Introduction: Newborn screening (NBS) programmes vary internationally in their approach to screening. Guidelines for congenital adrenal hyperplasia (CAH) screening recommend the use of two-tier testing and gestational age cutoffs to minimise false-positive results. The aims of this study were to describe (1) the approaches; (2) protocols used; and (3) available outcomes for CAH screening internationally. Methods: All members of the International Society for Neonatal Screening were asked to describe their CAH NBS protocols, with an emphasis on the use of second-tier testing, 17-hydroxyprogesterone (17OHP) cutoffs, and gestational age and birth weight adjustments. If available, screening outcomes were requested. Results: Representatives from 23 screening programmes provided data. Most (n = 14; 61%) recommend sampling at 48–72 h of life. Fourteen (61%) use single-tier testing and 9 have a two-tier testing protocol. Gestational age cutoffs are used in 10 programmes, birth weight cutoffs in 3, and a combination of both in 9. One programme does not use either method of adjusting 17OHP cutoffs. Case definition of a positive test and the response to a positive test differed between programmes. Conclusions: We have demonstrated significant variation across all aspects of NBS for CAH, including timing, the use of single versus two-tier testing and cutoff interpretation. Collaboration between international screening programmes and implementation of new techniques to improve screen efficacy will facilitate ongoing expansion and quality improvement in CAH NBS.

1.
Merke
DP
,
Auchus
RJ
.
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency
.
N Engl J Med
.
2020
;
383
(
13
):
1248
61
.
2.
Speiser
PW
,
Arlt
W
,
Auchus
RJ
,
Baskin
LS
,
Conway
GS
,
Merke
DP
et al
.
Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline
.
J Clin Endocrinol Metab
.
2018
;
103
(
11
):
4043
88
.
3.
Strnadová
KA
,
Votava
F
,
Lebl
J
,
Mühl
A
,
Item
C
,
Bodamer
OA
et al
.
Prevalence of congenital adrenal hyperplasia among sudden infant death in the Czech Republic and Austria
.
Eur J Pediatr
.
2007
;
166
(
1
):
1
4
.
4.
Gozzi
TG
,
Harris
NP
,
McGown
IN
,
Cowley
DM
,
Cotterill
AM
,
Campbell
PE
et al
.
Autopsy diagnosis of 21-hydroxylase deficiency CAH in a case of apparent SIDS
.
Pediatr Dev Pathol
.
2005
;
8
(
3
):
397
401
.
5.
Dorr
HG
,
Wollmann
HA
,
Hauffa
BP
,
Woelfle
J
German Society of Pediatric Endocrinology and Diabetology
.
Mortality in children with classic congenital adrenal hyperplasia and 21-hydroxylase deficiency (CAH) in Germany
.
BMC Endocr Disord
.
2018
;
18
(
1
):
37
.
6.
Gassner
HL
,
Toppari
J
,
Quinteiro Gonzalez
S
,
Miller
WL
.
Near-miss apparent SIDS from adrenal crisis
.
J Pediatr
.
2004
;
145
(
2
):
178
83
.
7.
Miranda
MC
,
Haddad
LBDP
,
Madureira
G
,
Mendonca
BB
,
Bachega
T
.
Adverse outcomes and economic burden of congenital adrenal hyperplasia late diagnosis in the newborn screening absence
.
J Endocr Soc
.
2020
4
2
bvz013
.
8.
White
PC
.
Neonatal screening for congenital adrenal hyperplasia
.
Nat Rev Endocrinol
.
2009
;
5
(
9
):
490
8
.
9.
Thil’en
A
,
Nordenström
A
,
Hagenfeldt
L
,
von Döbeln
U
,
Guthenberg
C
,
Larsson
A
.
Benefits of neonatal screening for congenital adrenal hyperplasia (21-hydroxylase deficiency) in Sweden
.
Pediatrics
.
1998
101
4
E11
.
10.
Therrell
BL
Jr
,
Berenbaum
SA
,
Manter-Kapanke
V
,
Simmank
J
,
Korman
K
,
Prentice
L
et al
.
Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia
.
Pediatrics
.
1998
101
4 Pt 1
583
90
.
11.
Van der Kamp
HJ
,
Noordam
K
,
Elvers
B
,
Van Baarle
M
,
Otten
BJ
,
Verkerk
PH
.
Newborn screening for congenital adrenal hyperplasia in The Netherlands
.
Pediatrics
.
2001
;
108
(
6
):
1320
4
.
12.
Pang
S
,
Murphey
W
,
Levine
LS
,
Spence
D
,
Leon
A
,
Lafranchi
S
et al
.
A pilot newborn screening for congenital adrenal hyperplasia(CAH)due to 21-hydroxylase deficiency at New York Hospital(NYH) and Alaska
.
Pediatr Res
.
1981
;
15
(
12
):
1545
.
13.
Speiser
PW
,
Chawla
R
,
Chen
M
,
Diaz-Thomas
A
,
Finlayson
C
,
Rutter
MM
et al
.
Newborn screening protocols and positive predictive value for congenital adrenal hyperplasia vary across the United States
.
Int J Neonatal Screen
.
2020
;
6
(
2
):
37
.
14.
Lai
F
,
Srinivasan
S
,
Wiley
V
.
Evaluation of a two-tier screening pathway for congenital adrenal hyperplasia in the new South wales newborn screening programme
.
Int J Neonatal Screen
.
2020
;
6
(
3
):
63
.
15.
Australian Government Department of Health and Aged Care
What is screened in the program
. Available from: https://www.health.gov.au/our-work/newborn-bloodspot-screening/what-is-screened-in-the-program (Accessed March 2023).
16.
Loeber
JG
,
Platis
D
,
Zetterström
RH
,
Almashanu
S
,
Boemer
F
,
Bonham
JR
et al
.
Neonatal screening in Europe revisited: an ISNS perspective on the current state and developments since 2010
.
Int J Neonatal Screen
.
2021
;
7
(
1
):
15
.
17.
Fingerhut
R
.
False positive rate in newborn screening for congenital adrenal hyperplasia (CAH)-ether extraction reveals two distinct reasons for elevated 17alpha-hydroxyprogesterone (17-OHP) values
.
Steroids
.
2009
;
74
(
8
):
662
5
.
18.
Grosse
SD
,
Van Vliet
G
.
How many deaths can Be prevented by newborn screening for congenital adrenal hyperplasia
.
Horm Res
.
2007
;
67
(
6
):
284
91
.
19.
Dabas
A
,
Bothra
M
,
Kapoor
S
.
CAH newborn screening in India: challenges and opportunities
.
Int J Neonatal Screen
.
2020
;
6
(
3
):
70
.
20.
Held
PK
,
Bird
IM
,
Heather
NL
.
Newborn screening for congenital adrenal hyperplasia: review of factors affecting screening accuracy
.
Int J Neonatal Screen
.
2020
;
6
(
3
):
67
.
21.
Nomura
S
.
Immature adrenal steroidogenesis in preterm infants
.
Early Hum Dev
.
1997
;
49
(
3
):
225
33
.
22.
Gidlöf
S
,
Wedell
A
,
Guthenberg
C
,
von Döbeln
U
,
Nordenström
A
.
Nationwide neonatal screening for congenital adrenal hyperplasia in Sweden: a 26-year longitudinal prospective population-based study
.
JAMA Pediatr
.
2014
;
168
(
6
):
567
74
.
23.
Murphy
JF
,
Joyce
BG
,
Dyas
J
,
Hughes
IA
.
Plasma 17-hydroxyprogesterone concentrations in ill newborn infants
.
Arch Dis Child
.
1983
;
58
(
7
):
532
4
.
24.
de Hora
MR
,
Heather
NL
,
Patel
T
,
Bresnahan
LG
,
Webster
D
,
Hofman
PL
.
Measurement of 17-hydroxyprogesterone by LCMSMS improves newborn screening for CAH due to 21-hydroxylase deficiency in New Zealand
.
Int J Neonatal Screen
.
2020
;
6
(
1
):
6
.
25.
Zetterström
RH
,
Karlsson
L
,
Falhammar
H
,
Lajic
S
,
Nordenström
A
.
Update on the Swedish newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency
.
Int J Neonatal Screen
.
2020
;
6
(
3
):
71
.
26.
Stroek
K
,
Ruiter
A
,
van der Linde
A
,
Ackermans
M
,
Bouva
MJ
,
Engel
H
et al
.
Second-tier testing for 21-hydroxylase deficiency in The Netherlands; a newborn screening pilot study
.
J Clin Endocrinol Metab
.
2021
;
106
(
11
):
e4487
96
.
27.
de Hora
MR
,
Heather
NL
,
Webster
D
,
Albert
BB
,
Hofman
PL
.
Birth weight– or gestational age–adjusted second-tier LCMSMS cutoffs improve newborn screening for CAH in New Zealand
.
J Clin Endocrinol Metab
.
2021
;
106
(
9
):
e3390
9
.
28.
Conlon
TA
,
Hawkes
CP
,
Brady
JJ
,
Murphy
NP
.
The presentation of congenital adrenal hyperplasia in an unscreened population
.
J Pediatr Endocrinol Metab
.
2021
;
34
(
9
):
1123
9
.
29.
van der Kamp
HJ
,
Oudshoorn
CG
,
Elvers
BH
,
van Baarle
M
,
Otten
BJ
,
Wit
JM
et al
.
Cutoff levels of 17-alpha-hydroxyprogesterone in neonatal screening for congenital adrenal hyperplasia should be based on gestational age rather than on birth weight
.
J Clin Endocrinol Metab
.
2005
;
90
(
7
):
3904
7
.
30.
Vats
P
,
Dabas
A
,
Jain
V
,
Seth
A
,
Yadav
S
,
Kabra
M
et al
.
Newborn screening and diagnosis of infants with congenital adrenal hyperplasia
.
Indian Pediatr
.
2020
;
57
(
1
):
49
55
.
31.
Jiang
X
,
Tang
F
,
Feng
Y
,
Li
B
,
Jia
X
,
Tang
C
et al
.
The adjustment of 17-hydroxyprogesterone cut-off values for congenital adrenal hyperplasia neonatal screening by GSP according to gestational age and age at sampling
.
J Pediatr Endocrinol Metab
.
2019
;
32
(
11
):
1253
8
.
32.
Hayashi
GY
,
Carvalho
DF
,
de Miranda
MC
,
Faure
C
,
Vallejos
C
,
Brito
VN
et al
.
Neonatal 17-hydroxyprogesterone levels adjusted according to age at sample collection and birthweight improve the efficacy of congenital adrenal hyperplasia newborn screening
.
Clin Endocrinol
.
2017
;
86
(
4
):
480
7
.
33.
Newborn Screening Timeliness Goals
. Official Website of the U.S. Health Resources & services Administration. Available from: https://www.hrsa.gov.advisory-committees/heritable-disorders/newborn-screening-timeliness.html (Accessed March 2023).
34.
Lacey
JM
,
Minutti
CZ
,
Magera
MJ
,
Tauscher
AL
,
Casetta
B
,
McCann
M
et al
.
Improved specificity of newborn screening for congenital adrenal hyperplasia by second-tier steroid profiling using tandem mass spectrometry
.
Clin Chem
.
2004
;
50
(
3
):
621
5
.
35.
Schwarz
E
,
Liu
A
,
Randall
H
,
Haslip
C
,
Keune
F
,
Murray
M
et al
.
Use of steroid profiling by UPLC-MS/MS as a second tier test in newborn screening for congenital adrenal hyperplasia: the Utah experience
.
Pediatr Res
.
2009
;
66
(
2
):
230
5
.
36.
Bialk
ER
,
Lasarev
MR
,
Held
PK
.
Wisconsin’s screening algorithm for the identification of newborns with congenital adrenal hyperplasia
.
Int J Neonatal Screen
.
2019
;
5
(
3
):
33
.
37.
White
PC
.
Optimizing newborn screening for congenital adrenal hyperplasia
.
J Pediatr
.
2013
;
163
(
1
):
10
2
.
38.
Sarafoglou
K
,
Banks
K
,
Kyllo
J
,
Pittock
S
,
Thomas
W
.
Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota
.
Jama
.
2012
;
307
(
22
):
2371
4
.
39.
Sarafoglou
K
,
Gaviglio
A
,
Hietala
A
,
Frogner
G
,
Banks
K
,
McCann
M
et al
.
Comparison of newborn screening protocols for congenital adrenal hyperplasia in preterm infants
.
J Pediatr
.
2014
;
164
(
5
):
1136
40
.
40.
Miller
J
,
Tuerck
J
,
Awad
K
,
Chace
D
,
Copeland
S
,
Rasmussen
S
Newborn screening for preterm, low birth weight, and sick newborns; approved guideline. CLSI document I/LA31-A
1st ed.
Wayne (PA)
Clinical and Laboratory Standards Institute
.
2009
.
41.
McGrath
N
,
Hawkes
CP
,
Mayne
P
,
Murphy
NP
.
Optimal timing of repeat newborn screening for congenital hypothyroidism in preterm infants to detect delayed thyroid-stimulating hormone elevation
.
J Pediatr
.
2019
;
205
:
77
82
.
42.
Miller
WL
.
Congenital adrenal hyperplasia: time to replace 17OHP with 21-deoxycortisol
.
Horm Res Paediatr
.
2019
;
91
(
6
):
416
20
.
43.
Held
PK
,
Bialk
ER
,
Lasarev
MR
,
Allen
DB
.
21-Deoxycortisol is a key screening marker for 21-hydroxylase deficiency
.
J Pediatr
.
2022
;
242
:
213
9.e1
.
44.
Janzen
N
,
Peter
M
,
Sander
S
,
Steuerwald
U
,
Terhardt
M
,
Holtkamp
U
et al
.
Newborn screening for congenital adrenal hyperplasia: additional steroid profile using liquid chromatography-tandem mass spectrometry
.
J Clin Endocrinol Metab
.
2007
;
92
(
7
):
2581
9
.
45.
Kamrath
C
,
Hartmann
MF
,
Boettcher
C
,
Zimmer
KP
,
Wudy
SA
.
Diagnosis of 21-hydroxylase deficiency by urinary metabolite ratios using gas chromatography-mass spectrometry analysis: Reference values for neonates and infants
.
J Steroid Biochem Mol Biol
.
2016
;
156
:
10
6
.
46.
Loeber
JG
.
European union should actively stimulate and harmonise neonatal screening initiatives
.
Int J Neonatal Screen
.
2018
;
4
(
4
):
32
.
47.
Heather
NL
,
Nordenstrom
A
.
Newborn screening for CAH-challenges and opportunities
.
Int J Neonatal Screen
.
2021
;
7
(
1
):
11
.
48.
Clayton
PE
,
Miller
WL
,
Oberfield
SE
,
Ritzén
EM
,
Sippell
WG
,
Speiser
PW
et al
.
Consensus statement on 21-hydroxylase deficiency from the European society for paediatric endocrinology and the lawson wilkins pediatric endocrine society
.
Horm Res
.
2002
;
58
(
4
):
188
95
.
49.
Balsamo
A
,
Cacciari
E
,
Piazzi
S
,
Cassio
A
,
Bozza
D
,
Pirazzoli
P
et al
.
Congenital adrenal hyperplasia: neonatal mass screening compared with clinical diagnosis only in the Emilia-Romagna region of Italy, 1980-1995
.
Pediatrics
.
1996
98
3 Pt 1
362
7
.
50.
Brosnan
PG
,
Brosnan
CA
,
Kemp
SF
,
Domek
DB
,
Jelley
DH
,
Blackett
PR
et al
.
Effect of newborn screening for congenital adrenal hyperplasia
.
Arch Pediatr Adolesc Med
.
1999
;
153
(
12
):
1272
8
.
51.
Pang
S
,
Shook
MK
.
Current status of neonatal screening for congenital adrenal hyperplasia
.
Curr Opin Pediatr
.
1997
;
9
(
4
):
419
23
.
52.
Nordenström
A
,
Lajic
S
,
Falhammar
H
.
Long-term outcomes of congenital adrenal hyperplasia
.
Endocrinol Metab
.
2022
;
37
(
4
):
587
98
.
53.
Grosse
SD
,
Van Vliet
G
.
Challenges in assessing the cost-effectiveness of newborn screening: the example of congenital adrenal hyperplasia
.
Int J Neonatal Screen
.
2020
;
6
(
4
):
82
.
54.
de Miranda
MC
,
Haddad
LBd P
,
Trindade
E
,
Cassenote
A
,
Hayashi
GY
,
Damiani
D
et al
.
The cost-effectiveness of congenital adrenal hyperplasia newborn screening in Brazil: a comparison between screened and unscreened cohorts
.
Front Pediatr
.
2021
;
9
:
659492
.
55.
Fox
DA
,
Ronsley
R
,
Khowaja
AR
,
Haim
A
,
Vallance
H
,
Sinclair
G
et al
.
Clinical impact and cost efficacy of newborn screening for congenital adrenal hyperplasia
.
J Pediatr
.
2020
;
220
:
101
8.e2
.
56.
Yoo
BK
,
Grosse
SD
.
The cost effectiveness of screening newborns for congenital adrenal hyperplasia
.
Public Health Genomics
.
2009
;
12
(
2
):
67
72
.
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