Fresh versus frozen: initial transfer or cumulative cycle results: how do we interpret results and design studies?

  • Marcelle I. Cedars
    Reprint requests: Marcelle I. Cedars, M.D., Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, 550 16th Street, 7th floor, San Francisco, California 94143.
    Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California
    Search for articles by this author
      The way we practice assisted reproductive technology has changed over time. In many ways these changes have been positive as technology has improved, in vitro culture has improved, and embryo selection increasingly allows a single embryo transfer with high success rates and ever smaller multiple birth rates. However, our specialty has often been criticized for not being critical with respect to the acceptance of new technology. Although the outcome of interest seems clear (increasing birth of a healthy baby), the approach can be more complicated; and as there is a de-linking of egg retrieval and ET, and as costs and procedures increase, we should be rigorous about our acceptance of change. This is not to stall change but to encourage the same rigor and questioning of accepted dogma expected in other fields of medicine. An approach based on standard clinical study design to allow appropriate comparisons between patients, and to allow the most comprehensive information for patient counseling, is presented.

      Key Words

      To read this article in full you will need to make a payment


        • Doody K.J.
        Cryopreservation and delayed embryo transfer-assisted reproductive technology registry and reporting implications.
        Fertil Steril. 2014; 102: 27-31
        • Wada I.
        • Matson P.L.
        • Troup S.A.
        • Morroll D.R.
        • Hunt L.
        • Lieberman B.A.
        Does elective cryopreservation of all embryos from women at risk of ovarian hyperstimulation syndrome reduce the incidence of the condition?.
        Br J Obstet Gynaecol. 1993; 100: 265-269
        • Pelkonen S.
        • Koivunen R.
        • Gissler M.
        • Nuojua-Huttunen S.
        • Suikkari A.M.
        • Hyden-Granskog C.
        • et al.
        Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995–2006.
        Hum Reprod. 2010; 25: 914-923
        • D'Angelo A.
        • Amso N.
        Embryo freezing for preventing ovarian hyperstimulation syndrome.
        Cochrane Database Syst Rev. 2007; : CD002806
        • Shapiro B.S.
        • Daneshmand S.T.
        • Garner F.C.
        • Aguirre M.
        • Hudson C.
        Freeze-all can be a superior therapy to another fresh cycle in patients with prior fresh blastocyst implantation failure.
        Reprod Biomed Online. 2014; 29: 286-290
        • Wong K.M.
        • Mastenbroek S.
        • Repping S.
        Cryopreservation of human embryos and its contribution to in vitro fertilization success rates.
        Fertil Steril. 2014; 102: 19-26
        • Weinerman R.
        • Mainigi M.
        Why we should transfer frozen instead of fresh embryos: the translational rationale.
        Fertil Steril. 2014; 102: 10-18
        • Wennerholm U.B.
        • Henningsen A.K.
        • Romundstad L.B.
        • Bergh C.
        • Pinborg A.
        • Skjaerven R.
        • et al.
        Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group.
        Hum Reprod. 2013; 28: 2545-2553
        • Williams R.S.
        • Doody K.J.
        • Schattman G.L.
        • Adashi E.Y.
        Public reporting of assisted reproductive technology outcomes: past, present, and future.
        Am J Obstet Gynecol. 2015; 212: 157-162
        • Glujovsky D.
        • Blake D.
        • Farquhar C.
        • Bardach A.
        Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology.
        Cochrane Database Syst Rev. 2012; : CD002118
        • Shapiro B.S.
        • Daneshmand S.T.
        • Garner F.C.
        • 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: 344-348
        • Shapiro B.S.
        • Daneshmand S.T.
        • Garner F.C.
        • 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 transfers in high responders.
        Fertil Steril. 2011; 96: 516-518
        • Scott Jr., R.T.
        • Upham K.M.
        • Forman E.J.
        • Hong K.H.
        • Scott K.L.
        • Taylor D.
        • et al.
        Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial.
        Fertil Steril. 2013; 100: 697-703
        • Yang Z.
        • Salem S.A.
        • Liu X.
        • Kuang Y.
        • Salem R.D.
        • Liu J.
        Selection of euploid blastocysts for cryopreservation with array comparative genomic hybridization (aCGH) results in increased implantation rates in subsequent frozen and thawed embryo transfer cycles.
        Mol Cytogenet. 2013; 6: 32
        • Forman E.J.
        • Upham K.M.
        • Cheng M.
        • Zhao T.
        • Hong K.H.
        • Treff N.R.
        • et al.
        Comprehensive chromosome screening alters traditional morphology-based embryo selection: a prospective study of 100 consecutive cycles of planned fresh euploid blastocyst transfer.
        Fertil Steril. 2013; 100: 718-724
        • Barnhart K.
        • Osheroff J.
        Follicle stimulating hormone as a predictor of fertility.
        Curr Opin Obstet Gynecol. 1998; 10: 227-232
        • Franasiak J.M.
        • Forman E.J.
        • Hong K.H.
        • Werner M.D.
        • Upham K.M.
        • Treff N.R.
        • et al.
        The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening.
        Fertil Steril. 2014; 101: 656-663.e1
        • Farhi J.
        • Ben-Haroush A.
        • Andrawus N.
        • Pinkas H.
        • Sapir O.
        • Fisch B.
        • et al.
        High serum oestradiol concentrations in IVF cycles increase the risk of pregnancy complications related to abnormal placentation.
        Reprod Biomed Online. 2010; 21: 331-337
        • Imudia A.N.
        • Awonuga A.O.
        • Doyle J.O.
        • Kaimal A.J.
        • Wright D.L.
        • Toth T.L.
        • 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: 1374-1379
        • Imudia A.N.
        • Awonuga A.O.
        • Kaimal A.J.
        • Wright D.L.
        • Styer A.K.
        • Toth T.L.
        Elective cryopreservation of all embryos with subsequent cryothaw embryo transfer in patients at risk for ovarian hyperstimulation syndrome reduces the risk of adverse obstetric outcomes: a preliminary study.
        Fertil Steril. 2013; 99: 168-173
        • Imudia A.N.
        • Goldman R.H.
        • Awonuga A.O.
        • Wright D.L.
        • Styer A.K.
        • Toth T.L.
        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: 65-71
        • Joo B.S.
        • Park S.H.
        • An B.M.
        • Kim K.S.
        • Moon S.E.
        • Moon H.S.
        Serum estradiol levels during controlled ovarian hyperstimulation influence the pregnancy outcome of in vitro fertilization in a concentration-dependent manner.
        Fertil Steril. 2010; 93: 442-446
        • Kyrou D.
        • Popovic-Todorovic B.
        • Fatemi H.M.
        • Bourgain C.
        • Haentjens P.
        • Van Landuyt L.
        • 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: 2902-2909
        • Fauser B.C.
        • de Jong D.
        • Olivennes F.
        • Wramsby H.
        • Tay C.
        • Itskovitz-Eldor J.
        • et al.
        Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization.
        J Clin Endocrinol Metab. 2002; 87: 709-715
        • Humaidan P.
        • Bredkjaer H.E.
        • Bungum L.
        • Bungum M.
        • Grondahl M.L.
        • Westergaard L.
        • et al.
        GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.
        Hum Reprod. 2005; 20: 1213-1220
        • Kolibianakis E.M.
        • Schultze-Mosgau A.
        • Schroer A.
        • van Steirteghem A.
        • Devroey P.
        • Diedrich K.
        • et al.
        A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists.
        Hum Reprod. 2005; 20: 2887-2892
        • Humaidan P.
        • Van Vaerenbergh I.
        • Bourgain C.
        • Alsbjerg B.
        • Blockeel C.
        • Schuit F.
        • et al.
        Endometrial gene expression in the early luteal phase is impacted by mode of triggering final oocyte maturation in recFSH stimulated and GnRH antagonist co-treated IVF cycles.
        Hum Reprod. 2012; 27: 3259-3272
        • Yding Andersen C.
        • Vilbour Andersen K.
        Improving the luteal phase after ovarian stimulation: reviewing new options.
        Reprod Biomed Online. 2014; 28: 552-559
        • Fatemi H.M.
        • Popovic-Todorovic B.
        Implantation in assisted reproduction: a look at endometrial receptivity.
        Reprod Biomed Online. 2013; 27: 530-538
        • Meyer W.R.
        • Novotny D.B.
        • Fritz M.A.
        • Beyler S.A.
        • Wolf L.J.
        • Lessey B.A.
        Effect of exogenous gonadotropins on endometrial maturation in oocyte donors.
        Fertil Steril. 1999; 71: 109-114
        • Liu Y.
        • Lee K.F.
        • Ng E.H.
        • Yeung W.S.
        • Ho P.C.
        Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles.
        Fertil Steril. 2008; 90: 2152-2164
        • Santos M.A.
        • Kuijk E.W.
        • Macklon N.S.
        The impact of ovarian stimulation for IVF on the developing embryo.
        Reproduction. 2010; 139: 23-34
        • Mainigi M.A.
        • Olalere D.
        • Burd I.
        • Sapienza C.
        • Bartolomei M.
        • Coutifaris C.
        Peri-implantation hormonal milieu: elucidating mechanisms of abnormal placentation and fetal growth.
        Biol Reprod. 2014; 90: 26
        • Kalra S.K.
        • Ratcliffe S.J.
        • Coutifaris C.
        • Molinaro T.
        • Barnhart K.T.
        Ovarian stimulation and low birth weight in newborns conceived through in vitro fertilization.
        Obstet Gynecol. 2011; 118: 863-871
        • Henningsen A.K.
        • Pinborg A.
        • Lidegaard O.
        • Vestergaard C.
        • Forman J.L.
        • Andersen A.N.
        Perinatal outcome of singleton siblings born after assisted reproductive technology and spontaneous conception: Danish national sibling-cohort study.
        Fertil Steril. 2011; 95: 959-963
        • Pinborg A.
        • Loft A.
        • Aaris Henningsen A.K.
        • Rasmussen S.
        • Andersen A.N.
        Infant outcome of 957 singletons born after frozen embryo replacement: the Danish National Cohort Study 1995–2006.
        Fertil Steril. 2010; 94: 1320-1327
        • Stehlik E.
        • Stehlik J.
        • Katayama K.P.
        • Kuwayama M.
        • Jambor V.
        • Brohammer R.
        • et al.
        Vitrification demonstrates significant improvement versus slow freezing of human blastocysts.
        Reprod Biomed Online. 2005; 11: 53-57
        • Balaban B.
        • Urman B.
        • Ata B.
        • Isiklar A.
        • Larman M.G.
        • 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: 1976-1982
        • Keskintepe L.
        • Sher G.
        • Machnicka A.
        • Tortoriello D.
        • Bayrak A.
        • Fisch J.
        • et al.
        Vitrification of human embryos subjected to blastomere biopsy for pre-implantation genetic screening produces higher survival and pregnancy rates than slow freezing.
        J Assist Reprod Genet. 2009; 26: 629-635
        • Son W.Y.
        • Chung J.T.
        • Gidoni Y.
        • Holzer H.
        • Levin D.
        • Chian R.C.
        • et al.
        Comparison of survival rate of cleavage stage embryos produced from in vitro maturation cycles after slow freezing and after vitrification.
        Fertil Steril. 2009; 92: 956-958
        • Shin M.R.
        • Choi H.W.
        • Kim M.K.
        • Lee S.H.
        • Lee H.S.
        • Lim C.K.
        In vitro development and gene expression of frozen-thawed 8-cell stage mouse embryos following slow freezing or vitrification.
        Clin Exp Reprod Med. 2011; 38: 203-209
        • Saenz-de-Juano M.D.
        • Marco-Jimenez F.
        • Viudes-de-Castro M.P.
        • Lavara R.
        • Vicente J.S.
        Direct comparison of the effects of slow freezing and vitrification on late blastocyst gene expression, development, implantation and offspring of rabbit morulae.
        Reprod Domest Anim. 2014; 49: 505-511
        • Staessen C.
        • Platteau P.
        • Van Assche E.
        • Michiels A.
        • Tournaye H.
        • Camus M.
        • et al.
        Comparison of blastocyst transfer with or without preimplantation genetic diagnosis for aneuploidy screening in couples with advanced maternal age: a prospective randomized controlled trial.
        Hum Reprod. 2004; 19: 2849-2858
        • Blockeel C.
        • Schutyser V.
        • De Vos A.
        • Verpoest W.
        • De Vos M.
        • Staessen C.
        • et al.
        Prospectively randomized controlled trial of PGS in IVF/ICSI patients with poor implantation.
        Reprod Biomed Online. 2008; 17: 848-854
        • Staessen C.
        • Verpoest W.
        • Donoso P.
        • Haentjens P.
        • Van der Elst J.
        • Liebaers I.
        • et al.
        Preimplantation genetic screening does not improve delivery rate in women under the age of 36 following single-embryo transfer.
        Hum Reprod. 2008; 23: 2818-2825
        • Garrisi J.G.
        • Colls P.
        • Ferry K.M.
        • Zheng X.
        • Garrisi M.G.
        • Munne S.
        Effect of infertility, maternal age, and number of previous miscarriages on the outcome of preimplantation genetic diagnosis for idiopathic recurrent pregnancy loss.
        Fertil Steril. 2009; 92: 288-295
        • Schoolcraft W.B.
        • Katz-Jaffe M.G.
        • Stevens J.
        • Rawlins M.
        • Munne S.
        Preimplantation aneuploidy testing for infertile patients of advanced maternal age: a randomized prospective trial.
        Fertil Steril. 2009; 92: 157-162
        • Debrock S.
        • Melotte C.
        • Spiessens C.
        • Peeraer K.
        • Vanneste E.
        • Meeuwis L.
        • et al.
        Preimplantation genetic screening for aneuploidy of embryos after in vitro fertilization in women aged at least 35 years: a prospective randomized trial.
        Fertil Steril. 2010; 93: 364-373
        • Ajduk A.
        • Zernicka-Goetz M.
        Advances in embryo selection methods.
        F1000 Biol Rep. 2012; 4: 11
        • Mantikou E.
        • Wong K.M.
        • Repping S.
        • Mastenbroek S.
        Molecular origin of mitotic aneuploidies in preimplantation embryos.
        Biochim Biophys Acta. 2012; 1822: 1921-1930
        • Scott Jr., R.T.
        • Upham K.M.
        • Forman E.J.
        • Zhao T.
        • Treff N.R.
        Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial.
        Fertil Steril. 2013; 100: 624-630
        • Lee E.
        • Illingworth P.
        • Wilton L.
        • Chambers G.M.
        The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review.
        Hum Reprod. 2015; 30: 473-483