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.

Xenopus cadherins: the maternal pool comprises distinguishable members of the family.

Three maternal cadherins have been reported to occur in the pregastrula Xenopus embryo. EP- and XB-cadherin are distinguished by their distinct cDNA sequences. U-cadherin has been characterized by its reaction with a specific monoclonal antibody (mAb 6D5). Thus far, lack of specific probes that discriminate between these molecules has prevented their identification as distinct cadherins. We now demonstrate by means of RNase protection assays that both EP- and XB-cadherin mRNAs are present in oocytes and mature eggs. By use of the Xenopus cadherin proteins expressed in mammalian cell lines, we find that mAb 6D5 crossreacts with XB-cadherin, but not with EP-cadherin. The major fraction of the maternal cadherins does not contain the 6D5 epitope and probably represents EP-cadherin. A minor fraction carries the 6D5 epitope indicative for the XB- and U-type of cadherins. We have termed this fraction XB/U-cadherin. The function of maternal cadherins was examined by in vitro cell adhesion assays. A newly developed antiserum with a broad specificity for various Xenopus cadherins efficiently blocks all calcium dependent cell adhesion in the early embryo. We conclude that the maternal cadherins play a central role in interblastomere adhesion in the early embryo and comprise at least two discrete cadherin forms, EP- and XB/U-cadherin.