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Re: Developing newborn screening: Crusaders or committees

The commentary[1] by Professors Hall and Davis on the development of national policy for neonatal hearing screening was both informative and restrained. They identified shortcomings in the mechanisms for translating evidence generated by the Health Technology Assessment Programme into policy, and referred briefly to the difficulties being experienced in developing newborn screening using tandem mass spectrometry (MS-MS).[2]

Two reviews on newborn metabolic screening were commissioned in the first round of the HTA programme in 1995.[3][4] Both surveyed the potential of MS-MS screening in some detail but otherwise covered a different selection of diseases, reflecting ambiguity in the commissioning brief. There were differences in the way the results of the literature searches were presented, as well as genuine differences in interpretation.[5] Nevertheless, both reviews concluded that it was practicable and potentially worthwhile to extend the range of diseases in the UK newborn screening programme by using MS-MS in place of the current methods for phenylketonuria screening. Both reports recommended preliminary field studies before general implementation was considered.

Though neonatal screening for phenylketonuria is well established and regarded as a successful programme, the proposal to extend it to other diseases aroused considerable controversy. The presentation of two differently constructed reports added to the confusion. Initially there was no obvious mechanism for taking matters forward but in late 1998 the topic was included in the HTA programme call for proposals. A multidisciplinary group, including some who had contributed to the HTA systematic reviews, designed a comprehensive study of screening performance, clinical outcomes, cost-effectiveness analysis and the effects of screening on parental quality of life. This study focused on a single disease, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, which is common enough in the UK to generate statistically valid results within a realistic time scale. It is fairly well understood condition though, because the benefits of treatment seem overwhelmingly obvious to the clinician (the "self-evident evidence paradox"[5]), there have been no controlled clinical studies. Despite considerable support the proposal eventually foundered 18 months later through a shortage of funding.

In its report (June 2000) to the National Screening Committee,[6] the Child Health Screening sub-group (CHSG) identified two outstanding issues relating to screening for MCAD deficiency:
1) unanswered questions about the laboratory performance of MS-MS screening in large-scale use, particularly whether sensitivity and specificity can be kept at a satisfactory level
2) the lack of evidence that screening (as opposed to later diagnosis after clinical presentation) improves overall outcome.

It concluded that there was fair evidence to reject screening as a national programme at present but good evidence to support further studies. However, in October 2000 the CHSG refused to endorse proposals for a more modest study, concentrating on screening performance and clinical effectiveness, because this did not address the issue of parental anxiety.

Given the natural history of undiagnosed MCAD deficiency[7] and the effectiveness of routine management,[8] it seems inherently unlikely that, as a whole, parents of MCAD deficient babies would be better off not knowing about it. Without screening, and ignoring cases with neonatal onset, about 60% of parents with MCAD deficient babies are spared the anxiety of managing the condition but one in three of their babies will die. (The other two are not false positives in the normal sense. It is not possible to predict which babies will be spared, any more than we can be certain which of us need not bother to fasten our seat belts). The remaining 40% of parents only have to worry about treatment after symptom-triggered diagnosis but one in two of their babies will by then have suffered some permanent neurological damage. Even if psychological data were collected they would, unless at one of the extremes, be difficult to incorporate into a decision model.

Several UK screening laboratories are using MS-MS to screen for phenylketonuria but have observed a moratorium on extending it to other diseases. However, worldwide over 1.5 million babies have now had extended screening by MS-MS and encouraging preliminary reports are available (as abstracts) for several programmes. The latest CHSG recommendation, which has been accepted by the National Screening Committee, is that we should await definitive publication of these results over the next few years and then undertake a further policy review. This is not really a satisfactory solution. Overseas experience can demonstrate the feasibility of MS-MS screening (indeed has done so) but is a poor guide to performance and impact; the genetic composition of the populations screened, age at screening, patterns of clinical care, and social attitudes are likely to be significantly different from those in the UK.

Historically, neonatal metabolic screening has been lead by crusaders, like the late Robert Guthrie, who got things done but occasionally over-reached themselves. Our experiences show that a committee-based approach can also be problematical. It is now some 7 years since I originally suggested MS-MS as a suitable topic for the nascent HTA programme and there is a certain clinically-driven sense of urgency.[9] Lack of progress is partly attributable to lack of research funding but, with finite resources, rare diseases will always be at a disadvantage compared to numerically more important conditions. Agreement on how to incorporate existing clear-cut but "low quality" clinical and laboratory evidence into a formal decision framework would be helpful.[10][11] Additionally, the criteria-based approach pioneered by Wilson and Jungner may need to be tempered by an element of risk management. Does the risk in residual uncertainties surrounding screening for MCAD deficiency still outweigh the largely predictable consequences of doing nothing?

R J Pollitt
Neonatal Screening Laboratory
Children's Hospital, Western Bank
Sheffield S10 2TH, UK

References
(1) Kennedy CR, Hall D, Davis A. Neonatal screening for hearing impairment [Commentary]. Arch Dis Child 2000;83:377-83.

(2) Bartlett K, Eaton SJ, Pourfarzam M. New developments in neonatal screening. Arch Dis Child Fetal Neonatal Ed 1997;77:F151-4.

(3) Pollitt RJ, Green A, McCabe CJ, et al. Neonatal screening for inborn errors of metabolism: cost, yield and outcome. Health Technol Assess 1997;1(7):1-203.

(4) Seymour CA, Thomason MJ, Chalmers RA, et al. Newborn screening for inborn errors of metabolism: a systematic review. Health Technol Assess 1997;1(11):1-95.

(5) Pollitt RJ. Principles and performance: assessing the evidence. Acta Paediatr 1999;88(Suppl 432):110-4.

(6) UK National Screening Committee. 1st National Screening Conference, London, 7th December 2000.

(7) Pollitt RJ, Leonard JV. Prospective surveillance study of medium-chain acyl-CoA dehydrogenase deficiency in the UK. Arch Dis Child 1998;79:116-19.

(8) Wilson CJ, Champion MP, Collins JE, Clayton PE, Leonard JV. Outcome in medium-chain acyl-CoA dehydrogenase deficiency after diagnosis. Arch Dis Child 1999;80:459-62.

(9) Tanner S, Sharrard M, Cleary M, et al. Screening for medium chain acyl-CoA dehydrogenase deficiency has still not been evaluated. BMJ 2001;322:112.

(10) Lilford RJ, Thornton JG, Braunholtz D. Clinical trials and rare diseases: a way out of the conundrum. BMJ 1995;311:1621-5.

(11) Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR. Bayesian methods in health technology: a review. Health Technol Asses 2000;4(38):1-129.