Journal of the Royal Society of Medicine Supplement No. 18 Volume 84 1991

Neonatal screening -should

we or

shouldn't we?

P H Weller MB FRCP J V West MB ChB MRCP Dudley Road Hospital, Dudley Road, Birmingham B18 7QH and The Children's Hospital, Ladywood Middleway, Ladywood, Birmingham B16 8ET Keywords: neonatal screening, cystic fibrosis, immunoreactive trypsin

Introduction Neonatal screening for cystic fibrosis (CF) is routinely performed in a number of centres using radioimmunoassay for trypsin"2. Immunoreactive trypsin (IRT) is measured using the blood spots from the Guthrie test and, if significantly raised, is repeated at 2-3 weeks of age. Quantitative pilocarpine iontophoresis sweat tests must then be performed to confirm the diagnosis. Is IRT testing sufficiently reliable to advocate national screening and does early diagnosis and treatment significantly improve the long-term outcome? The latter question of clinical benefit is the more controversial and also the more difficult to prove. The other criteria to be met before recommending CF neonatal screening have been discussed3. CF is an important health problem and, although very variable, the natural history is largely known. There is often a latent or early symptomatic state with delay in diagnosis. A screening test is available and the sweat test is diagnostic, provided it is performed by experienced staff4. Although there is continuing debate about differing treatment policies, the positive optimistic attitude and multidisciplinary team approach practised by the large CF centres world-wide are very similar. Whether a screening programme is cost effective will be difficult to prove, although reduced morbidity in the form of fewer hospital admissions and days in hospital have been noted in a screened population in early childhood5. The number of sweat tests may be reduced producing some cost benefit, but in reality, with earlier diagnosis, there is likely to be increased health costs. Other advantages of early diagnosis include the offer of genetic counselling, which, with pre-natal diagnosis, will prevent further CF affected patients in that family. This may be of great importance to an individual family, but will not have any significant effect on CF population numbers. Carrier testing in the general population, if implemented, would have a greater effect. Many of the treatments advocated and widely used in CF lack critical assessment, with little objective evidence of benefit. Screening could identify cohorts of infants allowing prospective controlled trials of different treatments. This could become very important in the future when more rational treatment based on the basic biochemical defect or gene therapy becomes available. There are also possible harmful effects from screening. Very early diagnosis could disrupt family relationships and bonding, but clinical experience suggests that this is uncommon. Most parents already suspect something is wrong with their infants and are relieved to have a definite diagnosis early2'6. In addition, there is the psychosocial impact on the

family of a false positive result which emphasizes the importance of public education and counselling required in any screening programme. Identifying patients with mild disease and instituting early treatment could adversely affect their prognosis, for example by leading to earlier colonization by Pseudomonas. The screening test The ideal test would be cheap, simple and reliable with few false negatives and few false positives. The BM test detecting increased albumin in meconium is unreliable when used to screen large populations, with too many false positives as well as infants with residual pancreatic function being missed7. Serum IRT is independent of any residual pancreatic function, being 2-5 times higher in neonates with CF8. The level decreases after 1-2 months and is unreliable after this age9. IRT levels in CF infants presenting with meconium ileus can be raised2 or

low'0. The early results of neonatal screening by IRT assay have been encouraging",2 and at a recent conference of neonatal screening in Caen in October 1988, the average initial false positive rate was around 0.5% with a false negative rate of between 4 and 7%. The Belfast experience was less encouraging: 108 240 infants were screened over a 4-year period with an initial false positive rate of 5%, resulting in second specimens being requested from 5120. One hundred and thirty-six of these second specimens were positive, leading to the identification of 34 patients after sweat testing. Fourteen patients were missed (false negatives) giving a sensitivity of only 73%. Between 1985 and 1990 in Wales and the West Midlands, IRT testing was performed on half the blood spots from each area, generating two comparable Table 1. Infants screened in Wales and West Midlands between January 1985 and December 1989 Total number of specimens Number positive on first IRT Number positive on second IRT False positive (sweat test negative) Identified CF (sweat test positive) 4 with meconium ileus with known CF sibling 4 not at risk 62 False negative CF specimens with meconium ileus 3 with known CF sibling 1 10 not at risk Total number of CF patients from screening Incidence of CF

230 076 957 (0.42%) 102 32 70

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Journal of the Royal Society of Medicine Supplement No. 18 Volume 84 1991

Table 2. Infants not screened in Wales and West Midlands between January 1985 and December 1989

246 959 Total number estimated 77 Number of CF patients clinically diagnosed 1: 3207 Incidence of CF 23 with meconium ileus with known CF sibling 11 43 not at risk

CF groups; those detected by screening and those not screened who would be diagnosed clinically. Over the first 3 years, more than 120 000 specimens were screened and 37 infants were detected with CF12. By December 1989, 230077 specimens were screened leading to the identification of 70 patients confirmed on sweat testing (Table 1). During this period, 14 patients are known to have been missed on screening (Table 1). Excluding those known to be at risk (meconium ileus or sibling with CF), there were still 10 false negatives, giving a sensitivity of 85%. More false negatives may still come to light, further reducing the sensitivity ofthe test. During this 5-year period, 77 CF patients have been diagnosed from an estimated unscreened population of 246 959 (Table 2). There is an increased number of meconium ileus infants in this population because, in the- West Midlands, these infants are managed at the Children's Hospital, Birmingham and were excluded from the possibility of IRT testing. When the at risk infants (meconium ileus and siblings) are excluded, there are fewer clinically diagnosed patients in the unscreened population and clinical cases have yet to be identified. Possible clinical benefits Although age of diagnosis is significantly reduced and the anxieties produced by a delay in diagnosis are avoided13'14, there is still controversy whether early treatment will give definite clinical benefit. Clinical observations have suggested that treatment started early in life will have a beneficial effect on the course of the disease15"16. These are anecdotal observations and have been disputed by others3. Some clinical benefit, in the form ofimproved weight gain and fewer chest infections, has been reported in a screened population from Brisbane when compared with an unscreened cohort17. Although there was some overlap, the screened and unscreened cohorts were not exactly comparable. There has been one longer term study following two groups ofpatients, one identified following a positive BM meconium test and the other clinically diagnosed during the same period'8. Survival rate was significantly better in the screened patients and clinical outcome, as judged by chest X-ray, clinical score, lower IgG levels and higher vitamin A levels, were also improved, although lung function at 9 years was similar in the two groups. However, the early management may have been different, more of the screened patients being managed in a CF centre. In Wales and the West Midlands, the two cohorts of patients identified by IRT testing and by clinical diagnosis (not screened), have been managed according to a defined protocol and followed by local paediatricians and their clinical progress compared. Annual assessment at the two centres have included anthropometry, chest X-ray and Shwachman scores, routine microbiology and biochemistry. Hospital

admissions data have been recorded and lung function (forced expiratory flows and volume) performed in the older patients, although only a few--have reached 5 years. Excluding patients with meconium ileus and siblings with CF, no significant anthropometric, clinical or radiological differences have yet to be found when these two 'not at risk' populations are compared14. However, there are fewer numbers in the clinical group suggesting that there. are undetected CF patients in the community and the numbers of older patients are small. Further follow-up is required before any definitive statement can be made on clinical effect from this screening study. Conclusion The only way to diagnose CF early is through neonatal screening, and the IRT test is the most reliable to date. Although its predictive value is such that national screening cannot yet be recommended, it is important that further work continues to improve its reliability. Diagnostic delay is avoided, with some evidence of improved morbidity in the first 2 years, but at the pre'sent time, objective'significant clinical benefit resulting from early diagnosis is still lacking, but this may appear later. Also, before a national programme is considered, it is vital thai diagnostic facilities' ar'e uniform and subsequent management and monitoring follow an agreed protocol. The identification of the' CF gene and its most common mutation (AF508), present in up to 75% of Northern Europe CF families19, allows testing for this mutation on the first positive IRT blood spot, as suggested by Bowling et al.20. This would reduce the number of 'false positives and sweat tests, but may not improve the sensitivity. Costs of screening would inevitably be increased, but this strategy does need fiurther evaluation. Although current data do not support nationwide screening, it is important that regional screening programmes continue where there is an established infrastructure, centralized diagnostic methods and planned follow-up arrangnements, with facilities for good data: storage. The limitations of the IRT test should not be forgotten and any patient with symptoms or signs suggestive of CF must still have a sweat test despite a negative screening test. Acknowledgments: The Wales and West Midlands Neonatal CF Screening Study is supported by the Cystic Fibrosis Research Trust. References 1 Heeley AF, Heeley ME, King DN, Kuzemko JA, Walsh MP. Screening for cystic fibrosis by dried blood spot trypsin assay. Arch Dis Child 1982;57:18-21 2 Wilcken B, Brown ARD, Urwin R, Brown DA. Cystic fibrosis screening by dried blood spot trypsin assay: results in 7500 newborn infants. JPediatr 1983;102-:383-7 3 Phelan PD. Screening for cystic fibrosis. In: Meadow SR, ed. Recent advances in paediatrics, No. 7. Edinburgh: Churchill Livingstone, 1984:103-20 4 Littlewood JM. The sweat test. Arch Dis, Child 1986; 61:1041-3 5 Wilcken B, Chalmers G. Reduced morbidity in patients with cystic fibrosis detected by neonstal screening. Lancet

1985;ii:1319-21 6 Al-Jader LN, Goodchild MC, Ryley HC, Harper PS. Attitudes of parents of cystic fibrosis children towards neonatal screening and antenatal diagnosis. Clin Genet 1990;38:460-5

Journal of the Royal Society of Medicine Supplement No. 18 Volume 84 1991 7 Desai N, Nousia-Arvanitaks S. False negative results in screening for cystic fibrosis. J Pediatr 1977;91: 447-8 8 Crossley JR, Elliott RB, Smith PA. Dried blood screening for cystic fibrosis in the newborn. Lancet 1979;i:472-4 9 Rock MJ, Mischler EH, Farrell PM, et al. Newborn screening for cystic fibrosis is complicated by age-related decline in immunoreactive trypsinogen levels. Pediatrics 1990;85:1001-7 10 Duhammel JF, Travert G, Delmas P, Bronard J, Venezia R. Special features of the time related evolution in IRT blood levels in six out of seven newborns with cystic fibrosis complicated by meconium ileus. In: Lawson D, ed. Cystic fibrosis: horizons. Chichester: John Wiley & Sons, 1984:208 11 Roberts G, Stanfield M, Black A, Redmond A. Screening for cystic fibrosis: a four year regional experience. Arch Dis Child 1988;63:1438-43 12 Ryley HC, Deam SM, Williams J, et al. Neonatal screening for cystic fibrosis in Wales and the West Midlands: 1. Evaluation of immunoreactive trypsin. J Clin Pathol 1988;41:726-9 13 Wilcken B, Towns SJ, Mellis CM. Diagnostic delay in cystic fibrosis: lessons from newborn screening. Arch Dis Child 1983;58:863-6

14 Chatfield S, Owen G, Ryley HC, et al. Neonatal Screening for cystic fibrosis in Wales and the West Midlands: Clinical assessment after 5 years of screening. Arch Dis Child 1991;66:29-33 15 Shwachman H, Redmond A, Khaw KT. Studies in cystic fibrosis: Report of 130 patients diagnosed under 3 months of age over a 20 year period. Pediatrics 1970;46:335-43 16 Orenstein DM, Boat TF, Stern RC, et al. The effect of early diagnosis and treatment in cystic fibrosis. A seven year study of 16 sibling pairs. Am J Dis Child 1977;131:973-5 17 Bowling F, Cleghorn G, Chester A, et al. Neonatal screening for cystic fibrosis. Arch Dis Child 1988; 63:196-8 18 Dankert-Roelse JE, te Meerman GJ, Martijn A, et al. Survival and clinical outcome in patients with cystic fibrosis, with and without neonatal screening. J Pediatr 1989;114:362-7 19 McIntosh I, Lorenzo M-L, Brock DJH. Frequency of AF508 mutation in cystic fibrosis chromosomes in UK. Lancet 1989;ii:1404-5 20 Bowling FG, McGill JJ, Shepherd RW, Danks DM. Screening for cystic fibrosis: use of AF508 mutation. Lancet 1990;335:925-6

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Neonatal screening--should we or shouldn't we?

Journal of the Royal Society of Medicine Supplement No. 18 Volume 84 1991 Neonatal screening -should we or shouldn't we? P H Weller MB FRCP J V We...
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