Comparison of one-tier and two-tier newborn screening metrics for congenital adrenal hyperplasia

BACKGROUND: Newborn screening (NBS) for the classic forms of congenital adrenal hyperplasia (CAH) is mandated in all states in the United States. Compared with other NBS disorders, the falsepositive rate (FPR) of CAH screening remains high and has not been significantly improved by adjusting 17a-hydroxyprogesterone cutoff values for birth weight and/or gestational age. Minnesota was the first state to initiate, and only 1 of 4 states currently performing, second-tier steroid profiling for CAH. False-negative rates (FNRs) for CAH are not well known. METHODS: This is a population-based study of all Minnesota infants (769 834) born 1999-2009, grouped by screening protocol (one-tier with repeat screen, January 1999 to May 2004; two-tier with secondtier steroid profiling, June 2004 to December 2009). FPR, FNR, and positive predictive value (PPV) were calculated per infant, rather than per sample, and compared between protocols. RESULTS: Overall, 15 false-negatives (4 salt-wasting, 11 simple-virilizing) and 45 true-positiveswere identified from1999 to 2009. With two-tier screening, FNR was 32%, FPR increased to 0.065%, and PPV decreased to 8%, but these changes were not statistically significant. Second-tier steroid profiling obviated repeat screens of borderline results (355 per year average). CONCLUSIONS: In comparing the 2 screening protocols, the FPR of CAH NBS remains high, the PPV remains low, and false-negatives occur more frequently than has been reported. Physicians should be cautioned that a negative NBS does not necessarily rule out classic CAH; therefore, any patient for whom there is clinical concern for CAH should receive immediate diagnostic testing.