Ukrainian Journal Health of Woman. 2025. 3(178): 59-66. doi: 10.15574/HW.2025.3(178).5966
Hychka N. M.^1,2, Beniuk V. O.¹, Dyndar O. A.¹, Chebotarova A. S.¹, Nazarova N. S.¹, Beniuk S. V.¹, Nykoniuk T. R.^1
1Bogomolets National Medical University, Kyiv, Ukraine
²MNPE Maternity and Childhood Center of the «Kyiv City Clinical Hospital No. 5», Ukraine

For citation: Hychka NM, Beniuk VO, Dyndar OA, Chebotarova AS, Nazarova NS, Beniuk SV, Nykoniuk TR. (2025). Preconceptional assessment of endothelial dysfunction markers in women with antenatal fetal death in anamnesis. Ukrainian Journal Health of Woman. 3(178): 59-66. doi: 10.15574/HW.2025.3(178).5966Article received: Mar 07, 2025. Accepted for publication: May 21, 2025.
Identification of endothelial dysfunction markers at stage of pregnancy planning enables risk stratification for prethrombotic conditions, optimization of preconception management strategies, and prevention of complications of pregnancy and childbirth in women with a history of antenatal fetal death (AFD).
Аim – to identify markers of endothelial dysfunction and the features of polymorphism of the encoding them genes, in women with a history of AFD at the stage of preconception preparation.
Materials and methods. At the stage of pregnancy planning, 38 women with a history of AFD (main group) and 35 women whose previous pregnancies resulted in live births (control group) were examined. Gene polymorphisms of coagulation factor V (FV Leiden) and 5,10-methylenetetrahydrofolate reductase (MTHFR) were determined using an allele-specific polymerase chain reaction. The presence of specific antiphospholipid antibodies and their cofactors, as well as the levels of vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and homocysteine were assessed by enzyme-linked immunosorbent assay (ELISA).
Results. In women of the main group, gene polymorphisms associated with inherited thrombophilia were diagnosed 2.3 times more frequently overall. Specifically, the frequency of FV Leiden was threefold higher, MTHFR polymorphism – 3.4 times higher, prothrombin gene mutation – 5.5 times higher, and plasminogen activator inhibitor (PAI-1) polymorphism – 8.5 times higher compared to the control group. The homocysteine level in the main group exceeded that of the control group by 2.4 times. Antiphospholipid antibodies were detected three times more often in the main group and, in combination with inherited thrombophilia gene polymorphisms, were present in 21.1% of cases. A significant 3.1-fold decrease in VEGF levels and a 2.1-fold increase in ET-1 concentration were observed in women of the main group compared with the control group (6.4±0.4 pg/mL respectively 3.1±0.2 pg/mL).
Conclusions. Determination of gene mutations associated with thrombophilia, antiphospholipid antibodies, and markers of endothelial dysfunction in women with a history of antenatal fetal death will enable timely adjustment of pregnancy management strategies and prevention of recurrent fetal and neonatal losses. The study was conducted in accordance with the principles of the Declaration of Helsinki.
The research protocol was approved by the Bioethics Committee of the Bogomolets National Medical University. Informed consent was obtained from all participants prior to their inclusion in the study.
The authors declare no conflict of interest.
Keywords: antenatal fetal death, preconceptional preparation, endothelial dysfunction, thrombophilia, antiphospholipid syndrome, endothelin-1.

REFERENCES

1. Alecsandru D, Klimczak AM, Velasco JAG, Pirtea P, Franasiak JM. (2021). Immunologic causes and thrombophilia in recurrent pregnancy loss. Fertility and sterility. 115(3): 561-566. https://doi.org/10.1016/j.fertnstert.2021.01.017; PMid:33610320

2. Arslanoğlu T, Bilirer KK, Demirkıran Cİ, Ceylan Y, Veliyeva S et al. (2025). Intrahepatic cholestasis of pregnancy and coagulation: a dual risk of hypercoagulability and bleeding. BMC Pregnancy and Childbirth. 25(1): 498. https://doi.org/10.1186/s12884-025-07623-y; PMid:40281473 PMCid:PMC12023602

3. Bahraini M, Fazeli A, Dorgalaleh A. (2024). Laboratory diagnosis of activated protein c resistance and factor V Leiden. In Seminars in thrombosis and hemostasis. Thieme Medical Publishers. 50(08): 1067-1083. https://doi.org/10.1055/s-0043-1776324; PMid:37879345

4. Benyuk V, Chebotarova A, Hychka N, Kovaliuk T, Beniuk S, Usevych I et al. (2023). Features of disorders and methods of correction of the hemostasis system in women with antenatal fetal death. Reproductive Health of Woman. (4): 50-58. https://doi.org/10.30841/2708-8731.4.2023.285765

5. Bucci T, Menichelli D, Palumbo IM, Pastori D, Ames PR et al. (2025). Statins as an Adjunctive Antithrombotic Agent in Thrombotic Antiphospholipid Syndrome: Mechanisms and Clinical Implications. Cells. 14(5): 353. https://doi.org/10.3390/cells14050353; PMid:40072082 PMCid:PMC11899080

6. Camarda N, Travers R, Yang VK, London C, Jaffe IZ. (2022). VEGF receptor inhibitor-induced hypertension: emerging mechanisms and clinical implications. Current oncology reports. 24(4): 463-474. https://doi.org/10.1007/s11912-022-01224-0; PMid:35179707 PMCid:PMC9218917

7. Chandran Latha K, Sreekumar A, Beena V, S S BR, Lakkappa RB et al. (2021). Shear stress alterations activate BMP4/pSMAD5 signaling and induce endothelial mesenchymal transition in varicose veins. Cells. 10(12): 3563. https://doi.org/10.3390/cells10123563; PMid:34944071 PMCid:PMC8700678

8. Chen T, Liu P, Zhang C, Jin S, Kong Y et al. (2025). Pathophysiology and genetic associations of varicose veins: a narrative review. Angiology. 76(7): 615-628. Epub 2024 Jan 16. https://doi.org/10.1177/00033197241227598; PMid:38226614

9. Chighizola CB, Pregnolato F, Andreoli L, Bodio C, Cesana L et al. (2018). Beyond thrombosis: Anti-β2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome. Journal of autoimmunity. 90: 76-83. https://doi.org/10.1016/j.jaut.2018.02.002; PMid:29454510

10. Czwalinna A, Bergmann F. (2020). Prevention of pregnancy complications in antiphospholipid syndrome. Hämostaseologie. 40(02): 174-183. https://doi.org/10.1055/a-1113-0689l PMid:32455458

11. D'Ippolito S, Barbaro G, Paciullo C, Tersigni C, Scambia G, Di Simone N. (2023). Antiphospholipid syndrome in pregnancy: new and old pathogenetic mechanisms. International journal of molecular sciences. 24(4): 3195. https://doi.org/10.3390/ijms24043195; PMid:36834614 PMCid:PMC9966557

12. Delis M, Emmanouilidou-Fotoulaki E, Chatzakis C, Theodoridis T, Sotiriadis A. (2025). Inherited thrombophilias and stillbirth: a systematic review and meta-analysis. Archives of Gynecology and Obstetrics. 312: 37-50. https://doi.org/10.1007/s00404-025-07989-6; PMid:40087172 PMCid:PMC12177024

13. Deng X, Pan B, Lai H, Sun Q, Lin X et al. (2024). Association of previous stillbirth with subsequent perinatal outcomes: a systematic review and meta-analysis of cohort studies. American journal of obstetrics and gynecology. 231(2): 211-222. https://doi.org/10.1016/j.ajog.2024.02.304; PMid:38437893

14. Dubyk LV, Chernetska NV. (2022). Сharacteristics of blood flow in uterine, radial and spiral arteries in early spontaneous abortions on the background of endothelial dysfunction. Actual Problems of Pediatrics, Obstetrics and Gynecology. 2(2022): 53-57. https://doi.org/10.11603/24116-4944.2022.2.13342

15. Finan RR, Beydoun N, Racoubian E, Bahia W, Ferchichi S, Almawi WY. (2024). High Prevalence of Anti-Prothrombin IgM and IgG Autoantibodies in Women With Unexplained Recurrent Pregnancy Loss. Reproductive Sciences. 31(12): 3851-3857. https://doi.org/10.1007/s43032-024-01725-2; PMid:39373852

16. Gao R, Zeng R, Qing P, Meng C, Cheng K et al. (2021). Antiphospholipid antibodies and pregnancy outcome of assisted reproductive treatment: A systematic review and meta‐analysis. American Journal of Reproductive Immunology. 86(4): e13470. https://doi.org/10.1111/aji.13470; PMid:34018271

17. Gibbins KJ, Mumford SL, Sjaarda LA, Branch DW, Perkins NJ et al. (2018). Preconception antiphospholipid antibodies and risk of subsequent early pregnancy loss. Lupus. 27(9): 1437-1445. https://doi.org/10.1177/0961203318776089; PMid:29771194 PMCid:PMC6027606

18. Guo X, Yi H, Li TC, Wang Y, Wang H, Chen X. (2021). Role of vascular endothelial growth factor (VEGF) in human embryo implantation: clinical implications. Biomolecules. 11(2): 253. https://doi.org/10.3390/biom11020253; PMid:33578823 PMCid:PMC7916576

19. Hamedi B, Feulefack J, Khan A, Sergi C. (2020). Association between factor V Leiden mutation and recurrent pregnancy loss in the middle east countries: a Newcastle-Ottawa meta-analysis. Archives of Gynecology and Obstetrics. 302: 345-354. https://doi.org/10.1007/s00404-020-05610-6; PMid:32472185

20. Knight JS, Branch DW, Ortel TL. (2023, Feb 27). Antiphospholipid syndrome: advances in diagnosis, pathogenesis, and management. BMJ. 380: e069717. https://doi.org/10.1136/bmj-2021-069717; PMid:36849186

21. Li X, Wu J, Fang F, Liu Y, Jiang W, Li G, Song J. (2024). Isolated gastric varices associated with antiphospholipid syndrome and protein S deficiency: a case report and review of the literature. Journal of International Medical Research. 52(4): 03000605241240579. https://doi.org/10.1177/03000605241240579; PMid:38603605 PMCid:PMC11010754

22. Liu X, Chen Y, Ye C, Xing D, Wu R, Li F, Wang T. (2021). Hereditary thrombophilia and recurrent pregnancy loss: a systematic review and meta-analysis. Human Reproduction 36(5): 1213-1229. https://doi.org/10.1093/humrep/deab010; PMid:33575779

23. Metz TD, Berry RS, Fretts RC, Reddy UM, Turrentine MA et al. (2020). Obstetric care consensus 10: management of stillbirth: (replaces practice bulletin number 102, March 2009). American Journal of Obstetrics and Gynecology. 222(3): B2-B20. https://doi.org/10.1016/j.ajog.2020.01.017; PMid:32004519

24. Sayal HB, Beksac MS. (2024). The effect of hereditary thrombophilia on recurrent pregnancy loss: a retrospective cohort study. BMC Pregnancy and Childbirth. 24(1): 719. https://doi.org/10.1186/s12884-024-06926-w; PMid:39497077 PMCid:PMC11536592

25. Tsikouras P, Deftereou T, Anthoulaki X, Bothou A, Chalkidou A et al. (2019). Thrombophilia and pregnancy: diagnosis and management. In Embolic diseases-evolving diagnostic and management approaches. IntechOpen. https://doi.org/10.5772/intechopen.85005

26. Tumian NR, Hunt BJ. (2022). Clinical management of thrombotic antiphospholipid syndrome. Journal of Clinical Medicine. 11(3): 735. https://doi.org/10.3390/jcm11030735; PMid:35160188 PMCid:PMC8836580

27. Wingeyer SP, Aranda F, Udry S, Latino J, de Larrañaga G. (2019). Inherited thrombophilia and pregnancy loss. Study of an Argentinian cohort. Medicina Clínica (English Edition). 152(7): 249-254. https://doi.org/10.1016/j.medcle.2017.12.044

28. Wu X, Wei C, Chen R, Yang L, Huang W et al. (2022). Fetal umbilical artery thrombosis: prenatal diagnosis, treatment and follow-up. Orphanet Journal of Rare Diseases. 17(1): 414. https://doi.org/10.1186/s13023-022-02563-8; PMid:36371215 PMCid:PMC9652808

29. Yaremchuk OZ, Posokhova KA, Klishch IM, Korda MM. (2022). Antyfosfolipidnyi syndrom. Monohrafiia. TNMU. Ukrmedknyha. 240(69). URL: https://repository.tdmu.edu.ua//handle/123456789/17878.

30. Zhuk S, Us І. (2021). Antiphospholipid antibodies and their role in the development of placental dysfunction. Reproductive Health of Woman. (9-10): 61-66. https://doi.org/10.30841/2708-8731.9-10.2021.252593