Reviewing efficacy of progestagenes in recurrent early reproductive losses




progestagenes, micronized progesterone, dydrogesterone, miscarriage, early reproductive losses


Recurrent miscarriages, defined as 2 or more spontaneous miscarriages in a row, are observed in 2% of all pregnancies. In the structure of all pregnancy losses, the recurrent miscarriage composes 5% to 20%. In addition, in clinical practice, there are large contradictions related to the domination of some factors and causes of reproductive losses. Although the lutein phase insufficiency (LPI) is not a confirmed reason of reproductive losses, there is a significant number of publications and scientific presentations which are focused on the use of progesterone for the reproductive losses treatment.

This article presents the author’s critical view on recent studies dedicated to the use of progestagenes therapy with the objective of the prevention of early reproductive losses.

Methodology, design and results of several studies of the efficacy of micronized progesterone and dydrogesterone have been analyzed. Generalized conclusions and critically important points of these studies have been defined.

Among other things, special attention was dedicated to the results of the double blind, randomized, parallel-groups, placebo-controlled study by Kumar (2014), and the multicenter,  randomized, placebo-controlled study PROMISE (2015). For example, in the author’s opinion, the comparison of the efficacy of dydrogesterone and micronized progesterone on the base of these studies can not be correct. As outlined in this article, progestagenes should be administered after the confirmation of the embryo viability. They should be used during the earlier stages of the pregnancy only in cases of clinically confirmed lutein phase insufficiency, as well as in patients participating in cycles and programs of assisted reproductive technologies.

The issue of the correct dosing of progestagenes used in the therapy of reproductive losses is also not highlighted enough. This issue requires additional investigation, as the efficacy of the treatment will depend not only on the fact of progestagenes administration, but also on the optimal doses for each individual patient.

The author expects that the accurate picture of progestagenes use for the treatment of miscarriages during the early stages of pregnancy will be reflected by the results of a randomized,  double blind, placebo-controlled study (PRISM) which are expected in 2018.

Author Biography

N. P. Veropotvelyan, Multiregional Center of Medical Genetics and Prenatal Diagnostics

PhD, Chief Physician 


  1. Sosnina, K.O. Immunogenetic prerequisites of early reproductive losses in human. Thesis abstract for PhD degree. Kyiv (2014).
  2. Early stages of pregnancy. Ed. by V.E. Radzinskyi, A.A. Orazmuradova. Moscow (2005): 448 p.
  3. Dobrokhotova, Y.E., Jobava, E.M., Ozerova, R.I. Non-developing pregnancy. Moscow. GEOTAR-Media (2010):144 p.
  4. Bessho, T., Sakamoto, H., Shiotani, T., et al. “Fetal loss in the first trimester after demonstration of cardiac activity: relation of cytogenetic and ultrasound findings.” Hum Reprod 10.10 (1995): 2696–9.
  5. Eiben, B., Bartels, I., Bahr-Porsch, S., et al. “Cytogenetic analysis of 750 spontaneous abortions with the direct-preparation method of chorionic villi and its implications for studying genetic causes of pregnancy wastage.” Am J Hum Genet 47.4 (1990): 656–63.
  6. Guerneri, S., Bettio, D., Simoni, G., et al. “Prevalence and distribution of chromosome abnormalities in a sample of first trimester internal abortions.” Hum Reprod 2.8 (1987): 735–9.
  7. Hogge, W.A., Byrnes, A.L., Lanasa, M.C., Surti, U. “The clinical use of karyotyping spontaneous abortions.” Am J Obstet Gynecol 189.2 (2003): 397–400. DOI: 10.1067/S0002-9378(03)00700-2
  8. Lathi, R.B., Milki, A.A. “Tissue sampling technique affects accuracy of karyotype from missed abortions.” J Assist Reprod Genet 19.11 (2002): 536–8. DOI: 10.1023/A:1020916003666
  9. Minelli, E., Buchi, C., Granata, P., et al. “Cytogenetic findings in echographically defined blighted ovum abortions.” Ann Genet 36.2 (1993): 107–10.
  10. Strom, C.M., Ginsberg, N., Applebaum, M., et al. “Analyses of 95 first-trimester spontaneous abortions by chorionic villus sampling and karyotype.” J Assist Reprod Genet 9.5 (1992): 458–61. DOI: 10.1007/BF01204052
  11. Spandorfer, S.D., Davis, O.K., Barmat, L.I., et al. “Relationship between maternal age and aneuploidy in in vitro fertilization pregnancy loss.” Fertil Steril 81.5 (2004): 1265–9. DOI: 10.1016/j.fertnstert.2003.09.057
  12. Schmidt-Sarosi, C., Schwartz, L.B., Lublin, J., et al. “Chromosomal analysis of early fetal losses in relation to transvaginal ultrasonographic detection of fetal heart motion after infertility.” Fertil Steril 69.2 (1998): 274–7. DOI: 10.1016/S0015-0282(97)00497-4
  13. Veropotvelyan, M.P., Kodunov, L.O., Veropotvelyan, P.M., et al. “Determining the primary population frequency of chromosomal aberrations and early embryonic mortality in Ukraine.” Women’s Health 9 (2012): 108–114.
  14. Veropotvelyan, N.P., Kodunov, L.A., Poguliai, Y.S. “Genetic causes of early reproductive losses. An analysis of more than 1,800 observations.” Reproductive medicine 2–3.27–28 (2016): 61–7.
  15. Chromosome abnormalities and genetic counseling. Fourth edition. Oxford monographs on medical genetics. Ed. by R.J. McKinlay Gardner (2011).
  16. Harvey, H.J. “Stern preimplantation genetic diagnosis: prenatal testing for embryos finally achilving its potential.” J Clin Med 3.1 (2014): 280–309.
  17. Wells, D., Delhaty, J.D. “Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization.” Mol Hum Reprod 6.11 (2000): 1055–62.
  18. Vollaire, L., et al. “Chromosome analysis of blastomeres from human embryos by using comparative genomic hybridization.” Hum Genet 106.2 (2000): 210–7.
  19. Achkasov, E.E., Miskarian, I.A. Medicine in aphorisms and popular expressions from the beginnings to the present day. Moscow. Profile 2C (2009): 448 p.
  20. Stanczyk, F.Z. “Pharmacocinetics and potency of Progestins used in Hormone Replacement Therapy and contraception.” Review in Endocrine & Medical disorders 3 (2002): 211–24.
  21. Giordano, G. Value of immuhistochemistry in uterine pathology: common and rare diagnostic dilemamas.” Pathol Res Pract 205.10 (2009): 663–76.
  22. Radzinskyi, V.E., Ordiyants, I.M., Pobedinskaya, O.S., Alieva, E.A. “The threat of spontaneous abortion: old kontraversions – new opportunities.” Reproductive Health. Eastern Europe 5.35 (2014): 164–73.
  23. American Society for Reproductive Medicine. “Current clinical irrelevance of luteal phase deficiency: a committee opinion, Practice Committee of the American Society for Reproductive Medicine.” Fertil Steril 103 (2015): 27–32.
  24. Berghella, V. Early pregnancy loss: Obstetric evidence based guidelines. 2nd edition. New York. CRC (2012): 142–9.
  25. Van der Linden, M., Buckingham, K., Farquhar, C., et al. “Luteal phase support for assisted reproduction cycles.” Cochrane Database Syst Rev 10 (2011): CD009154. DOI:10.1002/14651858.CD009154.pub2
  26. Schindler, A.E., et al. “European Progestin Club Guidelines for prevention and treatment of threatened or recurrent (habitual) miscarriage with progestogens.” Gynecol Endocrinol 31 (2015): 447–9.
  27. Wahabi, H.A., Abed Althagay, N.F., Elawad, M. “Progestogen for treating threatened miscarriage (Review).” Cochrane Database Syst Rev 12 (2011): CD005943. DOI: 10.1002/14651858.CD005943.pub4
  28. Coomarasamy, A., et al. “A Randomized Trial of Progesterone in Women with Recurrent Miscarriages.” N Engl J Med 373 (2015): 2141–8. DOI: 10.1056/NEJMoa1504927
  29. 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. DOI:10.1016/j.fertnstert.2014.07.1251
  30. Haas, D.M., Ramsey, P.S. “Progestogens for preventing miscarriage.” Cohrane Database Syst Rev 10 (2013): CD003511.
  31. Carpentier, P.A., Stanford, J.B., Boyle, P.C. “Progesterone in women with recurrent miscarriages.” N Engl J Med 374 (2016): 894. DOI: 10.1056/NEJMc1600491
  32. Zaqout, M., Aslem, E., Abuqamar, M., et al. “The Impact of Oral Intake of Dydrogesterone on Fetal Heart Development During Early Pregnancy.” Pediatr Cardiol 36.7 (2015): 1483–8. DOI: 10.1007/s00246-015-1190-9
  33. McNamara, H.C., Wood, R., Chalmers, J., et al. “STOPPIT Baby Follow-up Study: the effect of prophylactic progesterone in twin pregnancy on childhood outcome.” One 10.4 (2015): e0122341. DOI: 10.1371/journal.pone.0122341
  34. Barbosa, M.W., Silva, L.R., Navarro, P.A., et al. “Dydrogesterone vs progesterone for luteal-phase support: systematic review and meta-analysis of randomized controlled trials.” Ultrasound Obstet Gynecol 48.2 (2016): 161–70. DOI: 10.1002/uog.15814
  35. Chakravarty, B.N., Shirazee, H.H., Dam, P., et al. “Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.” J Steroid Biochem Mol Biol 97 (2005): 416–420.
  36. Saharkhiz, N., Zamaniyan, M., Salehpour, S., et al. “A comparative study of dydrogesterone and micronized progesterone for luteal phase support during in vitro fertilization (IVF) cycles.” Gynecol Endocrinol 32 (2016): 213–7.
  37. Salehpour, S., Tamimi, M., Saharkhiz, N. “Comparison of oral dydrogesterone with suppository vaginal progesterone for luteal-phase support in in vitro fertilization (IVF): A randomized clinical trial.” Iran J Reprod Med 11 (2013): 913–8.
  38. Chakravarty, B.N., Dam, P., Goswami, S.K., et al. “Oral dydrogesterone versus vaginal micronised progesterone as luteal phase support in ART cycles – evaluation based on correction of hormone profile and clinical outcome.” Hum Reprod 20 (2005): i139.
  39. Chakravarty, B.N., Sharma, S., Ghosh, S., et al. “Oral dydrogesterone vs. vaginal micronized progesterone as luteal support in art cycles: evaluation based on hormone profile and clinical outcome.” Hum Reprod 21 (2006): I83.
  40. Patki, A., Pawar, V.C. “Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone.” Gynecol Endocrinol 23 Suppl 1 (2007): 68–72.
  41. Tomic, V., Tomic, J., Klaic, D.Z., et al. “Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial.” Eur J Obstet Gynecol Reprod Biol 186 (2015): 49–53.
  42. Ganesh, A., Chakravorty, N., Mukherjee, R., et al. “Comparison of oral dydrogestrone with progesterone gel and micronized progesterone for luteal support in 1,373 women undergoing in vitro fertilization: a randomized clinical study.” Fertil Steril 95 (2011): 1961–5.
  43. Veropotvelyan, M.P., Kodunov, L.O. “Features of the ratio of chromosomal abnormalities and terms of persistence gestational sac of non-developing pregnancies in non-embrionyc and embrionyc cases (analysis of 1328 cases).” Women’s Health 5 (2015): 74–80.
  44. Makino, T., Iwasaki, K., Sugi, T., et al. “Statistical analysis of possible causes of repeated spontaneous abortions.” Nihon Sanka Fujinka Gakkai Zasshi 43.12 (1991): 1642–6. Article in Japanese.
  45. Sheldon, T. “Rising age of starting family in Netherlands reflects fall in younger not rise in older mothers.” BMJ 19.337 (7662) (2008): 134. DOI: 10.1136/bmj.a773
  46. Veropotvelian, N.P., Kodunov, L.A. “Association of maternal age with early reproductive losses of chromosomal etiology.” Women’s Health 2 (2015): 44–8.
  47. Munne, S., Sandalinas, M., Magli, C., et al. “Increased rate of aneuploidy embryos in young women with previous aneuploidy conception.” Prenat Diagn 24 (2004): 638–43.
  48. Marinkin, I.O., Aidagulova, S.V., Kuleshov, V.M. “Miscarriage and chronic endometritis: defining the priorities.” Reproductive medicine 2–3.27–28 (2016): 49–57.
  49. Aboallah, Y., et al. “Gestational sac and embryonic growth are not useful as criteria to define miscarriage: a multicentre observational study.” Ultrasound Obstet Gynecol 38 (2011): 503–9.
  50. Pankaj Desai. Recurrent spontaneous miscarriges. Second edition. Jaypee brothers medical publishers (2007).
  51. Gutikova, L.V., Yanushko, T.V. “The reasons that lead to the development of miscarriage.” Reproductive Health. Eastern Europe 5.35 (2014): 75–86.
  52. Lanari, C., et al. “The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer.” Endocr Relat Cancer 16/2 (2009): 333–50. DOI: 10.1677/ERC-08-0244



How to Cite

Veropotvelyan, N. P. (2016). Reviewing efficacy of progestagenes in recurrent early reproductive losses. REPRODUCTIVE ENDOCRINOLOGY, (31), 22–33.