Progestagens in high-risk pregnancy. What we know today

Literature review

Authors

DOI:

https://doi.org/10.18370/2309-4117.2023.68.22-28

Keywords:

miscarriages, progestogens, progesterone, dydrogesterone

Abstract

Miscarriage remains an important global problem: 23 million miscarriages are registered annually in the world, i.e. 44 pregnancy losses every minute, and the total risk of miscarriage is 15.3% of all pregnancies. Effective methods of pregnancy preservation (in case of idiopathic miscarriage and threatened miscarriage) include lifestyle modification and progestagen therapy. Progesterone is the main hormone necessary to maintain pregnancy.
The effectiveness of progestogens among medical methods that increase the chances of pregnancy preservation has been proven by numerous studies. Effectiveness and safety of various types of progestogens during pregnancy have been studied. As a result, progesterone and dydrogesterone became the only progestogens approved for use in obstetrics – micronized progesterone and dydrogesterone reduce the frequency of miscarriage in women with clinical diagnoses of threatened miscarriage and idiopathic recurrent miscarriage. In addition, the progestogens safety has been carefully studied in modern randomized studies, prospective trials and meta-analyses and the same safety profile of dydrogesterone and micronized progesterone for pregnant women and the fetus has been proven.
Studies have shown that oral dydrogesterone has relatively low antagonistic activity at glucocorticoid and mineralocorticoid receptors compared to progesterone and therefore well tolerated. Oral dydrogesterone due to the peculiarities of structure has improved bioavailability compared to progesterone, which allows a woman to avoid the inconvenience and discomfort associated with the intravaginal or intramuscular use of progesterone. In addition, dydrogesterone has a 1.5 times higher affinity for progesterone receptors compared to micronized progesterone and a pronounced anti-inflammatory and immunomodulation effect, which provides certain clinical advantages for patients after recurrent pregnancy losses.
Thus, progestogens are indicated for all patients with recurrent pregnancy losses from the moment of receiving a positive pregnancy test, as they reduce the risk of miscarriage. It is important that the use of progestagen drugs during the first and second trimester of pregnancy is not associated with side effects

Author Biographies

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

MD, professor, Department of Obstetrics, Gynecology and Perinatology

N.P. Goncharuk, P.L. Shupyk National Healthcare University of Ukraine, Kyiv City Maternity Hospital No. 1, Kyiv

MD, professor, Obstetrics, Gynecology and Perinatology Department;
Director

E.F. Chaikivska, Danylo Halytsky Lviv National Medical University, Lviv

PhD, associate professor, Obstetrics, Gynaecology and Perinatology Department, FPE;
Chief freelance specialist in Pediatric and Adolescent Gynecology Department in the Lviv region

T.F. Tatarchuk, SI “O.M. Lukyanova Institute of Pediatrics, Obstetrics and Gynecology 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;
Cchief researcher, Department of Reproductive Health

T.M. Tutchenko, SI “O.M. Lukyanova Institute of Pediatrics, Obstetrics and Gynecology of the NAMS of Ukraine”; SSI “Center for Innovative Medical Technologies of the NAS of Ukraine»; “DILA” Medical Laboratory, Kyiv

PhD, senior researcher, Endocrine Gynecology Department;
Department of Reproductive Health; 
Scientific consultant

References

  1. World Health Organization. Definitions and indicators in family planning and maternal and child health and reproductive health (2021). Available from: [https://apps.who.int/iris/bitstream/handle/10665/108284/E68459.pdf?seq], last accessed 09.02.2023.
  2. Quenby, S., Gallos, I.D., Dhillon-Smith, R.K., et al. “Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss.” Lancet 397.10285 (2021): 1658–67. DOI: 10.1016/S0140-6736(21)00682-6
  3. Cumming, G.P., Klein, S., Bolsover, D., et al. “The emotional burden of miscarriage for women and their partners: trajectories of anxiety and depression over 13 month.” BJOG 114.9 (2007): 1138–45. DOI: 10.1111/j.1471-0528.2007.01452.x
  4. Engelhard, I.M., van den Hout, M.A., Arntz, A. “Posttraumatic stress disorder after pregnancy loss.” Gen Hosp Psychiatry 23.2 (2001): 62–6. DOI: 10.1016/s0163-8343(01)00124-4
  5. National Institute for Health and Care Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management. NICE guideline [NG126]. Published: 17 April 2019. Last updated: 24 November (2021). PMID: 31393678. Bookshelf ID: NBK544906.
  6. ESHRE Guideline Group on RPL; Bender Atik, R., Christiansen, O.B., Elson, J., et al. “ESHRE guideline: recurrent pregnancy loss.” Hum Reprod Open 2018.2 (2018): hoy004.
  7. Toth, B., Würfel, W., Bohlmann, M., et al. “Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050).” Geburtshilfe Frauenheilkd 78.4 (2018): 364–81. DOI: 10.1055/a-0586-4568
  8. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Gynecology. “ACOG Practice Bulletin No. 200: Early Pregnancy Loss.” Obstet Gynecol 132.5 (2018): e197-e207. DOI: 10.1097/AOG.0000000000002899
  9. Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Progesterone support of the luteal phase and in the first trimester. Developed in November 2009, revised in March 2018. Available from: [https://ranzcog.edu.au/wp-content/uploads/2022/05/Progesterone-Support-of-the-Luteal-Phase-and-in-the-First-Trimester.pdf].
  10. Schindler, A.E., Campagnoli, C., Druckmann, R. “Classification and pharmacology of progestins.” Maturitas 61.1–2 (2008): 171–80. DOI: 10.1016/j.maturitas.2003.09.014
  11. Griesinger, G., Tournaye, H., Macklon, N. “Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction.” Reprod Biomed Online 38.2 (2019): 249–59. DOI: 10.1016/j.rbmo.2018.11.017
  12. Colombo, D., Ferraboschi, P., Prestileo, P., Toma, L. “A comparative molecular modeling study of dydrogesterone with other progestational agents through theoretical calculations and nuclear magnetic resonance spectroscopy.” J Steroid Biochem Mol Biol 98 (2006): 56–62. DOI: 10.1016/j.jsbmb.2005.07.009
  13. Jasem, Y., Khan, M., Taha, A., Thiemann, T. “Preparation of steroidal hormones with an emphasis on transformations of phytosterols and cholesterol – a review.” Med J Chem 3 (2014): 796–830.
  14. Stanczyk, F.Z., Hapgood, J.P., Winer, S., Mishell Jr., D.R. “Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.” Endocr Rev 34 (2013): 171–208. DOI: 10.1210/er.2012-1008
  15. Rižner, T.L., Brožič, P., Doucette, C., et al. “Selectivity and potency of the retroprogesterone dydrogesterone in vitro.” Steroids 76 (2011): 607–15. DOI: 10.1016/j.steroids.2011.02.043
  16. Schindler, A.E., Campagnoli, C., Druckmann, R., et al. “Classification and pharmacology of progestins.” Maturitas 46 (2003): S7–s16. DOI: 10.1016/j.maturitas.2003.09.014
  17. Daughton, C.G., Ruhoy, I.S. “Lower-dose prescribing: minimizing “side effects” of pharmaceuticals on society and the environment.” Sci Total Environ 443 (2013): 324–37. DOI: 10.1016/j.scitotenv.2012.10.092
  18. Paulson, R.J., Collins, M.G., Yankov, V.I. “Progesterone pharmacokinetics and pharmacodynamics with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert.” J Clin Endocrinol Metab 99 (2014): 4241–9. DOI: 10.1210/jc.2013-3937
  19. Doblinger, J., Cometti, B., Trevisan, S., Griesinger, G. “Subcutaneous progesterone is effective and safe for luteal phase support in IVF: an individual patient data meta-analysis of the Phase III trials.” PLoS One 11.3 (2016): e0151388. DOI: 10.1371/journal.pone.0151388
  20. Vermorken, A.J., Sultan, C., Goos, C.M. “Dydrogesterone has no peripheral (anti)-androgenic properties.” In Vivo 1 (1987): 167–71.
  21. World Health Organization. Definitions and indicators in family planning and maternal and child health and reproductive health. Revised March 1999 & January 2001. Available from: [https://apps.who.int/iris/bitstream/handle/10665/108284/E68459.pdf?seq].
  22. Carp, H.J.A. “Progestogens and pregnancy loss.” Climacteric 21.4 (2018): 380–4. DOI: 10.1080/13697137.2018.1436166
  23. Lee, H.J., Park, T.C., Kim, J.H. “The Influence of Oral Dydrogesterone and Vaginal Progesterone on Threatened Abortion: A Systematic Review and Meta- Analysis.” Biomed Res Int 2017 (2017): 3616875. DOI: 10.1155/2017/3616875
  24. Wahabi, H.A., Fayed, A.A., Esmaeil, S.A., Bahkali, K.H. “Progestogen for treating threatened miscarriage (Review).” Cochrane Database Syst Rev 8.8 (2018): Cd005943.
  25. Wang, X.-X., Luo, Q., Bai, W.-P. “Efficacy of progesterone on threatened miscarriage: Difference in drug types.” J Obstet Gynaecol Res 45.4 (2019): 794–802. DOI: 10.1111/jog.13909
  26. Li, L., Zhang, Y., Tan, H. “Effect of progestogen for women with threatened miscarriage: a systematic review and meta-analysis.” BJOG 127.9 (2020): 1055–63. DOI: 10.1111/1471-0528.16261
  27. Zhao, H., He, W., Yang., Z. “A pairwise and network meta-analysis comparing the efficacy and safety of progestogens in threatened abortion.” Int J Gynaecol Obstet 156.3 (2022): 383–93. DOI: 10.1002/ijgo.13707
  28. Pandian, R.U. “Dydrogesterone in threatened miscarriage: a Malaysian experience.” Maturitas 65.1 (2009): S47–50. DOI: 10.1016/j.maturitas.2009.11.016
  29. Kale, A.R., Kale, A.A., Yelikar, K. “A Comparative, Randomized Control Trial in Patients of Per Vaginal Bleeding Comparing Efficacy of Oral Dydrogesterone Versus Vaginal Progesterone in Successful Pregnancy Outcome for Patients with Recurrent Pregnancy Loss.” J Obstet Gynaecol India 71.6 (2021): 591–5. DOI: 10.1007/s13224-021-01473-2
  30. Dimitriadis, E., Menkhorst, E., Saito, S. “Recurrent pregnancy loss.” Nat Rev Dis Primers 6.1 (2020): 98. DOI: 10.1038/s41572-020-00228-z
  31. Arias-Sosa, L.A., Acosta, I.D., Lucena-Quevedo, E., et al. “Genetic and epigenetic variations associated with idiopathic recurrent pregnancy loss.” J Assist Reprod Genet 35.3 (2018): 355–66. DOI: 10.1007/s10815-017-1108-y
  32. Jauniaux, E., Farquharson, R.G., Christiansen, O.B., Exalto, N. “Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage.” Hum Reprod 21.9 (2006): 2216–22. DOI: 10.1093/humrep/del150
  33. Tien, J.C., Tan, T.Y.T. “Non-surgical interventions for threatened and recurrent miscarriages.” Singapore Med J 48.12 (2007): 1074–90; quiz 1090.
  34. Haas, D.M., Hathaway, T.J., Ramsey, P.S. “Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology.” Cochrane Database Syst Rev 10.10 (2018): CD003511. DOI: 10.1002/14651858.CD003511.pub4
  35. Saccone, G., Schoen, C., Franasiak, J.M., et al. “Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials.” Fertil Steril 107.2 (2017): 430–8. e3. DOI: 10.1016/j.fertnstert.2016.10.031
  36. Carp, H.“A systematic review of dydrogesterone for the treatment of recurrent miscarriage.” Gynecol Endocrinol 31.6 (2015): 422–30. DOI: 10.3109/09513590.2015.1006618
  37. Kumar, A., Begum, N., Prasad, S., et al. “Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized, parallel, placebo-controlled trial.” Fertil Steril 102.5 (2014): 1357–63.e3. DOI: 10.1016/j.fertnstert.2014.07.1251
  38. Bashiri, A., Galperin, G., Zeadna, A., et al. “Increased Live Birth Rate with Dydrogesterone among Patients with Recurrent Pregnancy Loss Regardless of Other Treatments.” J Clin Med 12 (2023): 1967. DOI: 10.3390/jcm12051967
  39. Schindler, A.E., Carp, H., Druckmann, R., et al. “European Progestin Club Guidelines for prevention and treatment of threatened or recurrent (habitual) miscarriage with progestogens.” Gynecol Endocrinol 31.6 (2015): 447–9. DOI: 10.3109/09513590.2015.1017459
  40. Haas, D.M., Hathaway, T.J., Ramsey, P.S. “Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology.” Cochrane Database Syst Rev 11 (2019): CD003511.
  41. Tournaye, H., Sukhikh, G.T., 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 32.5 (2017): 1019–27. DOI: 10.1093/humrep/dex023
  42. Griesinger, G., Blockeel, C., Sukhikh, G.T., et al. “Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial.” Hum Reprod 33.12 (2018): 2212–21. DOI: 10.1093/humrep/dey306
  43. 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 15.11 (2020): e0241044. DOI: 10.1371/journal.pone.0241044
  44. Schindler, A.E. “Present and future aspects of dydrogesterone in prevention or treatment of pregnancy disorders: An outlook.” Horm Mol Biol Clin Investig 27 (2016): 49–53.
  45. Raghupathy, R., Szekeres-Bartho, J. “Progesterone: A Unique Hormone with Immunomodulatory Roles in Pregnancy.” Int J Mol Sci 23.3 (2022): 1333. DOI: 10.3390/ijms23031333
  46. American College of Obstetricians and Gynecologists. Billing for Interruption of Pregnancy: Early Pregnancy Loss. Available from: [https://www.acog.org/practice-management/coding/coding-library/billing-for-interruption-of-early-pregnancy-loss].
  47. Huchon, C., Deffieux, X., Beucher, G., et al. “Pregnancy loss: French clinical practice guidelines.” Eur J Obstet Gynecol Reprod Biol 201 (2016): 18–26. DOI: 10.1016/j.ejogrb.2016.02.015
  48. Pirtea, P., Cicinelli, E., De Nola, R., et al. “Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis.” Fertil Steril 115.3 (2021): 546–60.
  49. Sundermann, A.C., Hartmann, K.E., Jones, S.H., et al. “Interpregnancy interval after pregnancy loss and risk of repeat miscarriage.” Obstet Gynecol 130.6 (2017): 1312–8.
  50. Schliep, K.C., Mitchell, E.M., Mumford, S.L., et al. “Trying to conceive after an early pregnancy loss: an assessment on how long couples should wait.” Obstet Gynecol 127.2 (2016): 204–12.
  51. Raghupathy, R., Al-Azemi, M. “Modulation of cytokine production by the dydrogesterone metabolite dihydrodydrogesterone.” Am J Reprod Immunol 74.5 (2015): 419–26.
  52. Ott, J., Egarter, C., Aguilera, A. “Dydrogesterone after 60 years: a glance at the safety profile.” Gynecol Endocrinol 38.4 (2022): 279–87. DOI: 10.1080/09513590.2021.2016692
  53. Katalinic, A., Shulman, L.P., Strauss, J.F., et al. “A critical appraisal of safety data of dydrogesterone for the support of early pregnancy: a scoping review and meta- analysis.” Reprod BioMed Online (2022). DOI: 10.1016/j.rbmo.2022.03.032

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Published

2023-06-30

How to Cite

Pedachenko, N., Goncharuk, N., Chaikivska, E., Tatarchuk, T., & Tutchenko, T. (2023). Progestagens in high-risk pregnancy. What we know today: Literature review. REPRODUCTIVE ENDOCRINOLOGY, (68), 22–28. https://doi.org/10.18370/2309-4117.2023.68.22-28

Issue

No. 68 (2023)

Section

Endocrinology

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Copyright (c) 2023 Н.Ю. Педаченко, Н.П. Гончарук, Е.Ф. Чайківська, Т.Ф. Татарчук, Т.М. Тутченко

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