Mass screening of the newborn for metabolic disease.

Over large parts of the world all newborn infants are, in principle or in practice, examined by some biochemical technique for phenylketonuria. This revolutionary practice is barely 10 years old; it is worth considering how it started and why it has spread. Until the development of a dietary treatment, phenylketonuria was considered, like the other inborn errors of metabolism, a suitable subject for academic research but of no importance to the practising paediatrician. This changed when it was found that dietary treatment of affected children aged more than a few months often led to improvement in their neurological and other signs and symptoms. However, some irreversible damage to the brain occurred during those first months-for optimum effect, treatment had to start within a few weeks of birth, long before any symptoms appeared (Woolf et al., 1958). Diagnosis had therefore to depend on biochemical tests of blood or urine from apparently well babies; and logically, such tests would have to be applied to all newborn infants. Preventive medicine of this type marks a revolution in medical thought; like all revolutions, it is not entirely unopposed, nor is it bloodless. The principle of screening all newborn infants for phenylketonuria has been very widely, though not quite universally, accepted-the major problems have been in obtaining the necessary specimens and in the tests themselves. The first attempt at mass screening all newborn infants in a city used liquid urine specimens collected by the mothers; the difficulties in obtaining suitable specimens of urine caused only 25% of newborn infants to be tested (Gibbs and Woolf, 1959). Use of 'Phenistix' by the health visitor improved the test rate to over 9900, but difficulties arose in carrying out and interpreting the test and in the later discovery of 'occult' phenylketonurics who gave negative results with Phenistix (Woolf, 1967a). For these and other reasons a considerable proportion of infants with phenylketonuria (perhaps 40%) were not diagnosed when Phenistix was nominally being widely used (Pitt and Wilmot, 1964; Stephenson and McBean, 1967; Woolf, 1967b; Carson, Carre, and Neill, 1968). Much more reliable laboratory tests are now available, e.g. the Guthrie inhibition assay using blood (Guthrie and Susi, 1963), spectrofluorometric assay of phenylalanine in blood (Hill et al., 1965; Searle et al., 1967), paper chromatographic detection of o-hydroxyphenylacetic acid in urine (Berry Umbarger, and Sutherland, 1965; Woolf, 1967a) or of phenylalanine in blood (Berry, 1962; Efron et al., 1964; Scriver, Davies, and Cullen, 1964; Mellon and Stiven, 1966). The blood specimens are collected by heel-prick on absorbent paper or in heparinized capillary tubes, the urine specimens by the mother placing absorbent paper in the infant's napkin. In Cardiff, for example, 98 9% of the infants born during 1967 were screened for phenylketonuria and six other inborn errors of metabolism by chromatographic examination of urine collected on filter paper. The chromatographic test for urinary o-hydroxyphenylacetic acid usually becomes positive at the same time as the Guthrie test on blood, on day 2-5 or occasionally later, and comparative tests have shown that the two are equally reliable: urine collection on or after day 10 to 14 is recommended for administrative and other reasons (Woolf, 1967a; and unpublished). Tests for urinary phenylpyruvic acid, in contrast, may not become positive for weeks, if at all. Testing filter paper urine specimens with ferric chloride overcomes the difficulties and uncertainties of collecting liquid specimens or using Phenistix on a wet napkin; however, a phenylketonuric might not give a positive result till he was 6 weeks old and, if he were of the occult type, not even then. Furthermore, phenylpyruvic acid gradually decomposes on filter paper (Centerwall, Berry, and Woolf, 1963), and a proportion of false negative results is to be expected from this cause. In this issue Cahalane (1968) reports the use of the Guthrie method in Ireland. The great bulk of the specimens of blood were collected, before discharge, in the hospitals in which the babies were born. Administratively this is by far the simplest