Early Cleavage Improves Ongoing Pregnancy Rate When Transferring Non-Top Quality Embryos in IVF Cycles

Abstract

To evaluate the development potential of embryos with early cleavage into top quality embryos and the impact of early cleavage on ongoing pregnancy rates in women undergoing IVF treatment. Analysis of a large, randomized, open-label, assessor-blind, multicenter, multinational trial (MERIT) comparing two gonadotropin preparations in IVF cycles with the long GnRH agonist protocol. Embryo quality and ongoing pregnancy data were collected from 731 ovulatory women with tubal factor, mild male factor, endometriosis stage I/II or unexplained infertility. All were downregulated with triptorelin 0.1 mg SC daily from the mid-luteal phase and randomised to either HP-hMG (MENOPUR, Ferring Pharmaceuticals) (n=363) or recombinant FSH (GONAL-F, Serono) (n=368). The starting dose was 225 IU SC for the first five days and thereafter dose adjustments of 75 IU were allowed not more frequently than every four days. Recombinant hCG 250 μg SC was administered when 3 or more follicles of 17 mm or greater were observed. A total of 7535 oocytes were obtained. Embryo quality was evaluated at 28h, 44h and 68h (±1h) after standard IVF insemination locally at site and subsequently centrally by three independent embryologists based on digital images. All embryologists were blinded to treatment allocation and each others results. A top quality embryo was pre-defined as having 4-5 cells on Day 2, ≥ 7 cells of equal size and ≤ 20% fragmentation on Day 3 and no multinucleation. Transfer of 1-2 embryos of pre-defined quality criteria (minimum: ≥ 4 cells with no cleavage arrest and ≤ 20% fragmentation) was done on Day 3. Ongoing pregnancy was defined as at least one viable fetus 10-11 weeks after embryo transfer. The analysis was based on the central evaluation of embryos and included embryos for which individual outcome was determined, meaning all women with 0% or 100% ongoing implantation rate after single or double embryo transfer. A total of 1123 embryos were 2-cells at 28h based on the central evaluation. Embryos with 2-cells at 28h had a significantly (p<0.001) higher chance of developing into a top quality embryo (32%) compared to those embryos that were not 2-cells at 28h (5%). The ongoing pregnancy rate for women with transfer of top quality embryos was 39% with early cleaved embryos (2-cell at 28h) and 40% with not early cleaved embryos. Concerning non-top quality embryos, the ongoing pregnancy rate was 35% for women with transfer of early cleaved embryos which was significantly (p<0.05) higher than the 19% observed for embryos with no early cleavage. Among single embryo transfers, the ongoing pregnancy rate/implantation rate was 17% for embryos that were 1-cell at 28h compared to 36% for 2-cell embryos (p<0.05). For women with double-embryo transfer, the ongoing pregnancy rate was 36% when both embryos transferred were 2-cells at 28h and 29% when both embryos were 1-cells. Embryos that reach the 2-cells stage at 28h after insemination have a significantly higher chance of developing into top quality embryos. Information on early cleavage will not increase pregnancy rates when transferring top quality embryos on Day 3, but will dramatically increase the pregnancy rates if the embryo transferred is of non-top quality.