Newborn screening for hyperphenylalaninemia on day 5: is 240 mumol/liter the most appropriate cut-off level?

In most countries, including the UK, Sweden, Japan, and the FRG, blood samples for newborn screening are not taken until Day 5, in contrast to Day 3 in the United States. This results in fundamentally different conditions with respect to the amount of phenylalanine ingested by the newborn until the day of sampling. Nevertheless those countries who routinely screen on Day 5 have adopted the U.S. cut-off level of 240 mumol/liter (4 mg/dl). This study is the first to compare, via direct evaluation of a regional screening program, whether a higher or a lower cut-off level would be more appropriate for phenylalanine screening on Day 5. In a prospective study on phenylalanine screening with 132,638 infants (cut-off level 120 mumol/liter) the number of recalls was 152. Among them 14 cases with a permanent disorder of phenylalanine metabolism were detected. With the officially recommended cut-off level of 240 mumol/liter as well as with the 360 mumol/liter level used in some centers, the recall rate would have been lower, specificity higher, and the predictive values of a positive result higher. On the other hand sensitivity would have been significantly lower (only 80%). Because in newborn screening the crucial point is sensitivity, our data suggest that in phenylalanine screening done on Day 5 cut-off levels of 240 or 360 mumol/liter are less appropriate than a lower cut-off level. With higher cut-off levels a large proportion of patients (one-fifth) with a permanent disorder of phenylalanine metabolism would be missed.