The role of vascular endothelial growth factor receptors (VEGFR1, VEGFR2) in the development of placental insufficiency in women with recurrent miscarriage
Protsenko E.V., Talanova I.E., Malyshkina A.I., Kulida L.V.
Objective. Exploration of the role of vascular endothelial growth factor receptors (VEGFR1, VEGFR2) in formation of placental insufficiency in women with recurrent miscarriage (RM).
Materials and methods. A total of 347 pregnant women were examined: 247 women with RM, and 104 with a history of pregnancy without RM. Of the total number of women, 75 placental samples underwent histological and immunohistochemical examinations with antibodies to VEGFR1 and VEGFR2. Placental samples that underwent pathomorphological examination were divided into 3 groups. Group 1 included placentas of women with RM, who gave birth at term (n=25). Group 2 included placentas of women who gave at 260–366 weeks (n=20). Group 3 (the comparison group) included placentas of 30 patients without a history of RM, who gave birth at 37–40 weeks. Statistical processing of the results was performed using Excel-2010 and STATISTICA 13.0 software packages.
Results. The women with RM had complications during pregnancy. The most common complication of pregnancy was threatened miscarriage in all trimesters of pregnancy that ended with preterm birth. The average gestational age for preterm birth was 311 (260–363) weeks. Immunohistochemical analysis of placental samples showed that in preterm birth, expression of VEGFR1 in decidual cells and VEGFR2 in syncytiotrophoblast of chorial villi was significantly lower (p=0.0002) compared with full-term pregnancy. In addition, preterm birth was associated with premature placental abruption, that commonly occurs with failure of physiologic transformation of spiral arteries.
Conclusion. The most frequent pregnancy complications in women with RM miscarriage were threatened miscarriage with high rates of preterm delivery and placental insufficiency. According to our data, the mechanisms of formation of pregnancy complications in women with RM are associated with low expression of VEGFR1 and VEGFR2 in the placenta, leading to impaired gestational restructuring of the uteroplacental arteries and vascularization of the villous chorion, that should be considered as an element of chronic placental insufficiency and taken into account at the pregravid stage.
Authors' contributions. Protsenko E.V., Kulida L.V. – study concept and design; Talanova I.E. – material collection and processing, statistical data processing; Protsenko E.V., Kulida L.V., Talanova I.E., Malyshkina A.I. – manuscript writing; Malyshkina A.I. – manuscript editing.
Conflicts of interest. The authors confirm that they have no conflict of interest to declare.
Funding. The study was carried out without any sponsorship.
Ethical Approval. The study was approved by the local Ethics Committee of V.N. Gorodkov Ivanovo Research Institute of Maternity and Childhood, Ministry of Health of Russia.
Generative Artificial Intelligence. No generative AI was used in preparing this article.
Patient Consent for Publication. The patients have signed informed consent for publication of their data.
Authors' Data Sharing Statement. The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Protsenko E.V., Talanova I.E., Malyshkina A.I., Kulida L.V. The role of vascular endothelial growth factor receptors (VEGFR1, VEGFR2) in the development of placental insufficiency in women with recurrent miscarriage.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2026; (6): 60-67 (in Russian)
https://dx.doi.org/10.18565/aig.2025.349
Keywords
recurrent miscarriage
preterm birth
placenta. placental insufficiency
VEGFR1
VEGFR2
References
- Министерство здравоохранения Российской Федерации. Клинические рекомендации. Привычный выкидыш. 2025. [Ministry of Health of the Russian Federation. Clinical guidelines. Recurrent miscarriage. 2025 (in Russian)].
- Тетруашвили Н.К. Привычный выкидыш. Акушерство и гинекология: новости, мнения, обучение. 2017; 4: 70-87. https://dx.doi.org/10.24411/2303-9698-2017-00010 [Tetruashvili N.K. Recurrent abortion. Obstetrics and Gynecology: News, Opinions, Training. 2017; 4: 70-87 (in Russian). https://dx.doi.org/10.24411/2303-9698-2017-00010].
- Vomstein K., Aulitzky A, Strobel L., Bohlmann M., Feil K., Rudnik-Schöneborn S. et al. Recurrent spontaneous miscarriage: a comparison of international guidelines. Geburtshilfe Frauenheilkd. 2021; 81(07): 769-79. https://dx.doi.org/10.1055/a-1380-3657
- Ali N., Elbarazi I., Ghazal-Aswad S., Al-Maskari F., Al-Rifai R., Oulhaj A. et al. Impact of recurrent miscarriage on maternal outcomes in subsequent pregnancy: The Mutaba'ah Study. Int. J. Womens Health. 2020; 12: 1171-9. https://dx.doi.org/10.2147/IJWH.S264229
- Колесникова А.М., Малышкина А.И., Таланова И.Е. Особенности анамнеза, течения гестации и перинатальных исходов у женщин с привычным невынашиванием беременности. Вестник Ивановской медицинской академии. 2024; 29(2): 32-8. https://dx.doi.org/10.52246/1606-8157_2024_29_2_32 [Kolesnikova A.M., Malyshkina A.I., Talanova I.E. Features of the anamnesis, course of gestation and perinatal outcomes in women with habitual miscarriage. Bulletin of the Ivanovo Medical Academy. 2024, 29(2): 32-8 (in Russian). https://dx.doi.org/10.52246/1606-8157_2024_29_2_32].
- Linehan L.A., San Lazaro Campillo I., Hennessy M., Flannery C., O'Donoghue K. Reproductive outcomes following recurrent first-trimester miscarriage: a retrospective cohort study. Hum. Reprod. Open. 2022; 2022(4): hoac045. https://dx.doi.org/10.1093/hropen/hoac045
- Приходько Н.Г. Роль факторов роста в инвазии трофобласта и их ассоциация с патологическим течением беременности. Бюллетень физиологии и патологии дыхания. 2019; 74: 111-8. https://dx.doi.org/10.36604/1998-5029-2019-74-111-118 [Prikhodko N.G. The role of growth factors in trophoblast invasion and their association with the pathological course of pregnancy. Bulletin of Respiratory Physiology and Pathology. 2019; 74: 111-8 (in Russian). https://dx.doi.org/10.36604/1998-5029-2019-74-111-118].
- Хомякова Е.В., Зиганшина М.М., Баев О.Р. Факторы, регулирующие ангио/васкулогенез плаценты при осложненном течении беременности и родов. Акушерство и гинекология. 2023; 9: 12-21. https://dx.doi.org/10.18565/aig.2023.149 [Khomyakova E.V., Ziganshina М.М., Baev O.R. Factors regulating placental angio/vasculogenesis in complications of pregnancy and childbirth. Obstetrics and Gynecology. 2023; (9): 12-21 (in Russian). https://dx.doi.org/10.18565/aig.2023.149].
- Redline R.W., Boyd T.K., Roberts D.J., eds. Placental and gestational pathology. Cambridge University Press; 2018; 350 p. https://dx.doi.org/10.1017/9781316848616
- Brosens I., Puttemans P., Benagiano G. Placental bed research: 1. The placental bed. From spiral arteries remodeling to the great obstetrical syndromes. American Journal of Obstetrics and Gynecology. 2019; 221(5): 437-56. https://doi.org/10.1016/j.ajog.2019. 05.044
- Толибова Г.Х., Траль Т.Г., Клещев М.А., Кветной И.М., Айламазян Э.К. Эндометриальная дисфункция: алгоритм гистологического и иммуногистохимического исследования. Журнал акушерства и женских болезней. 2015; 64(4): 69-77. [Tolibova G.Kh., Tral' T.G., Kleshchov M.A., Kvetnoy I.M., Aylamazyan E.K. Endometrial dysfunction: an algorithm for histological and immunohistochemical studies. Journal of Obstetrics and Women's Diseases. 2015; 64(4): 69-77 (in Russian)].
- Abu-Ghazaleh N., Brennecke S.; Murthi P., Karanam V. Association of vascular endothelial growth factors (VEGFs) with recurrent miscarriage: a systematic review of the literature. Int. J. Mol. Sci. 2023; 24(11): 9449. https://dx.doi.org/10.3390/ijms24119449
- Молчанова О.К., Ордиянц И.М., Луценко И.В., Подставкина В.А. Современные представления о молекулярных механизмах регуляции имплантации. Акушерство и гинекология: новости, мнения, обучение. 2020; 8(3) Приложение: 106-11. https://dx.doi.org/10.24411/2303-9698-2020-13917 [Molchanova O.K., Ordiyants I.M., Lucenko I.V., Podstavkina V.A. Modern concepts of molecular mechanisms of regulation of implantation. Obstetrics and Gynecology: News, Opinions, Training. 2020; 8(3) Supplement: 106-11 (in Russian). https://dx.doi.org/10.24411/2303-9698-2020-13917].
- Зенкина В.Г., Сахоненко В.А., Зенкин И.С. Патоморфологические особенности плаценты на разных этапах гестации. Современные проблемы науки и образования. 2019; 6: 129-38. [Zenkina V.G., Sakhonenko V.A., Zenkin I.S. Pathomorphological features of the placenta at different stages of gestation. Modern problems of science and education. 2019; 6: 129-38 (in Russian)].
Received 03.12.2025
Accepted 14.05.2026
About the Authors
Elena V. Protsenko, Dr. Med. Sci., Head of the Laboratory of Pathomorphology and Electron Microscopy, Ivanovo Research Institute of Maternity and Childhood named after V.N. Gorodkov, Ministry of Health of Russia, 153045, Russia, Ivanovo, Pobedy str., 20, SPIN: 1343-3881, Author ID: 160250, https://orcid.org/0000-0003-0490-5686Iya E. Talanova, PhD, Associate Professor at the Department of Obstetrics, Gynecology, and Medical Genetics, Ivanovo State Medical University, Ministry of Health of Russia, 153000, Ivanovo, Sheremetevsky Ave., 8, +7(910)982-05-48, iya-ta@yandex.ru, SPIN: 6865-5146, Author ID: 884142, https://orcid.org/0000-0003-4950-8174
Anna I. Malyshkina, Professor, Dr. Med. Sci., Director, Ivanovo Research Institute of Maternity and Childhood named after V.N. Gorodkov, Ministry of Health of Russia, 153045, Russia, Ivanovo, Pobedy str., 20; Head of the Department of Obstetrics, Gynecology and Medical Genetics, Ivanovo State Medical University of the Ministry of Healthcare of the Russian Federation, , +74932336263, anna_im@mail.ru, SPIN: 7937-9125, AuthorID:150323, https://orcid.org/0000-0002-1145-0563
Lyudmila V. Kulida, Dr. Med. Sci., Leading Researcher at the Laboratory of Pathomorphology and Electron Microscopy, Ivanovo Research Institute of Maternity and Childhood named V.N. Gorodkov, Ministry of Health of Russia, 153045, Russia, Ivanovo, Pobedy str., 20, SPIN: 6208-4487, Author ID: 160249, https://orcid.org/0000-0001-8962-9048
Corresponding author: Iya E. Talanova, iya-ta@yandex.ru
Similar Articles
