Newborn blood spot screening, commonly called the heel prick test, is a crucial public health initiative to identify metabolic and genetic disorders in infants, shortly after birth.1,2 This simple yet effective test has transformed the landscape of paediatric healthcare by enabling early diagnosis and intervention, which can significantly improve health outcomes. This test is typically performed within the first week of life, and it consists of drawing a small amount of blood from the infant’s heel and placed on filter paper. The sample is sent afterwards to the laboratory for analysis. 3The dried spot can be analysed by various techniques, detailed further in the Analysis Techniques chapter.
Newborn screening has evolved significantly since its inception, transforming from rudimentary methods to sophisticated techniques capable of detecting various genetic and metabolic disorders. This evolution reflects advancements in medical science, technology, and public health policy aimed at improving infant health outcomes.
Early Beginnings and Expansion of Screening Programs
- 1960s: The history of newborn screening began in the early 1960s with the introduction of the Guthrie test, developed by Dr. Robert Guthrie. This test was designed to detect phenylketonuria (PKU). The Guthrie test involved placing a dried blood sample on an agar plate containing a strain of Bacillus subtilis; if phenylalanine was present at elevated levels, it promoted bacterial growth, indicating a positive result for PKU.4
- 1970s: Following the success of the Guthrie test, other states and countries began implementing similar screening programs. The focus expanded beyond PKU to include additional metabolic disorders. By the late 1970s, many states in the US had established routine newborn screening programs. The Guthrie test was adopted in the UK shortly after its introduction in the US. Many European nations began adopting similar screening tests throughout the 1970s and 1980s. Countries such as Sweden, Denmark, and Germany incorporated newborn screening for PKU and other metabolic disorders into their public health systems.5
- 1980s: Introducing more advanced biochemical testing methods, such as fluorimetry, allowed for more sensitive detection of various conditions. This decade also saw the establishment of national guidelines for newborn screening, promoting standardization across different regions.
- 1990s: The development of tandem mass spectrometry (MS/MS) marked a significant leap forward in newborn screening technology. MS/MS allows for the simultaneous detection of multiple metabolites in a single blood sample, significantly increasing the efficiency and accuracy of screening programs. This method can identify PKU, other amino acid disorders, and fatty acid oxidation disorders.5
- 2000s: The rise of next-generation sequencing (NGS) further revolutionised newborn screening. NGS enables rapid sequencing of large panels of genes, allowing for comprehensive genetic testing that can identify numerous inherited disorders simultaneously. This technology has the potential to enhance early detection and intervention strategies significantly.6
Analysis Techniques:
Guthrie test
The Guthrie test has a significant place in the history of newborn screening, particularly for PKU.7,8 Developed as one of the first methods, the test involves a straightforward yet innovative process. A healthcare professional takes a small blood sample from the newborn and places it on an agar plate. This plate is specially prepared with a strain of bacteria that plays a crucial role in detecting elevated phenylalanine levels. If the blood sample contains high levels of phenylalanine, it encourages the growth of the bacteria on the plate, which indicates a positive result for PKU. The method is a bacterial inhibition assay designed to efficiently identify elevated phenylalanine levels. By employing a growth inhibitor within the agar, the test allows for detecting abnormal amino acid levels when the bacteria thrive.9,10 Although the Guthrie test is notable for its simplicity and low cost, it is historically significant as one of the pioneering mass screening methods for PKU. However, it is not without its drawbacks. Some studies have shown that it can yield higher rates of false negatives—up to 53%—meaning that some cases may go undetected. This is especially true for mild cases or those identified very early after birth, underscoring the need for ongoing advancements in screening techniques.
Fluorimetry
Fluorimetry is a technique that measures the fluorescence emitted during chemical reactions involving phenylalanine. This method has gained widespread adoption due to its remarkable sensitivity and ability to provide quantitative data regarding Phe levels.11 A fluorimetric assay can detect elevated phenylalanine concentrations, with a cut-off typically established around 120 to 160 µmol/L, though this can vary based on local guidelines.
This technique has gained attention due to its notable sensitivity, especially compared to the Guthrie test. It not only excels in detecting phenylalanine levels but also offers the advantage of providing quantitative data, allowing healthcare professionals to understand a patient’s condition better. However, there are still limitations regarding specificity, which means it may not accurately identify all cases of phenylalanine accumulation. When pitted against more advanced methods like mass spectrometry (MS/MS), it’s clear that this technique may fall short in specific scenarios.12
Tandem Mass Spectrometry
Tandem Mass Spectrometry (MS/MS) is currently viewed as one of the most advanced techniques for newborn screening. This remarkable method allows for the simultaneous detection of multiple metabolites, including phenylalanine and various amino acids. One of the significant advantages of MS/MS is its high sensitivity and specificity. This characteristic helps to significantly reduce both false positives and false negatives, making it a more reliable option than earlier screening methods. The process involves analysing the mass-to-charge ratio of ions, which enables the simultaneous detection and quantification of various metabolites. This capability is particularly beneficial because it allows healthcare providers to identify a range of metabolic disorders beyond phenylketonuria (PKU), all in a single test. However, while MS/MS offers numerous benefits, it has some drawbacks. The technique is more expensive and requires sophisticated laboratory equipment than traditional tests like the Guthrie test. Despite these challenges, the advantages of MS/MS make it a valuable tool in the early detection of metabolic disorders in newborns.12–14
Preferred Method
While all three methods have their advantages, tandem mass spectrometry (MS/MS) is increasingly preferred due to its accuracy and ability to screen for multiple metabolic disorders simultaneously.
Why Newborn Screening Tests Are Essential
Newborn screening tests are essential for several reasons. They enable early detection of serious health conditions that may not present symptoms at birth, allowing for timely intervention to prevent severe complications or even death. By screening every newborn, healthcare systems can significantly reduce the incidence of disabilities and improve overall population health. For example, untreated conditions like phenylketonuria (PKU) can lead to intellectual disabilities, but early intervention can avert this outcome. Additionally, newborn screening is often more cost-effective than treating advanced stages of disease, saving healthcare costs associated with long-term care for untreated conditions.15
Why Newborn Screening and Not Genetic Testing from the Beginning?
While genetic testing has become a significant asset in modern medicine, it cannot replace the vital role of newborn screening. Newborn screening is preferred for several compelling reasons. Firstly, newborn screening tests have a broader scope. They are specifically designed to detect a wide array of conditions simultaneously. In contrast, genetic testing tends to focus on specific disorders. This comprehensive approach ensures that multiple potential issues can be identified simultaneously, which is necessary for the health and well-being of the infant. Secondly, timeliness is a critical factor. Newborn screening is conducted within the first week of life, facilitating immediate follow-up and intervention if necessary. Genetic testing, however, often requires more time to process, and results may not provide results until after critical early intervention windows have passed. In summary, while genetic testing is valuable, newborn screening remains an indispensable procedure for promptly identifying potential health issues in infants16.
Conclusion
Newborn blood spot screening is an invaluable tool in modern healthcare that saves lives and enhances the quality of life for countless infants. By prioritising early detection through comprehensive testing methods like tandem mass spectrometry, we can promptly identify and treat more conditions. As the understanding of genetic disorders expands and the screening capabilities improve, we move closer to a future where every child can thrive from day one.
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If you’ve ever found value here, pay it forward.
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“The only thing standing between someone and the life-changing information they need… is whether we show up for each other.”
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You’re here because you care about knowledge, about real stories, about making a difference for people who need it most. You know that every breakthrough, every recipe, every insight on raremetabolicinsights.com is a lifeline for someone out there.
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Your support means we can publish more often, dive deeper, and reach more families who need answers.
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References
1. George, R. S. & Moat, S. J. Effect of Dried Blood Spot Quality on Newborn Screening Analyte Concentrations and Recommendations for Minimum Acceptance Criteria for Sample Analysis. Clinical Chemistry 62, 466–475 (2016).
2. McHugh, D. M. S. et al. Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: A worldwide collaborative project. Genet Med 13, 230–254 (2011).
3. Therrell, B. L. et al. Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023). International Journal of Neonatal Screening 10, 38 (2024).
4. Levy, H. L. Robert Guthrie and the Trials and Tribulations of Newborn Screening. Int J Neonatal Screen 7, 5 (2021).
5. Watson, M. S., Lloyd-Puryear, M. A. & Howell, R. R. The Progress and Future of US Newborn Screening. Int J Neonatal Screen 8, 41 (2022).
6. Jiang, S., Wang, H. & Gu, Y. Genome Sequencing for Newborn Screening—An Effective Approach for Tackling Rare Diseases. JAMA Network Open 6, e2331141 (2023).
7. Guthrie, R. Blood Screening for Phenylketonuria. JAMA 178, 863 (1961).
8. Guthrie, R. & Whitney, S. PHENYLKETONURIA, DETECTION IN THE NEWBORN INFANT AS A ROUTINE HOSPITAL PROCEDURE. (1964).
9. Robert, G. Bacteriologic testing method and means therefor. (1966).
10. Blumenfeld, C. M., Wallace, M. J. & Anderson, R. Phenylketonuria—The Guthrie Screening Test—A Method of Quantitation, Observations on Reliability and Suggestions for Improvement. California Medicine 105, 429 (1966).
11. Gerasimova, N. S., Steklova, I. V. & Tuuminen, T. Fluorometric method for phenylalanine microplate assay adapted for phenylketonuria screening. Clin Chem 35, 2112–2115 (1989).
12. Perko, D. et al. Comparison of Tandem Mass Spectrometry and the Fluorometric Method—Parallel Phenylalanine Measurement on a Large Fresh Sample Series and Implications for Newborn Screening for Phenylketonuria. International Journal of Molecular Sciences 24, 2487 (2023).
13. Millington, D. S. How mass spectrometry revolutionized newborn screening. Journal of Mass Spectrometry and Advances in the Clinical Lab 32, 1–10 (2024).
14. Levy, H. L. Newborn Screening by Tandem Mass Spectrometry: A New Era. Clinical Chemistry 44, 2401–2402 (1998).
15. Dubay, K. S. & Zach, T. L. Newborn Screening. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2024).
16. Green, N. S., Dolan, S. M. & Murray, T. H. Newborn Screening: Complexities in Universal Genetic Testing. Am J Public Health 96, 1955–1959 (2006).
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