Skip to main content
SpringerLink
Log in

The association between the type of progesterone supplementation and miscarriage risk in women who have had a positive pregnancy test following embryo transfer: a retrospective cohort study

  • Gynecologic Endocrinology and Reproductive Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to identify if switching from intramuscular (IM) to vaginal progesterone compared to staying on IM progesterone after a positive pregnancy test following embryo transfer (ET) is associated with miscarriage risk.

Methods

A retrospective cohort study was performed in a private university-affiliated fertility clinic and included women aged 18–50 years with a positive pregnancy test following ET. The two groups studied were: women who stayed on IM progesterone following a positive pregnancy test and those who switched to vaginal progesterone after a positive test. The main outcome measured was risk of miscarriage < 24 weeks gestation as a proportion of non-biochemical pregnancies.

Results

1988 women were included in the analysis. Among the baseline characteristics, the presence of prior miscarriages as well as prior failed ETs, and frozen cycles (vs fresh) as type of transfer were associated with IM progesterone use (p values ≤ 0.01). As per miscarriage risk < 24 weeks, 22.4% (274/1221) of patients in the IM progesterone group experienced a miscarriage compared with 20.7% (159/767) in the vaginal progesterone group (OR 0.90; 95% CI 0.73–1.13). A multivariable logistic regression model revealed an adjusted OR (aOR) of 0.97 (95% CI 0.77–1.22).

Conclusion

This study suggests that switching from IM to vaginal progesterone after a positive pregnancy test following an ET is not associated with miscarriage risk. Considering that IM progesterone imposes substantial discomfort, this study offers reassurance and some flexibility in treatment protocols. Further prospective studies are necessary to corroborate the results of this study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The authors confirm that the data supporting the findings of this study is available within the article. The final dataset used for the analysis in this study is available from the corresponding author upon reasonable request.

References

  1. Fatemi HM, Popovic-Todorovic B, Papanikolaou E, Donoso P, Devroey P (2007) An update of luteal phase support in stimulated IVF cycles. Hum Reprod Update 13(6):581–590. https://doi.org/10.1093/humupd/dmm021

    Article  CAS  PubMed  Google Scholar 

  2. van der Linden M, Buckingham K, Farquhar C, Kremer JAM (2015) Metwally M (2015) Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev 7:CD009154

    Google Scholar 

  3. Beltsos AN, Sanchez MD, Doody KJ, Bush MR, Domar AD, Collins MG (2014) Patients’ administration preferences: progesterone vaginal insert (Endometrin(R)) compared to intramuscular progesterone for Luteal phase support. Reprod Health 11:78. https://doi.org/10.1186/1742-4755-11-78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Propst AM, Hill JA, Ginsburg ES, Hurwitz S, Politch J, Yanushpolsky EH (2001) A randomized study comparing Crinone 8% and intramuscular progesterone supplementation in in vitro fertilization-embryo transfer cycles. Fertil Steril 76(6):1144–1149. https://doi.org/10.1016/s0015-0282(01)02872-2

    Article  CAS  PubMed  Google Scholar 

  5. Doody K, Bush M, Collins M (2012) Progesterone supplementation for luteal support: efficacy and patient experiences with vaginal inserts (Endometrin®) versus intramuscular injection. Fertil Steril 97(3):S18. https://doi.org/10.1016/j.fertnstert.2012.01.040

    Article  Google Scholar 

  6. Yanushpolsky E, Hurwitz S, Greenberg L, Racowsky C, Hornstein M (2010) Crinone vaginal gel is equally effective and better tolerated than intramuscular progesterone for luteal phase support in in vitro fertilization-embryo transfer cycles: a prospective randomized study. Fertil Steril 94(7):2596–2599. https://doi.org/10.1016/j.fertnstert.2010.02.033

    Article  CAS  PubMed  Google Scholar 

  7. Cicinelli E, Schonauer LM, Galantino P, Matteo MG, Cassetta R, Pinto V (2000) Mechanisms of uterine specificity of vaginal progesterone. Hum Reprod 15(Suppl 1):159–165. https://doi.org/10.1093/humrep/15.suppl_1.159

    Article  CAS  PubMed  Google Scholar 

  8. Kahraman S, Karagozoglu SH, Karlikaya G (2010) The efficiency of progesterone vaginal gel versus intramuscular progesterone for luteal phase supplementation in gonadotropin-releasing hormone antagonist cycles: a prospective clinical trial. Fertil Steril 94(2):761–763. https://doi.org/10.1016/j.fertnstert.2009.10.004

    Article  CAS  PubMed  Google Scholar 

  9. Schoolcraft WB, Hesla JS, Gee MJ (2000) Experience with progesterone gel for luteal support in a highly successful IVF programme. Hum Reprod 15(6):1284–1288

    Article  CAS  PubMed  Google Scholar 

  10. Smitz J, Devroey P, Faguer B, Bourgain C, Camus M, Van Steirteghem AC (1992) A prospective randomized comparison of intramuscular or intravaginal natural progesterone as a luteal phase and early pregnancy supplement. Hum Reprod 7(2):168–175. https://doi.org/10.1093/oxfordjournals.humrep.a137611

    Article  CAS  PubMed  Google Scholar 

  11. Zarutskie PW, Phillips JA (2009) A meta-analysis of the route of administration of luteal phase support in assisted reproductive technology: vaginal versus intramuscular progesterone. Fertil Steril 92(1):163–169. https://doi.org/10.1016/j.fertnstert.2009.02.018

    Article  CAS  PubMed  Google Scholar 

  12. Abdelhakim AM, Abd-ElGawad M, Hussein RS, Abbas AM (2020) Vaginal versus intramuscular progesterone for luteal phase support in assisted reproductive techniques: a systematic review and meta-analysis of randomized controlled trials. Gynecol Endocrinol 36(5):389–397. https://doi.org/10.1080/09513590.2020.1727879

    Article  CAS  PubMed  Google Scholar 

  13. Silverberg KM, Vaughn TC, Hansard LJ, Burger NZ, Minter T (2012) Vaginal (Crinone 8%) gel vs. intramuscular progesterone in oil for luteal phase support in in vitro fertilization: a large prospective trial. Fertil Steril 97(2):344–348. https://doi.org/10.1016/j.fertnstert.2011.11.018

    Article  CAS  PubMed  Google Scholar 

  14. Unfer V, Casini ML, Costabile L, Gerli S, Baldini D, Di Renzo GC (2004) 17 alpha-hydroxyprogesterone caproate versus intravaginal progesterone in IVF-embryo transfer cycles: a prospective randomized study. Reprod Biomed Online 9(1):17–21

    Article  CAS  PubMed  Google Scholar 

  15. Dal Prato L, Bianchi L, Cattoli M, Tarozzi N, Flamigni C, Borini A (2008) Vaginal gel versus intramuscular progesterone for luteal phase supplementation: a prospective randomized trial. Reprod Biomed Online 16(3):361–367

    Article  Google Scholar 

  16. Chi HB, Liu NN, Li R, Tao LY, Chen LX, Qiao J (2018) Comparison of vaginal gel and intramuscular progesterone for in vitro fertilization and embryo transfer with gonadotropin-releasing hormone antagonist protocol. Chin Med J (Engl) 131(13):1557–1561. https://doi.org/10.4103/0366-6999.235106

    Article  CAS  PubMed  Google Scholar 

  17. Damario MA, Goudas VT, Session DR, Hammitt DG, Dumesic DA (1999) Crinone 8% vaginal progesterone gel results in lower embryonic implantation efficiency after in vitro fertilization-embryo transfer. Fertil Steril 72(5):830–836. https://doi.org/10.1016/s0015-0282(99)00364-7

    Article  CAS  PubMed  Google Scholar 

  18. Ho CH, Chen SU, Peng FS, Chang CY, Yang YS (2008) Luteal support for IVF/ICSI cycles with Crinone 8% (90 mg) twice daily results in higher pregnancy rates than with intramuscular progesterone. J Chin Med Assoc 71(8):386–391. https://doi.org/10.1016/s1726-4901(08)70088-1

    Article  CAS  PubMed  Google Scholar 

  19. Jabara S, Barnhart K, Schertz JC, Patrizio P (2009) Luteal phase bleeding after IVF cycles: comparison between progesterone vaginal gel and intramuscular progesterone and correlation with pregnancy outcomes. J Exp Clin Assist Reprod 6:6

    PubMed  PubMed Central  Google Scholar 

  20. Khan N, Richter KS, Newsome TL, Blake EJ, Yankov VI (2009) Matched-samples comparison of intramuscular versus vaginal progesterone for luteal phase support after in vitro fertilization and embryo transfer. Fertil Steril 91(6):2445–2450. https://doi.org/10.1016/j.fertnstert.2008.03.072

    Article  CAS  PubMed  Google Scholar 

  21. Mitwally MF, Diamond MP, Abuzeid M (2010) Vaginal micronized progesterone versus intramuscular progesterone for luteal support in women undergoing in vitro fertilization-embryo transfer. Fertil Steril 93(2):554–569. https://doi.org/10.1016/j.fertnstert.2009.02.047

    Article  CAS  PubMed  Google Scholar 

  22. Papaleo E, Quaranta L, Molgora M (2010) Intramuscular vs intravaginal natural progesterone in patients undergoing in vitro fertilization-embryo transfer cycles. A retrospective observational, case-control study. Eur Rev Med Pharmacol Sci 14(2):103–106

    CAS  PubMed  Google Scholar 

  23. Satir F, Toptas T, Inel M, Erman-Akar M, Taskin O (2013) Comparison of intravaginal progesterone gel and intramuscular 17-alpha-hydroxyprogesterone caproate in luteal phase support. Exp Ther Med 5(6):1740–1744. https://doi.org/10.3892/etm.2013.1049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Devine K, Richter KS, Jahandideh S, Widra EA, McKeeby JL (2021) Intramuscular progesterone optimizes live birth from programmed frozen embryo transfer: a randomized clinical trial. Fertil Steril 116(3):633–643. https://doi.org/10.1016/j.fertnstert.2021.04.013

    Article  CAS  PubMed  Google Scholar 

  25. Wang Y, He Y, Zhao X, Ji X, Hong Y, Wang Y, Zhu Q, Xu B, Sun Y (2015) Crinone gel for luteal phase support in frozen-thawed embryo transfer cycles: a prospective randomized clinical trial in the Chinese population. PLoS ONE 10(7):e0133027. https://doi.org/10.1371/journal.pone.0133027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Haddad G, Saguan DA, Maxwell R, Thomas MA (2007) Intramuscular route of progesterone administration increases pregnancy rates during non-downregulated frozen embryo transfer cycles. J Assist Reprod Genet 24(10):467–470. https://doi.org/10.1007/s10815-007-9168-z

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kaser DJ, Ginsburg ES, Missmer SA, Correia KF, Racowsky C (2012) Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support for day 3 cryopreserved embryo transfer. Fertil Steril 98(6):1464–1469. https://doi.org/10.1016/j.fertnstert.2012.08.007

    Article  CAS  PubMed  Google Scholar 

  28. Mathur N, Uhler ML, Feinberg EC (2013) Comparison of luteal phase support regimens in frozen embryo transfer (FET) cycles from comprehensive chromosome screening. Fertil Steril 1:S298

    Article  Google Scholar 

  29. Carr BR, Doody KJ (2009) Comparison of endometrin and intramuscular progesterone for frozen-thawed embryo transfer. Fertil Steril 1:S244

    Google Scholar 

  30. Shapiro DB, Pappadakis JA, Ellsworth NM, Hait HI, Nagy ZP (2014) Progesterone replacement with vaginal gel versus i.m. injection: cycle and pregnancy outcomes in IVF patients receiving vitrified blastocysts. Hum Reprod 29(8):1706–1711. https://doi.org/10.1093/humrep/deu121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bakkensen JB, Racowsky C, Thomas AM, Lanes A, Hornstein MD (2020) Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support following blastocyst cryopreserved single embryo transfer: a retrospective cohort study. Fertil Res Pract 6:10. https://doi.org/10.1186/s40738-020-00079-y

    Article  PubMed  PubMed Central  Google Scholar 

  32. Casper RF (2014) Luteal phase support for frozen embryo transfer cycles: intramuscular or vaginal progesterone? Fertil Steril 101(3):627–628. https://doi.org/10.1016/j.fertnstert.2014.01.018

    Article  PubMed  Google Scholar 

  33. Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, Nelen W, Peramo B, Quenby S, Vermeulen N, Goddijn M (2018) ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2:004. https://doi.org/10.1093/hropen/hoy004

    Article  Google Scholar 

  34. Devine K, Richter KS, Widra EA, McKeeby JL (2018) Vitrified blastocyst transfer cycles with the use of only vaginal progesterone replacement with Endometrin have inferior ongoing pregnancy rates: results from the planned interim analysis of a three-arm randomized controlled noninferiority trial. Fertil Steril 109(2):266–275. https://doi.org/10.1016/j.fertnstert.2017.11.004

    Article  CAS  PubMed  Google Scholar 

  35. Tal R, Seifer DB (2017) Ovarian reserve testing: a user’s guide. Am J Obstet Gynecol 217(2):129–140. https://doi.org/10.1016/j.ajog.2017.02.027

    Article  PubMed  Google Scholar 

  36. Wambach C, Ambartsumyan G, Surrey M, Hill D, Danzer H (2011) Mode of luteal phase progesterone support after frozen embryo transfer does not affect live birth rates. Fertil Steril 1:S26

    Article  Google Scholar 

  37. Lightman A, Kol S, Itskovitz-Eldor J (1999) A prospective randomized study comparing intramuscular with intravaginal natural progesterone in programmed thaw cycles. Hum Reprod 14(10):2596–2599. https://doi.org/10.1093/humrep/14.10.2596

    Article  CAS  PubMed  Google Scholar 

  38. Schoolcraft WB, Katz-Jaffe MG (2013) Comprehensive chromosome screening of trophectoderm with vitrification facilitates elective single-embryo transfer for infertile women with advanced maternal age. Fertil Steril 100(3):615–619. https://doi.org/10.1016/j.fertnstert.2013.07.1972

    Article  PubMed  Google Scholar 

  39. Grifo JA, Hodes-Wertz B, Lee HL, Amperloquio E, Clarke-Williams M, Adler A (2013) Single thawed euploid embryo transfer improves IVF pregnancy, miscarriage, and multiple gestation outcomes and has similar implantation rates as egg donation. J Assist Reprod Genet 30(2):259–264. https://doi.org/10.1007/s10815-012-9929-1

    Article  PubMed  PubMed Central  Google Scholar 

  40. Yang R, Guan Y, Perrot V, Ma J, Li R (2021) Comparison of the long-acting GnRH agonist follicular protocol with the GnRH antagonist protocol in women undergoing in vitro fertilization: a systematic review and meta-analysis. Adv Ther 38(5):2027–2037. https://doi.org/10.1007/s12325-020-01612-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yang AM, Xu X, Han Y, Wei JJ, Hao GM, Cui N, Zhao ZM, Wang W, Huang X (2021) Risk factors for different types of pregnancy losses: analysis of 15,210 pregnancies after embryo transfer. Front Endocrinol (Lausanne) 12:683236. https://doi.org/10.3389/fendo.2021.683236

    Article  PubMed  Google Scholar 

  42. Li R, Guan Y, Yang R, Perrot V, Juan MA (2020) Comparison of controlled ovary stimulation protocols for in vitro fertilisation: a meta-analysis. Fertil Steril 114(3):e442–e444. https://doi.org/10.1016/j.fertnstert.2020.08.1282

    Article  Google Scholar 

  43. Kadoura S, Alhalabi M, Nattouf AH (2022) Conventional GnRH antagonist protocols versus long GnRH agonist protocol in IVF/ICSI cycles of polycystic ovary syndrome women: a systematic review and meta-analysis. Sci Rep 12(1):4456. https://doi.org/10.1038/s41598-022-08400-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hu L, Du J, Lv H, Zhao J, Chen M, Wang Y, Wu F, Liu F, Chen X, Zhang J, Ma H, Jin G, Shen H, Chen L, Ling X, Hu Z (2018) Influencing factors of pregnancy loss and survival probability of clinical pregnancies conceived through assisted reproductive technology. Reprod Biol Endocrinol 16(1):74. https://doi.org/10.1186/s12958-018-0390-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kyrou D, Fatemi HM, Zepiridis L, Riva A, Papanikolaou EG, Tarlatzis BC, Devroey P (2011) Does cessation of progesterone supplementation during early pregnancy in patients treated with recFSH/GnRH antagonist affect ongoing pregnancy rates? A randomized controlled trial. Hum Reprod 26(5):1020–1024. https://doi.org/10.1093/humrep/der012

    Article  CAS  PubMed  Google Scholar 

  46. Pan SP, Chao KH, Huang CC, Wu MY, Chen MJ, Chang CH, Yang JH, Yang YS, Chen SU (2018) Early stop of progesterone supplementation after confirmation of pregnancy in IVF/ICSI fresh embryo transfer cycles of poor responders does not affect pregnancy outcome. PLoS ONE 13(8):e0201824. https://doi.org/10.1371/journal.pone.0201824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. Laura Woods (University of London) for her support throughout the project.

Funding

The authors declare that no funds, grants or other support was received during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. OVO Fertility Clinic, 8000 Decarie Blvd, Montreal, QC, H4P 2S4, Canada

    Talya Shaulov, Simon Phillips & Louise Lapensée

  2. Department of Obstetrics and Gynecology, University of Montreal, 2900 Edouard Montpetit Blvd, Montreal, QC, H3T 1J4, Canada

    Talya Shaulov, Nadège Zanré & Louise Lapensée

Authors
  1. Talya Shaulov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nadège Zanré
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simon Phillips
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Louise Lapensée
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation and data collection were performed by TS, NZ, LL and SP. Data analysis was performed by TS. The first draft of the manuscript was written by TS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Talya Shaulov.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval and consent

Access to patients’ files was approved by the Quebec Commission of access to information (ref: 1014586-S). Ethics approval was obtained by the University of Montreal Hospital Center Research Ethics Committee (CR-CHUM; ref: 15.387).

Consent to publish

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shaulov, T., Zanré, N., Phillips, S. et al. The association between the type of progesterone supplementation and miscarriage risk in women who have had a positive pregnancy test following embryo transfer: a retrospective cohort study. Arch Gynecol Obstet 308, 569–577 (2023). https://doi.org/10.1007/s00404-023-07047-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-023-07047-z

Keywords

Search

Navigation