STUDY QUESTION: Does single cleavage-stage (Day 3) embryo transfer using a time-lapse (TL) hierarchical classification model achieve comparable ongoing pregnancy rates (OPR) to single blastocyst (Day 5) transfer by conventional morphological (CM) selection?
SUMMARY ANSWER: Day 3 single embryo transfer (SET) with a hierarchical classification model had a significantly lower OPR compared with Day 5 SET with CM selection.
WHAT IS KNOWN ALREADY: Cleavage-stage SET is an alternative to blastocyst SET. Time-lapse imaging assists better embryo selection, based on studies of pregnancy outcomes when adding time-lapse imaging to CM selection at the cleavage or blastocyst stage.
STUDY DESIGN, SIZE, DURATION: This single-centre, randomized, open-label, active-controlled, non-inferiority study included 600 women between October 2015 and April 2017.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible patients were Chinese females, aged ≤36 years, who were undergoing their first or second fresh IVF cycle using their own oocytes, and who had FSH levels ≤12 IU/mL on Day 3 of the cycle and 10 or more oocytes retrieved. Patients who had underlying uterine conditions, oocyte donation, recurrent pregnancy loss, abnormal oocytes or <6 normally fertilized embryos (2PN) were excluded from the study participation. Patients were randomized 1:1 to either the cleavage-stage SET with a time-lapse hierarchical classification model for selection (D3 + TL) or blastocyst SET with CM selection (D5 + CM). All normally fertilized zygotes were cultured in Primo Vision. The study was conducted at a tertiary IVF centre (CITIC-Xiangya) and OPR was the primary outcome.
MAIN RESULTS AND THE ROLE OF CHANCE: A total of 600 patients were randomized to the two groups, among which 585 (D3 + TL = 290, D5 + CM = 295) were included in the Modified-intention-to-treat (mITT) population and 517 (D3 + TL = 261, D5 + CM = 256) were included in the PP population. In the per protocol (PP) population, OPR was significantly lower in the D3 group (59.4%, 155/261) than in the D5 group (68.4%, 175/256) (difference: -9.0%, 95% CI: -17.1%, -0.7%, P = 0.03). Analysis in mITT population showed a marginally significant difference in the OPR between the D3 + TL and D5 + CM groups (56.6 versus 64.1%, difference: -7.5%, 95% CI: -15.4%, 0.4%, P = 0.06). The D3 + TL group resulted in a markedly lower implantation rate than the D5 + CM group (64.4 versus 77.0%; P = 0.002) in the PP analysis, however, the early miscarriage rate did not significantly differ between the two groups.
LIMITATIONS, REASONS FOR CAUTION: The study lacked a direct comparison between time-lapse and CM selections at cleavage-stage SET and was statistically underpowered to detect non-inferiority. The subject's eligibility criteria favouring women with a good prognosis for IVF weakened the generalizability of the results.
WIDER IMPLICATIONS OF THE FINDINGS: The OPR from Day 3 cleavage-stage SET using hierarchical classification time-lapse selection was significantly lower compared with that from Day 5 blastocyst SET using conventional morphology, yet it appeared to be clinically acceptable in women underwent IVF.
STUDY FUNDING/COMPETING INTEREST(S): This study is supported by grants from Ferring Pharmaceuticals and the Program for New Century Excellent Talents in University, China.
TRIAL REGISTRATION NUMBER: ChiCTR-ICR-15006600.
TRIAL REGISTRATION DATE: 16 June 2015.
DATE OF FIRST PATIENT’S ENROLMENT: 1 October 2015.
PURPOSE: Is there a difference in implantation and pregnancy rates between embryos transferred electively at cleavage or blastocyst stage in infertile women ≤ 38 years with at least four zygotes on day 1 post retrieval?
METHODS: A randomized clinical trial was conducted in a single tertiary care hospital with a sample size of 194 patients in each arm for a total population of 388 women. Patients less than 39 years of age with more than three fertilized oocytes and less than four previous assisted reproductive technology (ART) attempts were inclusion criteria.
RESULTS: The two groups were similar for age, years of infertility, indication to treatment, basal antimüllerian hormone and FSH, number of previous ART cycles, primary or secondary infertility, type of induction protocol, days of stimulation, total gonadotrophin dose, and estradiol (E2) and progesterone (P) levels at trigger. No statistically significant differences were found in terms of number of retrieved oocytes, inseminated oocytes, fertilization rate, canceled transfers (7.73% in blastocyst and 3.61% in cleavage stage group), and cycles with frozen embryos and/or oocytes. Although a higher number of fertilized oocytes were in the blastocyst stage group (6.18 ± 1.46 vs 5.89 ± 1.54, p = 0.052), a statistically greater number of embryos/randomized cycle were transferred at cleavage stage (1.93 ± 0.371) compared with the number of transferred blastocysts (1.80 ± 0.56), probably due to the number of embryos not reaching blastocyst stage (3.09%). The implantation rate (28.37 vs 25.67%), pregnancy rate per cycle (36.06 vs38.66%), transfer (39.66 vs 40.11%), spontaneous abortions (19.72% vs 12.00%), delivery rate per cycle (27.84 vs 32.99%), and transfer (30.17 vs 34.22%) were not significantly different between the blastocyst and cleavage stage groups. The twin delivery rate was higher in the blastocyst stage group, although not significant (42.59 vs 28.12%). The mean numbers of frozen blastocyst (2.30 ± 1.40 vs 2.02 ± 1.00) and frozen oocytes (7.09 ± 3.55vs 6.79 ± 3.26) were not significantly different between the two groups.
CONCLUSIONS: Fresh blastocyst-stage transfer versus cleavage-stage transfer did not show any significant difference in terms of implantation and pregnancy rate in this selected group of patients. A high twin delivery rate in both groups (35.59%) was registered, and although not significant, they were higher in the blastocyst transfer group (42.59 vs 28.12%). Our conclusion supports considering single embryo transfer (SET) policy, even in cleavage stage in patients younger than 39 years with at least four zygotes.
TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT02639000.
Objective: This study aimed to show whether transferring day 5 embryos resulted in higher implantation and pregnancy rates than transferring day 3 embryos in Turkish women undergoing an intracytoplasmic sperm injection (ICSI) cycle. Materials and Methods: A total of 190 women who had ICSI after retrieval of more than four oocytes on the day of fertilization check were randomly assigned to undergo embryo transfer either on day 3 or day 5. Results: Day 3 and day 5 transfers were statistically similar with respect to the age of woman (p=0.107), duration of infertility (p=0.528), cause of infertility (p=0.850), number of collected oocytes (p=0.119), number of metaphase II oocytes (p=0.178), number of fertilized oocytes (p=0.092), and number of transferred embryos (p=0.556). The number of grade 1 embryos was significantly higher in day 5 transfers than in day 3 transfers (p=0.001). Day 3 and day 5 embryo transfers had statistically similar implantation, clinical pregnancy, twinning, and live birth rates (p=0.779, p=0.771, p=0.183, and p=0.649, respectively). The live birth rates in singleton pregnancies conceived after day 3 and day 5 embryo transfers were statistically similar (p=0.594). Conclusion: The efficacy of blastocyst transfer is not inferior to that of embryo transfer on cleavage stage. Performing blastocyst transfer may have benefits because it is associated with acceptable pregnancy rates and morphologic assessment on day 3 has limited predictive value for subsequent embryonic development.
STUDY QUESTION: Compared to D5 selection with conventional morphology (CM), does adjunctive use of the Eeva™ test on D3 or D5 improve the clinical pregnancy rate (CPR) per transfer?
SUMMARY ANSWER: The evidence is insufficient to conclude that adjunctive use of the Eeva™ test on D3 or D5 improves CPR per transfer as compared to D5 selection with CM.
WHAT IS KNOWN ALREADY: Time-lapse imaging is increasingly used for embryo selection, despite there being no class I data to support its clinical application.
STUDY DESIGN, SIZE, DURATION: Pilot randomized controlled trial included 163 patients from August 2014 to February 2016.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients up to age 41 years with a planned fresh autologous single embryo transfer (SET), less than four prior oocyte retrievals, and four or more zygotes were blocked according to age (<35, 35-37, 38-40 years) and randomized to one of three study arms: (1) D3 SET + EevaTM, (2) D5 SET + Eeva™ or (3) D5 SET with CM alone. All embryos were cultured in the same time-lapse system under identical conditions. Intention-to-treat (ITT) and as-treated analyses of the primary endpoint (CPR at 7 weeks) and secondary endpoint (ongoing pregnancy rate at 12 weeks) were performed. Multivariate regression analyses adjusted for patient age and ICSI.
MAIN RESULTS AND THE ROLE OF CHANCE: Of 478 eligible patients, 217 consented and 163 were randomized. Demographic characteristics were similar among the three study arms. There were no statistically significant differences in the clinical pregnancy rate or the ongoing pregnancy rate between the study arms for either the ITT or as-treated analyses (CPR ITT: D3 + Eeva™: 41.1% vs. D5 + Eeva™: 38.9% vs. D5 CM: 49.1%).
LIMITATIONS, REASONS FOR CAUTION: This study was designed as a pilot randomized controlled trial and was not powered to detect a statistically significant difference at α < 0.05. Importantly, the study was terminated prematurely by the sponsor due to a change in funding priorities, so the sample size is limited and the results should be interpreted with caution due to the role of chance. Furthermore, these findings may not be generalizable to other time-lapse systems.
WIDER IMPLICATIONS OF THE FINDINGS: Our findings do not support the clinical application of these time-lapse markers.
STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Progyny, Inc. There are no competing interests.
TRIAL REGISTRATION NUMBER: clinicaltrials.gov: NCT02218255.
TRIAL REGISTRATION DATE: 14 August 2014.
DATE OF FIRST PATIENT'S ENROLLMENT: 3 September 2014.
Blastocyst transfer has been introduced as an alternative for improving the chance for in vitro fertilizations (IVF) implantation. The present study was to evaluate pregnancy rates when embryo transfer was performed either on day 2-3 (cleavage stage) or on day 4-5 (blastocyst stage). This randomized clinical trial included 118 infertile women. All the study subjects underwent controlled ovarian stimulation using a long protocol and randomized into two groups. BS group (n = 57), the culture was extended to day 5 (blastocyst stage) and in the CS-group (n = 61), embryo culture was continued to day 3 (cleavage stage). Ongoing pregnancies, abortion, implantation rate were evaluated. No significant differences were seen in the pregnancy rate between the two groups (33.3% in the BS group versus 27.9% in the CS group; p = 0.519). Abortion, implantation rate in two groups are not significant. Despite the lack of statistical difference between the two study groups, our data suggest that blastocyst transfer may be associated with a higher pregnancy and an overall better implantation rates. However, further studies with larger sample size are mandatory to confirm these findings.
Results: A majority of patients (96.6 %) had a blastocyst transfer when at least 4 zygotes were obtained. The ongoing pregnancy rate was significantly higher in the day-5 group compared with the day-3 group (43.1 % vs. 24 %, p = 0.041). The cumulative ongoing pregnancy rate was higher (but not significantly) with blastocyst than with cleavage stage embryos (56.8 % vs. 43.4 %, p = 0.174). When analysed by age, patients 35 or older showed significantly higher ongoing pregnancy rate (48.4 % vs. 19.3 %, p = 0.016) and cumulative ongoing pregnancy rate (58 % vs. 25.8 %, p = 0.01) in the day-5 group compared to the day-3 group, while no such differences were observed in women under 35.
Conclusions: Blastocyst transfer can be suggested whenever there are at least 4 zygotes. While there are no differences in women under 35, the benefit of this option over cleavage stage transfer could be significant in women 35 or older.
Purpose: To determine if blastocyst transfer increases the ongoing and cumulative pregnancy rates, compared with day 3 embryo transfer, in women of all ages when at least 4 zygotes are obtained.
Methods: Prospective study including patients undergoing a first IVF/ICSI treatment and assigned to cleavage stage (n = 46) or blastocyst (n = 58) embryo transfer. Supernumerary embryos were vitrified and patients failing to achieve an ongoing pregnancy after fresh embryo transfer would go through cryopreserved cycles. The main outcome measure was the ongoing pregnancy rate after the fresh IVF/ICSI transfer and the cumulative ongoing pregnancy rate. Results were also analyzed according to age (under 35 and 35 or older).
Does single cleavage-stage (Day 3) embryo transfer using a time-lapse (TL) hierarchical classification model achieve comparable ongoing pregnancy rates (OPR) to single blastocyst (Day 5) transfer by conventional morphological (CM) selection?
SUMMARY ANSWER:
Day 3 single embryo transfer (SET) with a hierarchical classification model had a significantly lower OPR compared with Day 5 SET with CM selection.
WHAT IS KNOWN ALREADY:
Cleavage-stage SET is an alternative to blastocyst SET. Time-lapse imaging assists better embryo selection, based on studies of pregnancy outcomes when adding time-lapse imaging to CM selection at the cleavage or blastocyst stage.
STUDY DESIGN, SIZE, DURATION:
This single-centre, randomized, open-label, active-controlled, non-inferiority study included 600 women between October 2015 and April 2017.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
Eligible patients were Chinese females, aged ≤36 years, who were undergoing their first or second fresh IVF cycle using their own oocytes, and who had FSH levels ≤12 IU/mL on Day 3 of the cycle and 10 or more oocytes retrieved. Patients who had underlying uterine conditions, oocyte donation, recurrent pregnancy loss, abnormal oocytes or <6 normally fertilized embryos (2PN) were excluded from the study participation. Patients were randomized 1:1 to either the cleavage-stage SET with a time-lapse hierarchical classification model for selection (D3 + TL) or blastocyst SET with CM selection (D5 + CM). All normally fertilized zygotes were cultured in Primo Vision. The study was conducted at a tertiary IVF centre (CITIC-Xiangya) and OPR was the primary outcome.
MAIN RESULTS AND THE ROLE OF CHANCE:
A total of 600 patients were randomized to the two groups, among which 585 (D3 + TL = 290, D5 + CM = 295) were included in the Modified-intention-to-treat (mITT) population and 517 (D3 + TL = 261, D5 + CM = 256) were included in the PP population. In the per protocol (PP) population, OPR was significantly lower in the D3 group (59.4%, 155/261) than in the D5 group (68.4%, 175/256) (difference: -9.0%, 95% CI.: -17.1%, -0.7%, P = 0.03). Analysis in mITT population showed a marginally significant difference in the OPR between the D3 + TL and D5 + CM groups (56.6 versus 64.1%, difference: -7.5%, 95% CI.: -15.4%, 0.4%, P = 0.06). The D3 + TL group resulted in a markedly lower implantation rate than the D5 + CM group (64.4 versus 77.0%; P = 0.002) in the PP analysis, however, the early miscarriage rate did not significantly differ between the two groups.
LIMITATIONS, REASONS FOR CAUTION:
The study lacked a direct comparison between time-lapse and CM selections at cleavage-stage SET and was statistically underpowered to detect non-inferiority. The subject's eligibility criteria favouring women with a good prognosis for IVF weakened the generalizability of the results.
WIDER IMPLICATIONS OF THE FINDINGS:
The OPR from Day 3 cleavage-stage SET using hierarchical classification time-lapse selection was significantly lower compared with that from Day 5 blastocyst SET using conventional morphology, yet it appeared to be clinically acceptable in women underwent IVF. STUDY FUNDING/COMPETING INTEREST(S): This study is supported by grants from Ferring Pharmaceuticals and the Program for New Century Excellent Talents in University, China.
