The adjustment of 17-hydroxyprogesterone cut-off values for congenital adrenal hyperplasia neonatal screening by GSP according to gestational age and age at sampling

Abstract Background Congenital adrenal hyperplasia (CAH) screening is facing great challenges because of a high false-positive rate and a low positive predictive value (PPV). We established and optimized 17-hydroxyprogesterone (17-OHP) cut-off values for CAH neonatal screening using a genetic screening processor (GSP) according to gestational age (GA), birth weight (BW) and age at sampling. Methods The 17-OHP concentrations in dried blood spots were measured by time-resolved immunofluorescence and were grouped in terms of GA, BW and age at sampling for 48,592 newborns. The 99.5th percentile was used to set an initial cut-off value as a reference. Results Significant differences in 17-OHP concentrations were observed among newborns with different GAs and BWs. A significant difference was observed among different sampling age groups. Finally, we defined new multitier cut-off concentrations based on GA and age at sampling. Application of the new cut-off values resulted in a 30% reduction of the positive rate and a 40% increase of the PPV. Conclusions GA, BW and sampling age time influenced the concentrations of 17-OHP. The efficiency of congenital adrenal hyperplasia screening can be substantially improved by adjusting the multitier cut-off value according to GA and age at sampling.

Download Full-text

30 Predicting gestational age improves newborn screening for congenital adrenal hyperplasia

Paediatrics & Child Health ◽

10.1093/pch/pxaa068.029 ◽

2020 ◽

Vol 25 (Supplement_2) ◽

pp. e11-e11

Author(s):

Danny Jomaa ◽

Matthew Henderson ◽

Steven Hawken ◽

Pranesh Chakraborty

Keyword(s):

Positive Predictive Value ◽

Congenital Adrenal Hyperplasia ◽

Newborn Screening ◽

Gestational Age ◽

Predictive Value ◽

False Positive ◽

False Positive Rate ◽

Adrenal Hyperplasia ◽

Positive Rate ◽

17 Hydroxyprogesterone

Abstract Background Newborn screening for congenital adrenal hyperplasia is performed using a two-tier approach. The first tier involves comparison of neonate 17-hydroxyprogesterone levels to gestational age (GA)-based thresholds. When GA is unreported, which occurs in approximately 5% of births, birth weight (BW)-based thresholds are the only available option. However, these have a lower specificity and result in more false positive results. Recently, a predictive model was developed to estimate GA based on newborn demographics and the screening analytes measured in a blood sample. Objectives The objective of this study was to determine whether supplying a predicted GA to newborns with unreported GA, and subsequent GA-based screening, has a higher positive predictive value than BW-based screening. Design/Methods Screening data was obtained for approximately 700,000 births that occurred in Canada between 2011 and 2015. Predicted GA was calculated using a model composed of demographic and screening analyte factors. The positive predictive values of BW- and predicted GA-based screening were calculated for newborns with unreported GA. A sequential approach was then developed whereby newborns with unreported GA were first screened by BW-based screening. Newborns that screened positive were then supplied with their predicted GA and screened using GA-based thresholds. Results First-tier CAH screening using GA-based 17-hydroxyprogesterone thresholds had a higher positive predictive value than using BW-based thresholds (1.30% vs. 0.82%). In the study time period, 3.61% of newborns had an unreported GA. For these newborns, predicted GA-based screening had a higher positive predictive value than BW-based screening (0.83% vs. 0.76%) and correctly identified the 2 infants with CAH whose GA was unreported. A sequential screening approach was then used: BW-based screening and, for the screen positive population, predicted GA-based screening. This further increased the positive predictive value compared to BW-based screening (0.95% vs. 0.76%), reduced the false positive rate, and correctly identified true positive cases. Conclusion Reducing the false positive rate of CAH screening is important to prevent unnecessary second-tier screening and referrals. For newborns with unreported GA (4-5% of all births), BW-based screening is the only currently available approach. However, this approach has a poor specificity and a high false positive rate compared to GA-based screening. This study is the first to demonstrate an alternative screening strategy with a higher positive predictive value for newborns with unreported GA.

Download Full-text

Cortisol assay in dried blood spots to reduce false positive rate in congenital adrenal hyperplasia screening

Clinica Chimica Acta ◽

10.1016/j.cca.2012.04.022 ◽

2012 ◽

Vol 413 (15-16) ◽

pp. 1306-1307

Author(s):

Julie Brossaud ◽

Pascal Barat ◽

Laurence Fagour ◽

Jean-Benoît Corcuff

Keyword(s):

Congenital Adrenal Hyperplasia ◽

False Positive ◽

False Positive Rate ◽

Dried Blood Spots ◽

Adrenal Hyperplasia ◽

Blood Spots ◽

Positive Rate

Download Full-text

NEONATAL SCREENING FOR CONGENITAL ADRENAL HYPERPLASIA (CAH) USING 17-HYDROXYPROGESTERONE (17-OHP) ASSAYS OF DRIED BLOOD SPOTS

Pediatric Research ◽

10.1203/00006450-198611000-00163 ◽

1986 ◽

Vol 20 (11) ◽

pp. 1201-1201

Author(s):

A Larsson ◽

T Cursted ◽

U von Döbeln ◽

J Gustafsson ◽

L Hagenfeldt ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Neonatal Screening ◽

Dried Blood Spots ◽

Adrenal Hyperplasia ◽

Blood Spots ◽

17 Hydroxyprogesterone

Download Full-text

Neonatal screening for congenital adrenal hyperplasia: a programme based on a novel direct radioimmunoassay for 17-hydroxyprogesterone in blood spots

Journal of Endocrinology ◽

10.1677/joe.0.1080299 ◽

1986 ◽

Vol 108 (2) ◽

pp. 299-308 ◽

Cited By ~ 36

Author(s):

A. M. Wallace ◽

G. H. Beastall ◽

B. Cook ◽

A. J. Currie ◽

A. M. Ross ◽

...

Keyword(s):

Retrospective Study ◽

Congenital Adrenal Hyperplasia ◽

Neonatal Screening ◽

Large Scale ◽

False Positive Rate ◽

Prospective Trial ◽

Adrenal Hyperplasia ◽

Guthrie Card ◽

Blood Spots ◽

17 Hydroxyprogesterone

ABSTRACT We have assessed the feasibility of screening newborn babies for congenital adrenal hyperplasia (CAH) by the direct measurement of 17-hydroxyprogesterone (17-OHP) in blood spots collected on filter paper (Guthrie cards) for the phenylketonuria, hypothyroidism and galactosaemia screening programmes run in Scotland. The procedure described for CAH uses an iodinated 17-OHP tracer and a specific 17-OHP antiserum sheathed within semipermeable nylon microcapsules. The method does not require a solvent extraction step, is inexpensive, precise, efficient and, therefore, practical for large-scale use. With this system the value of a neonatal screening programme was assessed in a retrospective analysis and a prospective trial. The retrospective study of 15 paediatric cases of CAH illustrated that at least half were not diagnosed within 3 weeks of birth. Analysis of the original Guthrie card samples revealed increased levels of 17-OHP in all cases. The prevalence of CAH as calculated in the retrospective study was 1 in 20 907 with a range (within 95% confidence limits) of from 1 in 12 675 to 1 in 32 604 (n = 301 450). In the prospective trial a total of 92 051 consecutive samples was screened. Five cases of CAH were correctly identified with a current false positive rate of 0·042%. Analysis of urinary steroids confirmed defective adrenal 21-hydroxylase activity in all positive cases. In the prospective trial the prevalence was 1 in 18 401 with a range of from 1 in 7 422 to 1 in 50006. We conclude that mass screening for CAH is both feasible and desirable. J. Endocr. (1986) 108, 299–308

Download Full-text

High Reliability of Neonatal Screening for Congenital Adrenal Hyperplasia in Switzerland

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2002-012093 ◽

2002 ◽

Vol 87 (9) ◽

pp. 4106-4110 ◽

Cited By ~ 29

Author(s):

Michael Steigert ◽

Eugen J. Schoenle ◽

Anna Biason-Lauber ◽

Toni Torresani

Keyword(s):

Positive Predictive Value ◽

Congenital Adrenal Hyperplasia ◽

Predictive Value ◽

Neonatal Screening ◽

Screening Program ◽

High Reliability ◽

Dried Blood Spots ◽

Recall Rate ◽

Adrenal Hyperplasia ◽

Salt Wasting

Newborn screening for congenital adrenal hyperplasia (CAH) is justified by the sometimes difficult clinical diagnosis and the risks associated with missed diagnosis, particularly the life-threatening salt-wasting crisis. In Switzerland, nationwide screening for CAH by measuring 17-hydroxyprogesterone levels in dried blood spots was introduced in 1992. At the Zurich University Children’s Hospital, 50% of the population of Switzerland is screened. The aim of the study was to evaluate the efficiency of the Zurich screening program. Between January 1, 1993, and May 31, 2001, 333,221 newborns were screened for CAH. Thirty-one newborns had CAH (incidence, 1 in 10,749); 30 were detected through screening (sensitivity, 97%). A recall for suspected CAH was performed in only 60 cases, corresponding to a very low recall rate (0.0018%). In 30 recalls CAH was confirmed (positive predictive value, 50%; specificity, 99.99%). Fifteen of 31 patients profited from screening, as CAH had not been recognized clinically. The timely availability of screening results made therapy possible within the first week of life in most cases and helped in preventing salt-wasting crisis in all patients. With a sensitivity of 97%, a specificity of 99.99%, and a positive predictive value of 50%, the Zurich neonatal screening program for CAH can be considered highly reliable.

Download Full-text

Screening for Congenital Adrenal Hyperplasia: The Delfia Screening Test Overestimates Serum 17-Hydroxyprogesterone in Preterm Infants

PEDIATRICS ◽

10.1542/peds.97.1.100 ◽

1996 ◽

Vol 97 (1) ◽

pp. 100-102 ◽

Cited By ~ 1

Author(s):

Saad Al Saedi ◽

Heather Dean ◽

William Dent ◽

Elizabeth Stockl ◽

Catherine Cronin

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Preterm Infants ◽

Gestational Age ◽

Adrenal Hyperplasia ◽

Blood Spots ◽

Healthy Infants ◽

Extraction Step ◽

Postconceptional Age ◽

17 Hydroxyprogesterone ◽

Over Time

Objective. To compare 17-hydroxyprogesterone (17-OHP) levels measured by quantitative serum radioimmunoassay (RIA), including an extraction step, and by screening fluoroimmnoassay (FIA) on blood spots in preterm infants. Methods. Subjects were 39 healthy infants born at less than 31 weeks' gestational age. Each infant had weekly blood sampling, and RIA and FIA were performed on each sample. Results. Two hundred twenty-seven samples were taken at 28 to 41 weeks' postconceptional age. Mean ± SD 17-OHP measured by RIA was 11.4 ± 11.1 nmol/L (0.4 ± 0.4 µg/dL), and decreased over time. Mean ± SD 17-OHP measured by FIA was 38.96 ± 37.3 nmol/L, greater than 17-OHP (RIA). Log(δFIA-RIA) was inversely related to postconceptional age (R2 = .39). Conclusion. Screening FIA of blood spots overestimates levels of 17-OHP in preterm infants and should not be used to determine the likelthood of congenital adrenal hyperplasia in this population. We have abandoned FIA screening for congenital adrenal hyperplasia in infants weiging less than 1500 g.

Download Full-text

Wisconsin’s Screening Algorithm for the Identification of Newborns with Congenital Adrenal Hyperplasia

International Journal of Neonatal Screening ◽

10.3390/ijns5030033 ◽

2019 ◽

Vol 5 (3) ◽

pp. 33 ◽

Cited By ~ 5

Author(s):

Eric R. Bialk ◽

Michael R. Lasarev ◽

Patrice K. Held

Keyword(s):

Birth Weight ◽

Congenital Adrenal Hyperplasia ◽

False Positive ◽

False Positive Rate ◽

Cross Reactivity ◽

Adrenal Hyperplasia ◽

Screening Assay ◽

Study Results ◽

Second Tier ◽

17 Hydroxyprogesterone

Newborn screening for congenital adrenal hyperplasia (CAH) has one of the highest false positive rates of any of the diseases on the Wisconsin panel. This is largely due to the first-tier immune assay cross-reactivity and physiological changes in the concentration of 17-hydroxyprogesterone during the first few days of life. To improve screening for CAH, Wisconsin developed a second-tier assay to quantify four different steroids (17-hydroxyprogesterone, 21-deoxycortisol, androstenedione, and cortisol) by liquid chromatography–tandem mass spectrometry (LC–MSMS) in dried blood spots. From validation studies which included the testing of confirmed CAH patients, Wisconsin established its own reporting algorithm that incorporates steroid concentrations as well as two different ratios—the birth weight and the collection time—to identify babies at risk for CAH. Using the newly developed method and algorithm, the false positive rate for the CAH screening was reduced by 95%. Patients with both classical forms of CAH, salt-wasting and simple virilizing, were identified. This study replicates and expands upon previous work to develop a second-tier LC–MSMS steroid profiling screening assay for CAH. The validation and prospective study results provide evidence for an extensive reporting algorithm that incorporates multiple steroids, birth weight, and collection times.

Download Full-text