Abstract
BackgroundNon-invasive oocyte quality scoring, based on cumulus gene expression analysis, in combination with morphology scoring, can increase the clinical pregnancy (CPR) and live birth rates (LBR) in Day 3 eSET (elective single embryo transfer) ICSI patients. This was first investigated in a pilot study and is now confirmed in a large patient cohort of 633 patients. It was investigated whether CPR, LBR and time-to-pregnancy could be improved by analyzing the gene expression profile of three predictive genes in the cumulus cells, compared to patients with morphology-based embryo selection only.MethodsA large interventional, non-randomized, assessor-blinded cohort study with 633 ICSI patients was conducted in a tertiary fertility center. Non-PCOS patients, 22–39 years old, with good ovarian reserve, were stimulated with HP-hMG using a GnRH antagonist protocol and planned for fresh Day 3 eSET. The cumulus cells from individually denuded oocytes were ranked by a lab-developed cumulus cell test: qRT-PCR for three predictive genes (CAMK1D, EFNB2 and SASH1) and two control genes (UBC, B2M). The embryo selected for transfer was highest ranked from the pool of morphologically transferable Day 3 embryos. Patients in the control (n = 520) and experimental arm (n = 113) were compared for clinical pregnancy and live birth, using a weighted generalized linear model, and time-to-pregnancy using Kaplan-Meier curves.ResultsThe CPR was 61% in the experimental arm (n = 113) vs 29% in the control arm (n = 520, p < 0.0001). The LBR in the experimental arm (50%) was significantly higher than in the control arm (27%,p < 0.0001). Time-to-pregnancy was significantly shortened by 3 transfer cycles independent of the number of embryos available on Day 3 (Kaplan-Meier, p < 0.0001).Cumulus cell tested patients < 35 years (n = 65) or ≥ 35 years (n = 48) had a CPR of 62 and 60% respectively (ns). For cumulus cell tested patients with 2, 3–4, or > 4 transferable embryos, the CPR was 66, 52, and 67% (ns) respectively, and thus independent of the number of transferable embryos on Day 3.ConclusionsThis study provides further evidence of the clinical usefulness of the non-invasive cumulus cell test over time in a larger patient cohort.Trial registrationClinicaltrials.gov, NCT03659786/NCT02962466 (Registered 6Sep2018/11Nov2016, retrospectively registered.
Highlights
Non-invasive oocyte quality scoring, based on cumulus gene expression analysis, in combination with morphology scoring, can increase the clinical pregnancy (CPR) and live birth rates (LBR) in Day 3 Elective single embryo transfer (eSET) intracytoplasmic sperm injection (ICSI) patients
Sample size calculation showed that, if we considered a 95% power, and 20% variability in a two-sided test, because the morphological evaluation is performed by several embryologists, 107 informative patients were needed in the experimental arm, after all drop-outs, to show a 25% increase of CPR after fresh eSET
The study was designed to validate a 25% increase in CPR by ranking transferable embryos based on gene expression in cumulus cells
Summary
Non-invasive oocyte quality scoring, based on cumulus gene expression analysis, in combination with morphology scoring, can increase the clinical pregnancy (CPR) and live birth rates (LBR) in Day 3 eSET (elective single embryo transfer) ICSI patients. This was first investigated in a pilot study and is confirmed in a large patient cohort of 633 patients. CPR and LBR rates for a fresh Day 3 SET are between 27 and 35% and 23–29% in Europe [5, 7, 22], respectively, for women between 22 and 38 of age with good ovarian reserve and for first or second ranked ICSI cycles. In highly selected cohorts of young patients, success rates of 50–60% per blastocyst transfer have been reported with a “freeze-all” strategy in combination with preimplantation genetic testing for aneuploidy screening (PGT-A) [24, 29]
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