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SSIEM SYMPOSIUM 2011
Newborn screening programmes in Europe;
arguments and efforts regarding harmonization.
Part 2 –From screening laboratory results to treatment,
follow-up and quality assurance
Peter Burgard &Kathrin Rupp &Martin Lindner &
Gisela Haege &Tessel Rigter &Stephanie S. Weinreich &
J. Gerard Loeber &Domenica Taruscio &
Luciano Vittozzi &Martina C. Cornel &
Georg F. Hoffmann
Received: 7 December 2011 / Revised: 13 March 2012 /Accepted: 28 March 2012
#SSIEM and Springer 2012
Abstract In a survey conducted in 2010/2011 data from the
28 EU member states, four EU candidate states (Croatia,
FYROM, Iceland, Turkey), three potential EU candidate
states (Bosnia Herzegovina, Montenegro, Serbia), and two
EFTA states (Norway and Switzerland) were collected. The
status and function of newborn screening (NBS) pro-
grammes were investigated from the information to prospec-
tive parents and the public via confirmation of a positive
screening result up to decisions on treatment. This article
summarises the results from screening laboratory findings to
start of treatment. In addition we asked about the existence
of feedback loops reporting the conclusions of confirmation
of screening results to the screening laboratory and commu-
nication of long-term outcome to diagnostic units and pos-
sibly existing central registries. Parallel to the description of
actual practices of where, how and by whom the different
steps of the programmes are executed, we also asked for the
existence of guidelines or directives regulating the screening
programmes, material to support information of parents
about diagnoses and treatment and training facilities for
professionals involved in the programmes. This survey
gives a first comprehensive overview of the steps following
a positive screening result in European NBS programmes.
The 37 data sets reveal substantial variation of national
screening panels, but also a lot of similarities. Analysis
across all countries revealed that actual practice is often
organised but not regulated by guidelines. Material to in-
form patients is available more often for explaining treat-
ment (69 %) than explaining the necessity of confirmatory
diagnostics (41 %). Training of professionals is rarely reg-
ulated by a guideline (2 %), but is offered for paediatricians
(40 %) and dieticians (29 %) and only rarely for other
professions (e.g. geneticists, clinical nurse specialists,
psychologists). Registry-based evaluation of long-term
outcome is as yet almost nonexistent (3 %).
Communicated by: Rodney Pollitt
Presented at the Annual Symposium of the SSIEM, Geneva,
Switzerland, August 30 –September 2, 2011.
Electronic supplementary material The online version of this article
(doi:10.1007/s10545-012-9484-z) contains supplementary material,
which is available to authorised users.
P. Burgard (*):K. Rupp :M. Lindner :G. Haege :
G. F. Hoffmann
Department of Paediatrics, University Hospital - Heidelberg (DE),
Im Neuenheimer Feld 430,
69120 Heidelberg, Germany
e-mail: peter.burgard@med.uni-heidelberg.de
T. Rigter :S. S. Weinreich :M. C. Cornel
Clinical Genetics/EMGO Institute,
VU University Medical Center - Amsterdam (NL),
Amsterdam, Netherlands
J. G. Loeber
National Institute for Public Health (RIVM),
Bilthoven (NL), Netherlands
D. Taruscio :L. Vittozzi
National Institute for Health - Rome (IT),
Rome, Italy
J Inherit Metab Dis
DOI 10.1007/s10545-012-9484-z
Introduction
The survey for the evaluation of regulations and practices of
population newborn (neonatal) screening (NBS) for rare
disorders in Member States of the European Union, as well
as candidate, potential candidate and EFTA countries,
originates from the actions launched by the European
Commission within the EU Programme of Community
Action in Public Health. The EU Council Recommendation
foranActionintheFieldofRareDiseases(European
Commission 2009) foresees the adoption of national plans
and strategies for rare diseases within 2013, and establishes
the lines for the cooperation and coordination among
Member States in order to better utilise national resources
and expertise as well as reducing inequalities in the access to
high quality care. The aim of the survey was to describe
current practices and existing regulations (guidelines and
directives) of NBS in all European States.
In a first step, a model for a complete NBS programme
was developed based on pertinent literature (e.g. Wilson and
Jungner 1968; Raffle and Gray 2007;seeFig.1). This
model has five structural modules: (A) the legal basis and
general provisions, (B) information to the public and pro-
spective parents, (C) blood sampling and informed consent;
(D) laboratory testing and blood spot storage, and (E)
confirmation and communication of diagnosis, and treat-
ment. Across all modules, guidelines, programme evalua-
tion and epidemiology, training of professionals and
resources and costs were investigated. The modules are
functionally interconnected by flow of information, samples
and people.
Although the modules are arranged in a logical sequence,
this does not necessarily represent the factual establishment
and development of a programme, for example screening
can start even before legislation or guidelines come into
practice.
Results of module B to D arereportedinaseparate
publication (Loeber et. al. this issue). In this article we focus
on the results of module E, covering the domains informa-
tion and communication of the laboratory screening to
parents, practices of confirmation of diagnosis, treatment
and monitoring of long-term outcome, epidemiological
evaluation, quality assurance, empowerment of patients
and training of professionals.
Material and methods
For a more comprehensive description of the survey proce-
dures the reader is referred to the accompanying paper by
Loeber et al. (this issue). For module E a questionnaire was
developed covering current practice and its regulation by
directives (defined as legally binding standardization by
state and/or health authorities) and/or by guidelines
(defined as information intended to advise how something
should be done).
The questionnaire was cross-reviewed within the project
and by external reviewers suggested by the Society of the
Fig. 1 Five modules of a NBS
programme
J Inherit Metab Dis
Study for Inborn Errors of Metabolism (SSIEM; Jim
Bonham, Philip Mayne), and converted to a web-based
instrument. In each country respondents nominated by dif-
ferent European professional societies (Society for the Study
of Inborn Errors of Metabolism (SSIEM), European Society
for Paediatric Endocrinology (ESPE), and European Cystic
Fibrosis Society (ECFS )) were asked to report national data
by remote data entry for all disorders (metabolic, endocri-
nologic, and cystic fibrosis) screened for in their country.
Respondents for haematological disorders were recommen-
ded by colleagues contacted for other disorders. The survey
started in August 2010 and was closed on January 14th, 2011,
with all data referring to the situation on September 1st, 2010.
Extensive reports of the project can be downloaded at http://
www.iss.it/cnmr/prog/cont.php?id01621&lang01&tipo064.
Results
Description of the data set
The data set for module E has three dimensions: (1)
countries, (2) disorders screened for, and (3) questions re-
lated to the screening programme (subdivided by current
practice and mode of regulation). Supplementary Table 1
(identical with Table 2in Loeber et al. this issue) gives an
overview of the 40 target countries/regions of the survey, as
well as the countries’screening panels (including conditions
investigated in research programmes). In Belgium NBS is
organised per legislation, and therefore data were collected
separately for the Flemish and the French speaking commu-
nities. As there is reportedly no screening in Albania and no
response was received from Kosovo (both potential candi-
date countries for the European Union), these countries were
excluded from further analysis. Newborn screening for
Liechtenstein is done in Switzerland, resulting in a total
number of 37 data sets.
The number of disorders included in national screening
panels ranges from one (Finland, FYROM, Montenegro) to
29 (Austria), with congenital hypothyroidism being the only
condition screened in all 37 countries and malonic aciduria
(MMA) only screened for in Iceland.
Most of the data presented in this article are based on an
analysis by disorder. In a first step answers related to single
disorders were averaged across all countries screening for
this disorder, and in a second step data have been aggregated
across disorders. For example MSUD is screened for in 12
countries, 11 countries have answered the question about the
method of confirmation of a positive screening result, five
out of 12 countries (42 %) reporting mutation analysis to
confirm a positive screening result. HPA is screened for in
33 countries, 32 countries have answered the question about
the method of confirmation of a positive screening result,
with 17 out of 33 countries (52 %) reporting mutation
analysis to confirm a positive screening result. Combining
the results for these two disorders would allow the conclu-
sion that on average mutation analysis is used for confirma-
tion of diagnoses in 47 % of the cases MSUD or HPA is
screened for.
Confirmation of screening results
As screening does not result in a diagnosis, positive screen-
ing results have to be confirmed or rejected by additional
investigations. Seven questions have been asked in the
domain of confirmative diagnostics (Table 1).
The questions aim at four aspects related to the structure,
process and outcome of the confirmation of diagnoses:
institutions (confirmatory investigations can be executed in
specialised centres, local hospitals, GP/Paediatricians, or
other institutions), methods (results are confirmed by quan-
titative analyses of metabolites/hormones, enzyme activity,
mutation analysis, and other methods), time (age at start and
end of confirmational procedures), and costs (for inpatient
and outpatient care and laboratory analysis).
Feedback of confirmed screening results to the screening
laboratory is particularly important, as it is necessary to im-
prove screening algorithms and cut-off values in the screening
laboratory. Costs and economic efficiency as well as quality of
care and timely management are essential parameters of NBS
programmes (Pandor et al. 2004). As soon after birth as
possible access to specialised clinical diagnostic and treatment
services will be particularly necessary when disorders with a
risk for neonatal decompensation are screened for.
In Europe screening results are almost always confirmed
in specialised centres. However, significant exceptions
among the more frequently screened disorders are biotini-
dase deficiency, galactosaemia, congenital hypothyroidism,
congenital adrenal hyperplasia and MCADD. These disor-
ders are screened in more than ten countries and are con-
firmed and treated in at least 15 % of the cases in local
hospitals. However, it should be noticed that “specialised
centre”is not a well-defined concept. Furthermore, as con-
firmation, follow-up and treatment is different for most
Table 1 Questions of the domain “Confirmative diagnostics”
1. Is there a directive/guideline where to confirm diagnosis?
2. Where are positive screening results predominantly confirmed?
3. Is there a directive/guideline how to confirm diagnosis?
4. How are positive screening diagnoses actually confirmed?
5. What are the average direct health costs of the different national
screening panels?
6. Is there a guideline concerning the age to confirm a suspected
diagnosis?
7. At what ages is confirmation actually started and terminated?
J Inherit Metab Dis
conditions more specification would be necessary for a
detailed evaluation.
Methods of confirmation show a complex pattern across
the different disorders, possibly also depending on the aims of
confirmation. For example, in the case of hyperphenylalani-
naemia (HPA) mutation analysis might be regarded as neces-
sary to establish the severity of phenylalanine hydroxylase
(PAH) deficiency and possible tetrahydrobiopterin (BH
4
)re-
sponsiveness whereas others may rely on pterine analysis and/
or a loading test with BH
4
. Local availability of tests will
determine the set of analyses applied. In disorders where
genetic counselling and prenatal diagnosis in further pregnan-
cies is needed, genetic analysis will be mandatory. On average
in 61 % of the cases where a disorder is screened for, mutation
analysis is included as a method to confirm screening results.
Process times
Twenty-six countries inform prospective parents about NBS
after birth at time of blood sampling, four of them also
provide information during the 3rd trimester of pregnancy,
11 countries reported informing parents any time during
pregnancy. Across all countries blood sampling is per-
formed at a median age of 2.8 days (min02.5, max03.5).
Laboratory screening analysis starts at a median age of
5.3 days (min04.1, max07.1). Confirmatory diagnostics
started at a median of 8.5 days (Q25 08.3, Q75 08.9). Me-
dian age at end of confirmation was 16.2 days (Q25015.2
Q75020.1) and treatment starts at a median age of 14.9 days
(Q25013, Q75016.7). Median age at start of treatment is
earlier than median age at end of confirmation because
treatment sometimes is initiated immediately after a positive
screening lab result in order to avoid early decompensation
following a risk-minimizing strategy. Overall for 75 % of all
screened disorders positive screening results are confirmed
within the first 20 days of life.
Costs
Table 2shows costs for confirmation of a single screening
result. Sum of costs was calculated as (number of days in
hospital × cost per hospital day) + (number of outpatient
visits × cost per visit) + laboratory costs + other costs. It
should be mentioned that in a strict sense the figures repre-
sent prices, i.e. amounts of money realised by the provider
and not the cost of the provider’s activities.
In order to make data from nations with different gross
domestic products and/or purchasing power comparable,
raw data from each respondent were converted to percent
of Gross Domestic Product (GDP) based on purchasing-
power-parity (PPP) per capita. Results show that total costs
show a large variation between disorders as well as between
countries screening for the same disorder. On average
confirmation of a screening result costs between 182 €
(UDP) and 3.077 €(GA II).
The large variability within disorders only can be compared
against the background of more detailed information, for
example the methods used to confirm a screening result.
Whether confirmation of a diagnosis is done on an inpatient
or an outpatient basis might depend on the disorder but also on
the geographical situation and medical practises of a country.
One of the pillars of economic analysis of health care
programmes is costs (Drummond et al. 2005). Although
respondents predominantly reported that figures have been
estimated, and source of data often has not been specified,
data could be interpreted as educated guesses and serve as a
basis for more in depth analysis.
Information and communication to parents
Legal and ethical norms require informed consent and some
confirmatory investigations necessitate practical coopera-
tion of parents (e.g. observation of the child or providing
parental blood samples for molecular biological analysis).
This domain was investigated by six questions, four dealing
with regulations and two with actual practice (Table 3).
The predominant first informant of parents about a pos-
itive NBS result is the GP or a paediatrician (80 %), but on
average, in 24 % of the cases a disorder is screened for, the
screening laboratory informs parents. The preponderant
mode of information is a phone call (87 %), but also in
50 % of the cases information is given in person. Parents
mostly already get detailed information during the first
contact (83 %). Paediatricians (97 %), dieticians (69 %)
and geneticists (65 %) are the key persons in teaching
parents about diagnosis and treatment.
Treatment
Presymptomatic start of treatment is the ultimate goal of
screening (Wilson and Jungner 1968). In those cases where
disorders with a substantial risk for acute neonatal decom-
pensation are included in a screening panel, age and clinical
status (asymptomatic vs. symptomatic) at start of treatment
become central outcome parameters of a NBS programme.
Structural features of NBS programmes are the type of
treatment units (specialised centres, local hospital or paedia-
tricians/GPs) and professionals involved (paediatricians
specialised in cystic fibrosis, metabolic, endocrinologic or
haematologic disorders, dieticians, psychologists, social
workers, clinical nurse specialists, geneticists).
In Europe patients are treated almost exclusively (mean0
95 %; median 098 %) in specialised centres. Professions
involved in the treatment are paediatricians (99 %), dieticians
(80 %), psychologists (46 %), clinical nurse specialists (19 %),
geneticists (17 %), and social workers (15 %).
J Inherit Metab Dis
Table 2 Average direct health costs to confirm or reject a positive screening result
Disorder
1
No. of countries
screening
No. of replies % Replies Sum of costs €% GDP PPP 2009
2
% countries reporting
calculated costs
% countries reporting
estimated costs
Mean SD Mean SD
PKU/HPA 33 25 76 1,746 1,947 9.0 6.7 15 52
BIO 10 10 100 832 399 3.9 1.9 20 40
GALT 10 7 70 1,760 1,406 7.6 5.4 10 60
UDP 3 1 33 182 - 0.7 - 33 0
CH 37 29 78 601 670 3.5 3.7 19 54
CAH 14 11 79 1,555 1,249 8.5 5.2 21 57
CF 9 8 89 764 571 4.2 3.0 22 56
ARG 4 2 50 2,165 555 8.8 1.2 0 25
ASA 6 4 67 1,855 630 9.0 1.0 17 33
CIT I 5 3 60 1,855 630 9.0 1.0 20 20
CIT II 2 2 100 2,165 555 8.8 1.2 0 50
HCI 7 4 57 1,675 1,288 8.0 5.0 14 43
HPT I_III 3 1 33 2,720 - 10.1 - 0 0
MSUD 12 9 75 3,030 1,517 13.2 4.9 8 58
TYR I 7 4 57 2,583 1,648 12.1 5.2 14 43
TYR II-III 3 2 67 3,070 1,835 14.4 5.0 33 33
CUD 6 4 67 1,855 630 9.0 1.0 17 33
CPT I 7 5 71 1,894 553 9.1 0.8 14 43
CPT II 7 5 71 1,888 548 9.1 0.8 14 43
LCHADD 8 5 63 1,648 637 8.0 1.7 13 38
MCADD 13 8 62 1,351 677 6.5 2.8 8 38
SCHADD 2 1 50 2,720 - 10.1 - 0 0
SCADDD 3 2 67 1,977 742 9.7 0.4 33 0
VLCADD 9 6 67 1,570 652 7.8 2.5 11 44
DECR 0 0 n.d. n.d. n.d. n.d. n.d. n.d. n.d.
3HMG 5 3 60 1,838 647 8.9 1.00 20 20
3MCC 6 3 50 1,838 647 8.9 1.00 17 17
GA I 10 7 70 2,890 1,471 13.0 4.8 10 50
GA II 6 4 67 3,077 2,218 13.36 7.8 17 33
HCSD 6 3 50 2,165 555 8.84 1.2 0 33
IVA 9 6 67 2,528 996 11.51 2.9 11 44
MMA 1 1 100 2,720 - 10.07 - 0 0
MMACBL 7 5 71 2,327 1,015 10.40 2.8 14 43
PA 7 5 71 2,327 1,015 8.88 1.0 14 43
BKT 3 2 67 1,952 767 9.52 0.6 33 0
BTHA 3 3 100 529 395 2.02 1.2 33 33
SC 3 3 100 529 395 2.02 1.2 33 33
S-S 4 4 100 881 614 3.77 3.0 0 75
1
3HMG 3-Hydroxy-3-methylglutaric aciduria; 3MCC 3-Methylcrotonyl-CoA carboxylase deficiency/3-Methylglutacon aciduria/2-methyl-3-OH-
butyric aciduria; ARG Argininemia; ASA Argininosuccinic aciduria; BIO Biotinidase deficiency; BKT Beta-ketothiolase deficiency; BTHA S, beta
0-thalassemia; CAH Congenital adrenal hyperplasia; CF Cystic fibrosis; CH Primary congenital hypothyroidism; CITI Citrullinemia type I; CITII
Citrullinemia type II; CPT I Carnitin palmitoyltransferase deficiency type I; CPT II Carnitin palmitoyltransferase type II-/Carnitine acylcarnitine
transporter deficiency; CUD Carnitine uptake defect; DECR 2,4-Dienoyl-CoA reductase deficiency; GAI Glutaric acidaemia type I; GAII Glutaric
acidaemia type II; GALT Classical galactosaemia; HCI Homocystinuria (CBS deficiency); HCSD Holocarboxylase synthetase deficiency; HPT
I_III Hypermethionemia types I, III; IVA Isovaleric acidemia (IVA)/ 2-Methylbutyrylglycinuria; LCHADD Long-chain L-3-hydroxyacyl-CoA
dehydrogenase deficiency/Trifunctional protein deficiency; MCADD Medium-chain acyl-CoA dehydrogenase deficiency; MMA Malonic acid-
aemia; MMACBL Methylmalonic acidaemia including Cbl A,B, C, D defects; MSUD Maple sirup urine disease; PA Propionic acidaemia; PKU/
HPA Phenylketonuria/Hyperphenylalaninaemia; S-S S,S disease (Sickle cell anaemia); SC S,C disease (Sickle –C disease); SCADD Short-chain
acyl-CoA dehydrogenase deficiency; SCHADD Medium-short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; TYRI Tyrosinaemia type I;
TYRII-III Tyrosinaemia types II, III; UDP UDP-galactose-4-epimerase deficiency; VLCADD Very long-chain acyl-CoA dehydrogenase deficiency
2
GDP PPP 2009 0Per capita Gross Domestic Product based on purchasing-power-parity (PPP) in International Dollar converted to Euro at the
currency exchange rate of 01.01.2009; Source: World Economic and Financial Surveys: World Economic Outlook Database. International
Monetary Fund. http://www.imf.org/external/pubs/ft/weo/2010/02/weodata/index.aspx. Retrieved on 04.04.2011 n.d. no data
J Inherit Metab Dis
The median of patients presenting asymptomatically at
the start of treatment is equal to 84 %. Disorders reported to
have relatively high rates of patients presenting symptomat-
ically at start of treatment are classical galactosaemia (50 %
symptomatic cases), β-ketothiolase deficiency (45 %), glutaric
aciduria type II (40 %), long-chain L-3-hydroxyacyl-CoA
dehydrogenase/trifunctional protein deficiency (33 %), and
congenital adrenal hyperplasia (32 %) (Fig. 2). It should be
noted that 67 % of the data are estimated and not calculated.
Epidemiological evaluation
Feedback of confirmed or rejected diagnoses and parameters
measured in the process of confirmation to the screening
laboratory helps to adjust screening algorithms, and feedback
of results of confirmation to a central registry will allow
calculation of prevalence data. On average feedback of diagno-
ses is regulated by guidelines in 88 % and by a directive in 27 %
of cases where a disorder is screened for. Guidelines are applied
on a national level in 68 % of the cases a disorder is screened for
whereas only 38 % of the directives have a national application.
Confirmed diagnoses are mostly (87 %) fed back to the screen-
ing laboratory and less often to a registry (19 %). Organisation
of feedback is reported to be predominantly “push”,i.e.the
clinical unit of confirmation actively delivers the results to the
screening laboratory. If feedback is given, predominantly not
only the diagnosis but also detailed results are transmitted.
Monitoring long-term outcome
Good long-term outcome is the ultimate goal of NBS and its
monitoring is necessary to evaluate the whole programme.
Table 3 Questions of the domain “Information and communication to parents”
1. Is there a guideline how professionals should inform parents about positive NBS?
2. Is there a directive/guideline who should inform parents about the necessity of confirmatory procedures?
3. Who actually informs parents on the necessity of confirmatory procedures?
4. Is there a guideline how professionals should explain the confirmed diagnosis and its overall implications?
5. Is there a guideline concerning the participation of professions to be involved in teaching parents about diagnosis and treatment?
6. Which professional groups actually participate in teaching parents?
0 102030405060
β Thalassaemia
HPA/PKU
Sickle cell anaemia/disease
Biotinidase D
Tyrosinaemia I
Tyrosinaemia III
MCADD
Homocystinuria
Hypermethionaemia I-III
Carnitine uptake D
GA I
ASA
Argininaemia
VLCADD
SCHADD
3 HMG CoA Lyase D
3 MCCD
Citrullinaemia II
Citrullinaemia I
CPT II
MMA
CHT
MSUD
IVA
Holocarboxylase synthetase D
CF
UDP-galactose-4-epimerase D
MMA cbl D
CPT I
SCADD
PA
CAH
LCHADD
GA II
β ketothiolase D
Classic Galactosaemia
% symptomatic
Metabolic Endocrinological CF Haematological
Fig. 2 Clinical presentation at
the start of treatment. For
abbreviations see Table 2
J Inherit Metab Dis
Averaged over all disorders data on long-term outcome are
evaluated in 80 % of the cases. However, the evaluation is
predominantly done on the level of treatment units and not
combined with the emphasis of evaluation of screening
practises. Data are reported in about 40 % of the cases to
the diagnostic unit but only in 3 % to a registry. A notewor-
thy exception is cystic fibrosis where three out of nine
(33 %) countries screening for the disorder report having a
registry.
Quality control and quality assurance
Quality control (QC) is defined as a system of routine
checks to assure that predefined requirements of the
programme are fulfilled, whereas quality assurance (QA)
activities include a planned system of review procedures
conducted by personnel not directly involved in the
programme. Actual practice of quality control and assurance
was investigated regarding seven steps of a screening
programme (see Fig. 3).
Quality measures were reported more often for QC than
for QA. Overall activities for systematic assurance of quality
are lacking in 60 to 90 % of the cases where a disorder is
screened for. Laboratory diagnostic procedures are nearly
always quality approved (either by QC of QA alone or by
both); process steps dealing with information of parents
show low levels for QC and/or QA.
Training of professionals
Across all four groups of disorders, systematic training is
most often offered to paediatricians (40 %) and dieticians
(29 %), followed by geneticists (16 %) and clinical nurse
specialists (14 %). Training for psychologists (8 %) and
social workers (4 %) is rarely offered. Analysis by groups
of disorders revealed that training is most often offered
for cystic fibrosis screening programmes (25 %), fol-
lowed by metabolic (20 %) and endocrine disorders
(17 %). For haemoglobinopathies, training is offered only
for the clinical nurse specialist and the geneticist. Figure 4
summarises the results regarding the different professional
groups involved in the confirmation of diagnosis and
treatment.
Awareness and support
Political support for NBS
Political support for NBS has been reported by all
responding countries. In most countries political support
is represented by public funding of NBS or by a service
of the public health system. In none of the answers was
reference made to international political support. Refer-
ence was made to the national plan for rare diseases by
Bulgaria, which has been stimulated by the EU. It is
possible that the role of the EU was overlooked because
the present survey was focused on collection of national
information.
Professional societies
National professional societies dealing with disorders
screened for (societies for human or medical genetics,
general paediatric societies, societies for endocrinology or
metabolic disorders or working groups for newborn screen-
ing) have been reported for 24 of 35 jurisdictions.
0 10203040506
0
7. Information about parents' and
patients' groups
6. Information of parents about
diagnosis and treatment
5. Feedback LTFU to confirmatory
diagnosis unit
4. Feedback confirmed diagnosis
to NBS lab
3. Ages at diagnosis and treatment
2. Where diagnostics and treatment
are done
1. Laboratory diagnostic procedures
%
QC QA QC & QA
Fig. 3 Mean percentages of
quality control (QC) and quality
assurance (QA) in seven steps
of the process of confirmation
of a positive screening result.
(FTFU 0long-term follow up)
J Inherit Metab Dis
Patient’/parents’groups for disorders screened
Twenty-eight of the 35 responding jurisdictions have patient
and/or parent associations for at least some of the screened
conditions. Examples of these groups are national PKU-
societies (http://www.espku.org/), societies of patients and/or
parents with cystic fibrosis (http://www.cfww.org/cfe/) and
organisations for rare diseases (http://www.eurordis.org/).
Involvement of patient organisations in changes
of screening programmes
Eighteen jurisdictions, which have expanded NBS during
the last five years, have patient advocacy groups specific to
screened disorders while two have not. In ten out of the 18
cases patient groups were reported to have been involved in
the decision to expand NBS. While it is not clear whether
these were disease-specific advocacy groups, it is notewor-
thy that in eight cases relevant advocacy groups were not
involved in the expansion of screening. However, it may be
the case that the disease-specific advocacy groups became
active only after NBS was expanded.
Empowerment
Most screened disorders are not only rare, but also do not fit
with common concepts of disease and illness. In general,
elaborated preventive treatment protocols have to be fol-
lowed by patients who have never had or will have any
symptoms. Providing parents/caretakers with instructive
material supplementing and supporting communication aims
to improve transmission of information, the understanding of
the child’s problem, compliance with recommendations, and
thus the outcome. Treatment of disorders screened for in NBS
programmes is mainly executed by parents, making empow-
erment of parents regarding understanding and execution of
preventive medicine a central issue. Material to support the
first communication of the meaning and consequences of a
positive NBS result was reported to be available less often
(41 %) than material explaining treatment (69 %). Quality of
these materials has not been investigated during the survey,
but there is evidence that parent educational material often
does not meet standards regarding completeness or readability
(Fant et al. 2005).
Guidelines and directives
Figure 5gives an overview on the regulation (by a guideline
or a directive) of different domains. Early steps proximal to
the positive laboratory screening result appear to be better
regulated than later or more distal steps
Overall confirmation of screening results (where, how,
when) is predominantly regulated by guidelines (75 %) and
less often by directives (29 %). The same was found for
information and communication to parents (50 % guidelines
and 37 % directives). Material describing how to inform
parents, associated with guidelines, is available digitally and
in print. Most often material seems to be produced locally,
but then applied on a national basis. Across countries at least
one (and often multiple) guidelines and at least one material
for first communication are available for each disorder
screened for somewhere in Europe.
0 102030405060
Other
Social worker
Psychologist
Geneticist
Clinical nurse specialist
Dietician
Paediatrician
% countries screening for disorders
Metabolic Endocrinologic CF Haemoglobin
Fig. 4 Training offered to
professionals
J Inherit Metab Dis
Issues related to treatment (age at start of treatment,
where to treat, professions to be involved in treatment,) are
regulated on average in 60 % of the cases a disorder is
screened for. Epidemiological evaluation is rarely regulated
by guidelines (15 %) or directives (18 %). However, in
practice on average evaluation was reported for 84 % of
the cases a disorder is screened for. The main parameters
evaluated are prevalence (79 %), subtypes of severity
(39 %) and ethnic origin (28 %). If evaluation is done,
it is performed in national registries (42 %) or on the
level of local databases (50 %). In 8 % data have not
been reported. Long-term outcome is scarcely monitored
on the basis of a guideline (21 %) or directive (2 %).
Feedback of long-term outcome to a registry or units for
confirmation is scarcely regulated by guidelines (31 %)
and never by a directive.
Correspondence between regulation
(guidelines and directives) and current practice
For many facets of NBS programmes current practice has
been reported to be organised, however, without being reg-
ulated by a guideline or directive. Therefore, the relationship
between current practice and its regulation was analysed for
the four domains of feedback of diagnoses to the screening
laboratory or registry, monitoring of long-term outcome,
feedback of long-term outcome to the diagnostic unit, and
epidemiological evaluation of the screening programme. For
each disorder and country four different results were possi-
ble in each domain: (1) there could be a practice and a
regulation (guideline or directive), (2) there could be a
practice without a regulation, (3) there could be a regulation
without a practice, and (4) there could be neither a practice
nor a regulation. Data were first averaged for each disorder
across countries and then across disorders. Table 4reports
the results of the analysis.
Results show that the most proximal process of commu-
nicating the results of confirmatory investigations to the
NBS laboratory seems to be very well regulated and organ-
ised. In a substantial number of cases, data collection and
evaluation of long-term outcome and other epidemiological
information is in place on a local level only without being
regulated by a guideline. Feedback of long-term outcome to
the diagnostic unit or to a registry was reported even less
frequently but mostly in association with the existence of a
guideline. The limited practice of this transmission of infor-
mation may be attributed to the number of intervening steps
and to the usually long time interval between the two events,
but may also be due to data protection regulations, as in
general it is not allowed to transmit patient data from treat-
ment units to screening laboratories. Overall exchange of
information across different steps of a NBS programme
often is locally organised even if there is no regulation by
a guideline or a directive.
Summary and discussion
The 37 data sets reveal substantial variation across national
screening panels, but also many similarities. Confirmation is
done almost always in specialised centres, and in about
75 % of the cases screening results are confirmed within
the first 20 days of life. However, the definition of a
specialised centre has not been elucidated. Although reported
costs for confirmation are predominantly based on respond-
ents’estimations, the figures can be taken as educated guesses
showing a large variation between disorders as well as for the
same disorder between countries.
The person informing about a positive NBS result is most
often the GP or a paediatrician, but also screening laboratories
can be the first to inform parents. The preponderant mode of
information is a phone call. Parents already get detailed infor-
mation during the first contact, and paediatricians, dieticians
0 10203040506070 8090100
Training of professionals
Monitoring long-term outcome
Information and communication to parents
Monitoring epidemiological evaluation
Treatment
Confirmative diagnostics
Domain
%
Fig. 5 Regulation (by
guidelines and/or directives) of
domains of European NBS
programmes
J Inherit Metab Dis
and geneticists are the key persons in teaching parents about
diagnosis and treatment. Material to support the first com-
munication of the meaning and consequences of a positive
NBS result was reported to be available less often than
material explaining treatment.
For most disorders patients present asymptomatically at
start of treatment, but for some disorders substantial numb-
ers are confirmed at a symptomatic stage (classical galacto-
saemia, β-ketothiolase deficiency, glutaric aciduria type II,
LCHADD, and CAH). Confirmed diagnoses are mostly fed
back to the screening laboratory and less often to a registry.
Long-term outcome is usually evaluated, however, the eval-
uation is predominantly done at the level of treatment units
and outcomes are rarely reported to a registry.
Training of professionals involved in confirmation is
most often offered to paediatricians, but less often to dieti-
cians, geneticists, clinical nurse specialists, psychologists,
and social workers.
Political support for newborn screening by public fund-
ing of newborn screening or by a service of the public health
system seems to be present in all countries. Professional
societies for screened disorders have been reported to exist
in two thirds of the jurisdictions. Most countries have
patient and/or parent associations for at least some of the
screened conditions. Patient advocacy groups exist in about
half of the countries where newborn screening was recently
expanded, but these groups were rarely involved in the
decision to expand newborn screening.
Guidelines are nearly always available for laboratory
diagnostic procedures, often for confirmation of screening
results, but information to parents showed low levels for
regulation and quality control. Epidemiological evaluation
is rarely regulated by guidelines or directives, but practiced
in most of the cases. Long-term outcome is scarcely moni-
tored on the basis of a regulation.
Based on the results of the survey, scientific evidence and
clinical practice, the European Network of Experts on
Newborn Screening (EUNENBS), which was set up with
experts of health authorities of EU member states, relevant
European learned societies and European parents’/patients’
associations to prepare a consensus document to support
discussion for a future policy initiative has formulated 70
recommendations on how to develop NBS in Europe
(Cornel et al. 2011). In the following we summarise the
most important recommendations, but the reader is referred
to the original document for more detailed information (http://
www.iss.it/cnmr/prog/cont.php?id01621&lang01&tipo064).
1. There is a clear need to develop case definitions for all
disorders screened for, including an attempt to achieve
agreement on these case definitions within the EU
to facilitate assessment and international outcome
studies.
2. The decision whether a screening programme should
be performed can be based on a framework of screen-
ing criteria updated from the traditional Wilson and
Jungner (1968) criteria, relating to disease, treatment,
test and cost.
3. The interest of the child should be central in the
assessment of pros and cons.
4. A European NBS body (or the national NBS bodies)
should further elaborate the specifications and the op-
erative application of the screening criteria through
discussion and agreement with the EU national
authorities.
5. The European NBS body (or the national NBS bodies)
should consider other potential advantages, especially
(a) avoiding a diagnostic odyssey and (b) informed
reproductive choice for the next pregnancy(ies) of the
parents, and later for the child, and the provision of
genetic counselling to the family.
6. Health Technology Assessment to evaluate the evi-
dence on the effectiveness of early detection through
newborn screening and treatment should be achievable
in practice. For rare conditions, best level evidence
should be used. Methods need to be developed to both
optimise health benefit and careful evaluation.
7. Universal screening is generally preferable to ethnically
targeted screening. If there are sound reasons (e.g. health
gain) for targeted screening it is important to avoid
stigmatisation.
8. The health system should ensure treatment to all
confirmed cases diagnosed by screening.
9. Systems should be developed in order to support
screening in countries where it would be beneficial
but not affordable for economic and/or social reasons.
Table 4 Correspondence of guidelines and actual practice
Regulation &
practice
No regulation
but practice
Regulation but
no practice
No regulation &
no practice
1. Feedback of final diagnosis to screening labs/registry 94 % 6 % 0 % 0 %
2. Monitoring long-term outcome 22 % 60 % 0 % 18 %
3. Feedback of long-term outcome to diagnostic unit 27 % 16 % 4 % 53 %
4. Epidemiological evaluation of screening programmes 25 % 60 % 1 % 14 %
J Inherit Metab Dis
10. The EU should put in place systems for helping those
countries where treatment is not yet available for all
confirmed cases. The target of treatment for all con-
firmed cases should be achieved without reducing the
quality of treatment.
11. Screening methodology should aim to avoid unintended
findings, such as cases with mild forms and information
on carrier status, as much as possible.
12. If unintended results are found (such as carrier status),
member states need to consider carefully how results
are communicated. Parents need to be informed
adequately in a way which is consistent with the indi-
vidual data protection rights and the right to privacy as
well as patient rights.
13. Economic evaluations of NBS programmes are needed.
Balancing the right to care of all patients needs to take
rare disorders into account.
Following an extensive discussion of the results of the
survey as well as current scientific evidence and clinical
experience the EUNENBS approved a list of disorders to
be considered in the gradual expansion of NBS in the
European Union (Table 5).
Over 50 disorders can be detected by NBS based on
blood samples with varying methods, but also with varying
certainty. It should be stressed that NBS is a comprehensive
programme: it can not be focussed or even reduced to the
part of the screening laboratory. Screening includes confir-
mation of the positive screening result, decision for or
against treatment, choice of appropriate treatment options
(e.g. diet, drugs, behavioural measures or mere observation)
as well as long-term follow-up of patients and evaluation of
outcome (Rembold 1998; Wilcken et al. 2012,seealso
Fig. 1). This expanded concept of NBS is not really new,
as it can already be found in the seminal work by Wilson
and Jungner (1968) on principles and practice of screening
for disease.
An important framework to put principles into practice
has recently been published by the US Secretary for Health
and Human Services Advisory Committee on Heritable
Disorders in Newborns and Children (Hinton et al. 2011).
A two axes model of long-term follow-up (LTFU) for new-
born screening has been formulated. Axis one comprises
four components of LTFU (care coordination, evidence-
based treatment, continuous quality improvement, and re-
search), axis two deals with stakeholders after NBS (chil-
dren and families, primary care providers, specialists and
clinical researchers, and national state entities). There are
four central tasks to be done in effective and efficient NBS
follow-up. First, coordination of the different disciplines and
Table 5 Disorders
1
suggested by the EUNENBS to be considered in the expansion of NBS in the European Union
Group 1a N of countries
screening
Group 1b Disorders with
lower prevalence, the test is
not too difficult and health
gain is proven
N of countries
screening
Group 2 N of countries
screeningDisorders with a relatively
high prevalence, the test is
not too difficult and health
gain is proven
Candidates disorders where screening
is more challenging according to the
criteria by Wilson and Jungner 1968;
cost-effectiveness, RCTs
HPA 33 MSUD 12 BIO 10
CH 37 GAI 10 CMV infection not surveyed
CAH 14 GALT 10 CPTII 7
CF 9 CACT not surveyed
MCAD 13 GAII 6
S_S/SC/BTHA
2
3-4 3HMG 5
HCSD 6
HCI 7
IVA 9
BKT 3
LCHAD 8
lysosomal storage disorders not surveyed
3MCC 6
SCIDD not surveyed
TYRI & TYRII_III 7-3
VLCAD 9
Vitamin B12 DEFICIENCY not surveyed
1
For abbreviations see Table 2
2
in Mediterranean countries and countries with migrant populations
J Inherit Metab Dis
individuals involved in treatment and care. Second, coordi-
nation of all stakeholders in new knowledge discovery and
translational research. The third task is information flow
between professionals and from professionals to patients
and vice versa. Finally, there should be a structured process
of quality improvement of care, knowledge and information.
The suggested solution for these tasks is the concept of a
medical home for the patient, a focal point for collaboration
and coordination (van Dyck and Edwards 2006). Basically
the medical home is a concrete physical entity where the
patient can address all his/her questions and problems,
linked with all specialists needed for information, treatment
and care, i.e. a physical but also a virtual centre for diagno-
sis, treatment and care.
These requirements can at least implicitly already be
identified in an article published by Blumberg more than
half a century ago (Blumberg 1957) defining the objectives
of screening programmes by obtaining epidemiological data
on the nature of the disease, perfecting the screening proce-
dures for future use, increasing the likelihood of future
acceptance of other screening programmes, and improving
the health of those in the screened community. The author
also formulated four questions to be answered in a screening
programme: 1. What is the outlook for a person with the
disease?, 2. Who is going to do the diagnostic follow-up?, 3.
What facilities exist for treating cases found?, and last but
not least 4. What mental status accompanies knowledge or
suspicion of the disease?
Our survey revealed that there are positive examples of
NBS programmes that can be used as templates for further
research and practice. In Europe for each disorder screened
for there exists at least one guideline for each step of a
screening programme. Furthermore, detailed outcome stud-
ies have been published for the Australian (Wilcken et al.
2009) and German (Lindner et al. 2011) screening panels,
but also for single disorders (e.g. glutaric aciduria type I;
Kölker et al. 2006; Heringer et al. 2010). Evidence-based
guidelines are available for cystic fibrosis (Castellani et al.
2009), congenital adrenal hyperplasia (Auchus et al. 2010),
and glutaric aciduria type I (Kölker et al. 2011), and the
German Working Group for inborn errors of metabolism has
approved a guideline on how to confirm positive screening
results (Lindner 2010).
There is an ongoing discussion about guiding criteria for
inclusion of single disorders into a screening panel (e.g.
Petros 2011) and professionals will have to face the ques-
tions (not only for research purposes but also as they are
asked by parents) “why are we all doing different things”
(Pollitt 2007) and “how are we travelling, and where should
we be going”(Wilcken 2011). We hope that the EU Council
Recommendation for an Action in the Field of Rare Diseases
(European Commission 2009) will lead to the establishment
of lines for the cooperation and coordination among Member
States in order to better utilise national resources and expertise
as well as reducing inequalities in the access to high quality
care. Continued support of research and other activities to
tackle these challenges will be required.
Acknowledgement We thank all respondents for contributing their
data to the survey
This work was funded by the European Union (Contract number
2009 62 06 of the Executive Agency for Health and Consumers) and
by the Dietmar Hopp Foundation, St. Leon -Rot.
Conflict of interest None.
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Supplementary Table 1 Screening panels of countries (including research programs) and frequency distribution of disorders screened for
(Endo)
(Endo)
(Cys F.)
(AAD)
(AAD)
(AAD)
(AAD)
(AAD)
(AAD)
(AAD)
(AAD)
(AAD)
(AAD)
(OA)
(OA)
(OA)
(OA)
(OA)
(OA)
(OA)
(OA)
(OA)
(OA)
(FAOD)
(FAOD)
(FAOD)
(FAOD)
(FAOD)
(FAOD)
(FAOD)
(FAOD)
(FAOD)
(Hemo)
(Hemo)
(Hemo)
(M)
(M)
(M)
Country
ch
cah
cf
pku/hpa
msud
hci
tyrI
asa
citI
arg
hptI_III
tyrII_III
citII
gaI
iva
mmacbl
pa
3mcc
gaII
hcsd
3hmg
bkt
mma
mcadd
vlcadd
lchadd
cptI
cptII
cud
scadd
schadd
decr
s-s
btha
sc
bio
galt
udp
N disorders
screened for
Albania 0
Austria X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 29
Belgium (Flemish) X X X X X X X X X X X 11
Belgium (French) X X2 X X X X X X 8
Bosnia-Herzegovina X X X 3
Bulgaria X X X 3
Croatia X X 2
Cyprus X X 2
Czech Republic X X X X X X X X X X X X 12
Denmark X X X X X X X X X X X X X X X 15
Estonia X X 2
Finland X 1
France X X X X X 5
FYROM X 1
Germany X X X X X X X X X X X X X X X 15
Greece X X X 3
Hungary X X X X X X X X X X X X X X X X X X X X X X X X X 25
Iceland X X X X X X X X X X X X X X X X X X X X X X X X X X 26
Ireland X X X X X 5
Italy X X2 X 3
Kosovo 0
Latvia X X 2
Lithuania X X 2
Luxembourg X X X X 4
Malta X X X 3
Montenegro X 1
Netherlands X X X X X X X X X X X X X X X X X X X X 20
Norway X X 2
Poland X X X 3
Portugal X X X X X X X X X X X X X X X X X X X X X X X X X 25
Romania X X 2
Serbia X X 2
Slovakia X X X X 4
Slovenia X X 2
Spain X X X X X X X X X X X X X X X X X X X X X X X X X X X 27
Sweden X X X X X 5
Switzerland1 X X X X X X X 7
Turkey X X X 3
United Kingdom X X X X X X X 7
Frequency 37 15 10 33 12 7 7 6 5 4 3 3 2 10 9 7 7 6 6 6 5 3 1 13 9 8 7 7 6 3 2 0 4 3 3 10 10 3
1 including Liechtenstein
2 Belgium (French) screens for CAH not nationwide; likewise Italy screens for CF but not nationwide
Abbreviations
3HMG 3-Hydroxy-3-methylglutaric aciduria; 3MCC 3-Methylcrotonyl-CoA carboxylase deficiency/3-Methylglutacon aciduria/2-methyl-3-OH-butyric aciduria; AAD
Disorders of amino acid metabolism; ARG Argininemia; ASA Argininosuccinic aciduria; BIO Biotinidase deficiency; BKT Beta-ketothiolase deficiency; BTHA S, beta 0-
thalassemia; CAH Congenital adrenal hyperplasia; CF Cystic fibrosis; CH Primary congenital hypothyroidism; CITI Citrullinemia type I; CITII Citrullinemia type II; CPT I
Carnitin palmitoyltransferase deficiency type I; CPT II Carnitin palmitoyltransferase type II-/Carnitine acylcarnitine transporter deficiency; CUD Carnitine uptake defect;
DECR 2,4-Dienoyl-CoA reductase deficiency; Endo Endocrinopathies; FAOD Disorders of fatty acid metabolism; GAI Glutaric acidaemia type I; GAII Glutaric acidaemia
type II; GALT Classical galactosaemia; HCI Homocystinuria (CBS deficiency); HCSD Holocarboxylase synthetase deficiency; Hemo/ HpB Hemoglobinopathies; HPT I, III
Hypermethionemia types I, III; IVA Isovaleric acidemia (IVA)/ 2-Methylbutyrylglycinuria; LCHADD Long-chain L-3-hydroxyacyl-CoA dehydrogenase
deficiency/Trifunctional protein deficiency; M Miscellaneous disorders; MCADD Medium-chain acyl-CoA dehydrogenase deficiency; MMA Malonic acidaemia; MMACBL
Methylmalonic acidaemia including Cbl A,B, C, D defects; MSUD Maple sirup urine disease; OA Disorders of organic acid metabolism; PA Propionic acidaemia; PKU/HPA
Phenylketonuria/Hyperphenylalaninaemia; S-S S,S disease (Sickle cell anaemia); SC S,C disease (Sickle – C disease); SCADD Short-chain acyl-CoA dehydrogenase
deficiency; SCHADD Medium-short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; TYRI Tyrosinaemia type I; TYRII-III Tyrosinaemia types II, III; UDP UDP-
galactose-4-epimerase deficiency; VLCADD Very long-chain acyl-CoA dehydrogenase deficiency
