Blastocyst-stage versus cleavage-stage embryo transfer in assisted reproductive technology

RATIONALE: Blastocyst-stage transfer has increasingly replaced cleavage-stage transfer in IVF (in vitro fertilisation) programmes. It is thought to improve live birth rates by better synchronising embryo development with the endometrium and allowing self-selection of viable embryos. However, it remains uncertain whether extended culture confers a true biological advantage or mainly reflects selection in vitro, and whether benefits per transfer translate into improved cumulative live birth rates across different patient populations and laboratory settings. OBJECTIVES: To assess the effects of blastocyst-stage (day 5 to 6) embryo transfer compared with cleavage-stage (day 2 to 3) embryo transfer on cumulative live birth rate per woman (defined as the occurrence of at least one live birth resulting from the fresh transfer and all subsequent frozen-thawed embryo transfers derived from the same oocyte retrieval), live birth rate per fresh transfer, and cumulative preterm birth outcomes using the same definition. SEARCH METHODS: On 1 October 2024, we searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. In addition, we searched two trial registries, reference lists of relevant papers, and contacted experts in the field for any additional trials. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that involved women undergoing an assisted reproductive technology cycle and compared blastocyst-stage versus cleavage-stage embryo transfers. OUTCOMES: Our critical outcomes of interest were cumulative live birth rate from fresh and frozen-thawed cycles, live birth rate per fresh transfer, and cumulative preterm birth rate from fresh and frozen-thawed cycles. Our important outcomes of interest were clinical pregnancy rate per fresh transfer, miscarriage rate per fresh transfer, embryo freezing rate, and failure-to-transfer rate. RISK OF BIAS: We assessed the risk of bias in the evidence using Cochrane's RoB 2 tool. SYNTHESIS METHODS: We synthesised results for each outcome using meta-analysis where possible (with a fixed-effect Mantel-Haenszel model). Where this was not possible due to the nature of the data, we provided a narrative description of the results. We used GRADE to assess the certainty of the evidence. INCLUDED STUDIES: We included 36 parallel-design RCTs (8389 participants). Three studies reported cumulative live birth rate (cLBR); two studies reported cumulative obstetric and perinatal outcomes; and 19 studies reported live birth rate (LBR) per fresh transfer. SYNTHESIS OF RESULTS: Blastocyst-stage transfer may increase cLBR within 12 months after oocyte retrieval (OR 1.24, 95% CI 1.04 to 1.47; I² = 70%; 3 studies, 2328 women; low certainty). The high heterogeneity appeared to be explained by one large study in which women underwent an average of two or more embryo transfers, with little or no difference found between strategies (OR 1.02, 95% CI 0.81 to 1.28; 1202 women; low certainty). The meta-analysis result indicates that if 62% of women achieve a live birth after fresh or frozen cleavage-stage transfer, between 63% and 70% would do so with blastocyst-stage transfer. LBR per fresh transfer was probably higher with blastocyst-stage transfer (OR 1.39, 95% CI 1.23 to 1.56; 19 studies, 4787 women; moderate certainty). For fresh transfers, this suggests that if 32% of women achieve a live birth after cleavage-stage transfer, between 37% and 43% would do so after blastocyst-stage transfer. Cumulative preterm birth rates following fresh and frozen transfers are probably higher with blastocyst-stage transfers (OR 1.72, 95% CI 1.14 to 2.59; 2 studies, 2194 women; moderate certainty). This suggests that if 3.5% of women experience preterm birth after cleavage-stage transfer, between 3.9% and 8.5% will do so after blastocyst-stage transfer. The clinical pregnancy rate (CPR) per fresh transfer may be higher with blastocyst-stage transfers (OR 1.31, 95% CI 1.20 to 1.44; I² = 52%; 36 studies, 8389 women; low certainty). This suggests that if 39% of women achieve clinical pregnancy after fresh cleavage-stage transfer, between 43% and 48% will likely do so with blastocyst-stage transfer. There may be little to no difference between groups in miscarriage rate (OR 1.12, 95% CI 0.94 to 1.33; I² = 0%; 25 studies; 6674 women; low certainty). The proportion of women with supernumerary embryos available for cryopreservation for use in a later transfer may be lower in the blastocyst-stage transfer group (OR 0.44, 95% CI 0.38 to 0.52; I² = 82%; 17 studies; 4620 women; low certainty). The failure-to-transfer rate may be higher in the blastocyst-stage transfer group (OR 2.69, 95% CI 1.94 to 3.73; I² = 35%; 21 studies; 5145 women; low certainty). The certainty of evidence was low for most outcomes; it was limited by risk of bias, heterogeneity, imprecision, and poor reporting of randomisation methods. In sensitivity analyses, the findings were similar when we removed data from studies at high risk of bias. AUTHORS' CONCLUSIONS: In the first 12 months of follow-up, cumulative live birth rate (cLBR) may be higher after blastocyst-stage embryo transfer than cleavage-stage transfer in women with a good prognosis for pregnancy. However, while some participants may have used all available embryos within this timeframe, others would have had embryos remaining, so cLBR estimates may be different after complete embryo exhaustion. Fresh blastocyst-stage transfer probably increases live birth rates and may improve clinical pregnancy rates compared to cleavage-stage transfer in women with a good prognosis, but may have little to no effect on miscarriage rate. Cumulative preterm birth (< 37 weeks) probably increases with blastocyst-stage transfer. Embryo freezing may be more common and failure-to-transfer less frequent with cleavage-stage embryos. However, it remains unclear whether these differences translate into higher cumulative live birth rates or instead reflect longer treatment trajectories with increased costs and time to pregnancy. None of these findings should be generalised to women with poor prognoses, who were underrepresented in most included studies. Future research should prioritise the assessment of cumulative live birth rate at extended follow-up, the measurement of miscarriage rates, and the evaluation of obstetric outcomes, particularly in women with poor prognoses. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: Protocol available via DOI 10.1001/14651858: https://doi.org/10.1002/14651858.CD002118. Review versions: https://doi.org/10.1002/14651858.CD002118.pub2; https://doi.org/10.1002/14651858.CD002118.pub3; https://doi.org/10.1002/14651858.CD002118.pub4; https://doi.org/10.1002/14651858.CD002118.pub5; https://doi.org/10.1002/14651858.CD002118.pub6.