In the United States (US), the American College of Medical Genetics published the document newborn screening: toward a uniform screening panel and system in 2006 with the aim of establishing a uniform screening programme across its states.9 The document was developed by a group of experts, who identified 29 diseases as primary targets for screening, of which 20 can be detected by MS/MS. They also identified a second group of 25 diseases considered secondary targets, since the benefits of their detection were less clear, of which 22 were detectable by MS/MS. This was the first study of the kind and it led to the establishment by the United States secretary of health and human services of the recommended uniform screening panel, an established and homogeneous screening programme that includes a large group of diseases. This initial work has served as a reference and is periodically updated with ongoing evaluation of additional diseases that could be included. At the time of this writing, the recommended uniform screening panel includes 35 primary targets and more than 26 secondary targets (Table 1).10 As a result of these recommendations, there is significant homogeneity in the diseases screened in each of the states in the country. Due to this approach to screening, the US is considered one of the most liberal countries when it comes to the interpretation of the Wilson and Jungner criteria. The recommended uniform screening panel is also considered a reference for the purpose of debate and evaluation in other countries.

In Canada, newborn screening also includes a considerable number of metabolic disorders, although fewer compared to the US.11 Some countries in Central and South America have high-quality, well-established NBS programmes, especially Costa Rica12 and Uruguay,13 where all newborns are screened for a large number of metabolic disorders by means of MS/MS. However, most screening programmes in South America include a limited number of diseases in addition to PKU, and few regions use MS/MS for newborn screening.

In these regions, too, the level of development of the economy and the public health systems is reflected in their NBS programmes. For instance, in Australia14 and Japan15 all newborns are screened for a substantial number of metabolic diseases with MS/MS, but many other countries with fewer resources have not instituted any NBS programmes. In China, screening already covers 80% of newborns and includes PKU, and in some regions includes testing by MS/MS.15 In the Middle East, there are countries, such as Qatar or Saudi Arabia, with programmes that screen all newborns for a broad range of metabolic disorders; others that only include 2 diseases in their NBS programme, such as United Arab Emirates and Kuwait, and a third group continues to not have any form of screening programme.16

We ought to differentiate between countries in Northern Africa and countries in Sub-Saharan Africa. Egypt has an established NBS programme, with use of MS/MS in part of the population, and other North African countries are developing projects aimed at the establishment of routine newborn screening.16 The situation in Sub-Saharan Africa is quite different, with very few reports of NBS programmes, even in South Africa.17

In Spain, the first NBS programme was introduced in Granada in 1968 by initiative of professors Federico Mayor-Zaragoza, Magdalena Ugarte and Antonio Martínez Valverde. In 1978, the National Plan for Mental Retardation was established within the Real Patronato de Educación y Atención a Deficientes (Royal Council of Education and Care for Individuals with Disabilities), and several laboratories were established within its framework. Between 1982 and 1983, the authorities of each autonomous region (AR) in Spain took over the management of government-run programmes for the early detection of congenital and metabolic disorders.23

Between 2000 and 2015, there were significant differences in the NBS programmes of the different ARs, as many only included 2 or 3 diseases while others included more than 20.24,25 Each AR independently determined the number of diseases to be screened, and since there was no institution coordinating the development of these regional programmes, significant variation ensued.

With the aim of establishing the actual benefits of the early diagnosis of diseases susceptible of screening, the Federación Española de Fenilcetonuria y otros Trastornos del Metabolismo (Spanish Federation of Phenylketonuria and other Metabolic Disorders), along with a group of health professionals, agreed to review the existing NBS programmes in Spain to develop the broadest-possible consensus on aspects such as the criteria applied to select diseases for inclusion, the establishment of units for the diagnosis, treatment and followup of the detected diseases, and the institution of a national register of affected patients. They developed the consensus document Programas de cribado neonatal en España: Actualización y propuestas de futuro. Documento de consenso (2010) [newborn screening programmes: update and proposals for the future. consensus document].

In light of the heterogeneity of NBS programmes in Spain, the group drafted a list of actions detailing what may be required for the diagnosis and treatment of inborn errors of metabolism. To do so, they used as reference a document of the Spanish Ministry of Health, Estrategia en Enfermedades Raras del Sistema Nacional de Salud (Strategy for the Management of Rare Diseases of the National Health System, 2009). Among the listed actions was the need to improve NBS programmes, with a strong recommendation of strengthening the cooperation between ARs and establishing uniform health policies across all of them. All of the above led the Consejo Interterritorial (Interterritorial Council) of the National Health System (NHS) of Spain to create the Working Group for the Development of the Nationwide Health Care Service Portfolio of the NHS in 2012, within which a smaller subset of experts formed a group to select the specific diseases that ought to be included in newborn screening. The definitive proposal was based on reports that were commissioned to the Red de Agencias de Evaluación de Tecnologías Sanitarias (Health Technology Evaluation Agency Network, AETS). In July 2013, in a general assembly, the Consejo Interterritorial approved NBS programmes to test for endocrine and metabolic disorders, which would be thereon included in the nationwide basic services portfolio of the NHS, encouraging the establishment of consensus-based protocols within the framework of the NHS so that screening programmes could be implemented in all ARs in a uniform manner and based on rigorous quality criteria.

The diseases included in the proposed NBS programme, the screening of which, from this moment, became part of the nationwide basic services portfolio offered by the NHS and therefore recommended for inclusion in screening throughout Spain, are 7, out of which 4 are metabolic disorders (*)26:

• 1

  CHT.

• 2

  Phenylketonuria*

• 3

  Cystic fibrosis

• 4

  MCADD*

• 5

  Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency*

• 6

  Glutaric acidaemia type 1*

• 7

  Sickle cell disease.

Furthermore, this document mentioned the possibility of expanding the panel to include maple syrup urine disease, isovaleric acidaemia and homocystinuria after trying this option out in a “pilot programme”.

The Consejo Interterritorial also established that the introduction of these NBS programmes in the nationwide services portfolio of the NHS should be accompanied by the development of:

• none-

  A newborn screening information system to facilitate the appropriate follow-up and evaluation of newborn screening at the AR and national level.

• none-

  A quality assurance system to allow the homogeneous management of all processes in every AR, which would require as a key element the development of consensus-based protocols their implementation in the NHS.

On December 18, 2013, the Consejo Interterritorial of the NHS approved the Objectives and Quality Requirements for programmes for newborn screening of endocrine and metabolic disorders within the NHS. The document detailed the data and indicators that should be included in the newborn screening information system to allow the assessment of the established quality objectives.27 The AETS has continued to carry out cost-effectiveness analyses for the screening of additional diseases that could potentially be included in NBS programmes and determined that screening for biotinidase deficiency is cost-effective,36 while, on the contrary, it has concluded that when it comes to severe combined immunodeficiency (SCID),37 the evidence on the effectiveness of screening is of poor methodological quality, although the disease fulfils many of the criteria required for inclusion in screening programmes. The reports delivered by the AETS involve a long process, and by the time these reviews are published, they no longer reflect the current reality (for instance, the articles reviewed in relation to SCID date from between 2010 and 2016, while the report was published by the AETS in 2018).

At the time of this writing, all the ARs in Spain adhere to the requisite of including the minimum 7 diseases in their respective NBS programmes except for Galicia, where screening for sickle cell disease is not included, and many ARs, on the basis of current knowledge on the natural course of diseases and advances in medical treatment, screen for many more (Table 4).

While the definition of the minimum services that ought to be offered based on clear scientific criteria is a desirable goal, the fact remains that NBS programmes cannot and probably should not be completely uniform, as they must be adapted to the ethnic/genetic factors, social characteristics, health care capacity and economic circumstances of each country or region.

The number of studies published recently on this subject reflects a dynamism that is unprecedented in the history of newborn screening, which will drive an ongoing debate and updating of programmes and guidelines. As the literature on the subject and the evidence on future possibilities in this field continues to develop, the distinction between the concepts of newborn screening and of screening of newborns, which first emerged with the advent of screening by means of MS/MS, is gaining definition and being discussed in detail. Newborn screening reflects an approach to screening that focuses on direct benefits to the newborn, while the concept of screening of newborns goes a little further, taking into account not only newborns but also families and society at large. Spain should not adopt a passive stance in this situation, and both the professionals and the health authorities involved in the different aspects of newborn screening should make an effort to update screening programmes and include any diseases for which advances in medical knowledge and treatment options could lead to improvements in morbidity and mortality outcomes in affected individuals.

Without a doubt, the most important aspect to be debated in the future will be the limits of newborn screening and which aspects we wish to explore and understand in our newborns.