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The Journal "Obstetrics and Gynecology"Journal HistoryAims and ScopePolicies on Conflict of Interest, Human and Animal Rights, and Informed ConsentEditorial ProcessData sharing statementAdvertising PolicyThe Process for Handling Cases Requiring Corrections, Retractions, and Editorial Expressions of ConcernEditorial BoardEditorial CounsilInformation for ProfessionalsNewsContacts
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Obstetrics and Gynegology2025№12

Neonatal screening in the genomic era: expanding the capabilities of tandem mass spectrometry

DOI
https://dx.doi.org/10.18565/aig.2025.287

Eldarov Ch.M., Chagovets V.V., Novoselova A.V., Tokareva A.O., Frankevich V.E.

1) Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia; 2) Siberian State Medical University, Ministry of Health of Russia, Tomsk, Russia

Neonatal or newborn screening (NBS) represents a cornerstone of preventive pediatrics and it is aimed at the early detection of severe inherited disorders to enable timely intervention and improve clinical outcomes. This review examines in detail the historical development, modern methods, global differences and promising areas of development of NBS. The practice of NBS originated in the 1960s and was further developed in the 1970s and 1980s. In the 1990s, it underwent a qualitative improvement with the introduction of tandem mass spectrometry, which allows for simultaneous analysis of several metabolites. This technology has become the global gold standard. Modern diagnostic methods include the simultaneous detection of dozens of metabolites and their ratios for more than 50 pathologies, including multiplex approaches that combine several techniques. In order to improve specificity, the researchers use a comprehensive ranking system for metabolites, as well as strategies for additional second-tier testing using liquid chromatography-mass spectrometry (LC-MS/MS) or genetic methods. With the development of sequencing technologies, their role as first- and second-tier testing, including whole-genome and whole-exome studies, has increased. The use of omics technologies aimed at creating metabolic fingerprints and detecting biomarkers including new ones has expanded. Artificial intelligence and machine learning demonstrate significant potential in reducing the number of false positives and improving the quality of data interpretation.
Conclusion: The ethical aspects of genomic screening, the psychological impact of false positive results, and the need to address global inequalities in access to basic and advanced NBS services still remain unresolved.

Authors’ contributions: Eldarov Ch.M., Chagovets V.V., Novoselova A.V., Tokareva A.O., Frankevich V.E. – developing the concept of the study, writing the original text, reviewing and editing the text. All the authors read and agreed to the publication of the material.
Conflicts of interest: The authors claim that the study was conducted in the absence of any commercial or financial relationships that could be interpreted as a potential conflict of interest.
Funding: The study was performed within the framework of the state assignment of the Ministry of Health of the Russian Federation (registration number 125050605833-4).
For citation: Eldarov Ch.M., Chagovets V.V., Novoselova A.V., Tokareva A.O., Frankevich V.E. 
Neonatal screening in the genomic era: expanding the capabilities of tandem mass spectrometry.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2025; (12): 45-52 (in Russian)
https://dx.doi.org/10.18565/aig.2025.287

Keywords

neonatal screening
tandem mass spectrometry
congenital metabolic disorders
dried blood spots
Full text (in Russian)

References

  1. Aktuğlu Zeybek A.Ç. Newborn screening: from the past to the future. Turk. Arch. Pediatr. 2022; 57(5): 473-5. https://dx.doi.org/10.5152/TurkArchPediatr.2022.16082022
  2. Bhattacharya K., Wotton T., Wiley V. The evolution of blood-spot newborn screening. Transl. Pediatr. 2014; 3(2): 63-70. https://dx.doi.org/10.3978/j.issn.2224-4336.2014.03.08
  3. Ding S., Han L. Newborn screening for genetic disorders: current status and prospects for the future. Pediatr Investig. 2022; 6(4): 291-8. https://dx.doi.org/10.1002/ped4.12343
  4. Almannai M., Marom R., Reid Sutton V. Newborn screening: A review of history, recent advancements, and future perspectives in the era of next generation sequencing. Curr. Opin. Pediatr. 2016; 28(6): 694-9. https://dx.doi.org/10.1097/MOP.0000000000000414
  5. Guthrie R., Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963; 32: 338-43.
  6. Guthrie R. The origin of newborn screening. Screening. 1992; 1: 5-15. https://dx.doi.org/10.1016/0925-6164(92)90025-z
  7. Beutler E., Baluda M., Donnell G.N. A new method for the detection of galactoxemia and its carrier state. J. Lab. Clin. Med. 1964; 64: 694-705
  8. Efron M.L., Young D., Moser H. W., MacCready R.A. A simple chromatographic screening test for the detection of disorders of amino acid metabolism. A technic using whole blood or urine collected on filter paper. N. Engl. J. Med. 1964; 270: 1378-83. https://dx.doi.org/10.1056/NEJM196406252702602
  9. Naylor E.W., Guthrie R. Newborn screening for maple syrup urine disease (branched-chain ketoaciduria). Pediatrics. 1978; 61(2): 262-6.
  10. Taranger J., Berglund G., Claesson I., Victorin L. Screening for congenital hypothyroidism in the newborn. Lancet. 1973; 1(7801): 487. https://dx.doi.org/10.1016/s0140-6736(73)91914-4
  11. Pang S., Hotchkiss J., Drash A.L., Levine L.S., New M.I. Microfilter paper method for 17 alpha-hydroxyprogesterone radioimmunoassay: its application for rapid screening for congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 1977; 45(5): 1003-8. https://dx.doi.org/10.1210/jcem-45-5-1003
  12. Millington D.S., Kodo N., Norwood D.L., Roe C.R. Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism. J. Inherit. Metab. Dis. 1990; 13(3): 321-4. https://dx.doi.org/10.1007/BF01799385
  13. Simonsen H., Jensen U.G., Brandt N.J., Christensen E., Skovby F., Nørgaard-Pedersen B. Design of a pilot study to evaluate tandem mass spectrometry for neonatal screening. Southeast Asian J. Trop. Med. Public Health. 1999; 30 Suppl. 2: 166-9.
  14. Chace D.H., Kalas T.A., Naylor E.W. Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. Clin. Chem. 2003; 49(11): 1797-817. https://dx.doi.org/10.1373/clinchem.2003.022178
  15. Kononets V., Zharmakhanova G., Balmagambetova S., Syrlybayeva L., Berdesheva G., Zhussupova Z. et al. Tandem mass spectrometry in screening for inborn errors of metabolism: comprehensive bibliometric analysis. Front. Pediatr. 2025; 13: 1463294. https://dx.doi.org/10.3389/fped.2025.1463294
  16. Rinaldo P., Lim J., Tortorelli S., Gavrilov D., Matern D. Newborn screening of metabolic disorders: recent progress and future developments. Nestle Nutr. Work. Ser. Pediatr. Progr. 2008; 62: 81-93. https://dx.doi.org/10.1159/000146253
  17. Gelb M.H. Newborn screening for lysosomal storage diseases: Methodologies, screen positive rates, normalization of datasets, second-tier tests, and post-analysis tools. Int. J. Neonatal Screen. 2018; 4(3): 23. https://dx.doi.org/10.3390/ijns4030023
  18. Buckley R.H. The long quest for neonatal screening for severe combined immunodeficiency. J. Allergy Clin. Immunol. 2012; 129(3): 597-604. https://dx.doi.org/10.1016/j.jaci.2011.12.964
  19. la Marca G., Carling R.S., Moat S.J., Yahyaoui R., Ranieri E., Bonham J.R. et al. Current state and innovations in newborn screening: continuing to do good and avoid harm. Int. J. Neonatal Screen. 2023; 9(1): 15. https://dx.doi.org/10.3390/ijns9010015
  20. Hanley W.B., Demshar H., Preston M.A., Borczyk A., Schoonheyt W.E., Clarke J.T. et al. Newborn phenylketonuria (PKU) Guthrie (BIA) screening and early hospital discharge. Early Hum. Dev. 1997; 47(1): 87-96. https://dx.doi.org/10.1016/s0378-3782(96)01846-4
  21. Gerasimova N.S., Samutin A.A., Steklova I.V., Tuuminen T. Phenylketonuria screening in Moscow using a microplate fluorometric method. Screening. 1992; 1(1): 27-35. https://dx.doi.org/10.1016/0925-6164(92)90027-3
  22. Medical Advisory Secretariat. Neonatal screening of inborn errors of metabolism using tandem mass spectrometry: an evidence-based analysis. Ont. Health Technol. Assess. Ser. 2003; 3(3): 1-36.
  23. Pandor A., Eastham J., Chilcott J., Paisley S., Beverley C. Newborn screening using tandem mass spectrometry: a systematic review. Discussion Paper. (Unpublished). White Rose Research Online. 2006. Available at: https://eprints.whiterose.ac.uk/id/eprint/10925/
  24. Berardo C., Vasco A., Mauri A., Lucchi S., Cappelletti L., Saielli L. et al. Expanded newborn screening in Italy: the first report of Lombardy Region. Int. J. Neonatal Screening. 2025; 11(2): 31. https://dx.doi.org/10.3390/ijns11020031
  25. Messina M., Meli C., Raudino F., Pittalá A., Arena A., Barone R. et al. Expanded newborn screening using tandem mass spectrometry: seven years of experience in eastern Sicily. Int. J. Neonatal Screen. 2018; 4(2): 12. https://dx.doi.org/10.3390/ijns4020012
  26. Millington D.S., Stevens R.D. Acylcarnitines: analysis in plasma and whole blood using tandem mass spectrometry. Methods Mol. Biol. 2011; 708: 55-72. https://dx.doi.org/10.1007/978-1-61737-985-7_3
  27. Schnabel E., Kölker S., Gleich F., Feyh P., Hörster F., Haas D. et al. Combined newborn screening allows comprehensive identification also of attenuated phenotypes for methylmalonic acidurias and homocystinuria. Nutrients. 2023; 15(15): 3355. https://dx.doi.org/10.3390/nu15153355
  28. Schwarz E., Liu A., Randall H., Haslip C., Keune F., Murray M. et al. Use of steroid profiling by UPLC-MS/MS as a second tier test in newborn screening for congenital adrenal hyperplasia: the Utah experience. Pediatr. Res. 2009; 66(2): 230-5. https://dx.doi.org/10.1203/PDR.0b013e3181aa3777
  29. Gelb M.H., Basheeruddin K., Burlina A., Chen H.J., Chien Y.H., Dizikes G. et al. Liquid chromatography-tandem mass spectrometry in newborn screening laboratories. Int. J. Neonatal Screen. 2022; 8(4): 62. https://dx.doi.org/10.3390/ijns8040062
  30. Watson M.S., Lloyd-Puryear M.A., Howell R.R. The progress and future of US newborn screening. Int. J. Neonatal Screen. 2022; 8(3): 41. https://dx.doi.org/10.3390/ijns8030041
  31. Воронин С.В., Куцев С.И. Неонатальный скрининг на наследственные заболевания в России: вчера, сегодня, завтра. Неонатология: новости, мнения, обучение. 2022; 10(4): 34-9. [Voronin S.V., Kutsev S.I. Neonatal screening for hereditary diseases in Russia: yesterday, today, and tomorrow. Neonatology: News, Opinions, Training. 2022; 10(4): 34-9 (in Russian)]. https://dx.doi.org/10.33029/2308-2402-2022-10-4-34-39
  32. Ефимова Е.Ю., Мухина А.А., Балинова Н.В., Матулевич С.А., Першин Д.Е., Хорева А.Л., Марахонов А.В., Воронин С.В., Зинченко Р.А., Щербина А.Ю., Куцев С.И. Неонатальный скрининг на первичные иммунодефицитные состояния как способ выявления синдромальных форм патологии новорожденных: клинический случай синдрома 22q11.2DS. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2022; 21(4): 158-62. [Efimova E.Yu., Mukhina A.A., Balinova N.V., Matulevich S.A., Pershin D.E., Khoreva A.L., Marakhonov A.V., Voronin S.V., Zinchenko R.A., Shcherbina A.Yu., Kutsev S.I. Newborn screening for primary immunodeficiencies as a way to detect syndromal disorders in neonates: a clinical case of 22q11.2DS syndrome. Pediatric Hematology/Oncology and Immunopathology. 2022; 21(4): 158-62 (in Russian)]. https://dx.doi.org/10.24287/1726-1708-2022-21-4-158-162
  33. Воронин С.В., Захарова Е.Ю., Байдакова Г.В., Марахонов А.В., Щагина О.А., Рыжкова О.П., Шилова Н.В., Румянцев А.Г., Щербина А.Ю., Мухина А.А., Новичкова Г.А., Шешко Е.Л., Сахарова В.В., Ляхова Е.А., Ефимова И.Ю., Куцев С.И. Расширенный неонатальный скрининг на наследственные заболевания в России: первые итоги и перспективы. Педиатрия им. Г.Н. Сперанского. 2024; 103(1): 16-29. [Voronin S.V., Zakharova E.Yu., Baydakova G.V., Marakhonov A.V., Shchagina O.A., Ryzhkova O.P., Shilova N.V., Rumyantsev A.G., Shcherbina A.Yu., Mukhina A.A., Novichkova G.A., Sheshko E.L., Saharova V.V., Lyakhova E.A., Efimova I.Yu., Kutsev S.I. Advanced neonatal screening for hereditary diseases in Russia: first results and future prospects. Pediatria n.a. G.N. Speransky. 2024; 103(1): 16-29 (in Russian)]. https://dx.doi.org/10.24110/0031-403X-2024-103-1-16-29
  34. Therrell B.L., Padilla C.D., Borrajo G.J.C., Khneisser I., Schielen P.C.J.I., Knight-Madden J. et al. Current status of newborn bloodspot screening worldwide 2024: a comprehensive review of recent activities (2020–2023). Int. J. Neonatal Screen. 2024; 10(2): 38. https://dx.doi.org/10.3390/ijns10020038
  35. Borrajo G.J.C. Newborn screening in Latin America: a brief overview of the state of the art. Am. J. Med. Genet. C Semin. Med. Genet. 2021; 187(3): 322-8. https://dx.doi.org/10.1002/ajmg.c.31899
  36. Bean K., Jones S.A., Chakrapani A., Vijay S., Wu T., Church H. et al. Exploring the cost-effectiveness of newborn screening for metachromatic leukodystrophy (MLD) in the UK. Int. J. Neonatal Screen. 2024; 10(3): 45. https://dx.doi.org/10.3390/ijns10030045
  37. Kilgore M.B., Platis D., Lim T., Isenberg S., Pickens C.A., Cuthbert C. et al. Development of a universal second-Tier newborn screening LC-MS/MS method for amino acids, lysophosphatidylcholines, and organic acids. Anal. Chem. 2023; 95(6): 3187-94. https://dx.doi.org/10.1021/acs.analchem.2c03098
  38. Chen L., Dean B., Liang X. A technical overview of supercritical fluid chromatography-mass spectrometry (SFC-MS) and its recent applications in pharmaceutical research and development. Drug Discov. Today Technol. 2021; 40: 69-75. https://dx.doi.org/10.1016/j.ddtec.2021.10.002
  39. Luo X., Wang R., Fan Y., Gu X., Yu Y. Next-generation sequencing as a second-tier diagnostic test for newborn screening. J. Pediatr. Endocrinol. Metab. 2018; 31(8): 927-31. https://dx.doi.org/10.1515/jpem-2018-0088
  40. Chan T.C.H., Mak C.M., Yeung M.C.W., Law E.C.Y., Cheung J., Wong T.K. et al. Harnessing next-generation sequencing as a timely and accurate second-tier screening test for newborn screening of inborn errors of metabolism. Int. J. Neonatal Screen. 2024; 10(1): 19. https://dx.doi.org/10.3390/ijns10010019
  41. Chen T., Fan C., Huang Y., Feng J., Zhang Y., Miao J. et al. Genomic sequencing as a first-tier screening test and outcomes of newborn screening. JAMA Netw. Open. 2023; 6(9): E2331162. https://dx.doi.org/10.1001/jamanetworkopen.2023.31162
  42. Woerner A.C., Gallagher R.C., Vockley J., Adhikari A.N. The use of whole genome and exome sequencing for newborn screening: challenges and opportunities for population health. Front. Pediatr. 2021; 9: 663752. https://dx.doi.org/10.3389/fped.2021.663752
  43. Шубина Е., Павлова Н.С., Донников А.Е., Померанцева Е.А., Трофимов Д.Ю. Использование экзомного секвенирования для проведения неонатального скрининга: возможности и ограничения. Неонатология: новости, мнения, обучение. 2022; 10(4): 40-6. [Shubina Je., Pavlova N.S., Donnikov A.E., Pomerantseva E.A., Trofimov D.Yu. Perspectives and limitations of whole exome based neonatal screening. Neonatology: News, Opinions, Training. 2022; 10(4): 40-6 (in Russian)]. https://doi.org/10.33029/2308-2402-2022-10-4-40-46
  44. Adhikari A.N., Gallagher R.C., Wang Y., Currier R.J., Amatuni G., Bassaganyas L. et al. The role of exome sequencing in newborn screening for inborn errors of metabolism. Nat. Med. 2020; 26(9): 1392-7. https://doi.org/10.1038/s41591-020-0966-5
  45. Ceyhan-Birsoy O., Murry J.B., Machini K., Lebo M.S., Yu T.W., Fayer S. et al. Interpretation of genomic sequencing results in healthy and ill newborns: results from the BabySeq project. Am. J. Hum. Genet. 2019; 104(1): 76-93. https://dx.doi.org/10.1016/j.ajhg.2018.11.016
  46. Xiao Y., Zhou Y., Zhou K., Cai W. Targeted metabolomics reveals birth screening biomarkers for biliary atresia in dried blood spots. J. Proteome Res. 2022; 21(3): 721-6. https://dx.doi.org/10.1021/acs.jproteome.1c00775
  47. Courraud J., Ernst M., Laursen S.S., Hougaard D.M., Cohen A.S. Studying autism using untargeted metabolomics in newborn screening samples. J. Mol. Neurosci. 2021; 71(7): 1378-93. https://dx.doi.org/10.1007/s12031-020-01787-2
  48. Collins C.J., Chang I.J., Jung S., Dayuha R., Whiteaker J.R., Segundo G.R.S. et al. Rapid multiplexed proteomic screening for primary immunodeficiency disorders from dried blood spots. Front. Immunol. 2018; 9: 2756. https://dx.doi.org/10.3389/fimmu.2018.02756
  49. Zaunseder E., Mütze U., Garbade S.F., Haupt S., Feyh P., Hoffmann G.F. et al. Machine learning methods improve specificity in newborn screening for isovaleric aciduria. Metabolites. 2023; 13(2): 304. https://dx.doi.org/10.3390/metabo13020304
  50. Zhou M., Deng L., Huang Y., Xiao Y., Wen J., Liu N. et al. Application of the artificial intelligence algorithm model for screening of inborn errors of metabolism. Front. Pediatr. 2022; 10: 855943. https://dx.doi.org/10.3389/fped.2022.855943

Received 10.10.2025

Accepted 10.12.2025

About the Authors

Chupalav M. Eldarov, Senior Researcher at the Laboratory of Metabolomics and Bioinformatics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, chup4lav@yandex.ru, https://orcid.org/0000-0003-4027-6469
Vitaliy V. Chagovets, PhD, Head of the Laboratory of Metabolomics and Bioinformatics, Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, vvchagovets@gmail.com, https://orcid.org/0000-0002-5120-376X
Anastasia V. Novoselova, Researcher at the Laboratory of Metabolomics and Bioinformatics, Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, a_novoselova@oparina4.ru
Alisa O. Tokareva, PhD, Specialist at the Laboratory of Clinical Proteomics, Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, alisa.tokareva@phystech.edu, https://orcid.org/0000-0001-5918-9045
Vladimir E. Frankevich, Dr. Sci. (in Physics and Mathematics), Director of the Institute of Translational Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4; Leading Researcher at the Laboratory
of Translational Medicine, Siberian State Medical University, Ministry of Health of Russia, 634050, Russia, Tomsk, Moskovsky tract, 2, v_vfrankevich@oparina4.ru,
https://orcid.org/0000-0002-9780-4579
Corresponding author: Vladimir E. Frankevich, v_frankevich@oparina4.ru
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