Blastocyst vs cleavage-stage embryo transfer: systematic review and meta-analysis of reproductive outcomes.

OBJECTIVES: Blastocyst transfer in assisted reproduction techniques could be advantageous because the timing of exposure of the embryo to the uterine environment is more analogous to a natural cycle and permits embryo self-selection after activation of the embryonic genome on day 3. Conversely, the in-vitro environment is likely to be inferior to that in vivo, and in-vitro culture beyond embryonic genomic activation could potentially harm the embryo. Our objective was to identify, appraise and summarize the available evidence comparing the effectiveness of blastocyst vs cleavage-stage embryo transfer. METHODS: This was a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the transfer of blastocysts (days 5-6) with the transfer of cleavage-stage embryos (days 2-3) in women undergoing in-vitro fertilization or intracytoplasmic sperm injection. The last electronic searches were run on 1 August 2016. Abstracts and studies with a mean difference between the two study groups of > 0.5 for the number of embryos transferred were excluded. RESULTS: We screened 1187 records and assessed 33 potentially eligible studies. Twelve studies were included, comprising a total of 1200 women undergoing blastocyst transfer and 1218 undergoing cleavage-stage embryo transfer. We observed low-quality evidence of no significant difference of blastocyst transfer on live birth/ongoing pregnancy (relative risk (RR), 1.11 (95% CI, 0.92-1.35), 10 RCTs, 1940 women, I2 = 54%), clinical pregnancy (RR, 1.10 (95% CI, 0.93-1.31), 12 RCTs, 2418 women, I2 = 64%), cumulative pregnancy (RR, 0.89 (95% CI, 0.67-1.16), four RCTs, 524 women, I2 = 63%) and miscarriage (RR, 1.08 (95% CI, 0.74-1.56), 10 RCTs, 763 pregnancies, I2 = 0%). There was moderate-quality evidence of a decrease in the number of women with surplus embryos after the blastocyst-stage embryo transfer (RR, 0.78 (95% CI, 0.66-0.91)). Overall, the quality of the evidence was limited by the quality of the included studies and by unexplained inconsistency across studies. CONCLUSIONS: Current evidence shows no superiority of blastocyst compared with cleavage-stage embryo transfer in clinical practice. As the quality of the evidence for the primary outcomes is low, additional well-designed RCTs are still needed before robust conclusions can be drawn. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Obstetrical and perinatal outcomes following blastocyst transfer compared to cleavage transfer: a systematic review and meta-analysis.

STUDY QUESTION: Is blastocyst transfer safe when compared to cleavage stage embryo transfer regarding obstetric and perinatal outcomes? SUMMARY ANSWER: The clinical equipoise between blastocyst and cleavage stage embryo transfer remains as the evidence associating blastocyst transfer with some adverse perinatal outcomes is of low/very low quality. WHAT IS KNOWN ALREADY: Extended embryo culture to the blastocyst stage provides some theoretical advantages and disadvantages. While it permits embryo self-selection, it also exposes those embryos to possible harm due to the in vitro environment. Both effectiveness and safety should be weighed to permit evidence-based decisions in clinical practice. STUDY DESIGN, SIZE, DURATION: This is a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies reporting perinatal outcomes for singletons comparing the deliveries resulting from blastocyst and cleavage stage embryo transfer. Observational studies were included because the primary outcomes, perinatal mortality and birth defects, are rare and require a large number of participants (>50 000) to be properly assessed. The last electronic searches were last run on 11 March 2016. PARTICIPANTS/MATERIALS, SETTING, METHOD: There were 12 observational studies encompassing 195 325 singleton pregnancies included in the study. No RCT reported the studied outcomes. The quality of the included studies was evaluated according to the Newcastle-Ottawa Scale and the quality of the evidence was evaluated according to GRADE criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Blastocyst stage transfer was associated with increased risks of preterm birth (<37 weeks), very preterm birth (<32 weeks), large for gestational age and perinatal mortality, although the latter was only identified from one study. Conversely, blastocyst stage transfer was associated with a decrease in the risks of small for gestational age and vanishing twins, although the latter was reported by only one study. LIMITATIONS, REASONS FOR CAUTION: The observational nature of the included studies and some inconsistency and imprecision in the analysis contributed to decreasing our confidence in the estimates. WIDER IMPLICATIONS OF THE FINDINGS: Due to the overall low quality of available evidence, the clinical equipoise between cleavage stage and blastocyst transfer remains. More large well-conducted studies are needed to clarify the potential risks and benefits of blastocyst transfer. As this review was initiated to support global recommendations on best practice, and in light of the challenges in lower resource settings to offer extended culture to blastocyst stage, it is critical to take into consideration these obstetric and neonatal outcomes in order to ensure any recommendation will not result in the overburdening of existing maternal and child health care systems and services. STUDY FUNDING/COMPETING INTERESTS: No external funding was either sought or obtained for this study. The authors have no competing interests to declare. PROSPERO REGISTRATION NUMBER: CRD42015023910.

Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology.

BACKGROUND: Advances in cell culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage stage embryo transfer to blastocyst stage transfer. The rationale for blastocyst transfer is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos, thus resulting in better live birth rates. OBJECTIVES: To determine whether blastocyst stage (day 5 to 6) embryo transfers improve the live birth rate, and other associated outcomes, compared with cleavage stage (day 2 to 3) embryo transfers. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2016, Issue 4), MEDLINE, EMBASE, PsycINFO, CINAHL, and Bio extracts from inception to 4th April 2016. We also searched registers of ongoing trials and the reference lists of studies retrieved. SELECTION CRITERIA: We included randomised controlled trials (RCTs) which compared the effectiveness of blastocyst versus cleavage stage transfers. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth and cumulative clinical pregnancy rates. Secondary outcomes were clinical pregnancy, multiple pregnancy, high order pregnancy, miscarriage, failure to transfer embryos, and embryo freezing. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. MAIN RESULTS: We included 27 RCTs (4031 couples or women).The live birth rate following fresh transfer was higher in the blastocyst transfer group (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.20 to 1.82; 13 RCTs, 1630 women, I(2) = 45%, low quality evidence) following fresh transfer. This suggests that if 29% of women achieve live birth after fresh cleavage stage transfer, between 32% and 42% would do so after fresh blastocyst stage transfer.There was no evidence of a difference between the groups in rates per couple of cumulative pregnancy following fresh and frozen-thawed transfer after one oocyte retrieval (OR 0.89, 95% CI 0.64 to 1.22; 5 RCTs, 632 women, I(2) = 71%, very low quality evidence).The clinical pregnancy rate was also higher in the blastocyst transfer group, following fresh transfer (OR 1.30, 95% CI 1.14 to 1.47; 27 RCTs, 4031 women, I(2) = 56%, moderate quality evidence). This suggests that if 36% of women achieve clinical pregnancy after fresh cleavage stage transfer, between 39% and 46% would do so after fresh blastocyst stage transfer.There was no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; 19 RCTs, 3019 women, I(2) = 30%, low quality evidence), or miscarriage (OR 1.15, 95% CI 0.88 to 1.50; 18 RCTs, 2917 women, I(2) = 0%, low quality evidence). These data are incomplete as under 70% of studies reported these outcomes.Embryo freezing rates were lower in the blastocyst transfer group (OR 0.48, 95% CI 0.40 to 0.57; 14 RCTs, 2292 women, I(2) = 84%, low quality evidence). This suggests that if 60% of women have embryos frozen after cleavage stage transfer, between 37% and 46% would do so after blastocyst stage transfer. Failure to transfer any embryos was higher in the blastocyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; 17 RCTs, 2577 women, I(2) = 36%, moderate quality evidence). This suggests that if 1% of women have no embryos transferred in (planned) fresh cleavage stage transfer, between 2% and 4% will have no embryos transferred in (planned) fresh blastocyst stage transfer.The evidence was of low quality for most outcomes. The main limitation was serious risk of bias, associated with failure to describe acceptable methods of randomisation, and unclear or high risk of attrition bias. AUTHORS' CONCLUSIONS: There is low quality evidence for live birth and moderate quality evidence for clinical pregnancy that fresh blastocyst stage transfer is associated with higher rates than fresh cleavage stage transfer. There was no evidence of a difference between the groups in cumulative pregnancy rates derived from fresh and frozen-thawed cycles following a single oocyte retrieval, but the evidence for this outcome was very low quality. Thus, although there is a benefit favouring blastocyst transfer in fresh cycles, it remains unclear whether the day of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage to enable couples or women undergoing assisted reproductive technology (ART) and service providers to make well informed decisions on the best treatment option available.

Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology.

BACKGROUND: Advances in cell culture media have led to a shift in in vitro fertilization (IVF) practice from early cleavage embryo transfer to blastocyst stage transfer. The rationale for blastocyst culture is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos thus resulting in higher implantation rates. OBJECTIVES: To determine if blastocyst stage (Day 5 to 6) embryo transfers (ETs) improve live birth rate and other associated outcomes compared with cleavage stage (Day 2 to 3) ETs. SEARCH METHODS: Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE and Bio extracts. The last search date was 21 February 2012. SELECTION CRITERIA: Trials were included if they were randomised and compared the effectiveness of early cleavage versus blastocyst stage transfers. DATA COLLECTION AND ANALYSIS: Of the 50 trials that were identified, 23 randomised controlled trials (RCTs) met the inclusion criteria and were reviewed (five new studies were added in this update). The primary outcome was rate of live birth. Secondary outcomes were rates per couple of clinical pregnancy, cumulative clinical pregnancy, multiple pregnancy, high order pregnancy, miscarriage, failure to transfer embryos and cryopreservation. Quality assessment, data extraction and meta-analysis were performed following Cochrane guidelines. MAIN RESULTS: Twelve RCTs reported live birth rates and there was evidence of a significant difference in live birth rate per couple favouring blastocyst culture (1510 women, Peto OR 1.40, 95% CI 1.13 to 1.74) (Day 2 to 3: 31%; Day 5 to 6: 38.8%, I(2) = 40%). This means that for a typical rate of 31% in clinics that use early cleavage stage cycles, the rate of live births would increase to 32% to 42% if clinics used blastocyst transfer.There was no difference in clinical pregnancy rate between early cleavage and blastocyst transfer in the 23 RCTs (Peto OR 1.14, 95% CI 0.99 to 1.32) (Day 2 to 3: 38.6%; Day 5 to 6: 41.6%) and no difference in miscarriage rate (13 RCTs, Peto OR 1.18, 95% CI 0.86 to 1.60). The four RCTs that reported cumulative pregnancy rates (266 women, Peto OR 1.58, 95% CI 1.11 to 2.25) (Day 2 to 3: 56.8%; Day 5 to 6: 46.3%) significantly favoured early cleavage. Embryo freezing rates (11 RCTs, 1729 women, Peto OR 2.88, 95% CI 2.35 to 3.51) and failure to transfer embryos (16 RCTs, 2459 women, OR 0.35, 95% CI 0.24 to 0.51) (Day 2 to 3: 3.4%; Day 5 to 6: 8.9%) favoured cleavage stage transfer. AUTHORS' CONCLUSIONS: This review provides evidence that there is a small significant difference in live birth rates in favour of blastocyst transfer (Day 5 to 6) compared to cleavage stage transfer (Day 2 to 3). However, cumulative clinical pregnancy rates from cleavage stage (derived from fresh and thaw cycles) resulted in higher clinical pregnancy rates than from blastocyst cycles. The most likely explanation for this is the higher rates of frozen embryos and lower failure to transfer rates per couple obtained from cleavage stage protocols. Future RCTs should report miscarriage, live birth and cumulative live birth rates to enable ART consumers and service providers to make well informed decisions on the best treatment option available.

Embryo selection by the first cleavage parameter between 25 and 27 hours after ICSI.

PURPOSE: The objective of this study was to assess first embryo cleavage (FEC) 25-27 h after intracytoplasmic sperm injection (ICSI) as a parameter for the embryo selection process. METHODS: From January 1998 to December 1999, a total of 670 patients were subjected to the ICSI programme at the Centre for Human Reproduction, Sinhá Junqueira Maternity Foundation, and the FEC parameter was evaluated in three situations. RESULTS: In the first, a total of 300 zygotes were analyzed on the basis of a score (16-18 h after ICSI) and observed for the presence or absence of FEC (25-27 h after ICSI). A significant (p < 0.02) presence of FEC was observed in zygotes with a score of 15 (ideal score). In the second, a total of 200 patients were selected and divided into two groups matched for age and laboratory performance. Group I (n = 100) was subjected to transfer of embryos with the absence of FEC only (since in this cycle no embryos with FEC were detected within 25-27 h after ICSI) and Group II (n = 100) was subjected to transfer of embryos with the presence of FEC only. The age of Group I patients (33.8 +/- 4.2 years) did not differ significantly (p = 0.50) from that of Group II patients (33.5 +/- 4.3 years). The number of embryos transferred was similar (p = 0.07) for Group I (2.7 +/- 1.1) and Group II (2.9 +/- 0.88). In Group II, the 17.5% implantation rate was significantly higher (p < 0.01) than the 5.9% rate obtained for Group I. The pregnancy rate for Group II was significantly higher (p < 0.01) (33%) than that for Group I (12%). The incidence of abortion was 16.6% in Group I as compared with 6% in Group II. In the third situation, we observed the frequency of embryos with FEC in 36 patients whose implantation rate was 100% (ideal result) and obtained a value of 82%. CONCLUSIONS: The data suggest that the presence of the FEC parameter that was evaluated 25-27 h after ICSI could be used to select embryos with a higher implantation power. The data reported here may justify routine analysis of embryos with FEC for the process of embryo selection after ICSI.