Successful pregnancy: simply about the complicated

Authors

DOI:

https://doi.org/10.18370/2309-4117.2025.76.34-38

Keywords:

pregnancy, miscarriage, threatened miscarriage, luteal phase insufficiency, in vitro fertilization, progesterone, dydrogesterone

Abstract

Progesterone is a key hormone essential for maintaining pregnancy. Its deficiency can lead to the risk of miscarriage, recurrent pregnancy loss, and unsuccessful attempts at in vitro fertilization. In clinical practice, progestogens are used for luteal phase support, particularly in women with corpus luteum insufficiency or in assisted reproductive technologies cycles.
After the synthetic progestogen 17-hydroxyprogesterone caproate was withdrawn from the pharmaceutical market due to low efficacy and multiple side effects, only two effective agents remain in obstetrics and reproductive medicine – progesterone and dydrogesterone.
Dydrogesterone is a synthetic analog of natural progesterone with high oral bioavailability, making it a convenient alternative to other forms of progestogens. It selectively binds to progesterone receptors, ensuring stable endometrial support and promoting early pregnancy maintenance. Unlike some other progestogens, dydrogesterone has no androgenic, estrogenic, or glucocorticoid effects, which contributes to its better tolerability.
The evidence base supporting dydrogesterone’s efficacy includes numerous randomized controlled trials, particularly LOTUS I and LOTUS II, which demonstrated that oral dydrogesterone is as effective as vaginal progesterone for luteal phase support at in vitro fertilization cycles. Additionally, multiple meta-analyses confirm that dydrogesterone use in the first trimester significantly reduces the risk of miscarriage, and over 70 studies have confirmed the high efficacy and safety of its molecule for both women and fetuses.
The safety of dydrogesterone is particularly important. The international expert group on the safety of progestogens in early pregnancy REASSURE concluded that there is currently no basis for making statements about a causal relationship between the use of dydrogesterone in the first trimester and the risk of congenital malformations.
Thus, due to its proven efficacy and excellent safety profile, supported by over 60 years of clinical use, dydrogesterone is the optimal choice for luteal phase support in both natural cycles and assisted reproductive technologies.

Author Biographies

T.F. Tatarchuk, SI «All-Ukrainian Centre for Motherhood and Childhood of the NAMS of Ukraine»; SSI “Center for Innovative Medical Technologies of the NAS of Ukraine», Kyiv

MD, professor, corresponding member of the NAMS of Ukraine, deputy director for research work, head of the Endocrine Gynecology Department;
chief researcher of the Department of Reproductive Health

V.I. Pyrogova, Danylo Halytsky Lviv National Medical University, Lviv

MD, head of the Department of Obstetrics, Gynecology and Perinatology, Faculty of Postgraduate Education

N.P. Goncharuk, Kyiv City Maternity Hospital No. 1, Kyiv

MD, professor, director

N.Y. Pedachenko, P.L. Shupyk National Institute of Health Care of Ukraine, Kyiv

MD, professor, head of the Department of Obstetrics, Gynecology and Perinatology

D.G. Konkov, P.L. Shupyk National Institute of Health Care of Ukraine; Public organization «Association of Obstetricians and Gynecologists of Ukraine», Kyiv

MD, professor, director of the Scientific and Educational Institute of Innovative Medical and Educational Technologies;
executive director

References

  1. Anderson L, Martin W, Higgins C, et al. The effect of progesterone on myometrial contractility, potassium channels, and tocolytic efficacy. Reprod. Sci. 2009; 16: 1052–1061. DOI: 10.1177/1933719109340926
  2. Norman E. Progesterone and preterm birth Jane. Int J Gynaecol Obstet. 2020 Jul; 150(1):24–30. DOI: 10.1002/ijgo.13187.
  3. Coomarasamy A, Devall AJ, Brosens JJ, et al. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol. 2020 Aug; 223(2):167–176. DOI: 10.1016/j.ajog.2019.12.006.
  4. Labarta E, Rodríguez C. Progesterone use in assisted reproductive technology. Best Pract Res Clin. Obstet. Gynaecol. 2020 Nov:69:74–84. DOI: 10.1016/j.bpobgyn.2020.05.005.
  5. Norman JE, Marlow N, Messow CM, et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet. 2016;387(10033):2106–2116. DOI: 10.1016/S0140-6736(16)00350-0.
  6. Piette PCM. The pharmacodynamics and safety of progesterone. Best Pract Res Clin Obstet Gynaecol. 2020 Nov:69:13-29. DOI: 10.1016/j.bpobgyn.2020.06.002.
  7. Casarramona G, Lalmahomed T, Lemmen Chc, et al. The efficacy and safety of luteal phase support with progesterone following ovarian stimulation and intrauterine insemination: а systematic review and meta-analysis. Front Endocrinol (Lausanne). 2022 Sep 2:13:960393. DOI: 10.3389/fendo.2022.960393.
  8. Blackwell C, Gyamfi-Bannerman C, Biggio JR. 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial Sean. Am J Perinatol. 2020 Jan; 37(2):127–136. DOI: 10.1055/s-0039-3400227.
  9. Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas. 2003 Dec 10:46 Suppl 1:S7–S16. DOI: 10.1016/j.maturitas.2003.09.014.
  10. Hydroxyprogesterone-containing medicinal products Article 31-referral – Public assessment report [Internet]. European Medicines Agency (EMA). 2024 Jul 5. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/hydroxyprogesterone-caproate-containing-medicinal-products
  11. 17-Hydroxyprogesterone Caproate (17-OHPC): Cancellation of Product Registration and Product Recall. [Internet]. 14 October 2024. Available from: https://www.npra.gov.my/index.php/en/health-professionals/recent-updates/454-english/safety-alerts-main/safety-alerts-2024/1527659-updated-17-hydroxyprogesterone-caproate-17-ohpc-cancellation-of-product-registration-and-product-recall.html#:~:text=17%2DOHPC%20products%20 have%20been,congenital%20heart%20defects%20in%20 offspring.
  12. Griesinger G, Tournaye H, Macklon N, et al. Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction Reprod Biomed Online. 2019 Feb;38(2):249–259. DOI: 10.1016/j.rbmo.2018.11.017.
  13. Rižner TL, Brožič P, Doucette C, et al. Selectivity and potency of the retroprogesterone dydrogesterone in vitro. Steroids. 2011; 76: 607–615. DOI: 10.1016/j.steroids.2011.02.043.
  14. Schindler AE. Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium. Maturitas. 2009 Dec: 65 Suppl 1:S3–11. DOI: 10.1016/j.maturitas.2009.10.011.
  15. Tournaye H, Sukhikh GT, Kahler E, et al. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesteroneversus micronized vaginal progesterone for luteal support inin vitro fertilization. Hum. Reprod. 2017 May 1;32(5):1019–1027. DOI: 10.1093/humrep/dex023.
  16. Dailey J, Rosman L, Silbergeld EK. Evaluating biological plausibility in supporting evidence for action through systematic reviews in public health. Public Health. 2018 Dec:165:48–57. DOI: 10.1016/j.puhe.2018.08.015.
  17. Brent RL. Nongenital malformations following exposure to progestational drugs: the last chapter of an erroneous allegation. Birth Defects Res A Clin Mol Teratol. 2005 Nov;73(11):906–18. DOI: 10.1002/bdra.20184.
  18. Koren G, Bare Y, Kaplan YC. Fetal safety of medications used in treating infertility. Expert Rev Clin Pharmacol. 2020 Sep;13(9):991–1000. DOI: 10.1080/17512433.2020.1803738.
  19. Zaqout M, Aslem E, Abuqamar M, et al. The Impact of Oral Intake of Dydrogesterone on Fetal Heart Development During Early Pregnancy. Pediatr Cardiol. 2015 Oct;36(7):1483–8. DOI: 10.1007/s00246-015-1190-9. Epub 2015 May 15.
  20. Henry A, Santulli P, Bourdon M, et al. Birth defects reporting and the use of dydrogesterone: a disproportionality analysis from the World Health Organization pharmacovigilance database (VigiBase). Hum Reprod Open. 2025 Jan 2;2025(1):hoae072. DOI: 10.1093/hropen/hoae072.
  21. Li L, Wang K, Wang M, et al. The maternal drug exposure birth cohort (DEBC) in China. Nat Commun. 2024 Jun 21;15(1):5312. DOI: 10.1038/s41467-024-49623-0.
  22. van der Vet PE, Nijveen H. Propagation of errors in citation networks: a study involving the entire citation network of a widely cited paper published in, and later retracted from, the journal Nature. Res Integr Peer Rev. 2016 May 3:1:3. DOI: 10.1186/s41073-016-0008-5.
  23. McKiever M, Frey H, Costantine MM. Challenges in Conducting Clinical Research Studies in Pregnant Women. J Pharmacokinet Pharmacodyn. 2020 Apr 18;47(4):287–293. DOI: 10.1007/s10928-020-09687-z
  24. Sheffield JS, Siegel D, Mirochnick M, et al. Designing Drug Trials: Considerations for Pregnant Women. Clin Infect Dis. 2014 Dec 15;59 (Suppl 7):S437–S444. DOI: 10.1093/cid/ciu709.
  25. FDA Public Meeting: Study Approaches and Methods to Evaluate the Safety of Drugs and Biological Products during Pregnancy in the Post-Approval Setting. [Internet]. FDA. 2014. Available from: https://www.fda. gov/media/88387/download?utm_source=chatgpt.com
  26. The Retraction Watch Database. Version: 1.0.8.0 [Internet] 2025 [cited 2025 Mar 2]. Available from: http://retractiondatabase.org/RetractionSearch.aspx#?auth%3dKoren
  27. Henry A, Santulli P, Bourdon M, et al. Birth defects reporting and the use of dydrogesterone: a disproportionality analysis from the World Health Organization pharmacovigilance database (VigiBase). Hum Reprod Open. 2025 Jan 2;2025(1):hoae072. DOI: 10.1093/hropen/hoae072.
  28. Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod. 2017 May 1;32(5):1019–1027. DOI: 10.1093/humrep/dex023.
  29. Griesinger G, Blockeel C, Sukhikh GT, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial. Hum Reprod. 2018 Dec 1;33(12):2212–21. DOI: 10.1093/humrep/dey306.
  30. Ott J, Egarter C, Aguilera A. Dydrogesterone after 60 years: a glance at the safety profile. Gynecol. Endocrinol. 2022 Apr;38(4):279–287. DOI: 10.1080/09513590.2021.2016692.
  31. Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ. 2010 Feb 5:340:c221. DOI: 10.1136/bmj.c221.
  32. Griesinger G, Blockeel C, Kahler E, et al. Dydrogesterone as an oral alternative to vaginal progesterone for IVF luteal phase support: A systematic review and individual participant data meta-analysis. PLoS One. 2020;15(11):e241044. DOI:10.1371/journal.pone.0241044.
  33. Katalinic A, Shulman LP, Strauss JF. A critical appraisal of safety data on dydrogesterone for the support of early pregnancy: a scoping review and meta-analysis. Reprod Biomed Online. 2022 Aug;45(2):365–373. DOI: 10.1016/j.rbmo.2022.03.032.
  34. Katalinic A, Noftz MR, Garcia-Velasco JA, et al. No additional risk of congenital anomalies after first-trimester dydrogesterone use: a systematic review and meta-analysis. Human Reproduction Open, Volume 2024, Issue 1, 2024/DOI: 10.1093/hropen/hoae004.
  35. Yang W, Chi H, Yang R, et al. Congenital anomalies after first-trimester dydrogesterone therapy during in vitro fertilization. Fertility and Sterility. October 2023. 120(4):e72. DOI:10.1016/j.fertnstert.2023.08.222.
  36. Instructions for medical use of the drug Duphaston®. [Internet]. Regulatory and directive documents of the Ministry of Health of Ukraine. [cited 2025 Mar 2]. Available from: https://mozdocs.kiev.ua/likiview.php?id=15524

Downloads

Published

2025-03-31

How to Cite

Tatarchuk, T., Pyrogova, V., Goncharuk, N., Pedachenko, N., & Konkov, D. (2025). Successful pregnancy: simply about the complicated. REPRODUCTIVE ENDOCRINOLOGY, (76), 34–38. https://doi.org/10.18370/2309-4117.2025.76.34-38

Issue

No. 76 (2025)

Section

Pregnancy and childbirth

License

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors who publish with this journal agree to the following terms:

    1. Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.

    1. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.