negative.

In addition to testing for PKU, tandem mass spectrometry will be used to test for MCAD deficiency and a wide range of other metabolic disorders. The expanded testing will be phased in over a period of six to 12 months.

The final panel for expanded newborn screening is shown in Table 2 (see p. 35).

An important addition to the newborn screening program is a comprehensive education program for mothers and all relevant health-care providers.

This will take the form of written material, as well as video presentations, suitable for use in doctors’ offices and antenatal clinics in hospitals and in the community.

The goal is to ensure that all expectant mothers understand the purpose of the program before they go into labour, which is to identify infants at risk of having rare but serious diseases before they develop symptoms, and to prevent disability and death by early initiation of appropriate treatment.

All health-care providers involved in antenatal or postnatal care will also be provided with information packages to help them answer any questions patients may have about the program.

What happens when an infant has a positive screening test?
Attending physicians and midwives will be notified of positive tests by one of the five regional treatment centres in the province located at the five academic health science centres with expertise in the diagnosis and management of the disorders included in the test panel. Notification will be by both telephone and by mail.

An example of the report form is shown in Appendix I (see pp. 36-37).

When physicians are notified of positive screening tests, they will also be provided with information on the interpretation of the test result, including a brief summary of the disease, the signs and symptoms, treatment, prognosis, and genetics of the disorder.

An example of one of the information sheets is shown in Appendix II (see p. 38).

How is a definitive diagnosis established in infants with positive screening tests?
The screening technology to be used in the new, expanded Ontario newborn screening program will be the best available in the world. Nonetheless, we anticipate a certain number of false positives. Therefore, appropriate follow-up diagnostic testing will be necessary in all infants with screen positive tests. This will be arranged by the appropriate regional treatment centre.

The false positive rate of most newborn screening programs carrying out a range of tests similar to the Ontario panel is generally less than one per cent, which is actually lower than the current false positive rate for PKU using the Guthrie test.

Time is of the essence. In order to prevent serious disability or death, screen positive babies must be retrieved within 24-48 hours of the results of the screening test becoming available.

Since notification of the results of screening tests is carried out by personnel at the regional treatment centres, no delays are expected in referral to the appropriate consultant.

Who arranges treatment of infants with a confirmed diagnosis of one of the disorders detected by screening?
Treatment and follow-up will be initiated and supervised by specialists at the five regional treatment centres.

The parents of affected infants will be offered genetic counselling at the appropriate regional treatment centre.

The technology used in the screening program will identify carriers of sickle cell disease and some carriers of MCAD deficiency, as well as infants affected with the conditions.

Couples who have a baby who is found to be a carrier of either condition will be offered genetic counselling and further testing of apparently healthy siblings in order to identify affected infants who might have escaped earlier detection.

Who do you call if you have questions?
A summary of information on the new screening program can be found on the Ministry website (www.health.gov.on.ca/newbornscreening).
Questions may also be directed to staff at the Newborn Screening Centre at the Children’s Hospital of Eastern Ontario by calling the Genetic Counsellor or Laboratory Head at 613-738- 3222 (Newborn Screening Centre fax: 613-738-0853; Lab fax: 613-737-6531).

Correspondence can be forwarded to:
Dr. Joe T.R. Clarke, Division of Clinical & Metabolic Genetics, Hospital For Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8. Tel. 416-813-5340, fax 416-813-5345, e-mail: jtrc@sickkids.ca

Summary
Ontario was one of the first jurisdictions in the western world to introduce population-based newborn screening for PKU, one of the most important public health measures for the prevention of severe mental handicap.

The province was also among the first to expand newborn screening to detect infants with congenital hypothyroidism, another cause of preventable mental handicap.

Screening for hearing impairment was added in 2002, and now the program is being expanded to include testing for over 25 additional causes of preventable morbidity and death in infants and children.

This initiative represents a major move forward in the prevention of disability in the children of Ontario.

References

1. Dhondt JL, Farriaux JP, Sailly JC, Lebrun T. Economic evaluation of cost-benefit ratio of neonatal screening procedure for phenylketonuria and hypothyroidism. J Inher Metab Dis 1991;14:633-9.
   
2. Pollitt RJ, Green A, McCabe CJ, Booth A, Cooper NJ, Leonard JV, et al. Neonatal screening for inborn errors of metabolism: cost, yield and outcome. Health Technol Assess 1997; 1:1-202.
   
3. Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review. Health Technol Assess 2004;8:i-xiv, 1-134.
   
4. Rinaldo P, Tortorelli S, Matern M. Recent developments and new applications of tandem mass spectrometry in newborn screening. Curr Opini Pediatr 2004;16:427-33.
   
5. Consensus Development Panel, National Institutes of Health. Newborn screening for sickle cell disease and other hemoglobinopathies. JAMA 1987;258:1205-9.
   
6. Gaston MH, Verter JI, Woods G, Pegelow C, Kelleher J, Presbury C, et al. Prophylaxis with oral penicillin in children with sickle cell anemia: A randomized trial. N Engl J Med 1986; 314:1593-9.
   
7. Vichinsky E, Hurst D, Earles A, Kleman K, Lubin B. Newborn screening for sickle cell disease: Effect on mortality. Pediatrics 1988;81:749-55.
   
8. Tsevat J, Wong JB, Pauker SG, Steinberg MH. Neonatal screening for sickle cell disease: a cost-effectiveness analysis. J Pediatr 1991;118: 546-54.
   
9. Therrell BL Jr, Berenbaum SA, Manter-Kapanke V, Simmank J, Korman K, Prentice L, Gonzalez J, Gunn S. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 1998;101: 583-90.
   
10. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003;349:776-88.
    
11. Vliet GV, Czernichow P. Screening for neonatal endocrinopathies: rational, methods, and results. Semin Neonatol 2004;9:75-85.

Dr. Joe Clarke is Chair, Advisory Committee on Newborn and Childhood Screening, Division of Clinical & Metabolic Genetics, Hospital for Sick Children. Dr. Michael Geraghty is Director, Newborn Screening Centre, Children’s Hospital of Eastern Ontario. Dr. Alan Hudak is Chair, Ontario Medical Association Child Health Committee. Dr. Pranesh Chakraborty is Co-Director, Newborn Screening Laboratory, Children’s Hospital of Eastern Ontario.