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Expanded newborn screening: anticipating the future

16 June, 2008

Expanded newborn screening: anticipating the future

This a part-report of a joint whole-day meeting of the Forum on Maternity and the Newborn of the Royal Society of Medicine with the section of paediatrics and child health. The morning session was chaired by John Dodge, professor of child health at the University of Wales and president of the section of paediatrics and child health. The afternoon session was chaired by Dr Patricia Livsey, head of child health at London’s City University.
This a part-report of a joint whole-day meeting of the Forum on Maternity and the Newborn of the Royal Society of Medicine with the section of paediatrics and child health. The morning session was chaired by John Dodge, professor of child health at the University of Wales and president of the section of paediatrics and child health. The afternoon session was chaired by Dr Patricia Livsey, head of child health at London’s City University.


Basil Lee is a retired GP and obstetrician and secretary of the RSM Forum on Maternity and the Newborn 

Midwives magazine: August 2005

Extended newborn screening: which diseases?


Professor RJ Pollitt, neonatal screening laboratory, Sheffield Children’s Hospital In 1995 the NHS Health Technology Assessment Programme (HTA) launched its first year by commissioning a systematic review of the role of screening neonatal hearing in the detection of congenital deafness, two reviews on newborn screening for inborn errors of metabolism, and later reviews of screening for haemoglobinopathies and cystic fibrosis (CF).


Unfortunately, there was no clear path to implementing the findings of these reviews, generating a great deal of frustration among those who had invested time and effort, while other clinicians and academics 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 CF and extended screening for inborn errors of metabolism, progress has been slow. A major stumbling block has been the difficulty in assessing the complex 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 (1968) provided the foundations on which to build. Of particular importance among these principles were the following:

  • Thecondition must be an important problem, addressing both severity and incidence (for example, phenylketonuria (PKU) – severe, but rare – and obesity – very common, but less severe)

  • There must be accepted treatment for patients with the recognised disease

  • There must be a recognisable latent or early symptomatic stage n There must be 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 ministers on screening policy is centred in the National Screening Committee (NSC). Having decided what is to be done, ministers then instruct the Department of Health 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 being underpinned by the HTA.


In the NSC handbook,Wilson and Jungner’s principle that ‘there should be accepted treatment for patients with recognised disease’ is changed to ‘there should be effective treatment or intervention for patients identified’ and requires supporting ‘evidence from high-quality randomised controlled trials (RCT) that the screening programme is effective in reducing mortality or morbidity’, in itself a definition of the purpose of 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 RCT could be overcome. (Clinical equipoise means 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).


For the control group to demonstrate a 50% reduction in mortality would require it to include 20 to 30 additional deaths. 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). Paradoxically, the more effective an intervention is, the fewer scholarly publications will be devoted to it, and no one has set up an RCT on the control of arterial bleeding after a knife injury!


This universal framework creates additional problems when applied to newborn screening. 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 it can give and its role in easing thefamily journey. 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 screens should not be offered.


It has been suggested that screening is unnecessary where symptoms and signs are evident in the first ten 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. Very slow progress has been made in exploring the possibilities of tandem mass spectrometry (MS-MS) screening in the UK, though elsewhere in the world its use is becoming commonplace. This technique can replace older chromatographic methods of detecting PKU, which incidentally also provide the diagnosis of the very rare maple syrup urine disease. MS-MS, using the same Guthrie blood spot, can simultaneously screen selectively for a variety of other disorders of intermediary metabolism, so the choice of the diseases for which to screen suddenly becomes a matter of policy.


The technical complexity of the screening method and 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. A twoyear pilot study of MS-MS screening, initially limited to medium-chain acyl-CoA dehydrogenase deficiency, (MCADD) started in England in March 2004. This is providing encouraging data on test performance, and should give greater confidence in the practicability of the technique. The study also includes an economic evaluation and an assessment of the psychological impact of a positive result.


However, it is doubtful whether having firmer numerical data will make the decision of whether or not to continue or even to expand the screen much easier. It has truly been said that information without perspective is just a higher form of ignorance. Parents tend to want life years for their babies, and treatment to continue however hopeless, while the public health focus is on the quality of survival. Specificity and sensitivity vary between tests, which makes establishing the diagnostic cut-off point very difficult. Is a test of low sensitivity better than no test at all? The NSC is very concerned about false positives, but the public cannot be expected to tolerate missed cases.


In summary, the main factors in considering the range of diseases to be 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 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, for some conditions, the increasing ease with which very mild cases can be identified. Finally, it is regrettable that policy-makers are not accepting more input from paediatricians, who are increasingly reluctant to take on the care of some of these difficult cases.





Wilson JM, Jungner G. (1968) Principles and practice of screening for diseases. See: http://bmj.bmjjournals.com/cgi/content/full/ 322/7295/1174/T1 (accessed July 2005). Grosse SD, Boyle CA, Botkin JR, Comeau AM, Kharrazi M, Rosenfeld M,Wilfond BS. (2004) Newborn screening for cystic fibrosis: evaluation of benefits and risks and recommendations for state newborn screening programs. Morbidity and Mortality Weekly Report – Recommendations and Reports 53(RR-13): 1-36.


The practical implications of neonatal screening – the flow of information


Dr Ying Foo, head of chemical pathology and director of newborn screening, Great Ormond Street Hospital for Children, London The UK Newborn Screening Programme Centre began its work in 2001 to develop policies and standards to ensure a quality service. The efficient delivery of screening and the flow of information derived from it depend on the close cooperation of professionals in a number of organisations: midwifery, the screening laboratory, the hospital Trust clinical team, (metabolic consultants, endocrinologists, dieticians and specialist nurses), the Child Health Department and the primary care Trust (PCT). Midwives discuss screening with parents prenatally and provide them with information leaflets.


They must also obtain informed consent to the screening process, and it is their responsibility to take the blood spot samples by heel prick between days five and eight after a birth – ideally on day five. It is very important that blood spots are taken correctly – each circle must be filled with blood, and the same amount of blood must appear on both sides of the card; there must be no multi-spotting. Only in this way can false positive results be avoided. The card must be posted to the screening laboratory within 12 hours, avoiding hospital internal mail systems that can introduce delays. The laboratory’s requests for repeat samples have to be handled in the same way. The accuracy of data on the screening card is vital – it is preferable to provide the demographic details on a printed label, including the NHS number as a unique identifier, to facilitate tracking and to reduce transcription errors. If the parents decline screening, a blank card completed with demographic data is sent to the laboratory to indicate this and close the case. In the screening laboratory, the sample is assigned a number and the data entered on the computer.


Blood spots of 3mm are punched from the cards and the assays set up to run overnight. Using MS-MS a single spot can be screened for PKU and MCADD. A further punched spot is examined for congenital hypothyroidism, and these three conditions are given priority – the examination for sickle cell disease is done last. Repeats are requested when samples are borderline or rejected. Abnormal results are confirmed and available within four working days – PKU and MCADD cases are referred to metabolic clinicians and hypothyroidism to endocrinologists on the same day. Results will be downloaded directly to the Child Health Department’s computer for the information technology-linked districts, or hard copies sent to unlinked districts, and positive results reported by letter to GPs, clinicians, and the Child Health Department.


Specialist nurses and dieticians are also informed, and the parents and baby are given an appointment when confirmatory investigations are carried out and appropriate treatment started. Samples are rejected if they are insufficient, contaminated, collected before day five, delayed or damaged in the post. If a baby has received a blood transfusion, a repeat sample is requested for sickle cell disease after three months. If this proves positive, the baby is referred to a haematology consultant. Child health departments are responsible for maintaining demographic details, ensuring complete coverage of the newborn and reporting results to health visitors. Babies who have been missed should be identified by day 19 so that testing can be carried out immediately. The responsibilities of PCTs include informing parents of normal results, recording results in the child health records and overseeing screening performance in terms of quality issues, audit and risk management. The delivery of a quality service relies heavily on good communication between professionals and clear responsibility and accountability at every stage.


What is it like to be told that your ‘healthy’ baby has a disease?


 Wendy Cheale, parent We were a normal family, married, with a daughter Holly aged three (non-PKU) and a second child on the way. I was employed, but have since given up my job because of family pressures. My husband has a 35-yearold cousin with PKU. Alexander, apparently a healthy baby, was born in May 2000, but 13 days later I was told that the Guthrie test was positive and that he possibly had PKU.



I remembered the midwife mentioning an unpronounceable name and that she had never had a positive result in all her years of nursing. In fact, if that was the case I would rather she did not stick a needle in my baby – perhaps we could leave it, I asked? She then explained that she would have to record this and notify our GP, (another set of questions, I thought) so I consented. A nurse rang us, explained the condition and said that we must go to the hospital the next day. She mentioned a strict diet, that I must stop breastfeeding and brain damage with consequent learning difficulty if we did not follow the diet.We were devastated. Would Alexander be brain damaged? Disabled? Go to normal schools? Lead a normal life? We were fortunate that we could be seen the next day – I now know that some parents are informed of the Guthrie result on a Friday and have to wait over a weekend before seeing the expert.


We hope that the professionals will take note of that, and defer giving information to a day when parents can be seen without the weekend delay with its anxiety, and perhaps the guilt of continuing harmful breastfeeding for a further two days. Our consultant spent two hours explaining the condition and answering our questions. A second blood test for phenylalanine was taken (we hoped that meant that they had made a mistake, we were in denial).We were told we would have to learn to do blood tests ourselves – these tests were quite frequent at first, and we were relieved when our health visitor undertook them for about three months.


At last we found that we can easily use the Softclix pen devices developed for diabetics. Although the diet was explained to us, at that time we were not shown any of the available food substitutes, nor were we given a demonstration of mixing the powder supplement into a drink, all of which would have been helpful. I decided not to breastfeed, because all the foods needed to be weighed and measured. Now we were faced with making up the supplement, no easy matter. It had a terrible smell and was lumpy, but after a couple of hours and many attempts it became a drink.


Fortunately, Alexander did not mind it, he was such an easygoing baby. However, by the age of two he was refusing the evil-tasting supplement, it was taking hours to persuade him to drink it and we needed expert advice on getting round this. Our fear that he would be unable to eat most normal foods proved to be groundless, when eventually we learned that some were permitted as long as they were carefully weighed. This is less of an issue for children with mild disease.We take the special foods with us when eating out, asking restaurants for their permission to use it. Numerous problems crop up in the management of PKU, and we depended very much on weekly discussions with the dieticians, although we found that we came to know more than they did unless they were specialists.


The professional services tend to neglect the emotional needs of PKU families, and the National Society for PKU (NSPKU) has been an enormous support to us. Speaking to other parents with their experiences is invaluable, but it would be most helpful if a buddy PKU parent counsellor were assigned to a newborn child – to know you are not alone and to stress the importance of persevering with the dietary regime. NHS support is generally very good and the staff are dedicated, but there is still a knowledge gap – lacking experience, the consultant made inappropriate comments: ‘Nobody knows if PKU children will develop normally.’ Although NSPKU produce a leaflet, dental care has been a problem.We were unaware of the destructive action of supplement on the teeth and of the effect of the replacement diet, which is high in sugar. Now Alexander has some severe decay. The PKU diet can, unless one is very careful, lead to a child’s exclusion from children’s parties, eating out with friends, pancake day at school and so on. Alexander is very aware of being socially excluded in any way, and this will continue to affect him. But PKU is part of our daily lives now, just another long-term project to manage. Alexander is developing normally, a happy four-year-old who makes it all worthwhile.


What is it like to learn that your baby’s disease has been missed for lack of screening?


Tracey Randle, parent My youngest child Dion’s CF was not diagnosed until he was four and a half years old. ‘Maybe he has food allergies’, ‘Maybe he is allergic to milk’, ‘Maybe it’s toddler diarrhoea’, ‘It’s asthma’, I was told as I went from doctor to doctor seeking help for his illness. I was in great distress, feeling that only I realised how very ill he was, even after inconclusive testing at Great Ormond Street Hospital. My family and I could only watch as he deteriorated, vomiting and in severe pain. He was asleep much of the time, and I could only sit by, afraid that he would die in his sleep. My pleas for help were not heard or understood, and it was even suggested that the symptoms were in my imagination, until I rang to say that my son was unconscious on the floor with rectal prolapse. ‘Push it back up,’ I was told, ‘we’ll send you an appointment’. To which I could only scream ‘Help me, or tell me where I can go for help’. My experiences have left me lacking in trust for the professionals – when the soya milk recommended by a dietician did not suit him, I was told ‘We know what we’re doing’.


Whenever new medication is proposed I feel doubtful. Finally I was relieved to have the diagnosis of CF, but it was devastating to learn that this illness was incurable, even terminal, and that it had been missed due to lack of screening. If as a result of screening Dion’s CF had been diagnosed at the age of two months, I could have accepted the predictable course of the illness and his treatment by physiotherapy and antibiotics. As it is, I am left anxious and distrustful on the one hand, and on the other delighted by every sign of progress, such as his recent ability to swallow tablets. At present he is well, thanks to the treatment he should have been getting for over four years. Now I hope and pray that CF screening will be available for every newborn child in the near future. I cannot overpraise the support that I and other parents get from the CF Trust, but I cannot help sometimes feeling that all the help I get is ‘too little, too late’. If you remember one thing from my talk let it be this: lack of screening and unwillingness to listen nearly killed my son.


Further information


For more information about MS-MS, please visit:


This report appears in full on the Forum’s website, see: www.motherhood.org.uk  where references and the extensive discussion are included.


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