Adding Low Dose hCG to rFSH in GnRH Antagonist ICSI Cycles: A Randomized Controlled Trial

Inhibition of luteinizing hormone (LH) by gonadotropin releasing hormone (GnRH) antagonist may lead to suboptimal response during ovarian stimulation. In addition, several studies suggest that low level of LH is associated with lowered fertilization and implantation rate and increased early pregnancy loss rate. The aim of this study is to study the effect of adding low dose human chorionic gonadotropin (hCG - 200 IU), as an LH supplement, to recombinant follicle stimulating hormone (rFSH) in a GnRH antagonist cycles in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. Sixty-three infertile women undergoing IVF were randomly divided into two groups. One group was stimulated with the conventional stimulation protocol (rFSH alone), while the second group received 200 IU hCG in addition to rFSH in the late follicular phase (hCG + rFSH). Both groups' results including pregnancy rate, total dose of rFSH required, duration of stimulation, endometrial thickness, oocytes and embryos characteristic, serum hormone levels (Testosterone, Estradiol, Progesterone, and LH) and level of epidermal growth factor (EGF) were compared. The results show that pregnancy rate among the group of women who received the low dose hCG was higher than those who did not receive hCG. However, this difference did not reach statistical significance. Furthermore, other cycle outcomes and hormonal values were comparable between the two stimulation protocols.

P-777 Comparison of GnRH-a trigger and GnRH-a plus low-dose HCG trigger for high ovarian responders in IVF/ICSI: A retrospective study based on propensity score matching

Study question Does GnRH agonist trigger for high responders during IVF/ICSI cycles improve the number of good-quality embryos, the incidence of moderate-to-severe OHSS, and pregnancy outcome compared to GnRH-a plus low-dose HCG? Summary answer GnRH-a trigger alone can effectively reduce the incidence of moderate-to-severe OHSS in women with high ovarian responses without affecting embryo quality. What is known already Previous studies have shown conflicting results on the different trigger protocol in high responders in IVF/ICSI outcomes, and as for women with high ovarian response, there is little known about the effects of GnRH-a plus low-dose HCG versus GnRH-a alone on oocytes maturation, the rate of good quality embryos, the incidence of moderate-to-severe OHSS, and pregnancy outcome during IVF/ICSI cycles. Study design, size, duration A retrospective analysis was conducted on patients with high ovarian response who received IVF/ICSI treatment with a flexible GnRH antagonist regimen, at the Center of Reproductive Medicine, Chengdu Jinjiang Hospital for Maternal and Child Health Care, from January 1 2017 to December 31 2018. Using 1:1 propensity score matching, 513 cases entered each group (a total of 1,026 females). Participants/materials, setting, methods The high responders were included and assigned to groups A (0.2 mg triptorelin) and B (0.2 mg triptorelin plus 2000 IU HCG) for final oocyte maturation. Their basic clinical characteristics, information about controlled ovarian stimulation cycle, embryologic data, and pregnancy outcome in FET were retrospectively compared. The main outcome measures of the study were the rate of good-quality embryos, the number of available embryos, the incidence of moderate-to-severe OHSS, and the cumulative live-birth rate. Main results and the role of chance Using 1:1 propensity score matching, 513 females were included in each group. No significant differences in baseline clinical data were found between the two groups, including age at diagnosis, spouse’s age, the duration of infertility, the infertility type, and the cause of infertility, BMI, anti-Müllerian hormone (AMH) levels, and the antral follicle count (AFC) (p > 0.05). None significant differences were found in the total doses of gonadotropin (Gn), the duration of ovarian stimulation, serum P and LH levels on the trigger day, the number of oocytes retrieved, the rate of 2PN embryos, and the rate of good-quality embryos (p > 0.05). The serum E2 level on the trigger day in group A was significantly higher than that in group B (p < 0.001). Women in group A had a lower incidence rate of moderate-to-severe OHSS than individuals in group B (p < 0.001). There was a non-significant difference in the cumulative live-birth rate between the two groups (p > 0.05). Limitations, reasons for caution As this is a retrospective study that uses data initially collected for other purposes, limitations may exist in the selection, implementation, and measurement biases that cannot be avoided. However, our study underlies the need for further prospective, multi-center joint-controlled studies to validate these findings. Wider implications of the findings This study demonstrates that GnRH-a alone can reduce the incidence of moderate-to-severe OHSS without harming embyro quality in women with high ovarian response. These findings need further prospective validations in hyperresponsive populations by multi-center, large-sample, randomized controlled studies. Trial registration number N/A

P–777 Comparison of GnRH-a trigger and GnRH-a plus low-dose HCG trigger for high ovarian responders in IVF/ICSI: A retrospective study based on propensity score matching

Study question Does GnRH agonist trigger for high responders during IVF/ICSI cycles improve the number of good-quality embryos, the incidence of moderate-to-severe OHSS, and pregnancy outcome compared to GnRH-a plus low-dose HCG? Summary answer GnRH-a trigger alone can effectively reduce the incidence of moderate-to-severe OHSS in women with high ovarian responses without affecting embryo quality. What is known already Previous studies have shown conflicting results on the different trigger protocol in high responders in IVF/ICSI outcomes, and as for women with high ovarian response, there is little known about the effects of GnRH-a plus low-dose HCG versus GnRH-a alone on oocytes maturation, the rate of good quality embryos, the incidence of moderate-to-severe OHSS, and pregnancy outcome during IVF/ICSI cycles. Study design, size, duration A retrospective analysis was conducted on patients with high ovarian response who received IVF/ICSI treatment with a flexible GnRH antagonist regimen, at the Center of Reproductive Medicine, Chengdu Jinjiang Hospital for Maternal and Child Health Care, from January 1 2017 to December 31 2018. Using 1:1 propensity score matching, 513 cases entered each group (a total of 1,026 females). Participants/materials, setting, methods The high responders were included and assigned to groups A (0.2 mg triptorelin) and B (0.2 mg triptorelin plus 2000 IU HCG) for final oocyte maturation. Their basic clinical characteristics, information about controlled ovarian stimulation cycle, embryologic data, and pregnancy outcome in FET were retrospectively compared. The main outcome measures of the study were the rate of good-quality embryos, the number of available embryos, the incidence of moderate-to-severe OHSS, and the cumulative live-birth rate. Main results and the role of chance Using 1:1 propensity score matching, 513 females were included in each group. No significant differences in baseline clinical data were found between the two groups, including age at diagnosis, spouse’s age, the duration of infertility, the infertility type, and the cause of infertility, BMI, anti-Müllerian hormone (AMH) levels, and the antral follicle count (AFC) (p > 0.05). None significant differences were found in the total doses of gonadotropin (Gn), the duration of ovarian stimulation, serum P and LH levels on the trigger day, the number of oocytes retrieved, the rate of 2PN embryos, and the rate of good-quality embryos (p > 0.05). The serum E2 level on the trigger day in group A was significantly higher than that in group B (p < 0.001). Women in group A had a lower incidence rate of moderate-to-severe OHSS than individuals in group B (p < 0.001). There was a non-significant difference in the cumulative live-birth rate between the two groups (p > 0.05). Limitations, reasons for caution As this is a retrospective study that uses data initially collected for other purposes, limitations may exist in the selection, implementation, and measurement biases that cannot be avoided. However, our study underlies the need for further prospective, multi-center joint-controlled studies to validate these findings. Wider implications of the findings: This study demonstrates that GnRH-a alone can reduce the incidence of moderate-to-severe OHSS without harming embyro quality in women with high ovarian response. These findings need further prospective validations in hyperresponsive populations by multi-center, large-sample, randomized controlled studies. Trial registration number N/A

Low dose hCG supplementation in a Gn-RH-agonist trigger protocol is associated with worse pregnancy outcomes: a retrospective cohort study

Background A number of studies have looked at dual triggers with hCG and GnRH agonist (GnRHa) in varying doses, but the question remains: what is the optimal dose of hCG to minimize ovarian hyperstimulation syndrome (OHSS) and still offer adequate pregnancy rates? The purpose of this study was to compare pregnancy and OHSS rates following dual trigger for oocyte maturation with GnRHa and a low-dose hCG versus hCG alone. A secondary objective was the assess pregnancy outcomes in subsequent frozen cycles for the same population. Methods A total of 963 women < 41 years old, with a BMI 18–40 kg/m2 and an AMH > 2 ng/mL who underwent fresh autologous in vitro fertilization (IVF) with GnRH antagonist protocol at a University-based fertility center were included in this retrospective cohort study. Those who received a low dose dual trigger with hCG (1000u) and GnRHa (2 mg) were compared to those who received hCG alone (10,000u hCG/250-500 μg Ovidrel). Differences in implantation rates, pregnancy, live birth, and OHSS were investigated. Results The dual trigger group was younger (mean 33.6 vs 34.1 years), had a higher AMH (6.3 vs 4.9 ng/mL,) more oocytes retrieved (18.1 vs 14.9) and a higher fertilized oocyte rate (80% vs 77%) compared with the hCG only group. Yet, the dual trigger group had a lower probability of clinical pregnancy (gestational sac, 43.4% vs 52.8%) and live birth (33.4% vs 45.8%), all of which were statistically significant. There were 3 cases of OHSS, all in the hCG-only trigger group. In subsequent frozen cycles, pregnancy rates were comparable between the two groups. Conclusions The dual trigger group had a better prognosis based on age and AMH levels and had better stimulation outcomes, but significantly worse pregnancy outcomes, suggesting the low dose hCG (1000u) in the dual trigger may not have provided adequate luteal support, compared to an hCG-only trigger (10,000u hCG/250-500 μg Ovidrel). Interestingly, the pregnancy rates were comparable in subsequent frozen cycles, further supporting the hypothesis that the issue lies in inadequate luteal phase support, rather than embryo quality. Based on these findings, our program has changed the protocol to 1500u of hCG in a dual trigger.

Dual trigger in normally-responding assisted reproductive technology patients increases the number of top-quality embryos

Objective: The feasibility of a gonadotropin-releasing hormone agonist (GnRHa) trigger in normal responders is still a matter of debate. The aim of this study was to compare the number of mature oocytes, the number of good-quality embryos, and the live birth rate in normal responders triggered by GnRHa alone, GnRHa and human chorionic gonadotropin (hCG; a dual trigger), and hCG alone.Methods: A retrospective cohort study was conducted at the infertility clinic of a university hospital. Data from 200 normal responders who underwent controlled ovarian hyperstimulation and intracytoplasmic sperm injection with a GnRH antagonist protocol between January 2016 and January 2017 were reviewed. The first study group consisted of patients with cycles triggered by GnRHa alone. The second study group consisted of patients with cycles triggered by both GnRHa and low-dose hCG (a dual trigger). The control group consisted of patients with cycles triggered by hCG alone.Results: The groups were comparable in terms of demographics and cycle characteristics. The numbers of total oocytes retrieved and metaphase II oocytes were similar between the groups. The total numbers of grade A embryos were 3.2±2.9 in the GnRHa group, 4.4±3.2 in the dual-trigger group, and 2.9±2.1 in the hCG group (p=0.014). The live birth rates were 21.4%, 30.5%, and 28.2% in those groups, respectively (p=0.126).Conclusion: In normal responders, a dual-trigger approach appears superior to an hCG trigger alone with regard to the number of top-quality embryos produced. However, no clinical benefit was apparent in terms of live birth rates.

The freeze-all strategy versus agonist triggering with low-dose hCG for luteal phase support in IVF/ICSI for high responders: a randomized controlled trial

STUDY QUESTION Does the freeze-all strategy in high-responders increase pregnancy rates and improve safety outcomes when compared with GnRH agonist triggering followed by low-dose hCG intensified luteal support with a fresh embryo transfer? SUMMARY ANSWER Pregnancy rates after either fresh embryo transfer with intensified luteal phase support using low-dose hCG or the freeze-all strategy did not vary significantly; however, moderate-to-severe ovarian hyperstimulation syndrome (OHSS) occurred more frequently in the women who attempted a fresh embryo transfer. WHAT IS KNOWN ALREADY Two strategies following GnRH agonist triggering (the freeze-all approach and a fresh embryo transfer attempt using a low-dose of hCG for intensified luteal phase support) are safer alternatives when compared with conventional hCG triggering with similar pregnancy outcomes. However, these two strategies have never been compared head-to-head in an unrestricted predicted hyper-responder population. STUDY DESIGN, SIZE, DURATION This study included women with an excessive response to ovarian stimulation (≥18 follicles measuring ≥11 mm) undergoing IVF/ICSI in a GnRH antagonist suppressed cycle between 2014 and 2017. Our primary outcome was clinical pregnancy at 7 weeks after the first embryo transfer. Secondary outcomes included live birth and the development of moderate-to-severe OHSS. PARTICIPANTS/MATERIALS, SETTING, METHODS Following GnRH agonist triggering, women were randomized either to cryopreserve all good-quality embryos followed by a frozen embryo transfer in an subsequent artificial cycle or to perform a fresh embryo transfer with intensified luteal phase support (1500 IU hCG on the day of oocyte retrieval, plus oral estradiol 2 mg two times a day, plus 200 mg of micronized vaginal progesterone three times a day). MAIN RESULTS AND THE ROLE OF CHANCE A total of 212 patients (106 in each arm) were recruited in the study, with three patients (one in the fresh embryo transfer group and two in the freeze-all group) later withdrawing their consent to participate in the study. One patient in the freeze-all group became pregnant naturally (clinical pregnancy diagnosed 38 days after randomization) prior to the first frozen embryo transfer. The study arms did not vary significantly in terms of the number of oocytes retrieved and embryos produced/transferred. The intention to treat clinical pregnancy and live birth rates (with the latter excluding four cases lost to follow-up: one in the fresh transfer and three in the freeze-all arms, respectively) after the first embryo transfer did not vary significantly among the fresh embryo transfer and freeze-all study arms: 51/105 (48.6%) versus 57/104 (54.8%) and 41/104 (39.4%) versus 42/101 (41.6%), respectively (relative risk for clinical pregnancy 1.13, 95% CI 0.87–1.47; P = 0.41). However, moderate-to-severe OHSS occurred solely in the group that received low-dose hCG (9/105, 8.6%, 95% CI 3.2% to 13.9% vs 0/104, 95% CI 0 to 3.7, P &lt; 0.01). LIMITATIONS, REASONS FOR CAUTION The sample size calculation was based on a 19% absolute difference in terms of clinical pregnancy rates, therefore smaller differences, as observed in the trial, cannot be reliably excluded as non-significant. WIDER IMPLICATIONS OF THE FINDINGS This study offers the first comparative analysis of two common strategies applied to women performing IVF/ICSI with a high risk to develop OHSS. While pregnancy rates did not vary significantly, a fresh embryo transfer with intensified luteal phase support may still not avoid the risk of moderate-to-severe OHSS and serious consideration should be made before recommending it as a routine first-line treatment. Future trials may allow us to confirm these findings. STUDY FUNDING/COMPETING INTEREST(S) The authors have no conflicts of interest to disclose. No external funding was obtained for this study. TRIAL REGISTRATION NUMBER ClinicalTrials.gov identifier NCT02148393. TRIAL REGISTRATION DATE 28 May 2014 DATE OF FIRST PATIENT’S ENROLMENT 30 May 2014