Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial

Abstract

ObjectiveTo compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment.DesignMulticentre, randomised controlled superiority trial.SettingOutpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain.Participants460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracytoplasmic sperm injection.InterventionsWomen were randomised at baseline on cycle day 2 or 3 to one of two treatment groups: the freeze-all group (elective freezing of all embryos) who received gonadotropin releasing hormone agonist triggering and single frozen-thawed blastocyst transfer in a subsequent modified natural cycle; or the fresh transfer group who received human chorionic gonadotropin triggering and single blastocyst transfer in the fresh cycle. Women in the fresh transfer group with more than 18 follicles larger than 11 mm on the day of triggering had elective freezing of all embryos and postponement of transfer as a safety measure.Main outcome measuresThe primary outcome was the ongoing pregnancy rate defined as a detectable fetal heart beat after eight weeks of gestation. Secondary outcomes were live birth rate, positive human chorionic gonadotropin rate, time to pregnancy, and pregnancy related, obstetric, and neonatal complications. The primary analysis was performed according to the intention-to-treat principle.ResultsOngoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups (27.8% (62/223) v 29.6% (68/230); risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.76). Additionally, no significant difference was found in the live birth rate (27.4% (61/223) for the freeze-all group and 28.7% (66/230) for the fresh transfer group; risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.83). No significant differences between groups were observed for positive human chorionic gonadotropin rate or pregnancy loss, and none of the women had severe ovarian hyperstimulation syndrome; only one hospital admission related to this condition occurred in the fresh transfer group. The risks of pregnancy related, obstetric, and neonatal complications did not differ between the two groups except for a higher mean birth weight after frozen blastocyst transfer and an increased risk of prematurity after fresh blastocyst transfer. Time to pregnancy was longer in the freeze-all group.ConclusionsIn women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy and live birth rates than a fresh transfer strategy. The findings warrant caution in the indiscriminate application of a freeze-all strategy when no apparent risk of ovarian hyperstimulation syndrome is present.Trial registrationClinicaltrials.gov NCT02746562.

Assisted reproductive technology in Japan: A summary report for 2018 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology

“…A recent multicenter RCT conducted in Europe investigated the effect of freeze‐all and fresh blastocyst ET strategies with a gonadotropin releasing hormone agonist used to trigger final oocyte maturation among 460 women with regular menstrual cycles (mean age of participants 32.4 years in the freeze‐all group and 32.3 years in fresh ET group) demonstrated that the ongoing pregnancy rate, live birth rate, and obstetric and neonatal complications did not differ between the two groups. The study concluded that their findings warrant caution in the indiscriminate application of a freeze‐all strategy when there is no apparent risk of OHSS 10 …”

“…Supraphysiological hormonal environment in fresh ET cycles might affect endometrial receptivity and implantation rate 7 . However, clinical evidence on the effect of a freeze‐all strategy for women with regular menstrual cycles is conflicting 8‐10 . A recently published meta‐analysis including 11 randomized controlled trials (RCTs) with 5379 patients reported that freeze‐all and subsequent elective FET demonstrated that importantly, neither the live birth rate (relative risk, RR 1.03, 95% confidence interval [CI], 0.91‐1.17) in the subgroup of normal responders nor the cumulative live birth rate in the entire population (RR 1.04, 95% CI, 0.97‐1.11) were significantly different between the two groups 7 .…”

Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial

“…The contribution of frozen cycles to cumulative live birth rate was not investigated in this trial, but both dosing approaches were associated with supernumerary blastocysts after stimulation and transfer in the fresh cycle. Knowledge about patient preferences and experiences, including reasons for not pursuing further care or cycles, are important for meeting the needs of the patients, and time to pregnancy plays a critical role in this context (Roque and Simon, 2020;Stormlund et al, 2020).…”

The freeze-all strategy after IVF: which indications?

“…Another important outcome when comparing two different ART strategies, is the time to pregnancy (TTP). Unfortunately, few studies have focused on this matter so far (Stormlund et al, 2020;Vuong et al, 2018b), reporting an increase in the TTP in the freeze-all approach. Based on these findings, it seems inappropriate to implement the freeze-all strategy in all patients undergoing ART, and we will try, hereafter, to discuss the clinical scenarios in which the freeze-all could offer an improvement in terms of pregnancy outcomes or safety.…”

“…Regarding the patients' perspective, one could suppose that couples would naturally opt for the ET strategy minimizing their time to pregnancy, therefore favoring the fresh ET approach (Stormlund et al, 2020;Vuong et al, 2018b). Surprisingly, in a cohort study of 165 patients focusing on their preferences about the ET strategy (Stormlund et al, 2019), the freeze-all strategy was favored by most.…”