Predicting chronic placental insufficiency in patients with a complicated obstetric history at pregnancy planning stage

Introduction. Chronic placental insufficiency (CPI) is one of the leading causes of fetal growth restriction (FGR), perinatal loss, and complicated pregnancy. Currently, no validated methods for predicting CPI during pregnancy planning are available, which complicates high-risk patient stratification early and enabling timely prevention.

Aim: to develop a mathematical model for predicting CPI risk in women with a complicated obstetric history at the pre-pregnancy preparation stage.

Materials and Methods. A retrospective clinical study assessing 462 patients with a complicated obstetric history was conducted. The outcomes of previous pregnancies, concomitant extragenital diseases, circulation of criterial (anti-β2glycoprotein and anti-cardiolipin antibodies, lupus anticoagulant) and non-criterial (anti-annexin 5, anti-phosphatidylserine, anti-phosphatidylinositol, anti-prothrombin, anti-human chorionic gonadotropin) antiphospholipid antibodies (APA), indicators of lymphocyte subpopulation composition, coagulation profile, and genetic thrombophilia were evaluated. Enzyme-linked immunosorbent assay, flow cytometry, ultrasound, and histological diagnostics were used. Binary logistic regression was applied to construct a prognostic model, and the diagnostic significance of the indicators was assessed using ROC curves.

Results. Detected APA high titers and/or lupus anticoagulant were associated with significantly elevated CPI incidence (63.1% vs. 4.6%; p < 0.001) and FGR (43.4% vs. 4.6%; p < 0.001). Immunological imbalance (increased percentage of B-lymphocytes and NK cells) increased CPI risk by 1.3–5.5 times. The constructed prediction model, which included indicators of immunological activity and comorbidity, demonstrated high accuracy: AUC = 0.89, sensitivity 85.7%, specificity 85.7%.

Conclusion. The developed mathematical model allows for highly accurate prediction of CPI risk developing in women with a complicated obstetric history even before pregnancy, which opens up avenues for personalized selection of preventive measures, including immunomodulatory therapy and dynamic monitoring, and contributes to lowering frequency of perinatal complications.

1. Savelyeva G.M., Serov V.N., Sukhikh G.T. Obstetrics: national leadership. [Akusherstvo. Nacional'noe rukovodstvo]. Moscow: GEOTAR-Media, 2022. 1080 p. (In Russ.).

2. Mayrink J., Costa M.L., Cecatti J.G. Preeclampsia in 2018: revisiting concepts, physiopathology and prediction. Sci World J. 2018;2018(1):6268276. https://doi.org/10.1155/2018/6268276.

3. Vorontsova Z.A., Zhilyaeva O.D., Zolotareva S.N., Logacheva V.V. Experimental modeling of placental insufficiency and fetal growth retardation syndrome (literature review). [Eksperimental'noe modelirovanie placentarnoj nedostatochnosti i sindroma zaderzhki rosta ploda (obzor literatury). Vestnik novyh medicinskih tekhnologij. 2021;15(1):35–46. (In Russ.). https://doi.org/10.24412/2075-4094-2021-1-1-5. (In Russ.).

4. Brosens I., Pijnenborg R., Vercruysse L., Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204(3):193–201. https://doi.org/10.1016/j.ajog.2010.08.009.

5. Mifsud W., Sebire N.J. Placental pathology in early-onset and late-onset fetal growth restriction. Fetal Diagn Ther. 2014;36(2):117–28. https://doi.org/10.1159/000359969.

6. Miyakis S., Lockshin M.D., Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306. https://doi.org/10.1111/j.1538-7836.2006.01753.x.

7. Branch D.W., Gibson M., Silver R.M. Recurrent miscarriage. N Engl J Med. 2010;363(18):1740–7. https://doi.org/10.1056/NEJMcp1005330.

8. Giannakopoulos B., Krilis S.A. The pathogenesis of the antiphospholipid syndrome. N Engl J Med. 2013;368(11):1033–44. https://doi.org/10.1056/nejmra1112830.

9. Orudzhova E.A., Samburova N.A., Anichkova E.V. et al. Thrombophilia in the pathogenesis of fetal growth retardation. [Trombofilii v patogeneze zaderzhki rosta ploda]. Obstetrics, Gynecology and Reproduction. 2021;15(2):189–200. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2021.223.

10. Erlebacher A. Immunology of the maternal-fetal interface. Annu Rev Immunol. 2013;31:387–411. https://doi.org/10.1146/annurevimmunol-032712-100003.

11. Guleria I., Pollard J.W. The trophoblast is a component of the innate immune system during pregnancy. Nat Med. 2000;6(5):589–93. https://doi.org/10.1038/75074.

12. Kwak J.Y.H., Beaman K.D., Gilman-Sachs A. et al. Up-regulated expression of CD56+, CD56+/CD16+, and CD19+ cells in peripheral blood lymphocytes in pregnant women with recurrent pregnancy losses. Am J Reprod Immunol. 1995;34(2):93–9. https://doi.org/10.1111/j.1600-0897.1995.tb00924.x.

13. Hadlock F.P., Harrist R.B., Sharman R.S. et al. Estimation of fetal weight with the use of head, body, and femur measurements-a prospective study. Am J Obstet Gynecol. 1985;151(3):333–7. https://doi.org/10.1016/0002-9378(85)90298-4.

14. Gordijn S.J., Beune I.M., Thilaganathan B. et al. Consensus definition of fetal growth restriction: a Delphi procedure. Ultrasound Obstet Gynecol. 2016;48(3):333–9. https://doi.org/10.1002/uog.15884.

15. Pavlova N.G., Arzhanova O.N., Zainulina M.S., Kolobov A.V. Placental insufficiency: educational and methodological manual. [Placentarnaya nedostatochnost': uchebno-metodicheskoe posobie]. Saint Petersburg, 2007. 28 р. (In Russ.).

16. Ignatko I.V., Denisova Yu.V., Filippova Yu.A., Dubinin A.O. Differential diagnosis of early and late forms of fetal delay syndrome. [Differencial'naya diagnostika rannej i pozdnej form sindroma zaderzhki razvitiya ploda]. Ural'skij medicinskij zhurnal. 2020;(12):91–7. (In Russ.). https://doi.org/10.25694/URMJ.2020.12.22.

17. Chekhonin V.P., Gurina O.I., Dmitrieva T.B. Monoclonal antibodies to neurospecific proteins. [Monoklonal'nye antitela k nejrospecificheskim belkam]. Moscow: Medicina, 2007. 344 p. (In Russ.).

18. Erkan D., Aguiar C.L., Andrade D. et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev. 2014;13(6):685–96. https://doi.org/10.1016/j.autrev.2014.01.

19. Tong M., Johansson C., Xiao F. et al. Antiphospholipid antibodies increase the levels of mitochondrial DNA in placental extracellular vesicles: Alarmin-g for preeclampsia. Sci Rep. 2017;7:16556. https://doi.org/10.1038/s41598-017-16448-5.

20. Tong M., Viall C.A., Chamley L.W. Antiphospholipid antibodies and the placenta: A systematic review of their In vitro effects and modulation by treatment. Hum Reprod Update. 2015;21(1):97–118. https://doi.org/10.1093/humupd/dmu049.

21. Hoxha A., Tormene D., Campello E., Simioni P. Treatment of refractory/ high-risk pregnancies with antiphospholipid syndrome: a systematic review of the literature. Front Pharmacol. 2022;13:849692. https://doi.org/10.3389/fphar.2022.849692.

22. Moore J.M., Nahlen B.L., Lal A.A., Udhayakumar V. Immunologic memory in the placenta: a lymphocyte recirculation hypothesis. Med Hypotheses. 2000;54(3):505–10. https://doi.org/10.1054/mehy.1999.0888.

23. Racicot K., Kwon J.Y., Aldo P. et al. Understanding the complexity of the immune system during pregnancy. Am J Reprod Immunol. 2014;72(2):107–16. https://doi.org/10.1111/aji.12289.

24. Dekker G.A. Risk factors for preeclampsia. Clin Obstet Gynecol. 1999;42(3):422. https://doi.org/10.1097/00003081-199909000-00002.

25. Tong M., Abrahams V.M. Immunology of the рlacenta. Obstet Gynecol Clin North Am. 2020;47(1):49–63. https://doi.org/10.1016/j.ogc.2019.10.006.

26. Tong M., Kayani T., Jones D.M. et al. Antiphospholipid antibodies increase endometrial stromal cell decidualization, senescence, and inflammation via toll-like receptor 4, reactive oxygen species, and p38 MAPK signaling. Arthritis Rheumatol. 2022;74(6):1001–12. https://doi.org/10.1002/art.42068.

27. Eremeeva D.R., Zainulina M.S. Assessing the effectiveness of preventing placenta-associated complications in patients with burdened obstetric history and circulating antiphospholipid antibodies. [Otsenka effektivnosti profilaktiki platsenta-assotsiirovannykh oslozhnenii u patsientok s otiazhchennym akusherskim anamnezom i tsirkuliatsiei antifosfolipidnykh antitel]. Obstetrics, Gynecology and Reproduction. 2024;18(4):475–91. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2024.479.

28. Kornacki J., Gutaj P., Kalantarova A. et al. Endothelial dysfunction in pregnancy complications. Biomedicines. 2021;9(12):1756. https://doi.org/10.3390/biomedicines9121756.

29. Egerup P., Lindschou J., Gluud C. et al. The effects of intravenous immunoglobulins in women with recurrent miscarriages: a systematic review of randomised trials with meta-analyses and trial sequential analyses including individual patient data. PLoS One. 2015;10(10):e0141588. https://doi.org/10.1371/journal.pone.0141588.

30. Tektonidou M.G., Andreoli L., Limper M. et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019;78(10):1296–1304. https://doi.org/10.1136/annrheumdis-2019-215213.

31. Gao R., Qin L. Correspondence on “EULAR recommendations for the management of antiphospholipid syndrome in adults”. Ann Rheum Dis. 2023;82(5):e107. https://doi.org/10.1136/annrheumdis-2021-220092.