Does a freeze-all strategy improve live birth rates in women of different age groups?
Retrospective cohort study of 1882 first embryo transfer cycles, performed between January 2013 and December 2015. Reproductive outcomes between fresh (FRESH) or frozen (FROZEN) embryo transfers were compared in patients stratified by age: < 35, between 35 and 38, or > 38 years. Student’s t test for independent samples and χ2 analyses were used as needed. A multivariable logistic regression analysis was performed adjusting for age, triggering drug, number of retrieved oocytes, number of transferred embryos, and percentage of top-quality embryos.
Main results and the role of chance
Live birth rates (LBR) were significantly higher for FROZEN in the < 35 years group (43.7% vs 24%; p < 0.001). In both the 35–38 and > 38 years groups, LBR for FROZEN vs FRESH were not statistically different (30.9% in the FROZEN group vs 29.3% in the FRESH group, p = 0.70, and 19.8% in the FROZEN group vs 12.7% in the FRESH group, p = 0.07, respectively). The multivariate analysis found a significantly positive effect of performing FROZEN on LBR in the younger group (OR 2.46, 95% CI 1.31–4.62; p = 0.005) but had no impact in women between 35 and 38 years (OR 1.01, 95% CI 0.55–1.83; p = 0.98) or older (OR 0.96, 95% CI 0.43–2.13; p = 0.92).
Performing a freeze-all strategy seems to result in better reproductive outcomes when compared with a fresh ET in women under 35 years, with no significant impact on older women.
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Edwards RG, Steptoe PC, Purdy JM. Establishing full-term human pregnancies using cleaving embryos grown in vitro. Br J Obstet Gynaecol. 1980;87(9):737–56. https://doi.org/10.1111/j.1471-0528.1980.tb04610.x.
Barnhart KT. Introduction: are we ready to eliminate the transfer of fresh embryos in in vitro fertilization? Fertil Steril. 2014;102(1):1–2. https://doi.org/10.1016/j.fertnstert.2014.05.024.
Ubaldi F, Bourgain C, Tournaye H, Smitz J, Van Steirteghem A, Devroey P. Endometrial evaluation by aspiration biopsy on the day of oocyte retrieval in the embryo transfer cycles in patients with serum progesterone rise during the follicular phase. Fertil Steril. 1997;67(3):521–6. https://doi.org/10.1016/s0015-0282(97)80080-5.
Kolibianakis E, Bourgain C, Albano C, Osmanagaoglu K, Smitz J, Van Steirteghem A, et al. Effect of ovarian stimulation with recombinant follicle-stimulating hormone, gonadotropin releasing hormone antagonists, and human chorionic gonadotropin on endometrial maturation on the day of oocyte pick-up. Fertil Steril. 2002;78(5):1025–9. https://doi.org/10.1016/s0015-0282(02)03323-x.
Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer in normal responders. Fertil Steril. 2011;96(2):344–8. https://doi.org/10.1016/j.fertnstert.2011.05.050.
Check JH, Choe JK, Katsoff D, Summers-Chase D, Wilson C. Controlled ovarian hyperstimulation adversely affects implantation following in vitro fertilization-embryo transfer. J Assist Reprod Genet. 1999;16(8):416–20. https://doi.org/10.1023/a:1020565408018.
Horcajadas JA, Riesewijk A, Polman J, van Os R, Pellicer A, Mosselman S, et al. Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles. Mol Hum Reprod. 2005;11(3):195–205. https://doi.org/10.1093/molehr/gah150.
Horcajadas JA, Minguez P, Dopazo J, Esteban FJ, Dominguez F, Giudice LC, et al. Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications. J Clin Endocrinol Metab. 2008;93(11):4500–10. https://doi.org/10.1210/jc.2008-0588.
Simon C, Oberye J, Bellver J, Vidal C, Bosch E, Horcajadas JA, et al. Similar endometrial development in oocyte donors treated with either high- or standard-dose GnRH antagonist compared to treatment with a GnRH agonist or in natural cycles. Hum Reprod. 2005;20(12):3318–27. https://doi.org/10.1093/humrep/dei243.
Haouzi D, Assou S, Mahmoud K, Tondeur S, Reme T, Hedon B, et al. Gene expression profile of human endometrial receptivity: comparison between natural and stimulated cycles for the same patients. Hum Reprod. 2009;24(6):1436–45. https://doi.org/10.1093/humrep/dep039.
Venetis CA, Kolibianakis EM, Bosdou JK, Tarlatzis BC. Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles. Hum Reprod Update. 2013;19(5):433–57. https://doi.org/10.1093/humupd/dmt014.
Venetis CA, Kolibianakis EM, Bosdou JK, Lainas GT, Sfontouris IA, Tarlatzis BC, et al. Estimating the net effect of progesterone elevation on the day of hCG on live birth rates after IVF: a cohort analysis of 3296 IVF cycles. Hum Reprod. 2015;30(3):684–91. https://doi.org/10.1093/humrep/deu362.
Roque M. Freeze-all policy: is it time for that? J Assist Reprod Genet. 2015;32(2):171–6. https://doi.org/10.1007/s10815-014-0391-0.
Wong KM, Mastenbroek S, Repping S. Cryopreservation of human embryos and its contribution to in vitro fertilization success rates. Fertil Steril. 2014;102(1):19–26. https://doi.org/10.1016/j.fertnstert.2014.05.027.
Balaban B, Urman B, Ata B, Isiklar A, Larman MG, Hamilton R, et al. A randomized controlled study of human day 3 embryo cryopreservation by slow freezing or vitrification: vitrification is associated with higher survival, metabolism and blastocyst formation. Hum Reprod. 2008;23(9):1976–82. https://doi.org/10.1093/humrep/den222.
Fasano G, Fontenelle N, Vannin AS, Biramane J, Devreker F, Englert Y, et al. A randomized controlled trial comparing two vitrification methods versus slow-freezing for cryopreservation of human cleavage stage embryos. J Assist Reprod Genet. 2014;31(2):241–7. https://doi.org/10.1007/s10815-013-0145-4.
Li Z, Wang YA, Ledger W, Edgar DH, Sullivan EA. Clinical outcomes following cryopreservation of blastocysts by vitrification or slow freezing: a population-based cohort study. Hum Reprod. 2014;29(12):2794–801. https://doi.org/10.1093/humrep/deu246.
Feng G, Zhang B, Zhou H, Shu J, Gan X, Wu F, et al. Comparable clinical outcomes and live births after single vitrified-warmed and fresh blastocyst transfer. Reprod BioMed Online. 2012;25(5):466–73. https://doi.org/10.1016/j.rbmo.2012.07.008.
Devroey P, Polyzos NP, Blockeel C. An OHSS-free clinic by segmentation of IVF treatment. Hum Reprod. 2011;26(10):2593–7. https://doi.org/10.1093/humrep/der251.
Shih W, Rushford DD, Bourne H, Garrett C, McBain JC, Healy DL, et al. Factors affecting low birthweight after assisted reproduction technology: difference between transfer of fresh and cryopreserved embryos suggests an adverse effect of oocyte collection. Hum Reprod. 2008;23(7):1644–53. https://doi.org/10.1093/humrep/den150.
Healy DL, Breheny S, Halliday J, Jaques A, Rushford D, Garrett C, et al. Prevalence and risk factors for obstetric haemorrhage in 6730 singleton births after assisted reproductive technology in Victoria Australia. Hum Reprod. 2010;25(1):265–74. https://doi.org/10.1093/humrep/dep376.
Londra L, Moreau C, Strobino D, Garcia J, Zacur H, Zhao Y. Ectopic pregnancy after in vitro fertilization: differences between fresh and frozen-thawed cycles. Fertil Steril. 2015;104(1):110–8. https://doi.org/10.1016/j.fertnstert.2015.04.009.
Maheshwari A, Pandey S, Amalraj Raja E, Shetty A, Hamilton M, Bhattacharya S. Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Hum Reprod Update. 2018;24(1):35–58. https://doi.org/10.1093/humupd/dmx031.
Maheshwari A, Pandey S, Shetty A, Hamilton M, Bhattacharya S. Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis. Fertil Steril. 2012;98(2):368–77 e1–9. https://doi.org/10.1016/j.fertnstert.2012.05.019.
Pelkonen S, Gissler M, Koivurova S, Lehtinen S, Martikainen H, Hartikainen AL, et al. Physical health of singleton children born after frozen embryo transfer using slow freezing: a 3-year follow-up study. Hum Reprod. 2015;30(10):2411–8. https://doi.org/10.1093/humrep/dev203.
Pelkonen S, Hartikainen AL, Ritvanen A, Koivunen R, Martikainen H, Gissler M, et al. Major congenital anomalies in children born after frozen embryo transfer: a cohort study 1995-2006. Hum Reprod. 2014;29(7):1552–7. https://doi.org/10.1093/humrep/deu088.
Doody KJ. Cryopreservation and delayed embryo transfer-assisted reproductive technology registry and reporting implications. Fertil Steril. 2014;102(1):27–31. https://doi.org/10.1016/j.fertnstert.2014.04.048.
Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C. Clinical rationale for cryopreservation of entire embryo cohorts in lieu of fresh transfer. Fertil Steril. 2014;102(1):3–9. https://doi.org/10.1016/j.fertnstert.2014.04.018.
Wong KM, van Wely M, Mol F, Repping S, Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev. 2017;3:CD011184. https://doi.org/10.1002/14651858.CD011184.pub2.
Shi Y, Sun Y, Hao C, Zhang H, Wei D, Zhang Y, et al. Transfer of fresh versus frozen embryos in ovulatory women. N Engl J Med. 2018;378(2):126–36. https://doi.org/10.1056/NEJMoa1705334.
Vuong LN, Dang VQ, Ho TM, Huynh BG, Ha DT, Pham TD, et al. IVF transfer of fresh or frozen embryos in women without polycystic ovaries. N Engl J Med. 2018;378(2):137–47. https://doi.org/10.1056/NEJMoa1703768.
Wei D, Liu JY, Sun Y, Shi Y, Zhang B, Liu JQ, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet. 2019;393(10178):1310–8. https://doi.org/10.1016/S0140-6736(18)32843-5.
Basile N, Garcia-Velasco JA. The state of “freeze-for-all” in human ARTs. J Assist Reprod Genet. 2016;33(12):1543–50. https://doi.org/10.1007/s10815-016-0799-9.
Lopez S, Lattes K, Vassena R, Brassesco M, Vernaeve V. Freeze-all in older women: benefit or loss? Hum Reprod. 2016;31:i5.
Santistevan AHCK, Arredondo F, Miller B, Ory S, Leondires M. Multi-center study demonstrates freeze-all IVF protocols are correlated with higher ongoing pregnancy rates in women of advanced maternal age. Hum Reprod. 2016;3:1i102–3.
Grunfeld L, Walker B, Bergh PA, Sandler B, Hofmann G, Navot D. High-resolution endovaginal ultrasonography of the endometrium: a noninvasive test for endometrial adequacy. Obstet Gynecol. 1991;78(2):200–4.
Alpha Scientists In Reproductive M. The Alpha consensus meeting on cryopreservation key performance indicators and benchmarks: proceedings of an expert meeting. Reprod BioMed Online. 2012;25(2):146–67. https://doi.org/10.1016/j.rbmo.2012.05.006.
Giorlandino C, Cignini P, Padula F, Giannarelli D, d’Emidio L, Aloisi A, et al. Effects of exogenous progesterone on fetal nuchal translucency: an observational prospective study. Am J Obstet Gynecol. 2015;212(3):335 e1–7. https://doi.org/10.1016/j.ajog.2014.10.003.
Bosdou JK, Venetis CA, Tarlatzis BC, Grimbizis GF, Kolibianakis EM. Higher probability of live-birth in high, but not normal, responders after first frozen-embryo transfer in a freeze-only cycle strategy compared to fresh-embryo transfer: a meta-analysis. Hum Reprod. 2019;34(3):491–505. https://doi.org/10.1093/humrep/dey388.
Wang A, Santistevan A, Hunter Cohn K, Copperman A, Nulsen J, Miller BT, 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):254–61 e4. https://doi.org/10.1016/j.fertnstert.2017.05.007.
Polyzos NP, Sunkara SK. Sub-optimal responders following controlled ovarian stimulation: an overlooked group? Hum Reprod. 2015;30(9):2005–8. https://doi.org/10.1093/humrep/dev149.
Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, et al. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod. 2016;31(2):370–6. https://doi.org/10.1093/humrep/dev316.
Roque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update. 2019;25(1):2–14. https://doi.org/10.1093/humupd/dmy033.
Zhang W, Xiao X, Zhang J, Wang W, Wu J, Peng L, et al. Clinical outcomes of frozen embryo versus fresh embryo transfer following in vitro fertilization: a meta-analysis of randomized controlled trials. Arch Gynecol Obstet. 2018;298(2):259–72. https://doi.org/10.1007/s00404-018-4786-5.
We would like to thank Rosa Borràs, Maite Castro, Enrique Fabián, Manuel Gómez, Sara López, and Alicia Maqueda for their collaboration in recruiting, providing, and caring for study patients. We would also like to thank Francesc Figueras for statistical advice.
This study was approved by the local Research Ethics Committee.
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The authors declare that they have no conflict of interest.
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Lattes, K., López, S., Checa, M.A. et al. A freeze-all strategy does not increase live birth rates in women of advanced reproductive age. J Assist Reprod Genet 37, 2443–2451 (2020). https://doi.org/10.1007/s10815-020-01934-z
- Frozen embryo transfer
- Embryo transfer
- Endometrial receptivity