Non-inferiority of cleavage-stage versus blastocyst-stage embryo transfer in poor prognosis IVF patients (PRECiSE trial): study protocol for a randomized controlled trial.
ABSTRACT: BACKGROUND:With improvements in in vitro culture techniques there has been a steady shift in practice to transfer embryos at the blastocyst stage (post fertilization day (p.f.d.) 5-7), when embryos reach the endometrial cavity during natural conception. For patients with >?5 zygotes on day 1 of embryo development, fresh blastocyst embryo transfer (ET) increases live birth rates when compared to cleavage stage (p.f.d. 3) transfer. In poorer prognosis patients (? 5 zygotes) cleavage stage ET is commonly performed to reduce the risk of cycle cancellation if no embryo survives to the blastocyst stage. However, there is a dearth of randomized controlled trial (RCT) data demonstrating improved live birth rates per cycle for cleavage vs blastocyst stage ET in this subgroup of patients. The hypothesis of the PRECiSE (PooR Embryo Yield Cleavage Stage Versus blaStocyst Embryo Transfer) trial is that blastocyst ET is not inferior to cleavage stage ET with regard to live birth rates per retrieval in poorer prognosis patients. The adoption of routine blastocyst culture for all patients would result in higher rates of single embryo transfers (SET), reduced incidence of multiple pregnancies and simplified laboratory protocols, thereby reducing costs. METHODS/DESIGN:Multicenter, non-inferiority randomized controlled trial (RCT) comparing blastocyst to cleavage stage embryo transfer in poorer prognosis patients with ?5 zygotes on day 1 after fertilization. The primary outcome is live birth per retrieval. Secondary outcomes include: time to pregnancy, clinical pregnancy, ongoing pregnancy, miscarriage and multiple pregnancy rate (per retrieval). This trial will enroll 658 women with ?5 zygotes on day 1 at 6 IVF centers over the course of 22?months. DISCUSSION:If the hypothesis is proven true, the data from this trial may facilitate the adoption of uniform blastocyst culture in all IVF patients. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03764865. Registered 5 December 2019, Protocol issue date: 4 December 2018, Original.
Project description: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.
Project description:This study aims to evaluate the effect of blastocyst- and cleavage-stage embryo transfers with different numbers of transferred embryos on pregnancy outcomes in China. This was a retrospective cohort study that collected 24,422 frozen-thawed embryo transfer (FET) cycles in two affiliated hospitals of Peking University Health Science Center between January 2015 and May 2018. They were divided into four groups: the single cleavage-stage embryo transfer group (C-1) (763 cycles), double cleavage-stage embryo transfer group (C-2) (13,004 cycles), single blastocyst-stage embryo transfer group (B-1) (7913 cycles), and double blastocyst-stage embryo transfer group (B-2) (2046 cycles). Of the four groups, the live birth rate was the lowest in the C-1 group (11.8%) while it was the highest in the B-2 group (33.6%). However, the B-2 group was accompanied with higher risks of miscarriages, maternal complications, twin births, preterm births, and low birth weight. Compared with the C-2 group, the B-1 group had a lower live birth rate (23.0 vs 29.0%; aOR, 0.78; 95% CI, 0.72-0.85), but also had a lower risk for twin births (1.9 vs 23.4%; aOR, 0.06; 95% CI, 0.04-0.09) and preterm births (9.6 vs 16.1%; aOR, 0.51; 95% CI, 0.41-0.65). The probability of live birth in the B-1 group declined from 0.25 at 20-29 years old to 0.08 at >?40 years old, while the probabilities of adverse outcomes went up with maternal age. It can be concluded that single-blastocyst embryo transfer seems to be the best choice for all maternal ages. This group of embryo transfer has significantly reduced adverse neonatal outcomes. Especially, women with younger maternal age in this group appear to prominently benefit from single-blastocyst transfer.
Project description:OBJECTIVE:To evaluate if an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration is associated with a decrease in live-birth rate in patients with a good prognosis. DESIGN:Retrospective cohort study. SETTING:Large, private, assisted reproductive technology (ART) practice. PATIENT(S):One thousand six hundred twenty fresh autologous ART cycles. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Live-birth rate. RESULT(S):A total of 934 blastocyst and 686 cleavage-stage embryo transfer (ET) cycles were evaluated. Serum P levels were not associated with markers of oocyte or embryo quality, including fertilization, embryo stage at transfer, and embryos available for cryopreservation. Patient age, stage of ET, embryo quality, the number of embryos transferred, and P level on the day of hCG administration were all significantly associated with live birth. Higher P levels were associated with decreased odds of live birth for cleavage- and blastocyst-stage embryos, poor-fair and good-quality embryos, and poor- and high-responder patients. The nonsignificance of interaction tests of P levels with embryo stage, embryo quality, patient age, and ovarian response indicated that the relationship between P level and live birth was similar regardless of these factors. CONCLUSION(S):An elevated serum P level on the day of hCG administration was negatively associated with live birth, even in ETs with a good prognosis.
Project description:Objective: To assess the association between serum ovulation trigger progesterone (P) levels and the outcome of in vitro fertilization cycles. Design Setting: Real world single-center retrospective cohort study. Patient Intervention(s): All fresh cleavage and blastocyst-stage embryo transfers (ETs) performed from January 2012 to December 2016. Main outcome Measure(s): The impact of premature high serum P levels cycles in terms of clinical pregnancy rates (CPRs) and live birth rates (LBRs). Results: 8,034 ETs were performed: 7,597 cleavage-stage transfers and 437 blastocyst transfers. Serum P levels demonstrated to be inversely related to CPR (OR 0.72, p < 0.001) and LBR (OR 0.73, p < 0.001). The progressive decrease of LBR and CPR started when P levels were >1 ng/ml in a good prognosis cleavage ET subgroup, whereas in patients with worse prognosis only for P ? 1.75 ng/ml. In the blastocyst ET subgroup, the negative effect of P elevation was reported only if P was >1.75 ng/ml. CPR (OR 0.71 (0.62–0.80), p < 0.001) and LBR (OR 0.73 (0.63–0.84), p < 0.001) in thawed cycles resulted statistically significantly higher than in fresh cycles in the cleavage-stage subgroup. In the blastocyst group, no significant difference resulted between thawed and fresh cycles, independently of P levels [CPR OR 0. 37 (0.49–1.09), p = 0.123; LBR OR 0.71 (0.46–1.10), p = 0.126]. Conclusion: High P levels decrease CPR as well as LBR in both cleavage and blastocyst ET. In the cleavage group, for P levels below 1.75 ng/ml, our data suggest the possibility to wait until day 5 for ET, and if P level is ?1.75 ng/ml, it should be considered to freeze all embryos and postpone the ET. Clinical Trial Registration:ClinicalTrials.gov, ID: NCT04253470
Project description:Background:Previous studies have reported the association between embryo quality and perinatal outcomes in fresh cycles, after cleavage-stage or blastocyst embryo transfer, and found no significant difference. However, in terms of vitrified-warmed embryo transfer cycles, the impact of embryo quality on neonatal and maternal outcomes has not been evaluated. Objectives:To explore the association between the quality of a single vitrified-warmed embryo and perinatal outcomes. Methods:This retrospective study included 2403 live-born singletons derived from single vitrified-warmed embryo transfer cycles during January 2006 and July 2018. Neonatal and maternal outcomes were compared between singletons resulting from the use of single good quality embryo (GQE) (n = 1854) and single poor quality embryo (PQE) (n = 549) and analyzed in the group of cleavage-stage embryo transfer and the group of blastocyst transfer, respectively. Results:A significantly higher risk of low birthweight (LBW, birthweight <2500 g) was observed in the singletons derived from the transfer of single PQE compared with those derived from the transfer of single GQE both in cleavage and blastocyst stages (cleavage-stage, AOR 2.62, 95% CI 1.27-5.37; blastocyst stage, AOR 1.98, 95% CI 1.06-3.70). An increased risk of preterm birth (PTB, gestational age <37 weeks) was also observed in singletons born after transfer of a PQE of cleavage-stage compared with those after a GQE of cleavage-stage (AOR 2.40, 95% CI 1.28-4.49). The transfer of single poor quality blastocyst was associated with a higher risk of placenta previa compared with the transfer of single good quality blastocyst (AOR 2.65, 95% CI 1.26-5.57). Other maternal complications, neonatal malformations, and neonatal complications were similar between compared groups. Conclusion:In vitrified-warmed cycles with single embryo transfer, poor embryo quality would result in a significantly higher risk of LBW, regardless of cleavage-stage or blastocyst embryo transfer. Meanwhile, the transfer of poor cleavage-stage embryo was also associated with an increased incidence of PTB.
Project description:BACKGROUND:Blastomere movement (BMov) occurs after the first cell division in human embryos. This movement has been suggested as a prognostic parameter for pregnancy outcome prediction following cleavage-stage embryo transfer. However, the effect of BMov on preimplantation development and pregnancy outcome after blastocyst transfer remains unclear. Therefore, this study aimed to evaluate whether BMov after the first cell division is correlated with blastocyst formation rate and live birth rate after single vitrified-warmed blastocyst transfer (SVBT). METHODS:Nine hundred and sixty-six embryos cultured in the EmbryoScope+® time-lapse system were retrospectively analyzed. The BMov type was categorized into three groups; namely, bouncing, wobbling, and twist-and-crumble. The BMov duration (dBMov) between the first (t2) and second cell division (t3) was monitored, and the ratio of dBMov to the duration of the 2-cell stage was calculated [dBMov/(t3-t2)]. Developmental rates to the 4-cell, 8-cell, morula, blastocyst, and expanded blastocyst stages were assessed, as well as blastocyst morphological grade. The correlations between dBMov and clinical pregnancy, ongoing pregnancy, and live birth rates were evaluated. RESULTS:Increased dBMov/(t3-t2) was significantly correlated with decreased developmental rates to the 8-cell, morula, blastocyst, and expanded blastocyst stages, especially from the 4-cell stage to the morula stage. Analysis of different types of BMov revealed that embryos with bouncing movement exhibited significantly higher developmental rates to the 8-cell, morula, blastocyst, and expanded blastocyst stages compared with embryos with twist-and-crumble movement. The morphological quality of blastocyst-stage embryos with twist-and-crumble movement was significantly lower than that of embryos with bouncing and wobbling movements. The rates of clinical pregnancy, ongoing pregnancy, and live birth after SVBT were not correlated with BMov type or duration. CONCLUSIONS:Embryonic compaction and subsequent blastocyst formation are adversely affected by twist-and-crumble movement and prolonged movement after the first cell division. Our results indicate that the preimplantation developmental competence of human embryos could be predicted by assessing BMov after the first cell division on day 1.
Project description:<h4>Introduction</h4>In vitro fertilisation (IVF) has evolved as an intervention of choice to help couples with infertility to conceive. In the last decade, a strategy change in the day of embryo transfer has been developed. Many IVF centres choose nowadays to transfer at later stages of embryo development, for example, transferring embryos at blastocyst stage instead of cleavage stage. However, it still is not known which embryo transfer policy in IVF is more efficient in terms of cumulative live birth rate (cLBR), following a fresh and the subsequent frozen-thawed transfers after one oocyte retrieval. Furthermore, studies reporting on obstetric and neonatal outcomes from both transfer policies are limited.<h4>Methods and analysis</h4>We have set up a multicentre randomised superiority trial in the Netherlands, named the Three or Fivetrial. We plan to include 1200 women with an indication for IVF with at least four embryos available on day 2 after the oocyte retrieval. Women are randomly allocated to either (1) control group: embryo transfer on day 3 and cryopreservation of supernumerary good-quality embryos on day 3 or 4, or (2) intervention group: embryo transfer on day 5 and cryopreservation of supernumerary good-quality embryos on day 5 or 6. The primary outcome is the cLBR per oocyte retrieval. Secondary outcomes include LBR following fresh transfer, multiple pregnancy rate and time until pregnancy leading a live birth. We will also assess the obstetric and neonatal outcomes, costs and patients' treatment burden.<h4>Ethics and dissemination</h4>The study protocol has been approved by the Central Committee on Research involving Human Subjects in the Netherlands in June 2018 (CCMO NL 64060.000.18). The results of this trial will be submitted for publication in international peer-reviewed and in open access journals.<h4>Trial registration number</h4>Netherlands Trial Register (NL 6857).
Project description:Background:It is unclear whether we should focus attention on cleavage-stage embryo quality and embryo development speed when transferring single particular grade vitrified-warmed blastocysts, especially poor-quality blastocysts (grade "C"). Method:This retrospective study considered 3386 single vitrified-warmed blastocyst transfer cycles from January 2010 to December 2017. They were divided into group 1 (AA/AB/BA, n = 374), group 2 (BB, n = 1789), group 3 (BC, n = 901), and group 4 (CB, n = 322). The effects of cleavage-stage embryo quality and embryo development speed were measured in terms of clinical pregnancy and live birth rates in each group. Results:Pregnancy outcomes showed a worsening trend from groups 1 to 4; the proportion of embryos with better cleavage-stage quality and faster development speed decreased. In group 1, only the blastocyst expansion degree 3 was a negative factor in the clinical pregnancy rate (odds ratio (OR) [95% confidence interval (CI)]: 0.233 [0.091-0.595]) and live birth rate (0.280 [0.093-0.884]). In the other groups (BB, BC, and CB), blastocysts frozen on day 5 had significantly better clinical pregnancy outcomes than those frozen on day 6: 1.373 [1.095-1.722] for group 2, 1.523 [1.055-2.197] for group 3, and 3.627 [1.715-7.671] for group 4. The live birth rate was 1.342 [1.060-1.700] for group 2, 1.544 [1.058-2.253] in group 3, and 3.202 [1.509-6.795] in group 4, all Ps < 0.05). The degree of blastocoel expansion three for clinical pregnancy rate in group 2 (0.350 [0.135-0.906], P < 0.05) and day 3 blastomere number (>7) for live birth rate in group 4 (2.455 [1.190-5.063], P < 0.05) were two important factors. Conclusion:We should consider choosing BB/BC/CB grade blastocysts frozen on day 5, CB grade blastocysts with day 3 blastomere numbers (>7), and AA/AB/BA grade blastocysts with degrees of expansion (?4) to obtain better pregnancy outcomes.
Project description:BACKGROUND:Successful implantation and delivery require both the functional embryo and receptive endometrium in assisted reproductive technology (ART) cycles. However, little is known about embryo-endometrial interaction on live-birth. We aimed to investigate the independent effect and interaction of endometrial thickness (EMT) and embryo quality on live-birth in fresh embryo transfer (ET) cycles. METHODS:We conducted a retrospective cohort study including 15,012 ART cycles between 2013 and 2016 in three centers in China. Poisson regression with generalized estimating equations was employed to calculate relative risks (RRs) and 95% confidence intervals (CIs). We estimated the interaction of embryo quality and EMT on live-birth rate (LBR). RESULTS:The LBR per cycle was 42.8% overall. LBR increased with increasing EMT and reached a plateau (50.6 to 54.2%) when EMT was 11?mm or thicker. Embryo quality represented by cumulative score was associated with LBR independently of number of embryos transferred and EMT. LBR was not increased with thicker EMT when only Q1 cleavage-stage embryo transferred (aRR 0.95, 95%CI 0.61-1.46). LBR was not increased significantly with thicker EMT with transfer of two good-quality cleavage-stage embryos and any blastocyst combination except Q1 group. There was significant interaction between EMT and embryo quality on LBR for cleavage-stage ETs (P=0.023). CONCLUSIONS:This study demonstrated the nonlinear EMT-LBR association and the EMT cut-off value of 11?mm which may be of more clinical significance for predicting live-birth. Embryo quality is an independent prognostic tool for LBR. Our finding of significant embryo-endometrial interaction indicates combination of EMT and embryos quality might improve the prognostic value in clinical practice for live-birth in patients undergoing transfer of 1-2 fresh cleavage-stage embryos.
Project description:<h4>Objective</h4>To compare the effectiveness of elective single embryo transfer versus double embryo transfer on the outcomes of live birth, multiple live birth, miscarriage, preterm birth, term singleton birth, and low birth weight after fresh embryo transfer, and on the outcomes of cumulative live birth and multiple live birth after fresh and frozen embryo transfers.<h4>Design</h4>One stage meta-analysis of individual patient data.<h4>Data sources</h4>A systematic review of English and non-English articles from Medline, Embase, and the Cochrane Central Register of Controlled Trials (up to 2008). Additional studies were identified by contact with clinical experts and searches of bibliographies of all relevant primary articles. Search terms included embryo transfer, randomised controlled trial, controlled clinical trial, single embryo transfer, and double embryo transfer. Review methods Comparisons of the clinical effectiveness of cleavage stage (day 2 or 3) elective single versus double embryo transfer after fresh or frozen in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included. Trials were included if the intervention differed only in terms of the intended number of embryos to be transferred. Trials that involved only blastocyst (day five) transfers were excluded.<h4>Results</h4>Individual patient data were received for every patient recruited to all eight eligible trials (n=1367). A total of 683 and 684 women randomised to the single and double embryo transfer arms, respectively, were included in the analysis. Baseline characteristics in the two groups were comparable. The overall live birth rate in a fresh IVF cycle was lower after single (181/683, 27%) than double embryo transfer (285/683, 42%) (adjusted odds ratio 0.50, 95% confidence interval 0.39 to 0.63), as was the multiple birth rate (3/181 (2%) v 84/285 (29%)) (0.04, 0.01 to 0.12). An additional frozen single embryo transfer, however, resulted in a cumulative live birth rate not significantly lower than the rate after one fresh double embryo transfer (132/350 (38%) v 149/353 (42%) (0.85, 0.62 to 1.15), with a minimal cumulative risk of multiple birth (1/132 (1%) v 47/149 (32%)). The odds of a term singleton birth (that is, over 37 weeks) after elective single embryo transfer was almost five times higher than the odds after double embryo transfer (4.93, 2.98 to 8.18).<h4>Conclusions</h4>Elective single embryo transfer results in a higher chance of delivering a term singleton live birth compared with double embryo transfer. Although this strategy yields a lower pregnancy rate than a double embryo transfer in a fresh IVF cycle, this difference is almost completely overcome by an additional frozen single embryo transfer cycle. The multiple pregnancy rate after elective single embryo transfer is comparable with that observed in spontaneous pregnancies.