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

Abstract

Introduction: Early detection of salt-wasting congenital adrenal hyperplasia (SW-CAH) is important to reduce CAH related morbidity. However, neonatal screening has shown to have a low positive predictive value (PPV), especially among preterm newborns. Here, the Danish CAH screening is evaluated by comparing incidence and morbidity of SW-CAH ten years before and after introduction of screening. Furthermore, sensitivity, specificity and PPV are determined. Methods: All newborns in Denmark born during 1999-2018 and diagnosed with SW-CAH were identified in the Danish National Patient Registry and/or at the Department of Clinical Genetics, Rigshospitalet. Newborns with a positive neonatal CAH screening were identified at Statens Serum Institut. Correct diagnosis was evaluated by medical record review. Results: A total of 65 newborns with SW-CAH were identified. The incidence of SW-CAH was 5:100,000 both before and after introduction of screening. Performance of sensitivity and specificity of the screening were 97% and 100%, respectively, and the PPV was 55% for the given period. Stratified according to gestational age, the PPV was 33% and 61% for pre -and fullterm newborns, respectively. Though not significant the proportion of newborns presenting with salt-wasting crisis decreased after introduction of screening from 29% vs. 10% (p=0.07). Discussion and Conclusion: Neonatal screening for SW-CAH has not led to an increase in the incidence of newborns diagnosed with SW-CAH. The screening algorithm has effectively identified newborns with SW-CAH. After 2009, there was a tendency towards a lower proportion of newborns with salt-wasting crisis at diagnosis. Finally, the study emphasizes the benefits of using second-tier screening as well as repeated screening of premature newborns.

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

“…Whilst the retrospective data analysis meant that we did not obtain follow-up samples from these cases, the babies were assumed to be unaffected. These findings are consistent with a recent report from the Danish NBS programme, which reported normal follow-up samples in four babies with mildly elevated 21DF levels on an initial sample [ 20 ]. Similarly, Held et al reported that 21DF concentrations in screening samples from unaffected babies ranged from 0.01 to 2.06 ng/mL (0.03 to 6.10 nmol/L) and overlapped with one confirmed CAH case [ 12 ].…”

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

“…We recently investigated all newborns born in Denmark diagnosed with CAH in a 10-year period before and after introduction of screening and found a prevalence of SW CAH of 5 per 100,000 newborns before as well as after screening. 7 Here, observing a much longer period, we report a prevalence of SW CAH of 6.4 per 100,000 newborn females and 5.6 per 100,000 newborn males.…”

“…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 ).…”

“… 3 , 4 , 5 It has also evened out the uneven sex ratio with more females than males being diagnosed, suggesting that prior to screening some males may have suffered non-diagnosis and death. 6 , 7 , 8 SV CAH is diagnosed in subjects with just slight residual 21-OH activity (1–5%), resulting in aldosterone synthesis adequate to avoid serious neonatal salt loss. However, cortisol deficiency with accompanying androgen excess still necessitates glucocorticoid treatment to avoid acute adrenal insufficiency and further virilization of females.…”

“… 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.…”