Prediction of Patients with Ovarian Hyperstimulation Syndrome in Gnrh-A Prolonged Protocol : A Retrospective Study

Background: OHSS (ovarian hyperstimulation syndrome) is a life-threatening complication and most common adverse effect of fertility treatmentObjectives: To investigate associated risk factors of ovarian hyperstimulation syndrome (OHSS) in stimulated ovarian cycles with assisted reproductive technology, may provide guidance for clinicians on how to prevent OHSS. Methods: A Logistic regression analysis was conducted in 336 patients who had completed IVF-ICSI/ET cycles between April 2019 and April 2020 in the first affiliated hospital of kunming medical university. Receiver-operating characteristic (ROC) curves for OHSS were calculated for each predictor using cut-off values. Area under the curve (AUC) analysis and logistic regression models were performed to compare the performance of laboratory biomarkers. Results: According to clinical diagnosis, 61 cycles developed OHSS of 336 cycles, with an incidence of 18.15%. Patients were graded according to their clinical symptoms and severity, including 27 cycles of moderate OHSS (8.04%) and 8 cycles of severe OHSS (2.38%). The cut-off value of AMH, E2 on HCG day, egg retrieved to predict moderate and severe OHSS were 7.495ng/ml, 4828pg/ml and 19.5 in GnRH-a Prolonged Protocol, with sensitivities of 77.0%, 67.2%, 80.3%, and specificity of 68.0%, 70.9%, 81.5% respectively. The area under the curve (AUC) values of AMH, E2 on HCG day, Number of oocytes retrieved to predict moderate and severe OHSS were 0.754, 0.738, 0.876, respectively. And the AUC value of combined index to predict moderate and severe OHSS was 0.898, achieved the highest AUC with 85.2% sensitivity and 83.6% specificity. Conclusions:AMH, E2 day of HCG and number of eggs obtained have a good predictive effect on the occurrence of OHSS, and the predictive ability is further improved after the combination of the three indicators.

Clinical Pregnancy and Incidence of Ovarian Hyperstimulation Syndrome in High Ovarian Responders Receiving Different Doses of hCG Supplementation in a GnRH-Agonist Trigger Protocol

Objective. Ovarian hyperstimulation syndrome (OHSS) is a side effect of the exogenous human chorionic gonadotropin (hCG) hormones used to trigger oocyte maturation. High ovarian responders represent a population with a higher risk of OHSS and are characterized by an exaggerated response to gonadotropin administration. In this study, we compared clinical pregnancy and incidence of OHSS in high ovarian responders receiving different doses of hCG supplementation in a GnRH-agonist trigger protocol. Methods. A total of 205 high ovarian responders who were to undergo in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles were recruited and randomly assigned to receive different doses of hCG supplementation in a GnRH-agonist trigger protocol: GnRH-a (n = 42), GnRH-a + 1000 IU hCG (n = 49), GnRH-a + 2000 IU hCG (n = 54), and GnRH-a + 3000 IU hCG (n = 60) groups. Results. The GnRH-a + 1000 IU hCG, GnRH-a + 2000 IU hCG, and GnRH-a + 3000 IU hCG groups had more oocytes retrieved, embryos, high-quality embryos, and a higher rate of high-quality embryos than the GnRH-a group ( p < 0.05 ). The GnRH-a + 1000 IU hCG group demonstrated more oocytes retrieved, embryos, high-quality embryos, and a higher rate of high-quality embryos than the GnRH-a + 2000 IU hCG and GnRH-a + 3000 IU hCG groups ( p < 0.05 ). No moderate and severe OHSS cases occurred in the GnRH-a and GnRH-a + 1000 IU hCG groups. The incidence rate of moderate and severe OHSS was remarkably lower in the GnRH-a group and GnRH-a + 1000 IU hCG groups than in the GnRH-a + 2000 IU hCG and GnRH-a + 3000 IU hCG groups ( p < 0.05 ). The GnRH-a + 1000 IU hCG, GnRH-a + 2000 IU hCG, and GnRH-a + 3000 IU hCG groups had a higher clinical pregnancy rate than the GnRH-a group, showing no significant difference ( p > 0.05 ). The GnRH-a + 1000 IU hCG, GnRH-a + 2000 IU hCG, and GnRH-a + 3000 IU hCG groups had a lower abortion rate than the GnRH-a group ( p < 0.05 ). Conclusion. Based on the data obtained from this prospective study, we recommend 1000 IU hCG supplementation in a GnRH-agonist trigger protocol for high ovarian responders during IVF/ICSI cycles considering a higher rate of high-quality embryos, a lower incidence rate of moderate and severe OHSS, and a lower abortion rate.

Coagulation and Fibrinolysis Biomarkers as Potential Indicators for the Diagnosis and Classification of Ovarian Hyperstimulation Syndrome

Background: Accurate diagnosis and classification of ovarian hyperstimulation syndrome (OHSS) is important for its management. We employed a new high-sensitivity chemiluminescence immunoassay to detect the thrombin-antithrombin complex (TAT), plasmin alpha2-plasmin inhibitor complex (PIC), soluble thrombomodulin (sTM), and tissue plasminogen activator-inhibitor complex (TPAI-C), and evaluated their diagnostic and classification performance for OHSS.Methods: A total of 106 women were enrolled, including 51 patients with OHSS (25 mild or moderate OHSS, 26 severe OHSS), and 55 without OHSS (control group). TAT, PIC, sTM, and TPAI-C levels were measured using the Sysmex HISCL5000 automated analyzer.Results: Compared to the control group, TAT, PIC, and TPAI-C levels were significantly higher (P &lt; 0.001, P &lt; 0.001, P &lt; 0.001, respectively), whereas the sTM level was significantly lower (P &lt; 0.001) in the patients with OHSS. The receiver operating characteristic was used to evaluate the diagnostic efficiency. For the diagnosis of OHSS, the area under the curves (AUCs) for TAT, PIC, sTM, and TPAI-C were 0.991, 0.973, 0.809, and 0.722, respectively. In particular, the sensitivity, specificity, positive predictive value, and negative predictive value for TAT and PIC were all above 90%. For the differential diagnosis of mild–moderate and severe OHSS, the AUCs for TAT, PIC, and TPAI-C were 0.736, 0.735, and 0.818, respectively. The cutoff values of TAT, PIC, and TPAI-C for the differential diagnosis of mild–moderate and severe OHSS were 11.5 ng/mL, 2.4 μg/mL, and 5.8 ng/mL, respectively. Based on these cutoff values, eight cases of mild–moderate OHSS exceeded the cutoff values, two of which developed to severe OHSS in the following days. However, of the remaining 17 cases of mild–moderate OHSS patients with negative biomarkers, none subsequently developed severe OHSS.Conclusions: TAT, PIC, sTM, and TPAI-C can be used as sensitive biomarkers in the diagnosis of OHSS. Meanwhile, TAT, PIC, and TPAI-C also displayed remarkable potential in the classification of OHSS. In addition, the levels of TAT, PIC, and TPAI-C above the cutoff values in patients with mild–moderate OHSS might predict a high risk of developing severe OHSS.

Cocktail Treatment by GnRH-Antagonist, Letrozole, and Mifepristone for the Prevention of Ovarian Hyperstimulation Syndrome: A Prospective Randomized Trial

Ovarian hyperstimulation syndrome (OHSS) is a major complication of controlled ovarian hyperstimulation. This study is aimed to determine the efficacy of a cocktail style treatment by combining GnRH-antagonist, letrozole, and mifepristone on the prevention of ovarian hyperstimulation syndrome (OHSS) in high-risk women. This prospective, randomized controlled clinical trial included 170 women who identified as high risk of OHSS during the ovarian hyperstimulation and underwent cryopreservation of whole embryos. On the day of oocyte retrieval, the combination group (89 cases) received 0.25 mg Cetrorelix for three days, 5 mg letrozole for five days, and 50 mg mifepristone for three days, the mifepristone group (80 cases) received 50 mg mifepristone for three days. 156 cases were included in final analysis. The combination group showed significantly decreased incidence of moderate and severe OHSS than mifepristone group (20.5% vs. 42.3%), with remarkably reduced serum estradiol level on hCG+3 and +5 day, decreased ovarian diameter, and shortened luteal phase. Oocyte retrieval number, levels of estradiol on hCG+0 and VEGF, and ovarian diameter on hCG+5 were associated with the severity of the symptoms. In Conclusion, the combination treatment effectively reduce the incidence of moderate/severe OHSS in high-risk women. Clinical trial registration information:Date of registration: 12-27-2017Date of initial participant enrollment: 01-01-2018Clinical trial identification number: ChiCTR-INR-17014174 URL of the registration site: www.chictr.org.cn

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 &gt; 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 &gt; 0.05). The serum E2 level on the trigger day in group A was significantly higher than that in group B (p &lt; 0.001). Women in group A had a lower incidence rate of moderate-to-severe OHSS than individuals in group B (p &lt; 0.001). There was a non-significant difference in the cumulative live-birth rate between the two groups (p &gt; 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 &gt; 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 &gt; 0.05). The serum E2 level on the trigger day in group A was significantly higher than that in group B (p &lt; 0.001). Women in group A had a lower incidence rate of moderate-to-severe OHSS than individuals in group B (p &lt; 0.001). There was a non-significant difference in the cumulative live-birth rate between the two groups (p &gt; 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

Pregnancy outcome in late-onset severe OHSS patients following different ascetic fluid drainage and comparison with the non-OHSS IVF patients

Introduction Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic serious complication of controlled ovarian stimulation during assisted reproductive technology, the aim of our research is to explore the differences of pregnancy outcome between severe OHSS patients and the non-OHSS IVF patients, and also compare the pregnancy ourtome of different ascites drainage way. Design This is a retrospective cohort analysis carried out in a University-affiliated reproductive center from 2012 to 2019, between 359 women with severe OHSS following ascites draining and 345 non-OHSS women (matched by age and retrieved oocyte number).We examined the rates of clinical pregnancy, multiple pregnancies, miscarriage, live birth and preterm delivery between the two groups. Within the OHSS group (central venous catheter group vs paracentesis group), odds ratios (ORs) and 95% confidence intervals (CIs) of measure of clinical pregnancy were also analyzed. Result The biochemical pregnancy loss rate of non-OHSS patients was significantly higher than that of severe OHSS patients (11.1% vs 0.6%), the live birth, multiple pregnancy (twin pregnancy) was much more in severe OHSS group than in control group(88.9% vs 73.5%; 57.6% vs 28.1% respectively), and there was no significant difference between singleton and twin preterm rate and neonatal birth weight between OHSS and control group. Binary logistic regression analysis revealed multiple pregnancy and long-protocol showed relatively high odds ratio, suggest that the long-protocol of COS and multiple pregnancy are the risk factor of severe OHSS. Among severe OHSS following ascites draining, in comparison with abdominal paracentesis and central venous catheter, the ascites volume in central venous catheter group was much more than abdominal paracentesis group, there was significant difference between the two groups. There was no significant difference between the two groups in comparison of live birth, and the birth weight of singleton and twin between these two groups. but the premature birth rate of singleton in group 1 was 9.3% (10/107), whereas in group 2, it was 3.75%. Conclusion In conclusion, this preliminary report suggests that for the IVF-ET patients, less basic follicle number, GnRH antagonist cycle, singleton maybe the protective factors for the late-onset OHSS. Paracentesis and central venous catheter are all the effective modality to manage the ascites for the severe OHSS patients. For the patients who have the possibility of repeated paracentesis, catheter is a safe and effective way.

Severe ovarian hyperstimulation syndrome with GnRH agonist trigger during the COVID pandemic: lessons learned from an unusual case

Background: Injectable gonadotropins stimulate multi-follicular recruitment and allows retrieval of multiple oocytes for assisted reproduction. The widespread utilization of gonadotropin releasing hormone agonist (GnRHa) to induce oocyte maturation for oocyte retrieval has nearly eliminated the risk of severe ovarian hyperstimulation syndrome (OHSS), and only a few cases have been reported in the literature. The rarity of severe OHSS may lead to the mistaken conclusion that gonadotropin stimulation can be safely administered with limited monitoring, even in high-risk patients. We present an unusual case of a woman with limited monitoring due to the COVID pandemic who developed severe OHSS before GnRH agonist trigger and oocyte. Case Presentation: A 29-year-old nulliparous woman with polycystic ovarian syndrome (PCOS) initiated ovarian stimulation for oocyte retrieval. She had a robust initial response, and developed worsening abdominal pain, bloating, nausea, vomiting, and decreased appetite before retrieval. GnRH agonist was given to “trigger ovulation and retrieval scheduled due to the low reported incidence of severe OHSS. Symptoms progressed, and on the morning of retrieval, ultrasound demonstrated bilaterally enlarged ovaries >10cm and 48 oocytes were retrieved for a planned cryo-all cycle. She was hospitalized on the day of retrieval for severe OHSS and had two large-volume paracenteses. She was stable and discharged home by day 5, and symptoms markedly improved with the onset of menses. She has an ongoing pregnancy from her first frozen embryo transfer. Conclusion: We add a rare case of severe OHSS with a GnRHa trigger and cryo-all protocol with the onset of symptoms before GnRH agonist administration. Although rare, severe OHSS may still occur with a GnRHa trigger, and caution is needed when an initial robust response is identified. Here we also provide an opportunity to review the important patient risk factors for the development of OHSS and measures to reduce the risk in excessive responders.

GnRH antagonist versus depot GnRH agonist protocol in polycystic ovary syndrome (PCOS): analysis using propensity score matching

IntroductionWomen with PCOS have been reported with low pregnancy rate and high OHSS risk in IVF programs due to the decreased endometrial receptivity and high ovarian reserve. The GnRH antagonist (GnRH-ant) protocol has been widely accepted as a prominent intervention to reduce the risk of OHSS, and the depot GnRH agonist (dGnRH-a) protocol are believed to improve endometrial receptivity and increase the pregnancy rate of fresh embryo transfer.Material and methodsThis study was a retrospective cohort study that included 2164 women with PCOS undergoing assisted reproductive technology (ART) treatment from January 2014 to April 2019. The two groups were matched by propensity scores with a ratio of 4:1 accounting for potential confounding factors.ResultsThe live birth per treatment cycle was higher in the dGnRH-a group than in the GnRH-ant group (58.22% vs. 41.78%, P=0.0004), the same with live birth per fresh transfer (64.42% vs. 44.64%, P=0.0045). There were no significant differences in the incidence of moderate-to-severe OHSS (4.28% vs. 2.05%, P=0.333) and the cost of COH (RMB: 7736.9 vs. 8046.54, P=0.113) between the two groups.ConclusionsOur results indicated that the dGnRH-a protocol has a higher live birth rate than GnRH-ant protocol, and the difference is mainly due to fresh embryo transfer. For safety and economic cost, the incidence of moderate-to-severe OHSS and cost of COH is similar in two groups. Nevertheless, the incidence of moderate-to-severe OHSS in the dGnRH-a group is numerically higher than GnRH-ant protocol with no statistical difference. A subsequent prospective randomized controlled study is needed to confirm these results.