Letrozole-induced endometrial preparation improved the pregnancy outcomes after frozen blastocyst transfer compared to the natural cycle: a retrospective cohort study

Kenji Ezoe, Junichiro Fukuda, Kazumi Takeshima, Kazunori Shinohara, Keiichi Kato, Kenji Ezoe, Junichiro Fukuda, Kazumi Takeshima, Kazunori Shinohara, Keiichi Kato

Abstract

Background: Letrozole treatment is considered an effective option in endometrial preparation for frozen embryo transfers in patients with ovulation disorders or irregular menstruation; however, the effectiveness of letrozole-induced endometrial preparation remains unclear in ovulatory patients. Furthermore, there is no comparative study reporting on pregnancy complications and congenital anomalies after frozen embryo transfers comparing natural and letrozole-assisted cycles. This study examined whether letrozole-induced endometrial preparation affected pregnancy outcomes, perinatal outcomes, and congenital anomalies after single vitrified-warmed blastocyst transfers (SVBTs) in ovulatory patients, as compared with the natural cycle.

Methods: This historic cohort study included only patients with unexplained infertility. Overall, 14,611 patients who underwent SVBTs between July 2015 and June 2020, comprising both natural and letrozole-assisted cycles, were included. Multiple covariates that impact outcomes were used for propensity score matching; 1,911 patients in the letrozole group were matched to 12,700 patients in the natural group, and the clinical records of 1,910 patients in each group were retrospectively analysed. Cycle characteristics, pregnancy outcomes (clinical pregnancy, ongoing pregnancy, and live birth), and incidence of pregnancy complications and congenital anomalies were statistically compared between the two groups.

Results: Multivariate logistic regression analysis showed that letrozole administration during SVBT cycles significantly improved the live birth rate (P = 0.0355). Gestational age, birth length, birth weight, and infant sex, as well as the incidence of pregnancy complications and birth defects, were statistically comparable between the two groups. Furthermore, multivariate logistic regression analysis revealed that the perinatal outcomes were not affected by letrozole-induced endometrial preparation.

Conclusions: Letrozole-induced endometrial preparation improved the live birth rate compared with the natural cycle, without adverse effects on perinatal outcomes and congenital anomalies after SVBTs. Therefore, letrozole-induced endometrial preparation might be a safe and more effective strategy, especially for patients with insufficient luteal function.

Keywords: Blastocyst transfer; Congenital anomalies; Live birth; Pregnancy complications; Propensity score.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

References

    1. Rose BI, Brown SE. A review of the physiology behind letrozole applications in infertility: are current protocols optimal? J Assist Reprod Genet. 2020;37(9):2093–2104.
    1. Malloch L, Rhoton-Vlasak A. An assessment of current clinical attitudes toward letrozole use in reproductive endocrinology practices. Fertil Steril. 2013;100(6):1740–1744.
    1. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril. 2001;75(2):305–309.
    1. Garcia-Velasco JA, Moreno L, Pacheco A, Guillen A, Duque L, Requena A, et al. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril. 2005;84(1):82–87.
    1. Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod. 2004;19(9):2031–2035.
    1. Jovanovic VP, Kort DH, Guarnaccia MM, Sauer MV, Lobo RA. Does the addition of clomiphene citrate or letrazole to gonadotropin treatment enhance the oocyte yield in poor responders undergoing IVF? J Assist Reprod Genet. 2011;28(11):1067–1072.
    1. Yarali H, Esinler I, Polat M, Bozdag G, Tiras B. Antagonist/letrozole protocol in poor ovarian responders for intracytoplasmic sperm injection: a comparative study with the microdose flare-up protocol. Fertil Steril. 2009;92(1):231–235.
    1. Bayar U, Basaran M, Kiran S, Coskun A, Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial. Fertil Steril. 2006;86(5):1447–1451.
    1. Begum MR, Ferdous J, Begum A, Quadir E. Comparison of efficacy of aromatase inhibitor and clomiphene citrate in induction of ovulation in polycystic ovarian syndrome. Fertil Steril. 2009;92(3):853–857.
    1. Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(2):119–129.
    1. Zhang J, Wei M, Bian X, Wu L, Zhang S, Mao X, et al. Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome. Am J Obstet Gynecol. 2021;225(1):59 e1–e9.
    1. Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, et al. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med. 2015;373(13):1230–1240.
    1. Huang P, Wei L, Li X, Lin Z. Modified hMG stimulated: an effective option in endometrial preparation for frozen-thawed embryo transfer in patients with normal menstrual cycles. Gynecol Endocrinol. 2018;34(9):772–774.
    1. Li SJ, Zhang YJ, Chai XS, Nie MF, Zhou YY, Chen JL, et al. Letrozole ovulation induction: an effective option in endometrial preparation for frozen-thawed embryo transfer. Arch Gynecol Obstet. 2014;289(3):687–693.
    1. Zhang J, Liu H, Wang Y, Mao X, Chen Q, Fan Y, et al. Letrozole use during frozen embryo transfer cycles in women with polycystic ovary syndrome. Fertil Steril. 2019;112(2):371–377.
    1. Hu YJ, Chen YZ, Zhu YM, Huang HF. Letrozole stimulation in endometrial preparation for cryopreserved-thawed embryo transfer in women with polycystic ovarian syndrome: a pilot study. Clin Endocrinol (Oxf) 2014;80(2):283–289.
    1. Cortinez A, De Carvalho I, Vantman D, Gabler F, Iniguez G, Vega M. Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil Steril. 2005;83(1):110–115.
    1. Miller PB, Parnell BA, Bushnell G, Tallman N, Forstein DA, Higdon HL, 3rd, et al. Endometrial receptivity defects during IVF cycles with and without letrozole. Hum Reprod. 2012;27(3):881–888.
    1. Li D, Khor S, Huang J, Chen Q, Lyu Q, Cai R, et al. Frozen Embryo Transfer in Mildly Stimulated Cycle With Letrozole Compared to Natural Cycle in Ovulatory Women: A Large Retrospective Study. Front Endocrinol (Lausanne) 2021;12:677689.
    1. Tatsumi T, Jwa SC, Kuwahara A, Irahara M, Kubota T, Saito H. Pregnancy and neonatal outcomes following letrozole use in frozen-thawed single embryo transfer cycles. Hum Reprod. 2017;32(6):1244–1248.
    1. Coughlan C, Ledger W, Wang Q, Liu F, Demirol A, Gurgan T, et al. Recurrent implantation failure: definition and management. Reprod Biomed Online. 2014;28(1):14–38.
    1. Karakida S, Ezoe K, Fukuda J, Yabuuchi A, Kobayashi T, Kato K. Effects of gonadotropin administration on clinical outcomes in clomiphene citrate-based minimal stimulation cycle IVF. Reprod Med Biol. 2020;19(2):128–134.
    1. Kato K, Ezoe K, Yabuuchi A, Fukuda J, Kuroda T, Ueno S, et al. Comparison of pregnancy outcomes following fresh and electively frozen single blastocyst transfer in natural cycle and clomiphene-stimulated IVF cycles. Hum Reprod Open. 2018;2018(3):hoy006.
    1. Nishihara S, Fukuda J, Ezoe K, Endo M, Nakagawa Y, Yamadera R, et al. Does the endometrial thickness on the day of the trigger affect the pregnancy outcomes after fresh cleaved embryo transfer in the clomiphene citrate-based minimal stimulation cycle? Reprod Med Biol. 2020;19(2):151–157.
    1. Ezoe K, Ohata K, Morita H, Ueno S, Miki T, Okimura T, et al. Prolonged blastomere movement induced by the delay of pronuclear fading and first cell division adversely affects pregnancy outcomes after fresh embryo transfer on Day 2: a time-lapse study. Reprod Biomed Online. 2019;38(5):659–668.
    1. Ohata K, Ezoe K, Miki T, Morita H, Tsuchiya R, Kaneko S, et al. Blastomere movement post first cell division correlates with embryonic compaction and subsequent blastocyst formation. Reprod Biol Endocrinol. 2019;17(1):44.
    1. Kato K, Ueno S, Yabuuchi A, Uchiyama K, Okuno T, Kobayashi T, et al. Women's age and embryo developmental speed accurately predict clinical pregnancy after single vitrified-warmed blastocyst transfer. Reprod Biomed Online. 2014;29(4):411–416.
    1. Mori C, Yabuuchi A, Ezoe K, Murata N, Takayama Y, Okimura T, et al. Hydroxypropyl cellulose as an option for supplementation of cryoprotectant solutions for embryo vitrification in human assisted reproductive technologies. Reprod Biomed Online. 2015;30(6):613–621.
    1. Onogi S, Ezoe K, Nishihara S, Fukuda J, Kobayashi T, Kato K. Endometrial thickness on the day of the LH surge: an effective predictor of pregnancy outcomes after modified natural cycle-frozen blastocyst transfer. Hum Reprod Open. 2020;2020(4):hoaa060.
    1. Ezoe K, Miki T, Okimura T, Uchiyama K, Yabuuchi A, Kobayashi T, et al. Characteristics of the cytoplasmic halo during fertilisation correlate with the live birth rate after fresh cleaved embryo transfer on day 2 in minimal ovarian stimulation cycles: a retrospective observational study. Reprod Biol Endocrinol. 2021;19(1):172.
    1. Ezoe K, Hickman C, Miki T, Okimura T, Uchiyama K, Yabuuchi A, et al. Cytoplasmic halo characteristics during fertilization and their implications for human preimplantation embryo development and pregnancy outcome. Reprod Biomed Online. 2020;41(2):191–202.
    1. Ueno S, Ezoe K, Abe T, Yabuuchi A, Uchiyama K, Okuno T, et al. Maternal age and initial beta-hCG levels predict pregnancy outcome after single vitrified-warmed blastocyst transfer. J Assist Reprod Genet. 2014;31(9):1175–1181.
    1. Onogi S, Ezoe K, Kawasaki N, Hayashi H, Kuroda T, Takeshima K, et al. Maternal and obstetric outcomes are influenced by developmental stage and cryopreservation of transferred embryos after clomiphene citrate-based minimal stimulation IVF. Hum Reprod Open. 2022;2022(2):hoac018.
    1. Takeshima K, Ezoe K, Kawasaki N, Hayashi H, Kuroda T, Kato K. Perinatal outcomes and congenital anomalies associated with letrozole and natural cycles in single fresh cleaved embryo transfers: A single-center, 10-year cohort study. F S Rep. 2022;3(2):138–144.
    1. Itabashi K, Fujimura M, Kusuda S, Tamura M, Hayashi T, Takahashi T, et al. New standard of average size and weight of newborn in Japan. Jap J Pediat. 2010;114:1271–93.
    1. World Health Organization. Internatilnal Stastical Classification of Diseases and Related Health Problems 10th Revison 2016 [updated September 20,2021. Available from: .
    1. Lou L, Xu Y, Lv M, Yu J, Xiao Q, Chen P, et al. Comparison of different endometrial preparation protocols on frozen embryo transfer pregnancy outcome in patients with normal ovulation. Reprod Biomed Online. 2022.
    1. Nardo LG, Sallam HN. Progesterone supplementation to prevent recurrent miscarriage and to reduce implantation failure in assisted reproduction cycles. Reprod Biomed Online. 2006;13(1):47–57.
    1. Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18(12):1754–1767.
    1. Takeshima K, Ezoe K, Kawasaki N, Hayashi H, Kuroda T, Kato K. Perinatal outcomes and congenital anomalies associated with letrozole and natural cycles in single fresh cleaved embryo transfers: A single-center, 10-year cohort study. F & S Reports. 2022;In Press.
    1. Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab. 1999;84(8):2951–2956.
    1. Hickey TE, Marrocco DL, Amato F, Ritter LJ, Norman RJ, Gilchrist RB, et al. Androgens augment the mitogenic effects of oocyte-secreted factors and growth differentiation factor 9 on porcine granulosa cells. Biol Reprod. 2005;73(4):825–832.
    1. Ortega I, Garcia Velasco JA. Progesterone supplementation in the frozen embryo transfer cycle. Curr Opin Obstet Gynecol. 2015;27(4):253–257.
    1. Ginstrom Ernstad E, Spangmose AL, Opdahl S, Henningsen AA, Romundstad LB, Tiitinen A, et al. Perinatal and maternal outcome after vitrification of blastocysts: a Nordic study in singletons from the CoNARTaS group. Hum Reprod. 2019;34(11):2282–2289.
    1. Saito K, Miyado K, Yamatoya K, Kuwahara A, Inoue E, Miyado M, et al. Increased incidence of post-term delivery and Cesarean section after frozen-thawed embryo transfer during a hormone replacement cycle. J Assist Reprod Genet. 2017;34(4):465–470.
    1. Saito K, Kuwahara A, Ishikawa T, Morisaki N, Miyado M, Miyado K, et al. Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus. Hum Reprod. 2019;34(8):1567–1575.
    1. von Versen-Hoynck F, Schaub AM, Chi YY, Chiu KH, Liu J, Lingis M, et al. Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum. Hypertension. 2019;73(3):640–649.
    1. Zaat TR, Brink AJ, de Bruin JP, Goddijn M, Broekmans FJM, Cohlen BJ, et al. Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers? Reprod Biomed Online. 2021;42(5):919–929.
    1. Ginstrom Ernstad E, Wennerholm UB, Khatibi A, Petzold M, Bergh C. Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles. Am J Obstet Gynecol. 2019;221(2):126 e1–e18.
    1. von Versen-Hoynck F, Narasimhan P, Selamet Tierney ES, Martinez N, Conrad KP, Baker VL, et al. Absent or Excessive Corpus Luteum Number Is Associated With Altered Maternal Vascular Health in Early Pregnancy. Hypertension. 2019;73(3):680–690.
    1. Zong L, Liu P, Zhou L, Wei D, Ding L, Qin Y. Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer. Reprod Biol Endocrinol. 2020;18(1):36.

Source: PubMed

3
Subscribe