photo RYM

History, current situation and future perspectives of neonatal screening for rare diseases in Spain

Dr. Raquel Yahyaoui Macias

Clinical biochemist. Head of the Metabolopathies Laboratory and Neonatal Screening Centre of Eastern Andalusia. Regional University Hospital of Malaga.


Neonatal screening is an essential secondary prevention activity in the context of public health aimed at the pre-symptomatic identification of certain congenital diseases in newborns. Screening tests in the first days of life allow early treatment to be initiated to prevent or reduce the morbidity and mortality associated with these diseases.

The most important newborn screening test is the so-called "heel prick test", which consists of collecting a few drops of capillary blood from the newborn's heel between 24 and 72 hours of life on filter paper. On the dried blood specimen on paper, also known as DBS ( Dried Blood Spot), certain biochemical and/or genetic analyses will be carried out in the neonatal screening laboratory in order to detect children at risk of suffering from any of the diseases included in the programme. Currently, all the diseases offered by the newborn screening programmes are rare diseases, as the prevalence of each of them is less than 1 in 2,000 newborns.

Neonatal screening tests are not considered diagnostic tests. In the event of a positive screening test result, further diagnostic tests (biochemical, enzymatic and/or genetic) must be performed to confirm or rule out the suspected disease. Such a result, therefore, does not indicate initiation of therapeutic measures, unless for preventive purposes until it is confirmed that the newborn has a disease that may threaten his or her health.

Although historically newborn screening programmes have focused more on the screening test, truly effective programmes also provide an infrastructure for universal access, education (to professionals and families) and clinical follow-up for all newborns with a positive screening result. A newborn screening programme is a comprehensive system of care that should encompass six main components: education, screening, diagnosis, therapeutic management, short- and long-term clinical follow-up and periodic evaluation of the programme's quality indicators. Any newborn screening programme should ensure equitable access to the service offered by the programme (screening, diagnosis and access to treatment), informed participation of families and protection of confidentiality.

In order to define criteria for the introduction of new diseases into population screening programmes, the World Health Organisation (WHO) published in 1968 the Wilson and Jungner principles, criteria that have been for many years a reference for evaluating candidate diseases (Table 1). The discovery of new biomarkers and technological advances in recent decades offer enormous possibilities to detect more diseases at a reasonable cost. All this, together with the availability of new effective therapies, has led the scientific community and the WHO itself to reconsider the application of the classic Wilson and Jungner criteria, which were defined on the basis of another reality, and need to be adapted to the present day. Although these criteria published by the WHO can serve as a guide for decision-making, the reality is that the differences in the recommendations for the inclusion of diseases in neonatal screening programmes are intrinsically dependent on political, socio-cultural and, above all, economic criteria.

History and current situation in Spain

In Spain, the first neonatal screening programme began in 1968, in Granada, for the early detection of phenylketonuria, at the initiative of Professor Federico Mayor Zaragoza. Subsequently, other territorial programmes were set up and developed around the "National Plan for the Prevention of Subnormality" created in 1978 and later called the "Plan for the Prevention of Handicap", integrated into the Royal Board on Disability. In 1982, budgets were transferred to the Autonomous Communities (CCAA), on which these programmes became dependent.

With the transfer of healthcare management to the different Autonomous Regions in 1982, the foundations began to be laid for population-based neonatal screening programmes to become an organised, multidisciplinary activity, integrated and coordinated by the National Health System. In 1992, coverage was already close to 100% of newborns for neonatal screening for congenital hypothyroidism and phenylketonuria. At that time, there were as many as twenty-two neonatal screening laboratories throughout Spain, which have been reduced to fifteen at present.

During the following years, some advances were made, such as the implementation of new screenings for cystic fibrosis and congenital adrenal hyperplasia. However, the most important technological advance applied to neonatal screening was undoubtedly the introduction by some ACs of tandem mass spectrometry for the detection of inherited metabolic diseases in 2000. This technology allows the simultaneous measurement of amino acids and acylcarnitines and the identification of newborns at risk for certain aminoacidopathies, some organic acidurias and defects in the beta-oxidation of fatty acids. This is known as "expanded" newborn screening and is estimated to potentially detect up to 60 metabolic diseases and other clinical conditions. This new model of newborn screening is so controversial that it has been the subject of international ethical debate for years, to the point that even today, many screening centres around the world, including in Spain, only report a limited number of pathologies that have been granted a higher level of scientific evidence to be included in the programmes. For all these reasons, the asymmetry in the organisation of the programmes and the great heterogeneity in the diseases included in each Autonomous Region was also increasing.

The first step towards the harmonisation of neonatal screening programmes by the Ministry of Health took place in July 2013, when the Interterritorial Council of the National Health System approved the basic common portfolio of health care services, which subsequently made neonatal screening for seven diseases mandatory by means of order SSI/2065/2014 of 6 November, which regulates population-based neonatal screening programmes for endocrine-metabolic diseases. These seven diseases are: congenital hypothyroidism, phenylketonuria, cystic fibrosis, sickle cell anaemia, glutaric aciduria type 1, medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD). In addition to these mandatory diseases, each programme is free to expand the number of diseases screened for through its complementary portfolio, so that the range of diseases screened for in the different Spanish programmes currently varies between seven and thirty-two.

Challenges and future prospects

From the Ministry of Health, the future outlook for neonatal screening in Spain is to continue progressing in the harmonisation of programmes and the evaluation of the inclusion of new candidate diseases. In February 2022, four more diseases (biotinidase deficiency, maple syrup urine disease, classical homocystinuria and congenital adrenal hyperplasia) have been added to the basic portfolio. Their detection will have to be incorporated in all programmes within a maximum of one year after their publication in the BOE. Other rare diseases, such as severe combined immunodeficiency or spinal muscular atrophy, have already started the screening process. Others such as galactosemia, X-linked adrenoleukodystrophy, creatine deficiency, several lysosomal deposit diseases (such as Pompe disease, mucopolysaccharidosis type I and type II) or Duchenne muscular dystrophy, among others, could be candidates in the short or medium term.

Because the processes established by the Ministry to evaluate the inclusion of these diseases are slow, local initiatives have recently been launched through regional pilot studies in order to demonstrate the clinical effectiveness of these screenings. Pilot studies are underway for the early detection of spinal muscular atrophy, severe combined immunodeficiency and X-linked adrenoleukodystrophy. Some of these aforementioned diseases are already being officially screened in some regional programmes (galactosemia in Galicia and severe combined immunodeficiency in Catalonia).

For the newborn screening laboratory, the introduction of expanded screening brought about a number of important changes in the interpretation of results. Adequate early detection of these pathologies and obtaining an accurate diagnosis was a major challenge for laboratory professionals, who are currently developing important advances to reduce the false positive rate inherent in the detection of more pathologies. These include the implementation of second-level biochemical/genetic tests, the development of diagnostic algorithms and computational tools based on Big Data. It has been shown that the combined use of these tools could reduce the false positive rate to close to 0%, bringing us ever closer to what could be termed "precision neonatal screening".

Finally, we cannot forget that one of the biggest challenges we will have to face in the next decade is the possibility of introducing newborn genetic screening by next generation sequencing (NGS), as a first or second line screening. This screening would improve the performance of current screening and substantially increase the number of potentially detectable genetic diseases. In this sense, a pilot study is also being developed in our country focused on the early detection of rare diseases that manifest themselves in childhood and are susceptible to treatment (GenNatal project).

Bibliography of interest

1. Castiñeras DE, Couce ML, Marín JL, et al. Current status of neonatal screening for metabolic diseases in Spain and worldwide. An Pediatr (Barc) 2019;91(2):128.e1-128.e14.

2. Marín-Soria JL, González de Aledo JM, Argudo-Ramírez A, et al. Initiation, evolution and current situation of neonatal screening programmes in Spain. 2021. Revista Española de Salud Pública;95:e1-29.

3. Order SSI/2065/2014 of 31 October, amending Annexes I, II and III of Royal Decree 1030/2006 of 15 September, which establishes the portfolio of common services of the National Health System and the procedure for updating it.

4. Wilson JMG, Jungner G. Principles and practice of screening for disease. Geneva: WHO; 1968.

5. Adermann A, Balncquaert I, Beauchamp S, Déry V. Revisiting Wilson and Jugner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organization 2008;86(4):317-319.

Table 1. Classical and emerging World Health Organisation criteria for inclusion of diseases in population-based screening programmes.

Classical criteria for population screening. Wilson and Jungner 1968.
1. The disease must be a major health problem
2. There must be an accepted treatment for patients with the disease
3. Diagnostic methods and treatment must be available
4. The disease must have a recognisable early or latent symptomatic stage
5. The screening test must be appropriate
6. The test must be acceptable to the population
7. The natural history of the disease must be well known
8. There must be consensus on the treatment of the disease
9. The cost of screening (including diagnosis and treatment) should be balanced against the total cost of health care
10. Case finding should be a continuous process
Synthesis of emerging criteria proposed in the 40 years since. Andermann et al. 2008
1. The screening programme should respond to a recognised need
2. The objectives of the screening programme should be defined from the outset
3. A target population should be defined
4. There should be scientific evidence of the effectiveness of the screening programme
5. The programme should integrate education, the analytical process, clinical services and programme management
6. There should be quality assurance of the programme, with appropriate mechanisms to minimise the potential risks of screening
7. The programme should ensure informed consent, confidentiality and respect for autonomy
8. The programme should promote equity and access to testing for the entire target population
9. Programme evaluation should be planned from the outset
10. The overall benefits of screening should outweigh the detrimental aspects.