Molecular genetic markers in the pathogenesis of fetal growth retardation

Gasymova Sh.R., Tyutyunnik V.L., Kan N.E., Volochaeva M.V., Borisova A.G.

Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia

The article presents the analysis of the data of modern literature on the actual aspects of fetal growth retardation (FGR) verification in terms of molecular genetic diagnostic methods. The review includes the data of foreign and Russian scientists published in PubMed and eLibrary. The problem of the FGR diagnosis remains relevant, despite the “golden standard” of diagnosis meeting the criteria adopted by the international consensus of Delphi which was introduced into the practice of obstetricians, gynecologists and ultrasound specialists. The article presents the results of the analysis of the literature data on the role of molecular genetic markers in the FGR pathogenesis, various mechanisms of the FGR development in terms of genomics, transcriptomics, as well as the analysis of their combination with the factors of the hemostasis system. Special attention is paid to the mechanisms of the FGR development due to the changes in immune processes, inflammatory reactions, as well as the changes in the processes of angiogenesis in the placenta. This study also examines the possibility of diagnosing a fetus with FGR using the assessment of the level of extracellular fetal DNA, the processes of methylation of genes-regulators of metabolic pathways and a number of immune processes. The literature data on the epigenetic regulation of gene expression in FGR are of particular interest; microRNAs isolated from the placenta and circulating in the blood of pregnant women are studied. The search for specific minimally invasive markers currently continues as they have already allowed the clinicians to improve the existing criteria for diagnosis.
Conclusion: Despite the progress in the field of molecular genetics, there is still a need for accurate diagnosis, prevention and rational management of pregnancy complicated by FGR to improve perinatal outcomes. The study of the molecular mechanisms underlying this syndrome may be useful for a better understanding of the signaling pathways involved in the FGR pathogenesis.

Authors’ contributions: Gasymova Sh.R., Tyutyunnik V.L., Kan N.E., Volochaeva M.V., Borisova A.G. – developing the concept and design of the study, obtaining the data for analysis, collecting publications, processing and analyzing the material on the issue, writing the text of the manuscript, editing the article.
Conflicts of interest: The authors declare no conflict of interest.
Funding: The study was conducted without sponsorship.
For citation: Gasymova Sh.R., Tyutyunnik V.L., Kan N.E., Volochaeva M.V., Borisova A.G. Molecular genetic markers in the pathogenesis of fetal growth retardation. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2023; (11): 20-26 (in Russian)


fetal growth retardation
molecular genetic markers
omics technologies
thrombophilic mutations


  1. Волочаева М.В., Баев О.Р. Современные представления о патогенезе задержки роста плода. Акушерство и гинекология. 2021; 8: 13-7. [Volochaeva M.V, Baev O.R. Modern ideas about the pathogenesis of fetal growth retardation. Obstetrics and Gynecology. 2021; (8): 13-7. (in Russian)].
  2. Fetal Growth Restriction: ACOG Practice Bulletin, Number 227. Obstet. Gyne-col. 2021; 137(2): e16-e28.
  3. Министерство здравоохранения Российской Федерации. Недостаточный рост плода, требующий предоставления медицинской помощи матери (задержка роста плода). Клинические рекомендации (протокол лечения). 2022; 71c. [Ministry of Health of the Russian Federation. Insufficient growth of the fetus, requiring the provision of medical care to the mother (fetal growth retardation). Clinical guidelines (treatment protocol). 2022; 71 p. (in Russian)].
  4. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics and the Society for Maternal-Fetal Medicin. ACOG Practice Bulletin No. 204: Fetal Growth Restriction. Obstet. Gynecol. 2019; 133(2): e97-e109.
  5. Липатов И.С., Тезиков Ю.В., Амосов М.С., Зуморина Э.М. Клинико-патогенетические варианты задержки роста плода различных сроков манифе-стации. Медицинский совет. 2021; (3): 54-65. [Lipatov I.S., Tezikov Yu.V, Amosov M.S., Zumorina E.M. Clinical and pathogenetic variants of fetal growth retardation of different periods of manifestation. Medical Council. 2021; (3): 54-65 (in Russian)].
  6. Ярыгина Т.А., Батаева Р.С., Гус А.И. Повышение эффективности ультра­звуковой диагностики в прогнозировании рождения маловесного для гестационного возраста доношенного ребенка. Ультразвуковая и функцио­нальная диагностика. 2020; 2: 34-47. [Yarygina T.A, Bataeva R.S, Gus A.I. Improving the effectiveness of diagnostic ultrasound in predicting of small-for-gestational age neonates at term pregnancies. Ultrasonic and functional diagnostics. 2020; 2: 34-47. (in Russian)].
  7. Bahado-Singh R.O., Turkoglu O., Yilmaz A., Kumar P., Zeb A., Konda S. et al. Metabolomic identification of placental alterations in fetal growth restriction. J. Matern. Fetal. Neonatal Med. 2022; 35(3): 447-56.
  8. Dimas A., Politi A., Papaioannou G., Barber T.M., Weickert M.O., Grammatopoulos D.K. et al. The gestational effects of maternal appetite axis molecules on fetal growth, metabolism and long-term metabolic health: a systematic review. Int. J. Mol. Sci. 2022; 23(2): 695.
  9. Figueras F., Meler E. Fetal growth patterns as early markers of fetal programming. Lancet Diabetes Endocrinol. 2022; 10(10): 683-4.
  10. Gong S., Gaccioli F., Dopierala J., Sovio U., Cook E., Volders P.J. et al. The RNA landscape of the human placenta in health and disease. Nat. Commun. 2021; 12(1): 2639.
  11. Karaer A., Mumcu A., Arda Düz S., Tuncay G., Doğan B. Metabolomics analysis of placental tissue obtained from patients with fetal growth restriction. J. Obstet. Gynaecol Res. 2022; 48(4): 920-9.
  12. Пальцев М.А., Чемезов А.С., Линькова Н.С., Дробинцева А.О., Полякова В.О., Белушкина Н.Н., Кветной И.М. Омиксные технологии: роль и значение для развития персонализированной медицины. Молекулярная медицина. 2019; 17(4): 3-8. [Paltsev M.A., Chemezov A.S., Linkova N.S., Drobintseva A.O., Polyakova V.O., Belushkina N.N., Kvetnoy I.M. OMICS technology: the role and significance for personalized medicine. Molecular Medicine. 2019; 17(4): 3-8.
  13. Lausman A., Kingdom J. How and when to recommend delivery of a growth-restricted fetus: A review. Best Pract. Res. Clin. Obstet. Gynaecol. 2021; 77: 119-28.
  14. Kochhar P., Vukku M., Rajashekhar R., Mukhopadhyay A. microRNA signatures associated with fetal growth restriction: a systematic review. Eur. J. Clin. Nutr. 2022; 76 (8): 1088-102.
  15. Говоруха И.Т., Железная А.А., Шаров К.В. Результативность использования биохимических маркеров пренатального скрининга для выявления синдрома задержки роста плода. Медико-социальные проблемы семьи. 2020; 25(3): 16-9. [Govorukha I.T., Zheleznaya A.A., Sharov K.V. Predictive value of biochemical markers of fetal growth restriction syndrome. Medico-social problems of the family. 2020; 25(3): 16-9. (in Russian)].
  16. Клычева О.И., Хурасева А.Б. Возможности прогнозирования степени риска развития синдрома задержки роста плода. Российский вестник акушера-гинеколога. 2020; 20(5): 68‑73. [Klycheva O.I, Khuraseva A.B. Possibilities of predicting the degree of risk of developing fetal growth retardation syndrome. Russian Bulletin of an obstetrician-gynecologist. 2020; 20(5): 68-73. (in Russian)].
  17. Andrikos A., Andrikos D., Schmidt B., Birdir C., Kimmig R., Gellhaus A. et al. Course of the sFlt-1/PlGF ratio in fetal growth restriction and correlation with biometric measurements, feto-maternal Doppler parameters and time to delivery. Arch. Gynecol. Obstet. 2022; 305(3): 597-605.
  18. Schierding W., Antony J., Karhunen V., Vääräsmäki M., Franks S., Elliott P. et al. GWAS on prolonged gestation (post-term birth): analysis of successive finnish birth cohorts. J. Med. Genet. 2018; 55(1): 55-63.
  19. Papastefanou I., Wright D., Syngelaki A., Akolekar R., Nicolaides K.H. Personalized stratification of pregnancy care for small for gestational age neonates from biophysical markers at midgestation. Am. J. Obstet. Gynecol. 2023; 229(1):57.e1-57.e14.
  20. Друккер Н.А., Авруцкая В.В., Селютина С.Н., Шкотова Е.О., Дурницына О.А., Ларичкин А.В. Биохимические факторы задержки роста плода. Россий-ский вестник акушера-гинеколога. 2019; 19(6): 11‑5. [Drukker N.A., Avrutskaya V.V., Selyutina S.N., Shkotova E.O., Durnitsyna O.A., Larichkin A.V. Biochemical factors of fetal growth retardation. Russian Bulletin of an obstetrician-gynecologist. 2019; 19(6): 11-5. (in Russian)].
  21. Stepan H., Galindo A., Hund M., Schlembach D., Sillman J., Surbek D., Vatish M. Clinical utility of sFlt-1 and PlGF in screening, prediction, diagnosis and monitoring of preeclampsia and fetal growth restriction. Ultrasound Obstet. Gynecol. 2023; 61(2): 168-80.
  22. Кан Н.Е., Тютюнник В.Л., Хачатрян З.В., Садекова А.А., Красный А.М. Метилирование генов TLR2 и импринтинг контролирующей области IGF2/H19 в плазме крови при задержке роста плода. Акушерство и гинекология. 2021; 5: 79-84. [Kan N.E., Tyutyunnik V.L., Khachatryan Z.V., Sadekova A.A., Krasnyi A.M. Methylation of the TLR2 genes and the IGF2/H19 imprinting-control region in blood plasma in fetal growth retardation. Obstetrics and Gynecology. 2021; (5): 79-84. (in Russian)].
  23. Хачатрян З.В., Кан Н.Е., Красный А.М., Садекова А.А., Куревлев С.В., Тютюнник В.Л. Метилирование генов в плаценте при задержке роста плода. Акушерство и гинекология. 2019; 12: 54-8. [Khachatryan Z.V., Kan N.E., Krasnyi A.M., Sadekova A.A., Kurevlev S.V., Tyutyunnik V.L. Methylation of genes in the placenta in fetal growth retardation. Obstetrics and gynecology. 2019; (12): 54-8. (in Russian)].
  24. Zhang C., Ding J., Li H., Wang T. Identification of key genes in pathogenesis of placental insufficiency intrauterine growth restriction. BMC Pregnancy Childbirth. 2022; 22(1): 77.
  25. Majewska M., Lipka A., Paukszto L., Jastrzebski J.P., Szeszko K., Gowkielewicz M. et al. Placenta transcriptome profiling in intrauterine growth restriction (IUGR). Int. J. Mol. Sci. 2019; 20 (6): 1510. 10.3390/ijms20061510.
  26. Spinillo A., Meroni A., Melito C., Scatigno A.L., Tzialla C., Fiandrino G. et al. Clinical correlates of placental pathologic features in early-onset fetal growth restriction. Fetal Diagn. Ther. 2022; 49(5-6): 215-24.
  27. Zhong Y., Johnson A.J., Byrd J.C., Dubovsky J.A. Targeting interleukin-2-inducible T-cell kinase (ITK) in T-cell related diseases. Postdoc. J. 2014; 2(6): 1-11.
  28. Napolitano R., Molloholli M., Donadono V., Ohuma E.O., Wanyonyi S.Z., Kemp B. et al. International Fetal and Newborn Growth Consortium for the 21st century (INTERGROWTH-21st). International standards for fetal brain structures based on serial ultrasound measurements from Fetal Growth Longitudinal Study of INTERGROWTH-21st Project. Ultrasound Obstet. Gynecol. 2020; 56(3): 359-70.
  29. Курцер М.А., Сичинава Л.Г., Шишкина Д.И., Латышкевич О.А., Бреусенко Л.Е., Спиридонов Д.С. Задержка роста плода: современные критерии диагностики, тактика ведения беременности и родов. Вопросы гинекологии, акушерства и перинатологии. 2023; 22(1): 5-11. [Kurtser M.A., Sichinava L.G., Shishkina D.I., Latyshkevich O.A., Breusenko L.E., Spiridonov D.S. Fetal growth retardation: modern diagnostic criteria, management of pregnancy and childbirth. Issues of gynecology, obstetrics and perinatology. 2023; 22(1): 5-11. (in Russian)].
  30. Bosma M., Gerling M., Pasto J., Georgiadi A., Graham E., Shilkova O. et al. FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice. Nat. Commun. 2016; 7: 11314.
  31. Smith G.C., Stenhouse E.J., Crossley J.A., Aitken D.A., Cameron A.D., Connor J.M. Early-pregnancy origins of low birth weight. Nature. 2002; 417(6892): 916.
  32. Smith G.C.S. Universal screening for foetal growth restriction. Best. Pract. Res. Clin. Obstet. Gynaecol. 2018; 49: 16-28.
  33. Gumina D.L, Su E.J. Mechanistic insights into the development of severe fetal growth restriction. Clin. Sci. (Lond). 2023; 137(8): 679-95.
  34. Dall'Asta A., Melito C., Morganelli G., Lees C., Ghi T. Determinants of placental insufficiency in fetal growth restriction. Ultrasound Obstet. Gynecol. 2023; 61(2): 152-7.
  35. Doan T.N.A., Briffa J.F., Phillips A.L., Leemaqz S.Y., Burton R.A., Romano T. et al. Epigenetic mechanisms involved in intrauterine growth restriction and aberrant kidney development and function. J. Dev. Orig. Health Dis. 2021; 12(6): 952-62.
  36. Tagliaferri S., Cepparulo P., Vinciguerra A., Campanile M., Esposito G., Maruotti G.M. et al. miR-16-5p, miR-103-3p, and miR-27b-3p as early peripheral biomarkers of fetal growth restriction. Front. Pediatr. 2021; 9: 611112.
  37. Ганичкина М.Б., Высоких М.Ю., Тютюнник В.Л., Чаговец В.В., Кан Н.Е. Дифференциальная диагностика ранней и поздней задержки роста плода на основании маркеров про- и антиоксидантной систем. Акушерство и гинекология. 2020; 9: 66-72. [Ganichkina M.B., Vysokykh M.Yu., Tyutyunnik V.L., Chagovets V.V., Kan N.E. Early- and late-onset fetal growth restriction: differential diagnosis based on pro- and antioxidant system markers. Obstetrics and Gynecology. 2020; (9): 66-72 (in Russian)].
  38. Salmeri N., CarboneI F., Cavoretto P.I., Farina A., Morano D. Epigenetics beyond fetal growth restriction: а comprehensive overview. Mol. Diagn. Ther. 2022; 26(6): 607-6.
  39. Bettiol A., Avagliano L., Lombardi N., Crescioli G., Emmi G., Urban M.L. et al. Pharmacological interventions for the prevention of fetal growth restriction: а systematic review and network meta-analysis. Clin. Pharmacol. Ther. 2021; 110(1): 189-99.
  40. Davenport B.N., Wilson R.L., Jones H.N. Interventions for placental insufficiency and fetal growth restriction. Placenta. 2022; 125: 4-9.
  41. Bonacina E., Mendoza M., Farràs A., Garcia-Manau P., Serrano B., Hurtado I. et al. Angiogenic factors for planning fetal surveillance in fetal growth restriction and small-for-gestational-age fetuses: а prospective observational study. BJOG. 2022; 129(11): 1870-7.
  42. Kucukbas G.N., Kara O., Yüce D., Uygur D. Maternal plasma endocan levels in intrauterine growth restriction. J. Matern. Fetal Neonatal. Med. 2022; 35(7): 1295-300.

Received 11.07.2023

Accepted 08.11.2023

About the Authors

Shagane R. Gasymova, Junior Researcher, Department of Fetal Medicine, Institute Of Obstetrics, ultrasound diagnostics doctor, Department of Ultrasound and Functional Diagnostics, obstetrician-gynecologist, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, +7(916)542-22-99,,, 117997, Russia, Moscow, Ac. Oparina str., 4.
Victor L. Tyutyunnik, Professor, MD, PhD, Leading Researcher of the Center for Scientific and Clinical Research, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, +7(903)969-50-41,, Researcher ID: B-2364-2015,
SPIN-код: 1963-1359, Authors ID: 213217, Scopus Author ID: 56190621500,, 117997, Russia, Moscow, Ac. Oparina str., 4.
Natalia E. Kan, Professor, MD, PhD, Deputy Director of Science, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology Ministry of Health of Russia, +7(926)220-86-55,, Researcher ID: B-2370-2015, SPIN-код: 5378-8437, Authors ID: 624900,
Scopus Author ID: 57008835600,, 117997, Russia, Moscow, Ac. Oparina str., 4.
Maria V. Volochaeva, PhD, Senior Researcher, Department of Regional Cooperation and Integration, Physician at the 1 Maternity Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, +7(919)968-72-98,,, 117997, Russia, Moscow, Ac. Oparina str., 4.
Anastasia G. Borisova, postgraduate student, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health
of Russia, +7(968)735-40-81,,, 117997, Russia, Moscow, Ac. Oparina str., 4.
Corresponding author: Shagane R. Gasymova,

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.