The effect of a new contraceptive with estetrol on the thrombotic safety profile of hormonal contraception

Akinshina S.V., Koloda Yu.A.

1) Deparment of Obstetrics and Gynecology, N.F. Filatov Clinical Institute of Children’s Health, I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia, Moscow, Russia; 2) Department of Obstetrics and Gynecology, Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia, Moscow, Russia
Thromboembolic complications are rare but potentially life-threatening adverse events associated with combined hormonal contraceptives (CHCs). The thrombogenic safety of CHCs is an issue that customarily causes the greatest concern among specialists and patients when choosing a birth control method, whereas the need to design new contraceptives with a minimal adverse effect on the hemostatic system has always remained relevant. Esteretta is the first CHC containing estetrol, a selective estrogen, which belongs to a fundamentally new class of estrogen with selective action in tissues and has a neutral metabolic profile and a minimal effect on the hemostatic system. The paper presents the current guidelines for selection of hormonal contraception in patients at high thrombotic risk; a review on the effect of various combined hormonal contraceptives on the hemostatic system; an analysis of the effects of the new contraceptive Esteretta on the parameters of the hemostatic system and on the risk of thromboembolic complications in the view of an obstetrician/gynecologist and hematologist.
Conclusion: Despite a more favorable safety profile with regard to the hemostatic system, contraindications to the use of Esterette are the same as to that of other CHCs, while the thrombotic safety of this drug remains to be analyzed from the results of studies involving a large number of patients and in terms of real clinical practice.


hormonal contraceptives


  1. Lete I., Chabbert-Buffet N., Jamin C., Lello S., Lobo P., Nappi R.E., Pintiaux A. Haemostatic and metabolic impact of estradiol pills and drospirenone-containing ethinylestradiol pills vs. levonorgestrel-containing ethinylestradiol pills: a literature review. Eur. J. Contracept. Reprod. Health Care. 2015; 20(5): 329-43.
  2. Макацария А.Д., ред. Тромбогеморрагические осложнения в акушерско-гинекологической практике. Руководство для врачей. М.: МИА; 2011. 1056с. [Makatsaria A.D., ed. Thrombohemorrhagic complications in obstetric and gynecological practice: A guide for medical specialists. M .: "Medical Information Agency". 2011. 1056 p. (in Russian)].
  3. Прилепская В.Н., Абакарова П.Р., Межевитинова Е.А., Довлетханова Э.Р.,Назарова Н.М. Современные принципы консультирования в контрацепции. Гормональная контрацепция. Акушерство и гинекология. 2021; 3(Приложение): 17-22. [Prilepskaya V.N., Abakarova P.R., Mezhevitinova E.A., Dovletkhanova E.R., Nazarova N.M. Modern principles of counseling in contraception. Hormonal contraception. Obstetrics and Gynecology. 2021; 3(Suppl): 17-22. (in Russian)].
  4. Якушевская О.В., Юренева С.В. Венозная тромбоэмболия и комбинированная оральная контрацепция. Акушерство и гинекология. 2016; 9: 20-6. [Yakushevskaya O.V., Yureneva S.V. Venous thromboembolism and combined oral contraception. Obstetrics and Gynecology. 2016; 9: 20-6. (in Russian)].
  5. Kemmeren J.M., Algra A., Grobbee D.E. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ. 2001; 323(7305): 131-4.
  6. Teede H.J., Misso M.L., Costello M.F., Dokras A., Laven J., Moran L.; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil. Steril. 2018; 110(3): 364-79.
  8. Lidegaard Ø., Løkkegaard E., Svendsen A.L., Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ. 2009; 339: b2890. b2890.
  9. van Hylckama Vlieg A., Helmerhorst F.M., Vandenbroucke J.P., Doggen C.J., Rosendaal F.R. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ. 2009; 339: b2921.
  10. Dinger J., Möhner S., Heinemann K. Cardiovascular risks associated with the use of drospirenone-containing combined oral contraceptives. Contraception. 2016; 93(5): 378-85.
  11. Dragoman M.V., Tepper N.K., Fu R., Curtis K.M., Chou R., Gaffield M.E. A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception. Int. J. Gynaecol. Obstet. 2018; 141(3): 287-94.
  12. Practice Committee of the American Society for Reproductive Medicine. Combined hormonal contraception and the risk of venous thromboembolism: a guideline. Fertil. Steril. 2017; 107(1): 43-51.
  13. ACOG Practice Bulletin No. 206. Use of hormonal contraception in women with coexisting medical conditions. Obstet. Gynecol. 2019; 133(2): e128-50.
  14. European Medicines Agency. Assessment report for combined hormonal contraceptives containing medicinal products-EMA/739865/2013. ISGE series. London: Springer; 2014.
  15. Heit J.A., Kobbervig C.E., James A.H., Petterson T.M., Bailey K.R., Melton L.J. 3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-years-based study. Ann. Intern. Med. 2005; 143(10): 697-706.
  16. Food and Drug Administration. FDA drug safety communication: updated information about the risk of blood clots in women taking birth control pills containing drospirenone. Silver Spring (MD): FDA; 2012. Available at: Retrieved 5.07. 2012.
  17. de Bastos M., Stegeman B.H., Rosendaal F.R., Van Hylckama Vlieg A.,Helmerhorst F.M., Stijnen T. et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst. Rev. 2014; 3;(3): CD010813CD010813.
  18. Heinemann L.A.J., Dinger J.C. Range of published estimates of venous thromboembolism incidence in young women. Contraception. 2007; 75(5): 328-36.
  19. Jensen J., Bitzer J., Serrani M. Comparison of the pharmacologic and clinical profiles of new combined oral contraceptives containing estradiol. Open Access J. Contraception. 2013; 2013(4): 39-50.
  20. Reed S.,, Koro C., DiBello J., Becker K., Bauerfeind A., Franke C., Heinemann K. Prospective controlled cohort study on the safety of a monophasic oral contraceptive containing nomegestrol acetate (2.5mg) and 17b-estradiol (1.5mg) (PRO-E2). Eur. J. Contracept. Reprod. Health Care. 2021; 26(6): 439-46.
  21. Creinin M.D., Westhoff C.L., Bouchard C., Chen M.J., Jensen J.T., Kaunitz A.M. et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021; 104(3): 222-8.
  22. Gemzell-Danielsson K., Apter D., Zatik J., Weyers S., Piltonen T., Suturina al. Estetrol-drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia. BJOG. 2022; 129(1): 63-71.
  23. Mawet M., Maillard C., Klipping C., Zimmerman Y., Foidart J.M., Coelingh Bennink H.J. Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur. J. Contracept. Reprod. Health Care. 2015; 20(6): 463-75.
  24. Kluft C., Zimmerman Y., Mawet M., Klipping C., Duijkers IJ.M., Neuteboom J. et al. Reduced haemostatic effects with drospirenone-based oral contraceptives containing estetrol versus ethinyl estradiol. Contraception. 2017; 95(2): 140-7.
  25. Douxfils J., Klipping C., Duijkers I., Kinet V., Mawet M., Maillard C. et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis. parameters. Contraception. 2020; 102(6): 396-402.
  26. Odlind V., Milsom I., Persson I., Victor A. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? Acta Obstet. Gynecol. Scand. 2002; 81(6): 482-90.
  27. Raps M., Helmerhorst F., Fleischer K., Thomassen S., Rosendaal F., Rosing J., Ballieux B.; VAN Vliet H. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J. Thromb. Haemost. 2012; 10(6): 992-7.
  28. European Medicines Agency. Guideline on clinical investigation of steroid contraceptives in women - EMEA/CPMP/EWP/519/98 Rev. vol. 1. London: EMEA ; 2005.
  29. Tchaikovski S.N., van Vliet H.A., Thomassen M.C., Bertina R.M., Rosendaal F.R., Sandset P.M. et al. Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography. Thromb. Haemost. 2007; 98(6): 1350-6.
  30. American College of Obstetricians and Gynecologists. Committee on Practice Bulletins–Obstetrics. ACOG Practice Bulletin No. 197: Inherited thrombophilias in pregnancy. Obstet. Gynecol. 2018; 132(1): e18-e34.
  31. Klipping C., Duijkers I., Mawet M., Maillard C., Bastidas A., Jost M., Foidart J.M. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception. 2021; 103(4): 213-21.
  32. Kurne A., Ertugrul A., Anil Yağcioğlu A.E., Yazici K.M. Venous thromboembolism and escitalopram. Gen. Hosp. Psychiatry. 2004; 26(6): 481-3.
  33. ВОЗ. Медицинские критерии приемлемости для использования методов контрацепции. 5-е изд. 2015. [Medical eligibility criteria for contraceptive methods. 2015, 5th edition. (in Russian)]. Available at:
  34. van Vlijmen E.F.W., Wiewel-Verschueren S., Monster T.B.M.., Meijer K. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta- analysis. J. Thromb. Haemost. 2016; 14(7):1393-403.
  35. Kujovich J.L. Factor V Leiden thrombophilia. Genet. Med. 2011; 13(1): 1-16.
  36. Mannucci P.M., Franchini M. Classic thrombophilic gene variants. Thromb. Haemost. 2015; 114(5): 885-9.
  37. Suchon P., Al Frouh F., Henneuse A., Ibrahim M., Brunet D., Barthet M.C. et al. Risk factors for venous thromboembolism in women under combined oral contraceptive. The PILl Genetic RIsk Monitoring (PILGRIM) Study. Thromb. Haemost. 2016; 115(1): 135-42.
  38. van Vlijmen E.F., Veeger N.J., Middeldorp S., Hamulyák K., Prins M.H., Kluin-Nelemans H.C., Meijer K. The impact of a male or female thrombotic family history on contraceptive counseling: a cohort study. J. Thromb. Haemost. 2016; 14(9): 1741-8.
  39. Bezemer I.D., v an der Meer F.J., Eikenboom J.C., Rosendaal F.R.,Doggen C.J. The value of family history as a risk indicator for venousthrombosis. Arch. Intern. Med. 2009; 169(6): 610-5.
  40. ASH Draft Recommendations for Thrombophilia Testin, 2021. Available at:
  41. Eichinger S. Homocysteine, vitamin B6 and the risk of recurrent venous thromboembolism. Pathophysiol . Haemost. Thromb .2003; 33(5-6): 342-4.
  42. Den Heijer M., Lewington S., Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J. Thromb. Haemost. 2005; 3(2): 292-9.
  43. Domagala T.B., Adamek L., Nizankowska E., Sanak M., Szczeklik A. Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease. Blood Coagul. Fibrinolysis. 2002; 13(5):423-31. 10.1097/00001721-200207000-00007.
  44. FSRH Guideline (January 2019) combined hormonal contraception (Revision due by January 2024). BMJ Sex. Reprod. Health. 2019; 45(Suppl. 1): 1-93.
  45. Gris J.C., Bourguignon C., Bouvier S., Nouvellon É., Laurent J., Perez-Martin A. et al. Combined oral contraceptive-associated venous thromboembolism revealing an antiphospholipid syndrome: International retrospective study of outcomes. Thromb. Res. 2022; 219: 102-8.
  46. US Medical Eligibility Criteria (US MEC) for contraceptive use. 2016. Available at:

Received 07.10.2022

Accepted 13.10.2022

About the Authors

Svetlana V. Akinshina, PhD, MD, obstetrician-gynecologist, hematologist, Assistant Professor of the Department of Obstetrics and Gynecology, Children’s Health Center,
I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia, +7(903)238-80-48,,, 119435, Russia, Moscow, B. Pirogovskaya str., 19-1.
Yulia A. Koloda, PhD., MD, obstetrician-gynecologist, Associate Professor of the Department of Obstetrics and Gynecology, Russian Medical Academy of Continuous Professional Education, Ministry of Health of Russia; medical director, Center for reproduction «LifeLine», Moscow, Russia, +7(903)105-31-89,,, 125993, Russia, Moscow, Barriсadnaya str., 2/1-1.
Corresponding author: Svetlana V. Akinshina,

Authors’ contributions: Akinshina S.V. – the topic material reviewing and processing, literature search and analysis, writing the text of the manuscript; Koloda Yu.A. – peer-reviewing, final article editing.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The paper has been written without sponsorship.
For citation: Akinshina S.V., Koloda Yu.A. The effect of a new contraceptive with estetrol on the thrombotic safety profile of hormonal contraception.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 10: 159-168 (in Russian)

Similar Articles

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