No evidences that implantation of vitrified euploid blastocysts is influenced by ovarian stimulation conducted in luteal vs follicular phase:interim analysis of a prospective multicentre study

Study question: Is there any difference in ongoing pregnancy rate after single embryo transfer (SET) of vitrified euploid blastocysts obtained after lutealphase- stimulation (LPS) vs follicular-phase-stimulation (FPS)? Summary answer: To date, FPS-derived and LPS-derived vitrified euploid blastocysts did not show any evidence of a different reproductive competence. What is known already: Multiple follicular waves can arise during a single menstrual cycle in humans, thereby highlighting a novel folliculogenesis pattern which overtakes the classic theory. Preliminary studies showed that oocytes obtained from anovulatory waves seem developmentally-similar to those obtained from conventional approaches (namely FPS) in terms of fertilization, blastulation and euploidy rates. These observations led to the introduction of novel protocols for ovarian stimulation: random-start, luteal phase-only stimulation and DuoStim (FPS plus LPS in the same menstrual cycle). Study design, size, duration: Multicenter prospective study. 278 poorprognosis women (AMH≤1.5 ng/ml and/or AFC≤6 and/or ≤5oocytes retrieved from a previous cycle and/or ≥35 yr) completed a DuoStim approach combined with preimplantation-genetic-testing (PGT) between October2015– July2017. To date, 174 patients obtained and transferred at least 1 euploid blastocyst either from FPS and/or LPS. Only the first SET performed was included in this study. The primary outcome was the ongoing implantation rate (>20weeks). Biochemical pregnancy loss (BPL), miscarriage and obstetrical/ perinatal outcomes were also monitored. Participants/materials, setting, methods: Both FPS and LPS were performed with gonadotrophins in an antagonist protocol. After the first retrieval from FPS we waited five days before starting LPS. All embryos were cultured to blastocyst, underwent trophectoderm biopsy and vitrification. The samples from FPS and LPS were analyzed in the same run. In presence of euploid blastocysts from both FPS and LPS, the first embryo to be transferred was randomly chosen. Frozen-SETs were performed in a modified-natural or artificial cycle. Main results and the role of chance: To achieve 80% power (α = 0.05) to rule out a 15% difference in ongoing implantation rate between FPS-derived and LPS-derived euploid blastocysts, we require 174 first SETs per arm (348 overall). In this interim analysis we reached 50% of this sample size. The positive pregnancy rates were 57.0% (n = 49/86) and 55.7% (n = 49/88) from FPSderived and LPS-derived euploid blastocysts, respectively. The BPL rates were 8.2% (n = 4/49) and 2.0% (n = 1/49), respectively. The miscarriage rates were 11.1% (n = 5/45) and 12.5% (n = 6/48), respectively. The ongoing pregnancy rates were 46.5% (n = 40/86) and 47.7% (42/88), respectively. To date, 30 FPS-derived and 32 LPS-derived babies have been delivered. Gestational age (38.1 ± 1.1 weeks, range 36-40 versus 38.0 ± 2.2 weeks, 36-41) and birthweight (3308 ± 880 g, 2200-4030 versus 3217 ± 584 g, 2010-4152) were similar so far between study arms. One FPS-derived euploid blastocyst underwent spontaneous embryo twinning and resulted in a multiple pregnancy. One and 2 gestational diabetes were reported in the two study groups, respectively. A FPS-derived pregnancy showed polidramnios and neonatal respiratory distress, which involved 7 days in the neonatal intensive care unit after birth. No neonatal issues have been reported for LPS-derived pregnancies up to now. Limitations, reasons for caution: This is an interim analysis; therefore, we are yet underpowered to draw clear conclusions from these data, especially dealing with obstetrical and perinatal outcomes. Moreover, embryo derived from LPS are obtainted only after DuoStim approach. Wider implications of the findings: LPS in a DuoStim-approach is promising for poor-prognosis (or oncological) patients that need to collect the highest number of oocytes in a short timeframe.Although, any stimulation protocol which exploits anovulatory waves needs a thorough investigation. Here, we produced clinical data to define the safety of the pregnancies achieved after LPS. Trial registration number: None.