Clinical significance for assessing adaptive hemostasis changes during multiple pregnancy after in vitro fertilization

   Aim: to assess adaptive hemostasis changes in multiple dichorionic pregnancy after in vitro fertilization (IVF).

   Materials and Methods. A prospective observational randomized controlled trial was conducted by examining 58 and 46 pregnant women with multiple dichorionic diamniotic twins resulting from applying assisted reproductive technologies (ART) and spontaneous delivery (comparison group), respectively. Hemostasis parameters were studied as follows: activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen, antithrombin, protein C, protein S, functions of protein С (РrоС Global test), D-dimer, platelet aggregation with adenosine-5-diphosphate (ADP), ristocetin, and collagen.

   Results. A high coagulation potential was revealed, more prominent after using ART (p < 0.05). Fibrinogen level gradually increased while gestation age increased, whereas APTT, PT and TT level decreased. In the group with natural conception, fibrinogen increased by 22 % in the second trimester, reaching 4.5 g/L (95 % CI = 4,2–4,8) and by 6 % in the third trimester, reaching 4.8 g/L (95 % CI = 4,3–5,4), whereas in the IVF group – by 26 %, reaching 5.3 g/L (95 % CI = 4,7–5,6) and by 21 %, reaching (6.5 g/L; 95 % CI = 5,2–6,8) in relevant trimester of pregnancy, respectively. Antithrombin level was lower in IVF patients – 76.8 % (95 % CI = 72.6 – 81.0) in the second trimester, reaching 70.6 % (95 % CI = 64.8–76.4) in the third trimester (p < 0.001). Protein C level did not differ significantly between groups and was low within the reference range. The aggregatogram demonstrated a high platelet hemostatic potential in IVF patients (p < 0.05) as early as in the first trimester: ADP-induced aggregation – 68.3 % (95 % CI = 62.9–73.7), ristocetin-induced aggregation – 53.1 % (95 % = CI 48.7–58.5), collagen-induced aggregation – 58.4 % (95 % CI = 52.1–64.7). In the third trimester, both platelet aggregation and functional activity (ADP-induced aggregation – 64.5 % [95 % CI = 59.3–69.7], ristocetin-induced aggregation – 68.4 % [95 % CI = 63.2–73.6], collagen-induced aggregation – 50.7 % [95 % CI = 44.3–57.1]; p < 0.05) and D-dimer level persistently increased, also more prominently in the IVF group (1.60 ± 0.46 ng/ml; p < 0.05).

   Conclusion. Gestational adaptation in induced multiple pregnancies is at high risk of breach in compensatory mechanisms and requires monitoring for timely detection of decompensation signs and their correction to prolong pregnancy till optimal delivery time frame.

1. Brenner B. Haemostatic changes in pregnancy. Thromb Res. 2004;114(5–6):409–14. doi: 10.1016/j.thromres.2004.08.004.

2. Cui C., Yang S., Zhang J. et al. Trimester-specific coagulation and anticoagulation reference intervals for healthy pregnancy. Thromb Res. 2017;156:82–6. doi: 10.1016/j.thromres.2017.05.021.

3. Momot A.P., Nikolaeva M.G., Serdyuk G.V. et al. Assessment of hemostasis in physiological pregnancy (methodic recommendations). [Ocenka sostoyaniya gemostaza pri fiziologicheski protekayushchej beremennosti (metodicheskie rekomendacii)]. Rossijskij vestnik akushera-ginekologa. 2018;18(3–2):2–37. (In Russ.).

4. Pabinger I. Thrombophilia and its impact on pregnancy. Thromb Res. 2009;123 Suppl 3: S16–S21. doi: 10.1016/S0049-3848(09)70128-8.

5. Khizroeva J.Kh., Antonova A.S., Egorova E.S., Makatsariya N.A. Recurrent failure of ART, thrombosis and thrombophilia. [Povtornye neudachi EKO, trombozy i trombofiliya]. Obstetrics, Gynecology and Reproduction. 2023;17(6):792–800. (In Russ.). doi: 10.17749/2313-7347/ob.gyn.rep.2023.467.

6. Ren K., Wei Y., Qiao R. et al. Changes in coagulation during twin pregnancies. Clin Appl Thromb Hemost. 2020;26:1076029620983898. doi: 10.1177/1076029620983898.

7. Morikawa M., Yamada T., Turega N. et al. Coagulation-fibrinolysis is more enhanced in twin than in singleton pregnancies. J Perinat Med. 2006; 34(5):392–7. doi: 10.1515/JPM.2006.078.

8. Lin L., Yang H., Xu Zh. et al. Explore the impact of abnormal coagulation test results on pregnancy complications and perinatal outcomes by establishing the trimester-specific reference intervals of singleton and twin pregnancies. Clin Chim Acta. 2023;541(Suppl 1):117265. doi: 10.1016/j.cca.2023.117265.

9. Momot A.P., Molchanova I.V., Tsyvkina L.P. Alterations of the hemostatic system in the IVF cycle and their influence on the procedure efficiency. [Izmeneniya sistemy gemostaza v cikle EKO i ih vliyanie na effektivnost' procedury]. Byulleten' medicinskoj nauki. 2017;4(8):77–81. (In Russ.). doi: 10.31684/2541-8475.2017.4(8).77-81.

10. Yang W., Sun Q., Zhou Z. et al. Coagulation parameters predictive of repeated implantation failure in Chinese women: a retrospective study. Medicine. 2020;99(48):e23320. doi: 10.1097/MD.0000000000023320.

11. Westerlund E., Henriksson P., Wallén H. et al. Detection of a procoagulable state during controlled ovarian hyperstimulation for in vitro fertilization with global assays of haemostasis. Thromb Res. 2012;130(4):649–53. doi: 10.1016/j.thromres.2011.11.024.

12. Grandone E., Di Micco P.P., Villani M. et al. Venous thromboembolism in women undergoing assisted reproductive technologies: data from the RIETE Registry. Thromb Haemost. 2018;118(11):1962–8. doi: 10.1055/s-0038-1673402.

13. Rizwan N., Abbasi R.M., Mughal R. Maternal morbidity and perinatal outcome with twin pregnancy. J Ayub Med Coll Abbottabad. 2010;22(2):105–7.

14. Yakovenko E.M., Yakovenko S.A. In vitro fertilization and other methods of overcoming infertility. [Ekstrakorporal'noe oplodotvorenie i drugie metody preodoleniya besplodiya]. Moscow, 2016. 280 p. (In Russ.).

15. Liu J., Yuan E., Lee L. Gestational age-specific reference intervals for routine haemostatic assays during normal pregnancy. Clin Chim Acta. 2012;413(1–2):258–61. doi: 10.1016/j.cca.2011.09.046.

16. Bar J., Blickstein D., Hod M. et al. Increased D-dimer levels in twin gestation. Thromb Res. 2000;98(6):485–9. doi: 10.1016/s0049-3848(00)00187-0.

17. Yamada T., Kawaguchi S., Araki N. et al. Difference in the D-dimer rise between women with singleton and multifetal pregnancies. Thromb Res. 2013;131(6):493–6. doi: 10.1016/j.thromres.2013.04.029.

18. Godzoeva A.O., Zazerskaya I.E., Vlasov V.S. et al. Fibrin monomer and D-dimer in infertile women undergoing assisted reproductive technology. [Ocenka fibrin-monomera i D-dimera u pacientok s besplodiem v programmah vspomogatel'nyh reproduktivnyh tekhnologij]. Akusherstvo i ginekologiya. 2020;9:73–81. (In Russ.). doi: 10.18565/aig.2020.9.73