Intended for healthcare professionals


Neonatal screening for cystic fibrosis

BMJ 1998; 316 doi: (Published 07 February 1998) Cite this as: BMJ 1998;316:404

No evidence yet of any benefit

  1. Nicholas J Wald, Professora,
  2. Joan K Morris, Senior lecturera
  1. a Wolfson Institute of Preventive Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, London EC1M 6BQ

    Neonatal screening for cystic fibrosis by using a simple test that can be performed on the “blood spots” routinely collected in screening for phenylketonuria and hypothyroidism raises exciting possibilities. The test is relatively easy to perform and the specimen is already collected, but even a simple test performed on millions of individuals will be costly, and the early knowledge of a serious disorder will cause more harm than good if there is no effective remedy. The results of a large randomised trial of neonatal screening for cystic fibrosis have recently been published in the New England Journal of Medicine.1 The trial involved two thirds of a million newborn infants and their subsequent follow up. The conclusion that screening and subsequent treatment improves the growth and development of children with cystic fibrosis was met with enthusiasm.2 Unfortunately the conclusion may not be justified, and the results suggest that any long term benefit is small.

    The neonates were randomised into two equal groups of about 325 000 and immunoreactive trypsinogen measured on the blood spots of all infants; towards the end of the study DNA testing was also performed. In the “screened” group the results were examined immediately and acted on if they were positive. In this group there were 74 cases of cystic fibrosis (15 with meconium ileus recognised at birth, 54 detected by screening, and five missed on screening but diagnosed later clinically). In the control group the trypsinogen results were stored and examined when the child was 4 years old. In this group there were 67 cases of cystic fibrosis (18 with meconium ileus recognised at birth, 40 who presented clinically before the age of 4, and nine who were diagnosed only when the trypsinogen results were examined at the age of 4). The expectation of benefit from screening can only be small because the median age at diagnosis was 23 weeks in the controls, only 16 weeks later than in the screened group. Screening materially advanced diagnosis in only a minority.

    The weights and heights of the two groups are reported in the paper. A difficulty that is not discussed in the report is that the data in children under 4 years are subject to selection bias. On average, affected infants in the screened group are likely to be healthier than identified affected infants in the control group, because the affected infants in the screened group are likely to include infants with less severe disease that would not have presented clinically had they not been screened. Only after 4 years are the two groups, in expectation, comparable, and only after this point does the randomised design ensure the avoidance of bias. The conclusion by the authors that screening is associated with taller and heavier children rests on the results in the whole period of 10 years, but this is statistically strongly influenced by the results in the first three years, which are open to selection bias. The authors do not present a separate analysis restricted to follow up after the first four years. The pattern of results shown in the graphs comparing height and weight at different times since birth suggests little difference between the two groups. The study design is an ingenious one, but the analysis of the results is problematic.

    One must conclude, therefore, that this trial provides no evidence of any benefit of screening. The pattern of results after four years weighs against a material benefit, but the number of cases is small, so failure to find a significant difference does not exclude a small benefit. Longer follow up (beyond the 10 years of age in this study) may be informative. When the children are older the key outcome measure should be lung disease because it is this above all that causes the severe disability and premature death in cystic fibrosis. This is not covered here, but with longer follow up the rate of hospital admissions for respiratory illness in the two groups could be reported.

    Although we cannot say at this stage whether neonatal screening is worth while, the present evidence is not encouraging and does not warrant any change in policy from that suggested by the National Institutes of Health consensus development statement,3 which concluded: “Offering cystic fibrosis genetic testing to newborn infants is not recommended.”


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