Journal of Inherited Metabolic Disease

, Volume 35, Issue 4, pp 603–611

Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 1 - From blood spot to screening result

Authors

    • National Institute for Public Health (RIVM)
  • Peter Burgard
    • Department of PaediatricsUniversity Hospital
  • Martina C. Cornel
    • Clinical Genetics/EMGO InstituteVU University Medical Centre
  • Tessel Rigter
    • Clinical Genetics/EMGO InstituteVU University Medical Centre
  • Stephanie S. Weinreich
    • Clinical Genetics/EMGO InstituteVU University Medical Centre
  • Kathrin Rupp
    • Department of PaediatricsUniversity Hospital
  • Georg F. Hoffmann
    • Department of PaediatricsUniversity Hospital
  • Luciano Vittozzi
    • National Centre for Rare Diseases
SSIEM Symposium 2011

DOI: 10.1007/s10545-012-9483-0

Cite this article as:
Loeber, J.G., Burgard, P., Cornel, M.C. et al. J Inherit Metab Dis (2012) 35: 603. doi:10.1007/s10545-012-9483-0

Abstract

In many European countries neonatal screening has been introduced over the last 50 years as an important public health programme. Depending on health care structure, available funds, local politics, input from professional groups, parent groups, and the general public this introduction has led to different approaches in the way the screening programmes have been set up, financed and governed. To get some insight about the current situation, in 2009 the European Union, via its EAHC agency, put out a call for a tender that was acquired by our project group. An online survey was compiled in which the whole screening programme was covered by a questionnaire. This survey covered the EU member states, (potential) candidate member states and EFTA countries, in total 40 countries. Results showed little consensus concerning 1. information of parents including informed consent; 2. which conditions are screened for, ranging from 1 to around 30 conditions; 3. sampling time post partum; 4. screening methodology including cut-offs values even between screening laboratories within countries.; 5. storage of residual specimens, varying from 3 months to 1000 years. In addition, confirmatory diagnostics and follow-up also show large discrepancies (Burgard et al. http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64 2011). In addition to the current practices report an expert opinion document has been produced with recommendations to the EU Commission for future improvements, e.g. in parallel to the way the USA has harmonized its practices based on recommendations by the American College of Medical Genetics (Watson et al., Pediatrics 117: S296-S307, 2006).

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-thalassaemia

CAH

Congenital adrenal hyperplasia

CF

Cystic fibrosis

CH

Primary congenital hypothyroidism

CITI

Citrullinaemia type I

CITII

Citrullinaemia 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

EFTA

European Free Trade Association

EAHC

Executive Agency for Health and Consumers

EQA(S)

External Quality Assessment (Scheme)

EUNENBS

European Network of Experts on Newborn Screening

FAOD

Disorders of fatty acid metabolism

FYROM

Former Yugoslavian Republic of Macedonia

GAI

Glutaric acidaemia type I

GAII

Glutaric acidaemia type II

GALT

Classical galactosaemia

HCI

Homocystinuria (CBS deficiency)

HCSD

Holocarboxylase synthetase deficiency

Hemo/ HpB

Haemoglobinopathies

HPLC

High performance liquid chromatography

HPT I III

Hypermethionaemia types I, III

ISO

International Standards Organization

IVA

Isovaleric acidaemia (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 Syrup Urine Disease

NBS

Neonatal (newborn) Screening

NEQAS

National External Quality Assessment Scheme (UK)

OA

Disorders of organic acid metabolism

PA

Propionic acidaemia

PKU/HPA

Phenylketonuria/Hyperphenylalaninaemia

QA/QC

Quality assurance/Quality control

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

UK

United Kingdom

VLCADD

Very long-chain acyl-CoA dehydrogenase deficiency

Introduction

Neonatal or newborn screening (NBS) programmes using dried blood spots were first developed in the 1960s, inspired by the work of Dr Robert Guthrie. In the early days the whole system was focused on the detection of one or just a couple of disorders (“conditions”). Tremendous technological improvements made it gradually possible to screen for a multitude of conditions almost simultaneously. Increased methodological sensitivity made it possible to perform reliable screening after 48 hours post partum.

By these improved performance characteristics NBS has firmly established its place in the group of cost-efficient public health tools. It has risen above the level of small scale amateur-enthusiasm and in many countries moved into well organised nation-wide long term health care provisions.

In the European Union treaties health care has always been left to the individual member states (“principle of subsidiarity”, see Maastricht Treaty Art 129 (1992)). Nevertheless in the last few years the EU has recognised the importance of close collaboration between member states especially in the detection and treatment of cases of rare diseases (less than 1 affected person per 2000 persons). Each member state by itself cannot cope with the multitude of rare diseases in a cost-effective way. This has been laid down in a number of relevant documents (e.g. Communication from the EU Commission (2008), Council Recommendation (2009), Aymé and Rodwell (2011)).

Based on these documents the European Agency for Health and Consumers in 2009 initiated a call for tender for a project aiming to make a survey of the current NBS practices in the EU member states and the (potential) candidate member states as well as to develop a set of recommendations for improvement and further expansion of NBS programmes. This and the subsequent paper (Burgard et al. 2012) highlight the most important survey results and recommendations.

Materials and methods

The project group viewed the NBS system as a process with five different aspects: a. preparation of the legal basis and general provisions; b. information to public and prospective parents; c. informed consent and blood sampling; d. laboratory screening procedures and blood spot storage; e. confirmatory diagnostics, communication of diagnosis, and treatment. See Fig. 1 in the accompanying paper by Burgard et al. (2012). For each aspect a series of questions were developed. All questions were converted into a web based survey to which respondents could log on with a given username and password. The project group members were able to view the replies from each respondent and could ask for further clarification and elaboration if needed.

The project group member identified the participants of the survey in collaboration with the European Union Network of Experts on Newborn Screening (EUNENBS), the International Society for Neonatal Screening (ISNS), the European Board of Clinical Obstetricians and Gynaecologists (EBCOG), the Society for the Study of Inborn Errors of Metabolism (SSIEM), the European Society for Paediatric Endocrinology (ESPE), and the European Cystic Fibrosis Society (ECFS) for the recruitment of knowledgeable colleagues in each of the 40 countries and jurisdictions. This recruitment was not always an easy process. In some countries the NBS practice is very much fragmented into regions and provinces without coordination on a national level. In other countries it was difficult to identify the persons having a good overview of the situation in that country. In some instances this resulted in partially incorrect data from such a country and conclusions which subsequently had to be corrected.

The project group repeatedly consulted with an advisory group consisting of around 30-40 experts from various professional disciplines, closely related to NBS in practice. In total three face-to-face conferences were organised to discuss the process of the project and the results.

The final documents were approved by this group of experts prior to submission to EAHC (Burgard et al. 2011; Cornel et al. 2011).

Results

Countries

Table 1 shows the list of countries included in the survey. The colours of the country names indicate whether the country is a European Union member, a candidate member, a potential candidate member country, or a member of the European Free Trade Association (EFTA), respectively. In general the results are presented per whole country with a few exceptions. Belgium has been regarded as two separate jurisdictions (Flemish respectively French Community). The Liechtenstein infants are screened in Switzerland. Therefore, for the purpose of this project the Liechtenstein data are not mentioned separately. In some countries, notably Italy and Spain, there appeared to be large regional differences, making a result per country not meaningful. For Turkey only information concerning questions about confirmatory diagnostics and treatment could be obtained. For Albania and Kosovo no results were available. There was only a general statement that there is no screening at all in Albania.
Table 1

Country data

https://static-content.springer.com/image/art%3A10.1007%2Fs10545-012-9483-0/MediaObjects/10545_2012_9483_Tab1_HTML.gif

https://static-content.springer.com/image/art%3A10.1007%2Fs10545-012-9483-0/MediaObjects/10545_2012_9483_Figa_HTML.gif

1http://www.census.gov/population/international/data/idb/rank.php (visited Aug 17, 2011)

2 Liechtenstein screening carried out in Switzerland

3 n.d. = no data; n.a. = not applicable

4 depending on region

5 Croatia: if <48 h, 2nd sample between 96-168 h

6 UK: preferably at 120 h

Table 1 also includes the population size, and the approximate number of newborns.

Informed consent

Table 1 shows in which countries there is (written) information for the prospective parents and if they are asked for informed consent for participation in NBS as well as for storage of the dried blood spot sample after the screening has been completed. In addition the length of storage is indicated.

In most countries information is available and consent is asked for but there are countries, mainly in central Europe that do not yet have all such policies available. In Austria, Belgium-French Community, parts of Bulgaria, Czech Republic and Romania, consent is asked without such written information.

The length of storage varies considerably between 3 months (Germany) to more or less indefinite (Denmark, Norway, Sweden).

Sampling and transport

Table 1 shows per country the interval between birth and sampling and the interval between sampling and start of analysis. For most analytes sampling should not be done before 48 post partum in view of physiological variation leading to potential false positive or negative results, but in general the sooner the better after 48 hours. Finland and Malta both use cord blood but do not screen for phenylketonuria. The interval between sampling and analysis, i.e. the time needed for transportation of the sample should be as short as possible to avoid unnecessary and potentially harmful delay in diagnosis and treatment. It is, however, often several days.

Laboratory quality and workload

Table 1 shows per country the number of screening laboratories, the average annual number of samples per laboratory and whether the laboratories operate under an accredited quality system. The average annual number of samples varies from 2050 (Malta) to 121852 (Greece) but the range per individual laboratory in countries with multiple laboratories varies as well.

In 19 countries there is some form of accreditation. However, different systems are in use. In 17 countries there is none at all.

The laboratories in all countries take part in some form of external quality assessment; in this respect there are no data for Bosnia-Hercegovina.

Panel of screened conditions

Table 2 provides an overview of the screening panels in the various countries. The number of conditions per country varies from 1 in Montenegro to 29 in Austria. The conditions most screened are congenital hypothyroidism (37 countries) followed by phenylketonuria/hyperphenylalaninaemia (33 countries). Congenital adrenal hyperplasia is in third place (15 countries). Where ms/ms technology has become available, MCADD is the condition that has first priority (13 countries), but many other amino acidaemias, organic acidurias and fatty acid oxidation defects are also screened for, be it to a different degree.
Table 2

Screening panels of countries (including research programs) and frequency distribution of disorders screened for (for explanations see abbreviation list)

Country

ch (Endo)

cah (Endo)

cf (Cys F.)

pku/hp (AAD)a

msud (AAD)

hci (AAD)

tyrI (AAD)

asa (AAD)

citI (AAD)

arg (AAD)

hptI_III (AAD)

tyrII_III (AAD)

citII (AAD)

gaI (OA)

iva (OA)

mmacbl (OA)

pa (OA)

3mcc (OA)

gaII (OA)

hcsd (OA)

3hmg (OA)

bkt (OA)

mma (OA)

mcadd (FAOD)

vlcadd (FAOD)

lchadd (FAOD)

cptI (FAOD)

cptII (FAOD)

cud (FAOD)

scadd (FAOD)

schadd (FAOD)

decr (FAOD)

s-s (Hemo)

btha (Hemo)

sc (Hemo)

bio (M)

galt (M)

udp (M)

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

Cut off limits (not shown) for each condition appear to differ to a certain extent. Long tem evaluation should provide evidence to better attune these limits.

Haemoglobinopathies are screened for in France, Malta and Spain, because of relatively high prevalences as well as number of immigrants, and in addition in The Netherlands and United Kingdom because of a large number of immigrants. Surprisingly, haemoglobinopathies are not screened for in the other Mediterranean countries.

Discussion

Countries

Although the original call for tender referred to a survey in the European Union member states only, the project group decided to extend the survey also to the candidate and potential candidate member states, in the expectation that in due time these countries will join the EU. Likewise, because of the close interrelationship between EU and EFTA countries, also Norway and Switzerland were included. The situation concerning newborn screening in Kosovo is somewhat unclear. At any rate, no contact person could be found to provide information on the NBS status. Likewise, contacts with Turkey were difficult. Only some limited information concerning confirmatory diagnostics and treatment was obtained. Furthermore, it became clear that in Albania there is no NBS at all yet. Out of the 39 countries data on only 36 could be obtained by the survey, although some additional data was obtained through other routes.

Informed consent

Participation in the NBS programme preferably is based on informed consent (or dissent). To achieve this, (prospective) parents must be informed about the aims of the programme. The optimal period to provide information seems to be during the last trimester of pregnancy, separated from all information on prenatal screening. It is obvious that the postpartum period should be avoided because the magnitude of events and emotions new parents have to face. Before delivery prospective parents have more time to read and understand the information, at least if that information is available to them. In order to provide such information it is imperative that the professionals concerned have themselves access to such information.

Informed consent for storage of the dried blood spot sample after the screening has been completed and for further (scientific) use of the blood sample is lacking in 16 countries while in another eight this information could not be obtained. Nevertheless, all countries store dried blood spot samples. It is not clear if storage without consent is legal. The storage period varies from only 3 months to 1000 years or actually “indefinitely”. Three months is obviously too short to use the cards for analytical checking in case of a possible missed case and has little practical value. It must be noted that over time (> 3 years) the biochemical parameters are difficult to analyse because they will degrade or not elute from the filter paper anymore, unless the cards are kept at -20o C with dessicant. This may be too costly for the programme organisations. However, for DNA-analysis cards can be used for a very long time, even if kept at room temperature without special conditions. It is unclear whether such biobanks are governed by regulations concerning physical access to prevent misuse.

Sampling and transport

In the first 48 h post partum blood concentrations of any analytes are subject to large variations. Analysis of a sample taken during that interval may lead to false positive or false negative screening results. However, many results obtained in this period are already reliable, and it is better to have at least a sample rather than no sample at all. In health care systems where it may be cumbersome to retrieve the newborns after 48 hours, early sampling is justified. Later sampling (> 96 h) may lead to an unwanted delay in screening, diagnostic and treatment process or even no screening with possible negative health effects.

Once the sample is available it should be analysed as quickly as possible, again in view of an unwanted delay if further steps should be needed. In addition, the quality of the dried blood spot sample may deteriorate over time. In most countries the collected samples are sent to the screening laboratory by normal mail or courier which should not last longer than 2 days.

Laboratory quality and workload

The quality of the screening laboratory depends on several factors.
  1. 1.

    The screening laboratory, as all medical laboratories, should operate under a quality system that preferably is accredited or certified by an external body. For the development and implementation of such quality systems several documents have become available. The most appropriate is ISO15189 (2007), specifically oriented towards medical laboratories. A more general document is the ISO9001 (2008) standard. In several countries screening laboratories can apply for accreditation or certification by an independent body. In other countries there may be national or local regulations or guidelines that are mandatory for the laboratories to follow. In several countries NBS is performed in laboratories that are not accredited, according to our respondents (Table 1). This may endanger the quality of the results.

     
  2. 2.

    The laboratory should participate in one or more external quality assessment schemes EQAS) to monitor the quality of the measurement of the screening parameters. An EQAS typically sends out a number of quality samples, several times per year, and asks the participants to analyse them as if they were routine samples and report back the results to the organiser. Reviewing the results of all participants provides insight about the performance of their own laboratory. The results of the survey show that the laboratories in all countries (no data for Bosnia-Herzegovina) participate in one or more EQA schemes.

     
  3. 3.

    The laboratory should analyse a minimum number of samples per year, not so much to attain a constant quality level, but more to obtain and keep a sufficient level of experience on what to do with a result that is outside the normal range, e.g. to inform the screening organising body or the medical professionals involved. The conditions screened for are usually rare, which means that aberrant results occur just occasionally. For many screened conditions time is critical in diagnostic confirmation and treatment, so all laboratory personnel must know what to do in such rare situations. It is not easy to state what should be the minimum number of samples per year, but a number of 30,000-50,000 is a good approximation. If a laboratory does not receive this minimum it should consider sending the samples to a neighbouring laboratory or it could be the responsibility of the screening organisation in a country to come to terms with all participating laboratories to reduce their number. In certain countries the number of births is less than 30,000. In that case the screening organisation can accept this or make a deal with a laboratory in a neighbouring country.

     

Panel of screened conditions

Policy making concerning which conditions to screen for varies per country. It may depend on national health care politics, local medical professional interests and habits, input from parent advocacy groups, etc. In many countries the criteria of Wilson and Jungner (1968), sometimes in a modified form, are the backbone of the screening policy. However, these criteria provide a number of questions to be answered and deliberations to be made, often with financial consequences. It was to be expected that countries with a lower socio-economic status have a smaller screening panel. On the other hand, preventive medicine through screening can be considered to be cost effective and even some countries with a relatively high socio-economic status still have a relatively small screening panel, so there must be other reasons as well, such as the structure of the health care system, national or local politics, requirements for scientific evidence, ethical considerations (e.g. detecting of carriers, uncertainty about treatability, etc). Unfortunately, not all conditions can be screened with a single methodology. Some require immunochemical techniques (CH, CAH, CF), some colorimetric techniques (GAL, BIO), some tandem mass spectrometry (MCADD and other fatty acid oxidation disorders, amino acidaemias, organic acidurias), high pressure liquid chromatography (SCD/thal), sometimes in combination with molecular biological techniques. For this broad spectrum of techniques extensive knowledge and experience both in the laboratory and of the medical professionals are necessary. Nonetheless, although several countries have all of this available, other countries slow reluctance to ask for assistance to reach the same goals. On the contrary, in some countries policy makers tend to want to obtain all experimental evidence in their own country before extending their own programme, which could take decades.

In comparison to previous surveys (Zabransky 2002; Bodamer et al. 2007; Loeber 2007) it is noted that there has been a large increase in the number of conditions screened for in at least 11 countries. The major impetus has been the introduction of the tandem mass spectrometry technique making multiplex screening for fatty acid oxidation disorders, amino acidaemias, and organic acidurias possible.

Conclusion

The results as outlined in this and the subsequent paper (Burgard et al. 2012) indicate that there are large variations in the design of the newborn screening programmes in the European countries and the day-to-day practices. To a large extent the programmes themselves run smoothly. However, efficiency can be improved by studying the details and learning from the experiences in other countries.

The recommendations of the project group (Cornel et al. 2011) include the use of a decision-making matrix. This should be stimulated by the European Commission and its subordinate governing bodies. The ultimate goal is to have a uniform screening panel as has been achieved in the USA (Watson et al. 2006; NNSGRC 2011) resulting in equal screening opportunities for all European newborn infants.

Acknowledgments

We thank all respondents for contributing their data to the survey.

This work was funded by the European Union contract number 2009 6206 of the Executive Agency for Health and Consumers.

Conflict of interest

None.

Copyright information

© SSIEM and Springer 2012