Neonatal screening is widely recognised as a biochemical test that enables the identification of various congenital disorders in newborns. If these conditions are not diagnosed and treated promptly, they can lead to cognitive and/or physical development delays, severe permanent damage, and, in some cases, even death.
Neonatal screening is a complex, integrated and multidisciplinary secondary healthcare prevention programme. The aim of the programme is to identify, within the entire neonatal population, individuals exhibiting biochemical abnormalities indicative of specific disorders. Following this, diagnostic confirmation is pursued, and, if the diagnosis is confirmed, the patient is referred for the appropriate treatment and is monitored over time.
Early detection is crucial, as it enables healthcare professionals to initiate the most effective treatment available before the onset of clinical symptoms, thereby significantly improving the prognosis and modifying the natural course of the disorder. A range of professionals are involved in this programme: birth centres where the samples are collected, neonatal screening laboratories that conduct the screening tests, biochemical and molecular diagnostic laboratories that confirm or exclude the diagnosis, medical facilities responsible for treatment and follow-up, and various coordinating and monitoring bodies at both regionally and nationally. The screening system encompasses a variety of professionals, including laboratory technicians, chemists, biologists, geneticists, administrative staff, nurses, dietitians and/or pharmacologists, psychologists, doctors specialising in metabolic disorders, paediatricians, general practitioners, and families.
The history of screening as a population-based test dates back to the early 1960s in the United States, when biologist Robert Guthrie developed a simple and cost-effective bacterial inhibition test capable of identifying the most common amino acid disorder: phenylketonuria. This method was gradually adopted in nearly all countries, including Italy (neonatal screening for phenylketonuria was introduced in Liguria in 1973 and then progressively expanded across the country). In the following decade, neonatal screening for congenital hypothyroidism was launched both in the USA and Europe, including Italy, followed by screening for cystic fibrosis (using various methods). Neonatal screening for these three conditions became mandatory for all newborns in Italy under Italian Law No. 104 of 5th February 1992, along with subsequent regulations. Some regions also conduct screening for additional congenital disorders, such as congenital adrenal hyperplasia, galactosemia, and biotinidase deficiency, although these are not yet fully covered nationwide.
In the 1990s, the development of analytical technologies, particularly tandem mass spectrometry with electrospray ionisation, enabled clinical chemistry laboratories to establish versatile, specific and sensitive methods. These advancements allow for the measurement of numerous biomarkers in a single, rapid analysis. Researchers in the field of neonatal screening recognised that by harnessing this technology, it would be possible to move from the concept of "one test – one disease" to "one test – many diseases", thus revolutionising the approach to neonatal screening.
Tandem mass spectrometry, for example, can quickly identify and quantify numerous metabolites such as acylcarnitines, amino acids, succinylacetone, and more recently, certain purines, in just around two minutes. These biomarkers enable the identification of newborns at risk of developing amino acid disorders, defects in the beta-oxidation of fatty acids, organic acidurias, urea cycle defects, and certain severe combined immunodeficiencies, all at a very early stage of life. Today, many laboratories worldwide conduct neonatal screening for 40 or more diseases with a single test, thanks to both pilot projects regulated at regional or national levels and well-established national programmes. The number of diseases included in these screening panels does not depend on the technology itself but rather on the public health strategies in place regionally or nationally.
There are universally recognised criteria for determining whether a disease should be included in a neonatal screening programme. The most well-known of these are the Wilson and Jungner criteria, first defined by the World Health Organization in 1963. These criteria take into account both the characteristics of the disease (severity, prevalence, treatability) and those of the test/screening programme (appropriateness, cost, acceptability by the population).
Over the years, these criteria have been discussed and, in part, redefined based on global experience. In particular, regarding the availability of effective treatment, there is now growing consensus that neonatal screening, followed by timely treatment, can alter the natural course of a condition. Another important, though less explicitly stated, criterion concerns the ability to offer genetic counselling and prenatal diagnosis to families who have had a child or relative affected by a metabolic disorder. Recently, Italian legislation (Italian Law 167 of 2016 and Italian Ministerial decree of 13 October 2016) has extended national neonatal screening to include a panel of approximately 40 metabolic disorders. These include phenylketonuria and hyperphenylalaninemias (which were already subject to mandatory screening), biotinidase deficiency and galactosemia.
As a result, neonatal screening is no longer an effective and isolated preventive test, but rather an integrated part of the public healthcare system, involving various professionals, including laboratory technicians, chemists, biologists, geneticists, administrative staff, nurses, dietitians and/or pharmacologists, psychologists, doctors specialising in metabolic disorders, paediatricians, general practitioners, and families.
How does neonatal screening work?
Between the 48th and 72nd hour of life, all newborns undergo a blood test at the birth facility. A few drops of blood are collected and placed on a special card, which also contains the newborn’s details. The sample is then promptly sent to the screening laboratory, where its quality is checked, accepted, and the necessary tests are conducted. The screening laboratory is also responsible for managing the newborn’s data, including any sensitive information. If one or more biomarkers are found to be altered, suggesting the presence of a condition under examination, a second follow-up sample is requested from the birth facility. Only if the alterations are confirmed will the newborn be referred to the appropriate medical facility and diagnostic laboratory for further confirmation testing. In some cases, depending on the severity of the detected alteration or the potential risks associated with the condition, the newborn may be referred directly to the medical facility without waiting for the results of the second follow-up test.
It is important to note that an abnormal result on the neonatal screening test, even if confirmed by the follow-up test, does not constitute a diagnosis of a condition. A diagnosis can only be confirmed through the diagnostic confirmation process. If a diagnosis is confirmed, the medical facility will take responsibility for the newborn’s care, promptly starting the specific treatment, initiating both clinical and biochemical follow-up, and, if necessary, completing the diagnostic process with further investigations, including molecular testing.
- Italian national legislation on neonatal screening:
- Italian Law no. 104 of 05 February 1992
- Decree of the President of the Italian Council of Ministers of 09 July 1999
- Italian Law no. 548 of 23 December 1993
- Italian Law no. 244 of 24 December 2007
- Italian Law no. 147 of 27 December 2013 - Article 1, paragraph 229
- Italian Law no. 167 of 19 August 2016
- Decree of the Italian Ministry of Health of 13 October 2016
- Information Guide for Parents on Neonatal Screening