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Study question Is follicular phase or luteal phase stimulation more effective in progestin primed double stimulation protocol in poor responders? Summary answer The luteal phase stimulation was more effective than follicular phase stimulation in the progestin primed dual stimulation protocol in poor responders. What is known already Poor ovarian responders involve 9–24% of patients undergoing in vitro fertilization (IVF), with the management of these patients posing an everyday practical challenge. Owing to the follicular waves theory, two or three waves of folliculogenesis were detected during the interovulatory interval, two consecutive ovarian stimulation protocols could be initiated in the follicular phase and the subsequent luteal phase. This is an effective way to increase the number of oocytes and embryos obtained over a relative short period of time. Furthermore, there is increasing evidence that progestins can be a reliable method of preventing premature LH surge during ovarian stimulation. Study design, size, duration This was a randomized controlled study performed at the Infertility and Assisted Reproduction Unit of ElShatby Maternity Hospital, Alexandria University and Madinah Fertility Centre. The study was conducted on 90 infertile women with poor ovarian response as defined by the Bologna criteria. 7 patients were excluded due to protocol violation, loss to follow-up and patient withdrawal. The study commenced in September 2020 and was finalized in September 2021. Participants/materials, setting, methods Group 1 45 patients were given the progestin primed double stimulation protocol. Dydrogesterone was started from the first day of the ovulation induction till the end of luteal phase stimulation. Embryo transfer was scheduled in a subsequent cycle. Group 2 45 patients were given the flexible GnRh antagonist protocol in 2 cycles. The best blastocyst from either cycle was transferred in the second cycle. Main results and the role of chance When comparing the follicular and luteal phases, the M2 oocytes number retrieved in the luteal phase was statistically significantly higher than the follicular phase, with the median number of 4 oocytes against a median number of 2 oocytes (P value 0.001). The fertilization rate was significantly higher in the M2 oocytes of the luteal phase stimulation (P value 0.04). The resultant embryos from the luteal stimulation phase were statistically significantly higher than the follicular phase, with the median number of 3 embryos against a median number of 1 embryo (P value <0.001). However, we found that the days of controlled ovarian hyperstimulation were statistically significant higher in stimulation of the luteal phase with the median of 12 days against the 10 days seen in follicular phase stimulation (P value 0.002). Consequently, the total dosage of gonadotropins was statistically significant higher in the luteal phase with a P value of 0.007. After Subgroup analysis, Poseidon Group 4 patients demonstrated that a significantly higher number of oocytes were retrieved after the progestin primed double stimulation than after two waves of flexible GnRh antagonist stimulation (median of 12 oocytes against a median of 10 oocytes with P value 0.01). Limitations, reasons for caution Firstly, preimplantation genetic testing was not performed to detect euploid embryos which could be vital when comparing both the phases and the protocols. Secondly, despite the importance of the live birth rate as an outcome measure, we did not enroll this measure. Wider implications of the findings In the light of our findings, we recommend the usage of progestin primed dual stimulation protocol in poor responder patients. Additionally, we call for multicentric randomized controlled research to verify this protocol as a first-line treatment protocol in poor responder patients. Trial registration number ClinicalTrials.gov ID: NCT04537078

Poor ovarian responders represent a daily clinical challenge to fertility practitioners. Dual stimulation protocols aim at maximizing the number of retrieved oocytes in the shortest time. In this study, the progestin primed double stimulation protocol was compared to 2 cycles of the flexible antagonist protocol in poor responders. Additionally, we have investigated both phases of the double stimulation and the effect of the progestin used, Dydrogesterone, on the ovarian response. 90 poor responders, defined according to Bologna criteria, were randomized into 2 groups. Group I, were stimulated using the progestin primed double stimulation protocol and group II, were stimulated by 2 cycles of the flexible antagonist protocol. Total days of controlled ovarian stimulation and the total gonadotropins requirements were comparable among both groups. However, the number of retrieved oocytes were significant higher in the dual stimulation group. There was no statistically significant difference, in the implantation rate, clinical or the ongoing pregnancy rates. In the dual stimulation group, we found that the stimulation days and the gonadotropins requirements were statistically higher in the luteal phase compared to the follicular phase. But we also noticed that luteal stimulation resulted in a significant increase in the number of mature oocytes, fertilization rate and embryos available for cryopreservation. So, we concluded that progestin primed double stimulation is a valuable option in poor ovarian responders. Trial registration number: ClinicalTrials.gov ID: NCT04537078

further discrimination amongst euploid blastocysts is needed. One consideration might be the quality of the embryos at the cleavage stage on day three.OBJECTIVE: This study seeks to determine if, amongst euploid blastocysts of a single morphologic grade, the day three embryo grade prognosticates differences in implantation rate for that embryo.MATERIALS AND METHODS: First transfer cycles for patients undergoing IVF with comprehensive chromosome screening from 2010 to 2014 were reviewed. Only cycles in which the embryos were cultured in individual droplets, allowing for embryo-specific identification throughout development, were selected. Embryos were graded on day three of development and again at the time of blastocyst biopsy. Using SART guidelines, each embryo was designated as poor, fair, or good at both time points. Euploid embryos were stratified by blastocyst and day three morphologic grade. c2 tests of proportions were used to determine if day three grading had a detectable impact on implantation rates beyond routine characterization of euploid blastocysts.RESULTS: 330 patients had 485 blastocysts transferred. Maternal age was 33.8 AE 4.0 years. As expected, blastocyst morphologic grading correlated with IR (p¼0.0016). In contrast, day three morphology did not correlate with outcomes overall (p¼0.9116). Furthermore, when day three grading was utilized in conjunction with blastocyst grading (table 1) there was no advantage in predicting implantation rate.