One fresh cleavage-stage single embryo transfer (SET) plus one frozen-thawed blastocyst-stage SET or one fresh cleavage-stage double embryo transfer? A retrospective matched cohort study

Study question: Are there significant differences in fertility outcomes between transferring two cleavage-stage embryos in a single fresh cycle and transferring one cleavage-stage embryo in a fresh cycle and one blastocyst-stage embryo in the subsequent frozen-thawed cycle?

Summary answer: In women aged <38 years with two embryos available, transferring one cleavage-stage embryo in a fresh cycle and one blastocyst-stage embryo in the subsequent frozen-thawed cycle increased live birth rates and decreased multiple live birth rates compared to transferring two cleavage-stage embryos in a single fresh cycle.

What is known already: The strategy of repeated single embryo transfer (SET) has emerged as a solution to address the reduced live birth rates associated with SET per cycle. There is substantial evidence indicating that the cumulative live birth rate after repeated SET is comparable to that of double embryo transfer (DET), while significantly reducing the incidence of multiple pregnancies. Evidence regarding the outcomes of transferring two cleavage-stage embryos in a single fresh cycle versus transferring one cleavage-stage embryo in one fresh cycle and one blastocyst-stage embryo in the subsequent frozen-thawed cycle is scarce.

Study design, size, duration: This study is a retrospective matched cohort study, where data were gathered from the clinical database of women who underwent IVF treatment at the Reproductive Center of Peking University Third Hospital between January 2011 and December 2019, with follow-up extending until December 2021.

Participants/materials, setting, methods: The study group included cycles with a fresh cleavage-stage SET and a subsequent frozen-thawed blastocyst-stage SET (2xSET, N = 976). Fresh cleavage-stage DET was the control group (DET, N = 976). Included cycles were divided into subgroups based on age (≥38 years vs <38 years) and total number of utilizable (transferred or cryopreserved) embryos (=2 vs >2).

Main results and the role of chance: The duration of infertility, prevalence of unexplained infertility, and controlled ovarian stimulation regimes differed significantly between the two groups and were adjusted for in the further analysis. We observed a significant increase in clinical pregnancies (55.5% vs 42%, adjusted odds ratio (OR) 1.87 [1.55-2.26]) and live births (44.8% vs 34.5%, adjusted OR 1.63 [1.35-1.97]) in favor of the 2xSET group. The preterm birth rate was lower in the study group (adjusted OR 0.64 [0.42-0.96]). Neonatal birth weight of singletons was similar between the two groups (adjusted B 4.94 g [-84.5 to 94.4]). The beneficial effect on the live birth rate disappeared in cases where aged 38 years and older or when only two embryos were utilizable.

Limitations, reasons for caution: This study is limited by differences in baseline characteristics of the two groups. Analyzing two consecutive SETs at the cleavage stage was not feasible. Additionally, the homogeneous population limits generalizability to other ethnic groups, which should be considered when interpreting the results broadly.

Wider implications of the findings: We recommend a combination strategy for women under 38 years old and with more than two embryos available: transfer one cleavage-stage embryo in the fresh cycle, followed by one blastocyst-stage embryo in the subsequent frozen-thawed cycle. This strategy reduces the risk of blastocyst culture failure while maintaining a high success rate. It offers hope to families seeking additional children and avoids unnecessary embryo disposal.

Study funding/competing interest(s): B.W.M. had received grants from NHMRC, Ferring, Merck, and Guerbet, consulting fees and stock options from ObsEva, is on the advisory board of ObsEva, and reports consultancy for Guerbet, none of which are in relation to the present manuscript. All other authors have no conflict of interest to declare.

Trial registration number: N/A.