Royal Society of Medicine Forum: Extended newborn screening – anticipating the future.
This is a report of a joint meeting of the Forum on Maternity and the Newborn of the Royal Society of Medicine with the Section of Paediatrics and Child Health, held on Tuesday 22nd February 2005.

This report is to be published in part in the Midwives Journal of the Royal College of Midwives. It is reproduced here with their consent and our thanks.

"Existing programmes; lessons learned, errors made".
Professor J.V Leonard (JL), Institute of Child Health, London.

Phenylketonuria (PKU) is caused by an inherited defect of the enzyme that converts the essential amino acid phenylalanine to tyrosine. The resulting accumulation of phenylalanine would, if not prevented, result in severe mental handicap in more than 80% of cases. Neonatal screening for phenylketonuria, which has an incidence of approximately 1:12,000 in the UK, became universal in the early 1970s. The disorder is treated with a low phenylalanine diet and overall it has been a considerable success in preventing severe brain damage. Initial optimism about the results of diet have been muted by the failure to recognise that there is a natural rise in IQ in normal subjects. After adjustment, it is clear that the mean IQ of the treated patients remained slightly below that of the general population. Nevertheless it is now accepted that the diet should be lifelong, albeit less strict after childhood except during pregnancy. Missed cases are rare and almost always the result of a failure of the screening process rather than a true false negative.

Screening for classical homocystinuria uses plasma methionine as a proxy marker for the plasma homocysteine concentration. As a result a significant proportion of patients are missed, particularly those with pyridoxine responsive variants. Untreated the patients have a substantial cognitive deficit and behavioural problems, as well as disorders in the eyes and skeleton. The outcome with dietary treatment with good compliance started at an early age is good but it is not easy. Betaine is also used, particularly in older patients and will usually arrest the progress of the disease. Although this is a rare condition in Western Europe, (less than 1:200,000) these details emphasise the need for early diagnosis.

Maple syrup urine disease, a defect in the metabolism of three essential aminoacids, leucine, isoleucine and valine, is a very rare disorder (1:250,000) in most populations. It often presents as a subacute encephalopathy in the newborn period. However, because there are no obvious clues that it is a metabolic disorder, a lengthy delay in the diagnosis is frequent. As a result the prognosis for these patients is poor and the burden of the disease can be severe, with neurological deficit and developmental delay. Early intervention improves the outlook, and there are few errors in screening. To achieve optimum results the screening sample should be collected and the result reported early to avoid delay in diagnosis.

Most patients with galactosaemia present in the newborn period with a serious illness, not uncommonly before screening results are available. The response to a galactose free diet, which must be instituted urgently, is often dramatic with rapid improvement. However the long-term outcome has been disappointing, with speech delay, cognitive deficit, and ovarian failure in females. There is no evidence that early detection improves the long term outlook, and screening in the UK has now been largely abandoned. The screening process also has an additional disadvantage in that patients with mild disease who need little or no treatment are detected.

Until now in most laboratories the tests for these conditions have had to be done separately, but this will change with the advent of tandem mass spectrometry. This technique examines groups of conditions including aminoacids and acylcarnitines It then becomes possible to screen for many more inborn errors.

Among these is MCADD: Medium Chain acyl CoA Dehydrogenase deficiency whose incidence 1:10-15,000. Undiagnosed, 20 – 25% of patients will die with an acute encephalopathy precipitated by fasting and/or acute infection. However treatment is simple and effective, making a very good case for screening. However this process will identify mild as well as severe cases, whose management is less clear. The value of identifying other patients with organic acidaemias and disorders of fatty acid oxidation is less clear. Ideally these would be subject to controlled trials but there are considerable difficulties establishing these.

Long term follow up is essential to establish the natural history of these conditions, Audit may tell us the value of screening when no treatment is given, and the effect on families where conditions are misdiagnosed. There should be guidelines about the management of mild cases and most importantly clear decisions need to be taken about the day of screening, prompt despatch of bloodspots, and day of reporting. Additionally there will be ethical issues about the value or otherwise of diagnosing untreatable conditions; families may be grateful to have such information, as it could assist them in making reproductive decisions.

Families now have easy access to more information as well as international comparisons. Furthermore society's expectations are that a child will grow up healthy and perhaps controversially this may mean that decisions about screening for rare disorders will need to be re-examined.


The speaker and the chair entered into a discussion about treatment and other matters. Screening for galactosaemia has been abandoned in Scotland because of the poor results of dietary treatment; while restricting the diet prevents acute episodes of illness, it does not prevent the late complications, and it is now being suggested that treatment in older patients is pointless. Some galactose production appears to be endogenous, and some of the complications appear to be unavoidable because prenatal in origin. The case for diagnosing cystic fibrosis (CF) and instituting treatment early is quite different, in view of the known if partial benefits of treatment.

Efficient reporting of false negative results would require a national registry, which would run up against the Data Protection Act. (JL) Surely there can be no objection to the use of personal data to ensure good follow up of very rare conditions, where it is impossible for one researcher to achieve a sufficient number of cases. This is only part of a general disappointment that our National Health Service is failing to produce so much valuable information.

A midwife regretted the lack of clear guidance as to when the blood spots should be taken. (JL) Screening too early is likely to lead to too many false negative results; screening too late will permit the onset of disease. (RP) Current guidelines prefer Days 5 to 8, with a preference for Day 5; midwives seem unhappy to take the sample on Sundays.

Mitch Blair, paediatrician, asked about parental informed consent, in view of the large numbers of conditions which can now be screened, and the possibility that screening will lead in a few cases to prolonged follow up. (JL) The UK Newborn Screening Programme Centre is preparing guidelines. We are screening for potentially lethal or very disabling conditions, against which the needs of privacy have somehow to be balanced. Even where milder cases are diagnosed, in my experience parents want the information.

(JL) Newborn screening, and now extended screening, requires education for the involved healthcare providers. The importance of taking blood samples at the right time and of submitting them urgently for testing; the need for written information for parents; the question of whether informed consent must be taken in writing or orally - these and other matters will have to be covered by education.

Screening for cystic fibrosis - the Brittany experience.
Professor Claude Ferec (Cl.F), Laboratory for Molecular Genetics, Brest, France

The elevation of a pancreatic enzyme in the blood of children with cystic fibrosis (CF) was first observed in 1979 (Crossley JR et al. 1981). In 1989 we set up a systematic neonatal screening programme in Brittany, France – a region of 2.8 million inhabitants of mostly Celtic origin, with one of the highest incidences of CF in Caucasians – 1:1,800 in the western area.

The classical condition is characterised by an anomaly of the secretions of exocrine glands, causing chronic pulmonary obstruction and infections, and disorders of digestion. The sweat test for chloride is positive. CF is the commonest severe recessive disorder in children, with an overall incidence of 1:4,000; life expectancy is limited to 30 to 40 years.

The screening programme is based on immunoreactive trypsin (IRT) assay from dried blood spots, combined with a direct search for gene mutations, of which there are more than 1200. There is considerable variation in the frequency of mutations depending on the geographic and ethnic origin of patients; the necessary technology, introduced in 1992, has simplified the search for known mutations and gene scanning. Since 2001 IRT assay has been combined with the use of a kit which identifies any of the 30 most common mutations with 98% sensitivity; testing can now be done earlier with a lower recall rate, and it is simple, efficient, reliable, and relatively inexpensive. 565,546 newborns have been screened for CF in 16 years; 196 children were found to be carriers of two mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) giving an incidence of 1:2885. There have been 8 false negative results. It is possible to carry out prenatal screening in subsequent pregnancies for women who have had affected babies before the first symptoms appear in the affected children; 6% of these mothers have chosen to have their pregnancies terminated. Six children diagnosed prenatally following the detection of an echogenic bowel, appearing abnormally bright on routine ultrasound examination, were included; all of these pregnancies were terminated.

Screening of the pregnant relatives of affected children has led to the diagnosis of CF in fetuses, enabling pregnancies to be terminated in 15.7% of cases. Cascade screening in affected families has identifiied some couples at 1:4 risk of having babies with CF, leading to 4% therapeutic abortions; this is important also for the relatives of unaffected carriers of CF genes, about 40 annually.

Termination of pregnancy is a painful remedy, and sensitive genetic counselling is a necessary adjunct to a testing programme which is sure to cause families substantial anxiety; informed consent is essential. Prolonged multidisciplinary follow up is required for atypical cases which may be asymptomatic or mild in early life but develop symptoms later, including sterility in most males due to congenital bilateral absence of the vas deferens (CBAVD). The programme has added significantly to our knowledge of the epidemiology of CF.

By including the CF-affected pregnancies that were terminated during these years the corrected birth prevalence of CF was 1:2000, a reduction in incidence of 30%, and an important public health benefit. This is a precise measure of CF birth prevalence and of its evolution through the combined effect of neonatal screening, prenatal diagnosis, ultrasound examination and family testing. As a result of our experience neonatal screening for CF has been implemented throughout France since January 2002.

A debate continues around the value of screening for CF, because of the lack of a cure for now, and because the value of any treatment is uncertain, despite real nutritional and respiratory benefits. My recommendation is to screen only for the common mutations; the question of whether testing for the carrier state should be made available to all couples requires further discussion. However, we have demonstrated the feasibility of a neonatal screening programme in Brittany (Scotet V et al.2000. Scotet V et al. 2002).


Crossley JR, Smith PA, Edgar BW, Gluckman PD, Elliot RB. Neonatal screening for cystic fibrosis, using immunoreactive trypsin assay in dried blood spots. Clin Chim Acta 1981; 113:111-121.

Scotet V, de Braekeleer M, Roussey M. Rault G, Parent P, Dagorne M, et al. 2000. Neonatal screening for cystic fibrosis in Brittany, France: assessment of 10 years' experience and impact on prenatal diagnosis. Lancet 2000, 356:789-794.

Scotet V, Gillet D, Dugueperoux I, Audrezet MP, Bellis G, Garnier B, Roussey M, Rault G, Parent P, De Braekeleer M, Ferec C, Reseau Mucoviscidose Bretagne Et Pays De Loire. 2002. Spatial and temporal distribution of cystic fibrosis and of its mutations in Brittany, France: a retrospective study from 1960. Hum Genet 2002,111:247-254.


(Cl.F) Surprisingly in our Catholic community religious beliefs have rarely stood in the way of decisions to terminate pregnancy. Testing for the carrier state is now well accepted in Brittany; the transmission of results falls to geneticists and paediatricians. Parents are left to inform affected children of their carrier state at an age they deem appropriate. In the rare case that the supposed father of a child with the carrier state is found not in fact to be the biological father, we have chosen not to provide this information in the hope of preserving the integrity of the family.

The Power of New Technologies to Extend the Scope of Screening.
Peter T Clayton (PC) MD FRCP FRCPCH, Professor of Paediatric Metabolic Disease and Hepatology, Institute of Child Health, UCL, and Great Ormond Street Hospital

Over the past 5 years there has been a dramatic increase in the number of disorders included in neonatal screening programmes in some parts of the world, notably in the USA, Germany and Australia. This development has been largely technology-driven and one major technique that has contributed has been the development of electrospray ionisation mass spectrometry (ESI-MS), for which John B. Fenn won a share of the Nobel Prize for chemistry in 2002. Part of a bloodspot is punched out, eluted with a solvent, and then this technique makes possible the ionisation of non-volatile analytes with masses ranging from that of the smallest aminoacid (glycine) to (in an instrument with a modified quadrupole) a small virus or organelle (e.g. a ribosome). Specificity is enhanced dramatically by the use of a collision cell and a second quadropole, or tandem mass spectrometry (ESI-MS/MS. This is a link to a detailed account). This is a link to an account for lay readers This is now routinely used for the detection of abnormal bloodspot concentrations of amino acids and acyl carnitines. Other analytes that can be measured in a bloodspot include bile acids, 17-hydroxyprogesterone, disialotransferrin and sickle haemoglobin. The list of metabolites that can be measured by ESI-MS/MS grows daily.

Koichi Tanaka also shared the chemistry Nobel Prize in 2002, for another development in mass spectrometry - matrix-assisted laser desorption ionisation, now usually used with time-of-flight mass spectrometry (TOF-MS) - MALDI-TOF-MS. This has made analysis of peptides and small proteins much more straightforward. The combination of a quadrupole, a collision cell and a time of flight section (a Q-TOF instrument) even makes it possible to sequence peptides derived from the tryptic digestion of a protein. For all but the most abundant proteins in a blood spot we currently have to employ a purification step in order to pull out the protein of interest. But it is already possible to prepare subfractions of proteins using surface technology on a chip (SE [surface-enhanced] LDI TOF-MS). This technique is being used to identify biomarkers of a disease without any prior hypothesis. I think we can anticipate the possibility of detecting an increasing number of genetic diseases from a bloodspot by analysis of the proteins.

Conditions which can be diagnosed include some that are untreatable and some that can only be treated by bone marrow transplantation or enzyme replacement (e.g. Gaucher, Fabry, Pompe). Treatment of a patient, which may involve intensive care as well as replacement therapy, can cost up to £40,000 annually.Other diseases for which the treatment is demanding or expensive include maple syrup urine disease, phenylketonuria, and sickle cell disease. Among the conditions amenable to simple effective treatments and which can quickly be diagnosed are MCADD, hypothyroidism, congenital adrenal hyperplasia, and some bile acid synthesis defects. We have developed blood spot methods that can detect defects of bile acid synthesis, which untreated lead to fatal liver disease or dementia in adolescence and early adult life. If diagnosed early the conditions are preventable and treatable by simple bile acid replacement therapy, and thus might well be candidates for neonatal screening.

DNA analysis is already in use as a second line test e.g. in deficiencies of medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain hydroxyacyl CoA dehydrogenase (LCHAD). DNA chip technology gives us a powerful tool for the detection of disorders for which there are a few common mutations, although this is not the case for many disorders.

While a few countries are screening for about 30 conditions, the technology is capable of adding many more. As the number of possibilities for screening increases, it will be important to look at the advantages and disadvantages very carefully for each disorder. In fact, the future should not be led by the technology but by a careful consideration of the power of measurement to prevent disability and death.

Drug companies that develop and market very expensive replacement therapies promote screening for conditions requiring this treatment, and naturally the parents of affected patients want the treatment. Epidemiologists and politicians favour screening for those conditions that are less expensive to treat but, if treated, avoid the need for long-term institutional care for damaged patients e.g. PKU and MCADD. So the pressure for screening may come from parents, paediatricians with particular interests, epidemiologists, politicians and industry and their priorities may be very different.

The choice of disorders for screening may reasonably be determined by the existence of or planning for good treatment of them, or those where a high proportion of the population is affected, such as CF and sickle cell disease. Screening can be justified for disorders for which no effective treatment is available, notably for Duchenne muscular dystrophy, to enable parents to make reproductive decisions such as opting for prenatal diagnosis. Where the existing screening test performs badly clinical biochemists will continue to look for new analytes and new methods. In making these choices the principle to do no harm must apply: we must not treat children who do not need treatment, and where possible we should avoid the psychological trauma of false positive results. And in the case of serious disorders where early treatment improves the quality of life for a child or family it is surely not for clinicians to make the choices.

Developments in mass spectrometry have had a major impact on what is possible; analyses which take a few seconds can be automated and more developments are to come. Once the machine is in use the cost of adding further disorders is relatively low, and the major pressure on cost will be that of some treatments. It is society which will be faced with the ethics of choice.

Extended newborn screening: Which diseases?
Professor R. J. Pollitt (RP), Neonatal Screening laboratory, The Children's Hospital, Sheffield S10 2TH

In 1995 the NHS Health Technology Assessment Programme (HTA) launched its first year by commissioning a systematic review of the role of the screening of neonatal hearing in the detection of congenital deafness, two reviews on newborn screening for inborn errors of metabolism, and later South reviews of screening for haemoglobinopathies and cystic fibrosis. Unfortunately, there was no clear path to implementing the findings of these reviews, generating a great deal of frustration amongst those who had invested time and effort in the initial reviews as well as other clinicians and academics who were eager to innovate and improve their services to patients. Newborn screening of hearing and for sickle cell disease are now well advanced, but with cystic fibrosis and extended screening for inborn errors of metabolism progress has been slow. A major stumbling block has been the difficulty of assessing the complex and diverse issues involved.

There have been many attempts to provide a universal framework within which prospective screening programmes can be evaluated. The ten principles promulgated by Wilson and Jungner (Wilson 1968), addressing severity and incidence (e.g. PKU, severe but rare, and obesity, very common but less severe), provided the foundations upon which to build. Of particular importance among these principles were the following:

· The condition must be an important problem.
· There must be accepted treatment for patients with recognised disease,
· a recognisable latent or early symptomatic stage, and
· a suitable test or examination.
· The test must be acceptable to the population.
· The natural course of the condition, including development from latent to declared disease, should be adequately understood.
· The costs of case finding (including diagnosis and treatment of patients diagnosed) must be economically balanced in relation to possible expenditure on medical care as a whole.

In the UK responsibility for advising on screening policy is now firmly centred in the National Screening Committee (NSC) which has developed the 10 principles into 23 criteria; it is their job to advise ministers on the screening policy. Having decided what is to be done, ministers then instruct the DH to set up the required organisation. National planning means high visibility, and leaves no room for error. In these days there have to be formal mechanisms and paper trails. The political climate, economics and the psychological impact of screening and its legal and ethical framework cannot be ignored, the whole process underpinned by the HTA.

The NSC changed Wilson and Jungner's principle that 'there should be accepted treatment for patients with recognised disease' to 'there should be effective treatment for identified patients'. In these days of evidence-based treatment this would require randomised controlled trials (RCT), proving that the screening programme is effective in reducing mortality or morbidity, in itself a definition of the purpose of newborn screening. For a control group to demonstrate a 50% reduction in mortality would require its including 20 to 30 additional deaths; RCTs are impractical for these rare diseases in view of the extended timescale and cost, and unethical where there is already proven effective treatment. Litigation by parents of babies in the control group ensued following the publication of the results of the Wisconsin trial of screening for CF (Grosse et al. 2004) . One might as well set up a RCT for the control of arterial bleeding after a knife injury. This presents us with the paradox that the more effective an intervention is, the fewer scholarly publications will be devoted to it.

The NSC Handbook provides a valuable basis for assessing prospective screens, and under 35 general headings describes 87 specific items of information that must be assessed by systematic review. However, such a universal framework can create problems when applied to newborn screening. For rare metabolic diseases, the specified level of evidence would be unachievable within a realistic cost and time frame, even if the ethical problem of equipoise within the required randomised controlled trial could be overcome. (Clinical equipoise means that there is a genuine uncertainty on the part of the expert medical community about the comparative therapeutic merits of each arm of a clinical trial). The new criteria, like the Wilson and Jungner originals, are predicated on screening adults; they ignore the family dimension implicit in screening newborns. For example, despite its inability to modify outcome, there is strong support from many parents for newborn screening for Duchenne muscular dystrophy, which is X-linked, because of the genetic information that it can give and its role in easing the family journey, and this applies also to other conditions for which there is no known effective treatment. Despite strongly held professional differences, if the concept of informed choice is to be taken seriously there seems no reason (other than the very real one of resource constraints) why such a screen should not be offered. Very slow progress has been made in exploring the possibilities of tandem mass spectrometry screening in the UK, though elsewhere in the world it is becoming commonplace. This technique can replace older chromatographic methods of detecting PKU which incidentally would also provide the diagnosis of the very rare maple syrup urine disease. MS-MS, using the same Guthrie blood spot, can simultaneously screen for a variety of other disorders of intermediary metabolism, so that the choice of the diseases for which to screen suddenly becomes a matter of policy. The technical complexity of the screening method and subsequent confirmatory tests, the multiplicity of disorders that can be covered and their differing natural history, and the lack of quantitative data on incidence and test performance have all caused problems during the debate. There is difficulty in reconciling the various professional paradigms and some of the NSC criteria appear inappropriate when considered in the context of everyday clinical experience. They suggest that screening is unnecessary where symptoms and signs are evident in the first 10 days of life; in practice the clinical diagnosis of inborn errors of metabolism in newborns who may only appear to be off colour is likely to be delayed or missed. In my opinion newborn screening is still of value even when the disease has presented.

A two year pilot study of MS-MS screening, initially limited to MCADD, started in England in April 2004. This will provide data on test performance, and should give greater confidence in the practicability of the technique, though within limits having firmer numerical data is unlikely to affect the decision whether to continue the screen. When thought is given to the choice of which disease to screen, consider the NSC refinement of its 23 criteria into 87 items. It has truly been said that information without perspective is just a higher form of ignorance. Most of the factors employed in weighing all this data, including quality adjusted life years (QALYs), the willingness to pay, and psychological impact have not proved to be helpful. The distinction between mild and severe cases is only discovered when treatment is attempted, and in any case parents tend to want life years for their babies, and treatment to continue however hopeless, while the the public health focus is on quality adjustment. When clinical reality is brought into the calculation we are faced with the fact that every disorder is heterogeneous, and specificity and sensitivity vary between tests, which makes establishing the diagnostic cut off point very difficult. Screening laboratories need clear guidance about this. The NSC is very concerned about false positives, but the public cannot be expected to tolerate missed cases. When the baby is already ill and diagnosed the screening diagnosis has caused no harm and conferred no benefit; if a baby dies undiagnosed the screening diagnosis causes no harm and there is some benefit in the explanation and genetic advice given.

The main factors in considering the range of diseases covered are likely to be the positive predictive value of an abnormal screening result and the ease with which a presumptive diagnosis can be confirmed. Other factors will be the adequacy of the screening test, the balance between costs and benefits, and in these days our ability to organise the programme. Problems with which we will have to live are the diagnosis of multiple conditions in one baby, and the increasing ease with which very mild cases can be identified (technology creep). Finally, it is regrettable that policy makers are not accepting input from paediatricians, who are increasingly reluctant to take on the care of some of these difficult cases.


Wilson JM. Geneva: World Health Organisation, 1968. See Appendix.

Grosse SD, Boyle CA, Botkin JR, Comeau AM, Kharrazi M, Rosenfeld M, Wilfond BS. Newborn screening for cystic fibrosis: evaluation of benefits and risks and recommendations for state newborn screening programs. MMWR Recomm Rep 2004 Oct 15;53(RR-13):1-36.

Panel discussion.

(PC) I agree that DNA screening can be useful for a disorder in which there are a number of common mutations such as CF, but new personal mutations are the rule in the conditions for which we screen, and this would require screening of the whole gene for each family, an impractical procedure. It is likely to keep its place as back-up testing.

(JL) There is a gradient in the incidence of CF from 1:4000 in the West of Ireland to 1:20,000 in Wessex.

(PC) There is already competition between laboratories for the use of the Guthrie blood spots. Adequacy in the taking of blood spots is crucial. (Cl.F) Our blood spots are first processed elsewhere, and when confirmation of the diagnosis of CF is required by IRT and DNA analysis they come to us as a reference laboratory.

(RP) Guidelines on the interval after birth to take a blood sample are as yet imperfect and variable. For PKU six days works well; that is a suitable interval for hypothyroidism in babies born at term, but the test needs to be delayed in prematures because of their immature pituitary-thyroid axis. Current guidelines prefer Days 5 to 8, with a preference for Day 5; midwives seem unhappy to take the sample on Sundays.
(RP) Why do we value informed choice so much? My impression after speaking to members of the public is that they are often confused and wish that the doctors would tell them what is best. If after having been informed you choose not to have your baby screened, are you not questioning the child's right to standard medical care? The offer of choice requires a decision and so increases anxiety. It is resource intensive; is it cost-effective? (JL) Finally the timing of the sample will be a compromise.

(RP) Screening policy is planned to be uniform across the UK; however it happened that screening for CF started in Scotland some time ago. The UK-wide screening policy is the cause of delay.

(JL) A national screening registration scheme will be very helpful and important, and with today's technology, and preferably input to it from laboratories, efficiency should be possible. Encryption of data and consent will be essential. Unfortunately the NSC is dragging its feet in this matter. (RP) Let commonsense be the guide. Why should blood spots be kept for some years in the UK because of their DNA content, while in France they must be destroyed after three weeks for the very same reason?
(Chair) The incidence of new mutations emphasises the need for a national register; without it there will be no way of discovering their significance.

(RP) Screening will identify some babies with mild disease not requiring treatment, for example for PKU. Theirs are not false positive results. In the case of MCADD positive results must never be regarded as false; a significant health event could be fatal, or may never happen.

(PC) Screening too can be fatal. The identification of cholestatic liver disease requires self-limiting hepatitis to be distinguished from biliary atresia; rushing into liver biopsy will cause the death of 2 per 1000 babies.

(RP) If a Guthrie test has to be repeated to clarify a diagnosis it should be done after an adequate interval, three weeks or more.

APPENDIX: Principles and practice of screening for diseases. Wilson and Jungner 1968

Routine screening of all newborns for genetic disease began with testing for phenylketonuria using the Guthrie procedure on infant blood spotted onto filter paper and air-dried. Currently all states in the US collect dried blood spots for mandatory screening of all newborns for a variety of conditions. Criteria for including diseases in screening panels first suggested by Wilson and Jungner in 1968 were as follows: The condition being screened for should be an important health problem.

The natural history of the condition should be well understood.

There should be a detectable early stage.

Treatment at an early stage should be of more benefit than at a later stage.

A suitable test should be devised for the early stage.

The test should be acceptable.

Intervals for repeating the test should be determined.

Adequate health service provision should be made for the extra clinical workload resulting from screening.

The risks, both physical and psychological, should be less than the benefits.

The costs should be balanced against the benefits.

Clearly, from the early days of screening there were value judgments required in the selection of diseases for screening, but priority has always been given to conditions for which there is effective treatment; for which the best outcomes are achieved with treatment instituted soon after birth; and which are not readily recognized in the nursery except by means of a special test. The number of conditions currently screened for varies between countries and between states within the US, but is increasing to encompass multiple assays for metabolic disorders, hypothyroidism, hemoglobinopathies, and other genetic diseases such as cystic fibrosis. In 2005 an extensive report assembled by Watson et al. of the American College of Medical Genetics established the goal of working toward evidence-based, uniform standards for newborn screening tests. This report was endorsed by the Advisory Committee to the Secretary for Health and Human Services, and several states have since moved to increase the number of conditions screened for. It is anticipated that tests for further conditions to be added to newborn screening panels in the future will be subjected to review using evidence-based criteria. In this report, SCID (Severe Combined Immunodeficiency) was noted to meet many criteria for inclusion in newborn screening panels, but at the time no SCID screening assay had been sufficiently validated for a complete rating to be possible.

Extended newborn screening