Evaluation of a Two-Tier Screening Pathway for Congenital Adrenal Hyperplasia in the New South Wales Newborn Screening Programme

Abstract

In Australia, all newborns born in New South Wales (NSW) and the Australia Capital Territory (ACT) have been offered screening for rare congenital conditions through the NSW Newborn Screening Programme since 1964. Following the development of the Australian Newborn Bloodspot Screening National Policy Framework, screening for congenital adrenal hyperplasia (CAH) was included in May 2018. As part of the assessment for addition of CAH, the national working group recommended a two-tier screening protocol determining 17α-hydroxyprogesterone (17OHP) concentration by immunoassay followed by steroid profile. A total of 202,960 newborns were screened from the 1 May 2018 to the 30 April 2020. A threshold level of 17OHP from first tier immunoassay over 22 nmol/L and/or top 2% of the daily assay was further tested using liquid chromatography tandem mass spectrometry (LC-MS/MS) steroid profiling for 17OHP (MS17OHP), androstenedione (A4) and cortisol. Samples with a ratio of (MS17OHP + A4)/cortisol > 2 and MS17OHP > 200 nmol/L were considered as presumptive positive. These newborns were referred for clinical review with a request for diagnostic testing and a confirmatory repeat dried blood spot (DBS). There were 10 newborns diagnosed with CAH, (9 newborns with salt wasting CAH). So far, no known false negatives have been notified, and the protocol has a sensitivity of 100%, specificity of 99.9% and a positive predictive value of 71.4%. All confirmed cases commenced treatment by day 11, with none reported as having an adrenal crisis by the start of treatment.

Neonatal Screening for Congenital Adrenal Hyperplasia in Denmark: 10 Years of Experience

“…The incidence of SW-CAH in populations with health care systems comparable to the Danish has been reported to range from 4.4 per 100,000 newborns to 6.0 per 100,000 newborns [3, 7, 8, 10, 22, 23], thus compatible with the incidence of SW-CAH in the present study. Further, the incidence is compatible to Swedish data, where the incidence of CAH was estimated to 5.8 per 100,000 newborns before (1969–1986) [24] and 6.0 per 100,000 newborns after (1986–2011) [25] introduction of the Swedish CAH newborn screening program.…”

“…Algorithms for CAH screening vary widely across countries regarding to time of sampling, analytical methods, steroid metabolites, steroid profiling ratios, and ways to stratify cut-off levels; thus, comparison of different programs is complicated. The sensitivity and specificity of the Danish CAH screening for SW-CAH were comparable to the sensitivity and specificity reported for other screening programs [8, 10, 22]. All except one Danish newborn boy with SW-CAH were identified by the screening.…”

Challenges in Assessing the Cost-Effectiveness of Newborn Screening: The Example of Congenital Adrenal Hyperplasia

“…Subsequently, timely reporting was achieved, and no neonatal SW crises were reported during 1994–2013 [ 89 ]. Some programs have likewise reported avoidance of SW crises through timely reporting of NBS results [ 17 , 23 ], whereas others report that even timely reporting does not eliminate crises [ 35 ].…”

“…Several programs have adopted second-tier screening to reduce the number of infants who need to be recalled for confirmatory testing. Some states conduct 17-OHP fluoroimmuoassay testing on repeat specimens, using extraction to remove cross-reacting steroid sulfates, other states conduct second-tier screening using liquid chromatography tandem mass spectrometry (LC–MS/MS) and still others conduct 17-OHP testing on repeat specimens to reduce the number of infants who need to be recalled for confirmatory testing [ 15 , 23 , 24 , 25 ]. A DNA-based second-tier screening test can also be used in place of LC–MS/MS.…”

Newborn Screening for CAH—Challenges and Opportunities

“…New South Wales was the first Australian state to commence NBS for CAH in 2018, also using a two-tier protocol. The results of the first 203,000 screened babies are reported here [ 11 ]. Samples above the 17OHP threshold level on first-tier immunoassay were further tested using LC-MS/MS, and those with a ratio of (17OHP + androstenedione)/cortisol > 2 and/or 17OHP > 200 nmol/L on LC-MS/MS were referred to as presumptive positive screens.…”