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High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes

  • Assisted Reproduction Technologies
  • Published:
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Abstract

Purpose

There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO).

Methods

We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2 ng/mL or 3-day area under the curve > 4.5 ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes.

Results

Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol \(\ge\) 4000 pg/mL had a greater likelihood of GBO compared to cycles < 1000 pg/mL (aRR = 1.32, 95% CI 1.13–1.54). Pairwise comparisons of estradiol between < 1000 pg/mL versus 1000–1999 pg/mL and 1000–1999 pg/mL versus 2000–2999 pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73–0.95; aRR 0.91, 95% CI 0.85–0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000–2999 pg/mL versus 3000–3999 pg/mL, aRR 1.04, 95% CI 0.97–1.11; 3000–3999 pg/mL versus \(\ge\) 4000 pg/mL, aRR 0.96, 95% CI 0.9–1.04).

Conclusion

In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000–2999 pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered.

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Data availability

The data that support the findings of this study are available from the corresponding author, IL, upon reasonable request.

References

  1. Ahart E, Luevano G, Marsh C. To freeze or not to freeze, what is the answer? Fertil Steril. 2023;119(2):195. https://doi.org/10.1016/j.fertnstert.2022.12.020.

    Article  PubMed  Google Scholar 

  2. Eapen A, Sparks A. Improved outcomes following frozen embryo transfer does not provide a “universal license to chill.” Fertil Steril. 2018;110(5):847–8. https://doi.org/10.1016/j.fertnstert.2018.06.033.

    Article  PubMed  Google Scholar 

  3. Chen Z-J, Legro RS. Fresh versus frozen embryos in polycystic ovary syndrome. N Engl J Med. 2016;375(20): e42. https://doi.org/10.1056/NEJMc1611871.

    Article  PubMed  Google Scholar 

  4. Wang A, Santistevan A, Hunter Cohn K, et al. Freeze-only versus fresh embryo transfer in a multicenter matched cohort study: contribution of progesterone and maternal age to success rates. Fertil Steril. 2017;108(2):254-261.e4. https://doi.org/10.1016/j.fertnstert.2017.05.007.

    Article  CAS  PubMed  Google Scholar 

  5. Acharya KS, Acharya CR, Bishop K, Harris B, Raburn D, Muasher SJ. Freezing of all embryos in in vitro fertilization is beneficial in high responders, but not intermediate and low responders: an analysis of 82,935 cycles from the Society for Assisted Reproductive Technology registry. Fertil Steril. 2018;110(5):880–7. https://doi.org/10.1016/j.fertnstert.2018.05.024.

    Article  PubMed  Google Scholar 

  6. Karatasiou GI, Bosdou JK, Venetis CA, et al. Is the probability of pregnancy after ovarian stimulation for IVF associated with serum estradiol levels on the day of triggering final oocyte maturation with hCG? A systematic review and meta-analysis. J Assist Reprod Genet. 2020;37(7):1531–41. https://doi.org/10.1007/s10815-020-01829-z.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Chenette PE, Sauer MV, Paulson RJ. Very high serum estradiol levels are not detrimental to clinical outcome of in vitro fertilization. Fertil Steril. 1990;54(5):858–63. https://doi.org/10.1016/s0015-0282(16)53946-6.

    Article  CAS  PubMed  Google Scholar 

  8. Imudia AN, Goldman RH, Awonuga AO, Wright DL, Styer AK, Toth TL. The impact of supraphysiologic serum estradiol levels on peri-implantation embryo development and early pregnancy outcome following in vitro fertilization cycles. J Assist Reprod Genet. 2014;31(1):65–71. https://doi.org/10.1007/s10815-013-0117-8.

    Article  PubMed  Google Scholar 

  9. Joo BS, Park SH, An BM, Kim KS, Moon SE, Moon HS. Serum estradiol levels during controlled ovarian hyperstimulation influence the pregnancy outcome of in vitro fertilization in a concentration-dependent manner. Fertil Steril. 2010;93(2):442–6. https://doi.org/10.1016/j.fertnstert.2009.02.066.

    Article  CAS  PubMed  Google Scholar 

  10. Mitwally MF, Bhakoo HS, Crickard K, Sullivan MW, Batt RE, Yeh J. Estradiol production during controlled ovarian hyperstimulation correlates with treatment outcome in women undergoing in vitro fertilization-embryo transfer. Fertil Steril. 2006;86(3):588–96. https://doi.org/10.1016/j.fertnstert.2006.02.086.

    Article  CAS  PubMed  Google Scholar 

  11. Pelkonen S, Koivunen R, Gissler M, et al. Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995–2006. Hum Reprod. 2010;25(4):914–23. https://doi.org/10.1093/humrep/dep477.

    Article  CAS  PubMed  Google Scholar 

  12. Sha T, Yin X, Cheng W, Massey IY. Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis. Fertil Steril. 2018;109(2):330-342.e9. https://doi.org/10.1016/j.fertnstert.2017.10.019.

    Article  PubMed  Google Scholar 

  13. Imudia AN, Awonuga AO, Doyle JO, et al. Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization. Fertil Steril. 2012;97(6):1374–9. https://doi.org/10.1016/j.fertnstert.2012.03.028.

    Article  CAS  PubMed  Google Scholar 

  14. Pereira N, Elias RT, Christos PJ, et al. Supraphysiologic estradiol is an independent predictor of low birth weight in full-term singletons born after fresh embryo transfer. Hum Reprod. 2017;32(7):1410–7. https://doi.org/10.1093/humrep/dex095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pereira N, Reichman DE, Goldschlag DE, Lekovich JP, Rosenwaks Z. Impact of elevated peak serum estradiol levels during controlled ovarian hyperstimulation on the birth weight of term singletons from fresh IVF-ET cycles. J Assist Reprod Genet. 2015;32(4):527–32. https://doi.org/10.1007/s10815-015-0434-1.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sunkara SK, La Marca A, Seed PT, Khalaf Y. Increased risk of preterm birth and low birthweight with very high number of oocytes following IVF: an analysis of 65 868 singleton live birth outcomes. Hum Reprod. 2015;30(6):1473–80. https://doi.org/10.1093/humrep/dev076.

    Article  CAS  PubMed  Google Scholar 

  17. Bourdon M, Ouazana M, Maignien C, et al. Impact of supraphysiological estradiol serum levels on birth weight in singletons born after fresh embryo transfer. Reprod Sci. 2020;27(9):1770–7. https://doi.org/10.1007/s43032-020-00174-x.

    Article  CAS  PubMed  Google Scholar 

  18. Royster GDI, Hill MJ, Zarek SM, et al. J. Three day progesterone area under the curve: a better test than progesterone on the day of hCG? Fertil Steril. 2014;102(3):85–6. https://doi.org/10.1016/j.fertnstert.2014.07.290.

    Article  Google Scholar 

  19. Heitmann RJ, Hill MJ, Richter KS, DeCherney AH, Widra EA. The simplified SART embryo scoring system is highly correlated to implantation and live birth in single blastocyst transfers. J Assist Reprod Genet. 2013;30(4):563–7. https://doi.org/10.1007/s10815-013-9932-1.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Harrison W, Goodman D. Epidemiologic trends in neonatal intensive care, 2007-2012 [published correction appears in JAMA Pediatr. 2015 Sep;169(9):878]. JAMA Pediatr. 2015;169(9):855–62. https://doi.org/10.1001/jamapediatrics.2015.1305.

    Article  PubMed  Google Scholar 

  21. Li M, Kort J, Baker VL. Embryo biopsy and perinatal outcomes of singleton pregnancies: an analysis of 16,246 frozen embryo transfer cycles reported in the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System. Am J Obstet Gynecol. 2021;224(5):500.e1-500.e18. https://doi.org/10.1016/j.ajog.2020.10.043.

    Article  CAS  PubMed  Google Scholar 

  22. Al-Azemi M, Kyrou D, Kolibianakis EM, et al. Elevated progesterone during ovarian stimulation for IVF. Reprod Biomed Online. 2012;24(4):381–8. https://doi.org/10.1016/j.rbmo.2012.01.010.

    Article  CAS  PubMed  Google Scholar 

  23. Healy MW, Patounakis G, Connell MT, et al. Does a frozen embryo transfer ameliorate the effect of elevated progesterone seen in fresh transfer cycles? Fertil Steril. 2016;105(1):93-9.e1. https://doi.org/10.1016/j.fertnstert.2015.09.015.

    Article  CAS  PubMed  Google Scholar 

  24. Kyrou D, Popovic-Todorovic B, Fatemi HM, et al. Does the estradiol level on the day of human chorionic gonadotrophin administration have an impact on pregnancy rates in patients treated with rec-FSH/GnRH antagonist? Hum Reprod. 2009;24(11):2902–9. https://doi.org/10.1093/humrep/dep290.

    Article  CAS  PubMed  Google Scholar 

  25. Ullah K, Rahman TU, Pan HT, et al. Serum estradiol levels in controlled ovarian stimulation directly affect the endometrium. J Mol Endocrinol. 2017;59(2):105–19. https://doi.org/10.1530/JME-17-0036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Valbuena D, Martin J, de Pablo JL, Remohí J, Pellicer A, Simón C. Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo. Fertil Steril. 2001;76(5):962–8. https://doi.org/10.1016/s0015-0282(01)02018-0.

    Article  CAS  PubMed  Google Scholar 

  27. Dunne C, Cho K, Shan A, et al. Peak serum estradiol level during controlled ovarian stimulation is not associated with lower levels of pregnancy-associated plasma protein-A or small for gestational age infants: a cohort study. J Obstet Gynaecol Can. 2017;39(10):870–9. https://doi.org/10.1016/j.jogc.2017.01.031.

    Article  PubMed  Google Scholar 

  28. Zavy MT, Craig LB, Wild RA, Kahn SN, O’Leary D, Hansen KR. In high responding patients undergoing an initial IVF cycle, elevated estradiol on the day of hCG has no effect on live birth rate. Reprod Biol Endocrinol. 2014;12:119. https://doi.org/10.1186/1477-7827-12-119. Published 2014 Nov 28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang M, Jin L, Shi J, et al. Estradiol on trigger day: irrelevant to live birth rates of fresh cycles but positively associated with cumulative live birth rates. Int J Gynaecol Obstet. 2023;163(2):627–38. https://doi.org/10.1002/ijgo.14887.

    Article  PubMed  Google Scholar 

  30. Yan J, Qin Y, Zhao H, et al. Live birth with or without preimplantation genetic testing for aneuploidy. N Engl J Med. 2021;385(22):2047–58. https://doi.org/10.1056/NEJMoa2103613.

    Article  CAS  PubMed  Google Scholar 

  31. Roeca C, Johnson RL, Truong T, Carlson NE, Polotsky AJ. Birth outcomes are superior after transfer of fresh versus frozen embryos for donor oocyte recipients. Hum Reprod. 2020;35(12):2850–9. https://doi.org/10.1093/humrep/deaa245.

    Article  PubMed  Google Scholar 

  32. Eaton JL, Truong T, Li YJ, Polotsky AJ. Prevalence of a good perinatal outcome with cryopreserved compared with fresh donor oocytes. Obstet Gynecol. 2020;135(3):709–16. https://doi.org/10.1097/AOG.0000000000003695.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Roeca C, Silva E, Barentsen C, Powell TL, Jansson T. Effects of vitrification and the superovulated environment on placental function and fetal growth in an IVF mouse model. Mol Hum Reprod. 2020;26(8):624–35. https://doi.org/10.1093/molehr/gaaa047.

    Article  CAS  PubMed  Google Scholar 

  34. Ganer Herman H, Volodarsky-Perel A, Ton Nu TN, et al. The effect of higher estradiol levels during stimulation on pregnancy complications and placental histology. Placenta. 2022;126:114–8. https://doi.org/10.1016/j.placenta.2022.06.013.

    Article  CAS  PubMed  Google Scholar 

  35. Schirmer DA 3rd, Kulkarni AD, Zhang Y, Kawwass JF, Boulet SL, Kissin DM. Ovarian hyperstimulation syndrome after assisted reproductive technologies: trends, predictors, and pregnancy outcomes. Fertil Steril. 2020;114(3):567–78. https://doi.org/10.1016/j.fertnstert.2020.04.004.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr. Heather Aldrich for proofreading our manuscript.

Author information

Authors and Affiliations

  1. University of Colorado, Aurora, CO, USA

    Ivy L. Lersten, Laura Grau, Cassandra Roeca, Mary D. Sammel & Alex J. Polotsky

  2. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, School of Medicine, 12631 E 17Th Ave, Mail Stop B-198, Aurora, CO, USA

    Ivy L. Lersten, Cassandra Roeca, Mary D. Sammel & Alex J. Polotsky

  3. Department of Biostatistics and Informatics, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA

    Laura Grau & Mary D. Sammel

  4. Shady Grove Fertility, Rockville, MD, USA

    Samad Jahandideh, Kate Devine & Laura Zalles

  5. Shady Grove Fertility, Tampa, FL, USA

    Shayne M. Plosker & Anthony N. Imudia

  6. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Shayne M. Plosker & Anthony N. Imudia

  7. IVF Florida Reproductive Associates, Margate, FL, USA

    Luis R. Hoyos

  8. Fertility Centers of Illinois, Chicago, IL, USA

    Meike L. Uhler

  9. Reproductive Science Center of the Bay Area, San Francisco, CA, USA

    Michael Homer

  10. Shady Grove Fertility, Greenwood Village, CO, USA

    Ivy L. Lersten, Cassandra Roeca & Alex J. Polotsky

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  1. Ivy L. Lersten
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Contributions

I.L.L., K.D., and A.J.P. were involved in the study conceptualization. I.L.L., L.G., K.D., S.M.P., A.N.I., M.D.S., and A.J.P. designed the study. I.L.L. and S.J. performed data collection. L.G. and M.D.S. performed statistical analyses. I.L.L. and L.Z. drafted the manuscript. All other authors were involved in the review and editing of the manuscript. All authors interpreted the data, critically revised the article, and approved the final version.

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Correspondence to Ivy L. Lersten.

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Lersten, I.L., Grau, L., Jahandideh, S. et al. High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes. J Assist Reprod Genet 41, 893–902 (2024). https://doi.org/10.1007/s10815-024-03062-4

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