Evaluation of a New Laboratory Protocol for Newborn Screening for Congenital Adrenal Hyperplasia in New Zealand

Abstract

Between 2005 and 2021, 49 cases of classical congenital adrenal hyperplasia were diagnosed in New Zealand, 39 were detected in newborns and 10 were not detected by screening. For every case of CAH detected by screening, 10 false-positive tests are encountered. Second-tier liquid chromatography-tandem mass spectrometry (LCMSMS) has the potential to improve screening sensitivity and specificity. A new laboratory protocol for newborn screening for CAH was evaluated. Birthweight-adjusted thresholds for first- and second-tier 17-hydroxyprogesterone, second-tier 21-deoxyicortisol and a steroid ratio were applied to 4 years of newborn screening data. The study was enriched with 35 newborn screening specimens from confirmed CAH cases. Newborn screening was conducted on 232,542 babies, and 11 cases of classical CAH were detected between 2018 and 2021. There were 98 false-positive tests (specificity 99.96%, PPV = 10.1%) using the existing protocol. Applying the new protocol, the same 11 cases were detected, and there were 13 false-positive tests (sensitivity > 99.99%, PPV = 45.8%, (X2 test p < 0.0001). Incorporating the retrospective specimens screening sensitivity for classical CAH was 78% (existing protocol), compared to 87% for the new protocol (X2 test p = 0.1338). Implementation of LCMSMS as a second-tier test will improve newborn screening for classical CAH in New Zealand.

Epidemiology and diagnostic trends of congenital adrenal hyperplasia in Denmark: a retrospective, population-based study

“…Screening for CAH has been implemented in neonatal screening programs in several countries worldwide, with the aim to achieve early identification of newborns with SW CAH to prevent salt-wasting adrenal crisis and reduce mortality. 3 , 18 Since the screening has a very high sensitivity for SW CAH, 7 , 9 prevalence estimates of SW CAH among newborns participating in screening are available from several countries. 3 In screening studies from countries with health care systems comparable to the Danish system, the reported prevalence of SW CAH range from 3.4 to 5.5 per 100,000 newborns (Sweden: 148 cases among ∼2,700,000 newborns 11 ; Netherlands: 114 cases among 2,235,931 newborns 19 ; New Zealand: 40 cases among 1,175,973 newborns 20 ).…”

“…17-OHP is the preferred metabolite for screening and reflects the residual activity of 21-hydroxylase. 21 Depending on the cut-off level, screening detects some newborns with SV CAH, and seldom also NC CAH, 7 , 9 , 10 though NC CAH is not a target disease of the screening. In the screening study from the Netherlands, 19 14 newborns with SV CAH were detected at screening, corresponding to a prevalence of 0.6 per 100,000.…”

“… 3 Because of neonatal screening the prevalence of CAH among screened newborns is available from various countries. 3 However, screening does not pick up all newborns with SV CAH, 7 , 9 and NC CAH is only occasionally detected. 10 Valid data on the incidence and prevalence of these forms of CAH are therefore not easy to obtain, nor are data regarding age at diagnosis.…”

The use of liquid chromatography-tandem mass spectrometry in newborn screening for congenital adrenal hyperplasia: improvements and future perspectives

“…In a retrospective analysis of 143 cases of CAH identified by newborn screening over 26 years in Sweden, the sensitivity of screening for SW-CAH, SV-CAH and NC-CAH were 100%, 79.7% and 32.4% respectively when molecular analysis was used to define disease classification ( 13 ). Higher 17OHP thresholds for babies born before term will improve the PPV of screening but may reduce the screening sensitivity for SV-CAH, although cases will be missed even with low screening thresholds for 17OHP ( 14 , 15 ). In general, variations in screening accuracy can also be associated with differences in the timing of sample collection ( 16 ), the number of repeat samples collected ( 9 , 16 ), whether second tier testing is used as part of the screening pathway ( 17 ) and how different screening programmes define a positive screening test.…”

“…However, collection of additional later samples, such as occurs routinely in two-screen states, increases the sensitivity of screening for SV-CAH and NC-CAH ( 9 ). In recent years, many screening protocols have incorporated second-tier liquid chromatography-tandem mass spectrometry testing, which accurately measures multiple informative steroids simultaneously and can further improve the efficiency of screening ( 15 , 18 , 19 ).…”