High Risk Of Ovarian Hyperstimulation Syndrome Research Articles

#86 : Use of Triptorelin Versus Human Chorionic Gonadotropin as Ovulation Trigger

Background and Aims: Gonadotropin releasing hormone agonist (GnRH-a) trigger has been shown to be associated with significantly lower risk of moderate or severe ovarian hyperstimulation syndrome (OHSS) when compared among women at high risk of OHSS. However, trigger failure has been shown to occur in 2% of cycles using GnRH-a as trigger. This study aims to review the use of GnRH-a as ovulation trigger. Method: Retrospective review of records in antagonist cycles from an ART unit in a tertiary hospital from 2017-2021 was performed. Follicles were considered mature when they reach [Formula: see text] 15 mm. Ovulation triggered with urinary human chorionic gonadotropin (uhCG) (5000-10000 IU), recombinant hCG (rhCG) 250 mcg, or triptorelin 0.2 mg when there were [Formula: see text] 3 mature follicles. All embryos obtained from cycles using triptorelin were cryopreserved. Outcome including the number of oocytes retrieved, the follicle to oocyte index, ovarian hyperstimulation syndrome were reviewed. Results: 1378 cycles were included. 1089 cycles had uhCG or rhCG as trigger, while 284 cycles had triptorelin as trigger. Women in the triptorelin group were significantly younger with a lower basal follicle stimulating hormone level and a higher antral follicle count (Table 1). In the triptorelin group, the total number of mature sized follicles, estrogen level at trigger, oocytes retrieved, number of blastocysts were significantly higher compared to the hCG group (Table 2). Follicle to oocyte index was significantly higher in the triptorelin group but the proportion of mature oocytes were similar in both groups. There were no cases of trigger failure and OHSS in the triptorelin group, but 30 cases of OHSS, with18 cases early onset, 12 cases late onset, amongst them 10 cases (1%) were severe OHSS) in the hCG group. Conclusion: GnRH-a trigger is a good candidate as ovulatory trigger in women at risk of OHSS without hampering the laboratory outcome.

Prevention of OHSS

Ovarian hyperstimulation syndrome (OHSS), perhaps the most serious complication arising from in vitro fertilization (IVF), is rare but life-threatening in some cases. In this lecture, we will first delve into the pathophysiology of OHSS and hallmark features such as hemoconcentration, hypercoagulability, electrolyte imbalances, fluid loss into third space, and renal insufficiency. In addition, clinical vignettes will illustrate some of the most severe cases of OHSS. Next, various methods for identifying patients at high risk of OHSS will be discussed. Available literature indicates that younger age and polycystic ovarian syndrome (PCOS) may be associated with the incidence of OHSS. Ovarian reserve markers such as anti-müllerian hormone (AMH) and antral follicle counts (AFC) have been suggested as useful screening tools. Also, stimulation cycle profiles, such as developing multiple follicles, peak serum estradiol levels, and the number of retrieved oocytes, may aid in identifying those at high risk. To lower the incidence of OHSS, modifying controlled ovarian stimulation (COS) protocols is essential. Evidence suggests that gonadotropin-releasing hormone (GnRH) antagonist protocol is beneficial in reducing the risk of OHSS. Medications such as dopamine agonists, aspirin, and metformin may be associated with lower risk while using clomiphene citrate remains controversial. “Coasting,” which is holding gonadotropins for several days to decrease the OHSS risk, has been suggested as another strategy. Triggering could be done differently using a GnRH agonist. Cycle segmentation by cryopreserving oocytes and embryos is also a feasible option. Close monitoring and early detection of symptoms are essential for prompt intervention and management of OHSS. By implementing preventative measures and closely monitoring patients, physicians may reduce the incidence and severity of OHSS and ensure safer fertility treatments.

Cocktail treatment by GnRH-antagonist, letrozole, and mifepristone for the prevention of ovarian hyperstimulation syndrome: a prospective randomized trial

Objective 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. Methods This prospective, randomized controlled clinical trial was performed between January 2018 and December 2018. A total of 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 received 0.25 mg Cetrorelix for 3 d, 5 mg letrozole for 5 d, and 50 mg mifepristone for 3 d, the mifepristone group received 50 mg mifepristone for 3 d. A total of 156 cases were included in final analysis. All the frozen embryo transfer (FET) cycles were followed up until December 2021. Results 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 d, 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. There was no significant difference in cumulative live birth rates (LBRs) between the combination and mifepristone group (74.4% vs. 76.9%). Conclusions The combination treatment effectively reduces the incidence of moderate/severe OHSS in high-risk women.

Beyond the Umbrella: A Systematic Review of the Interventions for the Prevention of and Reduction in the Incidence and Severity of Ovarian Hyperstimulation Syndrome in Patients Who Undergo In Vitro Fertilization Treatments.

Ovarian hyperstimulation syndrome (OHSS) is the main severe complication of ovarian stimulation for in vitro fertilization (IVF) cycles. The aim of the current study was to identify the interventions for the prevention of and reduction in the incidence and severity of OHSS in patients who undergo IVF not included in systematic reviews with meta-analyses of randomized controlled trials (RCTs) and assess and grade their efficacy and evidence base. The best available evidence for each specific intervention was identified, analyzed in terms of safety/efficacy ratio and risk of bias, and graded using the Oxford Centre for Evidence-Based Medicine (CEBM) hierarchy of evidence. A total of 15 interventions to prevent OHSS were included in the final analysis. In the IVF population not at a high risk for OHSS, follitropin delta for ovarian stimulation may reduce the incidence of early OHSS and/or preventive interventions for early OHSS. In high-risk patients, inositol pretreatment, ovulation triggering with low doses of urinary hCG, and the luteal phase administration of a GnRH antagonist may reduce OHSS risk. In conclusion, even if not supported by systematic reviews with homogeneity of the RCTs, several treatments/strategies to reduce the incidence and severity of OHSS have been shown to be promising.

The effects of high risk of ovarian hyperstimulation syndrome and duration of embryo cryopreservation on perinatal outcomes of single live births in the first frozen embryo transfer cycle after whole embryo cryopreservation

Objective: To investigate the effects of high risk of ovarian hyperstimulation syndrome (OHSS) and duration of embryo cryopreservation on perinatal outcomes of the first frozen-thawed cycle after whole embryo cryopreservation. Methods: The clinical data of 1 804 patients who underwent the first frozen-thawed cycle after whole embryo cryopreservation and achieved singleton live births in the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University from January 2016 to June 2021 were retrospectively analyzed. According to whether there was high risk of OHSS in the oocyte retrieval cycle, the patients were divided into high-risk group (n=790) and non-high-risk group (n=1 014). The baseline data and perinatal outcomes were compared between the two groups. Multivariate linear regression was applied to analyze the relative factors affecting neonatal weight. And the high-risk group was divided into three subgroups according to different cryopreservation time: the embryos of 96 cycles with a cryopreservation time less than 60 days were defined as group A; the embryos of 587 cycles with a cryopreservation time around 60 to 120 days were defined as group B; the embryos of 107 cycles with a cryopreservation time more than 120 days were defined as group C. The perinatal outcomes were compared among the three groups. The measurement data in this study were represented by［M（Q1，Q3）］. Results: The female age in the high-risk group was 30.0 (27.0, 32.0) years old, which was lower than that in the non-high-risk group 31.0 (29.0, 34.0) (P<0.001). The male age in high-risk group was 30.0 (28.0, 33.0), lower than that in non-high-risk group 32.0 (29.0, 35.0) (P<0.001). The birth weight of high-risk group [3 500.0 (3 200.0,3 800.0) g] was higher than that of control group [3 400.0 (3 150.0,3 800.0) g](P=0.045). Multivariate linear regression analysis showed that female BMI was correlated with neonatal weight, β (95%CI) was 15.37(8.33, 22.41) (P<0.001), and the high risk of OHSS was not correlated with neonatal weight, β (95%CI) was 19.40 (-38.07, 76.87) (P=0.508). There was significant difference in the incidence of low birth weight and very low birth weight among groups A, B and C (all P values<0.05), and the incidence of low birth weight and very low birth weight in group C was higher than that in group B (all P values<0.017). Conclusions: The risk of adverse perinatal outcomes in high-risk OHSS patients who underwent the first frozen-thawed cycle after whole embryo cryopreservation was not increased. However, prolonged cryopreservation of embryos may lead to increased risk of low birth weight and very low birth weight.

Retrospective analysis of GnRH-a prolonged protocol for in vitro fertilization in 18,272 cycles in China

BackgroundThis large-cohort, retrospective study investigates the relationship between the number of oocytes retrieved and the clinical outcomes for patients receiving the GnRH-a prolonged protocol (mGnRH-a protocol) for fertilization in vitro or intracytoplasmic sperm injection–embryo transfer (IVF/ICSI-ET) treatment.ResultsWe categorized 18,272 cycles into three groups by the number of oocytes retrieved (1–8, 9–17, and ≥ 18) during IVF with the GnRH-a prolonged protocol at the Reproductive Medical Center of Jiangxi Maternal and Child Health Hospital from January 2014 to December 2018 (excluding oocyte donation cycles), analyzing the associations among oocyte number and live birth rates (LBRs) or cumulative LBRs (CLBRs), as well as the rate of moderate-to-severe ovarian hyperstimulation syndrome (OHSS). We defined the primary outcome as LBR and the secondary outcome to include the rate of patients at high risk for OHSS. The LBR (with fresh ET) per cycle of oocyte pick-up increased as the number of retrieved oocytes increased from 1 to ~ 8, plateaued between 9 ~ 17, and steadily decreased thereafter. However, the CLBR per cycle continued to increase as the oocyte number increased, as did the incidence of moderate-to-severe OHSS.ConclusionsOur results show a strong relationship between the number of oocytes retrieved and the CLBR following IVF treatment. The balance between treatment success and the risk of complications, especially OHSS, should be investigated further. We recommend a fresh-ET strategy for the GnRH-a prolonged protocol because the endometrial receptivity in the fresh cycles was better than those in the frozen cycles.

Comparison of bromocriptine and hydroxyethyl starch in the prevention of ovarian hyperstimulation syndrome.

To evaluate the effectiveness of bromocriptine for prevention of ovarian hyperstimulation syndrome (OHSS). The retrospective study included women at risk of OHSS who were receiving gonadotropin-releasing hormone antagonist protocols, including 52 women given 2.5mg bromocriptine by rectal insertion, 52 women given 500 ml intravenous hydroxyethyl starch (HES), and 40 women who received no intervention. Treatments were administered daily for 5 days beginning on the day of oocyte retrieval. Baseline information and data related to OHSS were compared. No significant differences were found among groups in estradiol concentration on the day of trigger or in number of retrieved oocytes. Incidence of mild OHSS was not significantly different among groups, respectively 13.5%, 15.4%, and 17.5% (P> 0.05). The incidence of moderate to severe OHSS was significantly lower in the bromocriptine and HES groups compared with the control group, respectively 7.7%, 5.8%, and 22.5% (P< 0.05). D-dimer levels were significantly lower in the bromocriptine and HES groups compared with the control group on Day 5 after oocyte retrieval (P< 0.05). No differences in liver or renal function were found in the three groups. Bromocriptine was apparently as effective as intravenous HES in patients with high risk of OHSS.

Cabergoline versus calcium infusion in the prevention of ovarian hyperstimulation syndrome: a randomised controlled study

The aim of this study was to compare the efficacy of calcium infusion versus cabergoline in the prevention of ovarian hyperstimulation syndrome (OHSS) in IVF patients at high risk for OHSS. One hundred and seventy patients who were stimulated using the long luteal GnRH agonist protocol and at high risk for developing OHSS were randomised in a 1:1 ratio to cabergoline group and calcium gluconate group. In cabergoline group, 0.5 mg of cabergoline was administered once daily p.o. for eight days starting on the day of HCG administration. In calcium gluconate group, intravenous calcium gluconate (10%, 10 ml in 200 ml of physiologic saline) was administered daily for four days starting on the day of ovum pickup. Six patients in cabergoline group and eight patients in calcium gluconate group developed moderate OHSS. One patient in each group developed severe OHSS. The incidence of moderate/severe OHSS was comparable between both groups (8.24% vs. 10.59%, p value = .599, OR = 0.76, 95% CI [0.269–2.138]). The implantation, clinical and ongoing pregnancy rates were similar in the two groups (16.91% vs. 15.84%, p = .771, 35.29% vs. 32.94%, p = .746, and 30.59% vs. 28.24%, p = .736, respectively). In conclusion, calcium infusion and cabergoline have comparable effectiveness in the prevention of OHSS. Both drugs are well tolerated, cheap and have no adverse effects on the reproductive outcomes of IVF cycle. Clinical trial registration: The trial was registered on clinical trials.gov database [NCT02875587]. Impact Statement What is already known on this subject? The effectiveness of cabergoline in the prevention of OHSS in IVF patients at high risk for OHSS is confirmed by overwhelming scientific evidence. Calcium infusion is a novel strategy for prevention of OHSS. Few studies reported the use of calcium infusion in the prevention of OHSS. A retrospective study and a randomised controlled study revealed that calcium infusion reduces the incidence of OHSS. Moreover, a quasi-randomised study revealed that calcium infusion is as effective as cabergoline in the prevention of OHSS. What the results of this study add? Calcium infusion and cabergoline have comparable effectiveness in the prevention of OHSS. Both drugs are well tolerated, cheap and have no adverse effects on the reproductive outcomes of IVF cycle. What the implications are of these findings for clinical practice and/or further research? Calcium infusion should be used to minimise the incidence of OHSS in IVF patients at high risk for OHSS.

Endometrial HOXA10 mRNA Expression in PCOS Patients at High Risk for Ovarian Hyperstimulation Syndrome

Background: This study was designed to determine whether the risk of ovarian hyperstimulation syndrome (OHSS) contributes to the subfertility in PCOS. Endometrial HOXA-10 mRNA expression, a well-characterized gene essential to endometrial receptivity, was evaluated in PCOS patients whose embryos are planned to be frozen due to the risk of OHSSS. Methods: Twent-five women with PCOS in high risk group for OHSS and age and BMI matched 25 non-PCOS infertile patients were included the study. Five fertile women were accepted as positive control. Following egg collection each group of subject underwent total embryo freezing. After the egg collection, endometrial sampling was performed with a pipella cannula from each gruop of participant and fertile control. Expression levels of HOXA-10 mRNA were determined by RT-PCR. Gene expression results are presented as Ct (cycle threshold), ΔCt, and ΔΔCt. Reults: Average ΔCt value of HOXA-10 mRNA in PCOS, non-PCOS and fertile groups were found to 5.88, 6.77, and 7.79 respectively. Compared to endometrial HOXA-10 mRNA levels of fertile cases, the HOXA-10 mRNA levels of the patients in the PCOS group were found to be significantly lower (ΔCt 7.79 vs. ΔCt 5.88, p&lt;0.002). Similarly, endometrial HOXA-10 mRNA levels in the non-PCOS control group were significantly lower than the HOXA-10 mRNA levels in the fertile group (ΔCt 6.77 vs. ΔCt 7.79, p&lt;0.001). HOXA-10 mRNA levels in endometrial samples taken from patients in the PCOS group were found to be significantly lower than the HOXA-10 mRNA levels in non-PCOS control group. Conclusions: HOXA-10 mRNA levels were found to be lower in PCOS patients with high risk for OHSS compared to both fertile and infertile patients without PCOS. OHSS risk in PCOS decreases endometrial HOXA-10 mRNA expression.

Dopamine agonists for preventing ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of ovarian stimulation in assisted reproduction technology (ART). It is characterised by enlarged ovaries and an acute fluid shift from the intravascular space to the third space, resulting in bloating, increased risk of venous thromboembolism, and decreased organ perfusion. Most cases are mild, but forms of moderate or severe OHSS appear in 3% to 8% of in vitro fertilisation (IVF) cycles. Dopamine agonists were introduced as a secondary prevention intervention for OHSS in women at high risk of OHSS undergoing ART treatment. OBJECTIVES: To assess the effectiveness and safety of dopamine agonists in preventing OHSS in women at high risk of developing OHSS when undergoing ART treatment. We searched the following databases from inception to 4 May 2020: Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and PsycINFO for randomised controlled trials (RCTs) assessing the effect of dopamine agonists on OHSS rates. We also handsearched reference lists and grey literature. We considered RCTs for inclusion that compared dopamine agonists with placebo/no intervention or another intervention for preventing OHSS in ART. Primary outcome measures were incidence of moderate or severe OHSS and live birth rate. Secondary outcomes were rates of clinical pregnancy, multiple pregnancy, miscarriage, and adverse events. Two review authors independently screened titles, abstracts, and full texts of publications; selected studies; extracted data; and assessed risk of bias. We resolved disagreements by consensus. We reported pooled results as odds ratios (OR) and 95% confidence interval (CI) by the Mantel-Haenszel method. We applied GRADE criteria to judge overall quality of the evidence. The search identified six new RCTs, resulting in 22 included RCTs involving 3171 women at high risk of OHSS for this updated review. Thedopamine agonists were cabergoline, quinagolide, and bromocriptine. Dopamine agonists versus placebo or no intervention Dopamine agonists probably lowered the risk of moderate or severe OHSS compared to placebo/no intervention(OR 0.32, 95% CI 0.23 to 0.44; 10 studies, 1202 participants; moderate-quality evidence). This suggests that ifthe risk of moderate or severe OHSS following placebo/no intervention is assumed to be 27%, the risk following dopamine agonists would be between 8% and 14%.We are uncertain of the effect of dopamine agonists on rates of live birth(OR 0.96, 95% CI 0.60 to 1.55; 3 studies, 362 participants; low-quality evidence). We are also uncertain of the effect of dopamine agonists onclinical pregnancy, multiple pregnancy,miscarriageor adverse events(very low to low-quality evidence). Dopamine agonists plus co-intervention versus co-intervention Dopamine agonist plus co-intervention (hydroxyethyl starch, human albumin, or withholding ovarian stimulation 'coasting') may decrease the risk of moderate or severe OHSS compared to co-intervention(OR 0.48, 95% CI 0.28 to 0.84; 4 studies, 748 participants; low-quality evidence). Dopamine agonists may improve rates of live birth(OR 1.21, 95% CI 0.81 to 1.80; 2 studies, 400 participants; low-quality evidence). Dopamine agonists may improve rates of clinical pregnancyandmiscarriage, but we are uncertain if they improve rates ofmultiple pregnancy or adverse events (very low to low-quality evidence). Dopamine agonists versus other active interventions We are uncertain if cabergoline improves the risk of moderate or severe OHSScompared to human albumin (OR 0.21, 95% CI 0.12 to 0.38; 3 studies, 296 participants; very low-quality evidence), prednisolone (OR 0.27, 95% CI 0.05 to 1.33; 1 study; 150 participants; very low-quality evidence), hydroxyethyl starch (OR 2.69, 95% CI 0.48 to 15.10; 1 study, 61 participants; very low-quality evidence), coasting (OR 0.42, 95% CI 0.18 to 0.95; 3 studies, 320 participants; very low-quality evidence), calcium infusion (OR 1.83, 95% CI 0.88 to 3.81; I² = 81%; 2 studies, 400 participants; very low-quality evidence), or diosmin (OR 2.85, 95% CI 1.35 to 6.00; 1 study, 200 participants; very low-quality evidence). We are uncertain of the effect of dopamine agonists on rates oflive birth(OR 1.08, 95% CI 0.73 to 1.59; 2 studies, 430 participants; low-quality evidence). We are uncertain of the effect of dopamine agonists on clinical pregnancy, multiple pregnancy or miscarriage (low to moderate-quality evidence). There were no adverse events reported. Dopamine agonists probably reduce the incidence of moderate or severe OHSScompared to placebo/no intervention, while we are uncertain of the effect onadverse events andpregnancy outcomes (live birth, clinical pregnancy,miscarriage). Dopamine agonists plus co-intervention may decrease moderate or severe OHSS rates compared to co-intervention only, but we are uncertain whether dopamine agonists affect pregnancy outcomes. When compared to other active interventions, we are uncertain of the effects of dopamine agonists on moderate or severe OHSS and pregnancy outcomes.

Effect and Relationship of Seasons on the High Risk of Ovarian Hyperstimulation Syndrome After Oocyte Retrieval in Patients With Polycystic Ovary Syndrome.

ObjectiveTo investigate the effect of seasons on the incidence of high risk of ovarian hyperstimulation syndrome (OHSS) after in oocyte retrieval in patients with polycystic ovarian syndrome (PCOS) and to establish a nomogram to predict the risk of OHSS.DesignSingle-center, retrospective study.SettingUniversity-affiliated reproductive medicine center.Patient(s)A total of 2,030 infertility patients with PCOS underwent the follicular phase long-acting long protocol IVF/ICSI in the reproductive medicine center from January 2017 to December 2019.Intervention(s)None.Main outcome measure(s)Logistic regression analysis was used to analyze the factors associated with a high risk of OHSS. We established a nomogram to predict the risk of OHSS in infertility patients with PCOS after oocyte retrieval.Result(s)The incidence of patients at high risk of OHSS was significantly different from season-to-season and was especially higher in the summer and winter. Multivariate logistic analysis showed that gonadotropin dosage, number of retrieved oocytes, estradiol level, average bilateral ovarian diameter on the day human chorionic gonadotropin was administered, type of infertility, and average temperature were independent risk factors for OHSS after oocyte retrieval in PCOS patients. Based on the above independent risk factors, we constructed a prediction model for OHSS risk. To evaluate the efficiency of the prediction model, we calculated the C-index (0.849), area under the receiver operating characteristic curve (0.849), and internal validation C-index (0.846). Decision curve analysis suggested that the prediction model exhibited significant net benefits.Conclusion(s)The incidence of PCOS patients at high risk for OHSS after oocyte retrieval fluctuated with seasonal temperature changes, and was significantly higher in extreme climates. The prediction model had favorable predictive performance and clinical application value.

Pregnancy Rate in Frozen Cycles Transfer After Freeze-All Policy to Prevent Ovarian Hyper Stimulation Syndrome

Background: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic state, potentially lethal, and still one of the major complications encountered during controlled ovarian stimulation (COS) in IVF. It occurs in approximately 1–14 % of assisted reproductive technique (ART) cycles and is related to increased vascular permeability. There are two forms of (OHSS) early and late form. Objectives: The aim of the study was to evaluate the pregnancy rate from frozen thawed embryo transfer after freeze-all policy for patient with high risk for OHSS. Patients and methods: This is cohort study conducted at Genetics and Infertility Unit, Department of Obstetrics and Gynecology, Zagazig University and a private center (retro- prospective and record-based data). The study was carried out on 150 infertile cases. They were divided into three groups. Group A: Frozen thawed embryo transfer after freeze-all policy for cases of high risk to OHSS, group B: frozen thawed embryo transfer for cases with normal ovarian response and group C: Fresh embryo transfer in cycles with 6 or more oocytes with antagonist protocol. Results: The main results of the study revealed that there was high statistically significant difference between groups regarding pregnancy outcomes. Pregnancy rate in frozen cycles is better than fresh cycles in normal responders with no late OHSS and less severe early OHSS. Conclusion: Freeze-all policy improves pregnancy rate in high and normal responders. Also, it prevents late OHSS.

Rare genetic variants suggest dysregulation of signaling pathways in low- and high-risk patients developing severe ovarian hyperstimulation syndrome.

To investigate if rare gene variants in women with severe ovarian hyperstimulation syndrome (OHSS) provide clues to the mechanisms involved in the syndrome. Among participants in a prospective randomized study (Toftager et al. 2016), six women with predicted low and six women with predicted high risk of OHSS developing severe OHSS (grades 4 and 5, Golan classification) were selected. In the same cohort, six plus six matched controls developing no signs of OHSS (Golan grade 0) were selected. Whole-exome sequencing was performed. Analysis using a predefined in silico OHSS gene panel, variant filtering, and pathway analyses was done. We found no convincing monogenetic association with the development of OHSS using the in silico gene panel. Pathway analysis of OHSS variant lists showed substantial overlap in highly enriched top pathways (p value range p < 0.0001 and p > 9.8E-17) between the low- and high-risk group developing severe OHSS, i.e., "the integrin-linked kinase (ILK) signaling pathway" and the "axonal guidance signaling pathway," both being connected to vasoactive endothelial growth factor (VEGF) and endothelial function. Rare variants in OHSS cases with two distinct risk profiles enrich the same signaling pathways linked to VEGF and endothelial function. Clarification of the mechanism as well as potentially defining genetic predisposition of the high vascular permeability is important for future targeted treatment and prevention of OHSS; the potential roles of ILK signaling and the axonal guidance signaling need to be validated by functional studies.

A decision-making algorithm for performing or cancelling embryo transfer in patients at high risk for ovarian hyperstimulation syndrome after triggering final oocyte maturation with hCG.

STUDY QUESTIONCan the grade of ascites, haematocrit (Ht), white blood cell (WBC) count and maximal ovarian diameter (MOD) measured on Day 3 be used to construct a decision-making algorithm for performing or cancelling embryo transfer in patients at high risk for severe ovarian hyperstimulation syndrome (OHSS) after an hCG trigger?SUMMARY ANSWERUsing cut-offs of ascites grade>2, Ht>39.2%, WBC>12 900/mm3 and MOD>85 mm on Day 3, a decision-making algorithm was constructed that could predict subsequent development of severe OHSS on Day 5 with an AUC of 0.93, a sensitivity of 88.5% and a specificity of 84.2% in high-risk patients triggered with hCG.WHAT IS KNOWN ALREADYDespite the increasing popularity of GnRH agonist trigger for final oocyte maturation as a way to prevent OHSS, ≥75% of IVF cycles still involve an hCG trigger. Numerous risk factors and predictive models of OHSS have been proposed, but the measurement of these early predictors is restricted either prior to or during the controlled ovarian stimulation. In high-risk patients triggered with hCG, the identification of luteal-phase predictors assessed post-oocyte retrieval, which reflect the pathophysiological changes leading to severe early OHSS, is currently lacking.STUDY DESIGN, SIZE, DURATIONA retrospective study of 321 patients at high risk for severe OHSS following hCG triggering of final oocyte maturation. High risk for OHSS was defined as the presence of at least 19 follicles ≥11 mm on the day of triggering of final oocyte maturation.PARTICIPANTS/MATERIALS, SETTING, METHODSThe study includes IVF/ICSI patients at high risk for developing severe OHSS, who administered hCG to trigger final oocyte maturation. Ascites grade, MOD, Ht and WBC were assessed in the luteal phase starting from the day of oocyte retrieval. Outcome measures were the optimal thresholds of ascites grade, MOD, Ht and WBC measured on Day 3 post-oocyte retrieval to predict subsequent severe OHSS development on Day 5. These criteria were used to construct a decision-making algorithm for embryo transfer, based on the estimated probability of severe OHSS development on Day 5.MAIN RESULTS AND THE ROLE OF CHANCEThe optimal Day 3 cutoffs for severe OHSS prediction on Day 5 were ascites grade>2, Ht>39.2%, WBC>12 900/mm3 and MOD>85 mm. The probability of severe OHSS with no criteria fulfilled on Day 3 is 0% (95% CI: 0–5.5); with one criterion, 0.8% (95% CI: 0.15–4.6); with two criteria, 13.3% (95% CI: 7.4–22.8); with three criteria, 37.2% (95% CI: 24.4–52.1); and with four criteria, 88.9% (95% CI, 67.2–98.1). The predictive model of severe OHSS had an AUC of 0.93 with a sensitivity of 88.5% and a specificity of 84.2%.LIMITATIONS, REASONS FOR CAUTIONThis is a retrospective study, and therefore, it cannot be excluded that non-apparent sources of bias might be present. In addition, we acknowledge the lack of external validation of our model. We have created a web-based calculator (http://ohsspredict.org), for wider access and usage of our tool. By inserting the values of ascites grade, MOD, Ht and WBC of high-risk patients on Day 3 after oocyte retrieval, the clinician instantly receives the predicted probability of severe OHSS development on Day 5.WIDER IMPLICATIONS OF THE FINDINGSThe present study describes a novel decision-making algorithm for embryo transfer based on ascites, Ht, WBC and MOD measurements on Day 3. The algorithm may be useful for the management of high-risk patients triggered with hCG and for helping the clinician’s decision to proceed with, or to cancel, embryo transfer. It must be emphasized that the availability of the present decision-making algorithm should in no way encourage the use of hCG trigger in patients at high risk for OHSS. In these patients, the recommended approach is the use of GnRH antagonist protocols, GnRH agonist trigger and elective embryo cryopreservation. In addition, in patients triggered with hCG, freezing all embryos and luteal-phase GnRH antagonist administration should be considered for the outpatient management of severe early OHSS and prevention of late OHSS.STUDY FUNDING/COMPETING INTEREST(S)NHMRC Early Career Fellowship (GNT1147154) to C.A.V. No conflict of interest to declare.TRIAL REGISTRATION NUMBERN/A.

Diosmin for the prevention of ovarian hyperstimulation syndrome.

To evaluate the effect of oral diosmin on the incidence and severity of ovarian hyperstimulation syndrome (OHSS) and explore the value of diosmin in preventing and treating OHSS. A retrospective study of women attending a reproductive center in Guangzhou, China, between September and December 2016. The inclusion criterion was previous cancellation of embryo transfer after oocyte retrieval during IVF owing to a high risk of OHSS. The women were divided into two groups depending on whether they received oral diosmin (1000mg twice daily for 10days) after oocyte retrieval (diosmin group) or not (control group). Apart from diosmin, both groups underwent the same treatment. Baseline information and data related to OHSS were compared. Overall, 146 women were included: 74 in the diosmin group and 72 in the control group. The incidence of moderate-to-severe OHSS in the diosmin and control groups was 5/74 (6.2%) and 14/72 (13.4%), respectively (P=0.027). The control group included four cases of paracentesis due to ascites; there were no cases of paracentesis or severe OHSS in the diosmin group. Oral administration of diosmin effectively reduced both the incidence of moderate-to-severe OHSS and the severity of OHSS among high-risk women.

Letrozole versus gonadotropin-releasing hormone antagonist during luteal phase in the prevention of ovarian hyperstimulation syndrome: a randomized controlled trial

Objective: To explore and compare the preventive effect of using letrozole and gonadotropin-releasing hormone (GnRH) antagonist during luteal phase of patients at high risk for ovarian hyperstimulation syndrome (OHSS). Methods: A total of 99 infertile women undergoing in vitro fertilization and embryo transfer or intracytoplasmic sperm injection with high risk for OHSS were enrolled in this randomized controlled trial.The letrozole group (n=51) received letrozole of 7.5 mg daily for 3 days;the GnRH antagonist group (n=48) were given cetrorelix of 0.25 mg subcutaneously daily for 3 days. Both groups received support therapy combined with embryo cryopreservation. The incidence of OHSS was surveyed. And the serum concentration of estradiol, LH and progesterone on days 3, 5 and 8 after oocytes retrieval were measured. Results: There were no statistical differences in terms of baseline characteristics of patients and outcomes of controlled ovarian hyperstimulation between the two groups.The incidence of moderate and severe OHSS was found no significantly difference between letrozole group [11.8%(6/51)] and GnRH antagonist group [10.4%(5/48);P>0.05]. The estradiol concentration of the indicated days on days 3,5 and 8 after oocytes retrieval in letrozole group and GnRH antagonist group were (1 417±3 543) versus (15 210±9 921) pmol/L, (1 692±4 330) versus (18 680±11 567) pmol/L, (239±336) versus (3 582±5 427) pmol/L, respectively;compared with GnRH antagonist group, the estradiol level was significantly lower in the letrozole group (all P<0.01). The luteinizing hormone level in the letrozole group were (0.46±0.40), (0.56±0.55)and (0.67±0.58) U/L on days 3,5 and 8 after oocytes retrieval, which were significantly higher than those of GnRH antagonist group [(0.28±0.28), (0.30±0.19) and (0.45±0.37) U/L, respectively; all P<0.05]. There was no obvious differences on progesterone levels between letrozole group and GnRH antagonist group (all P>0.05),and on days 8 after oocytes retrieval,the level of progesterone in each group were significantly lower than those on day 3 and 5 after oocytes retrieval (P<0.05). Conclusion: Letrozole has the same efficiency as GnRH antagonist for the prevention of OHSS, faster and cheaper to use, but its efficacy seems not to be related to the suppression of steroidogenic during the luteal phase.

A novel GnRH-antagonist protocol by switching to medroxyprogesterone when patients being at risk of ovarian hyperstimulation syndrome during ovarian stimulation

Background/PurposeTo investigate whether switching GnRH antagonist (GnRHant) to medroxyprogesterone acetate (MPA) sequentially in the middle of controlled ovarian stimulation could effectively prevent premature LH surge in a GnRHant protocol in patients turn out to be at a high risk of ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation. MethodsThis is a retrospective cohort study. ResultsPremature LH surge did not occur in both groups of patients. The switch protocol group had a significantly fewer days of GnRHant treatment (3.1 ± 1.0 vs. 6.5 ± 1.2) compared with GnRHant protocol group. The mean duration of MPA treatment was 3.6 ± 1.1 days. There were no statistically significant differences in terms of live birth, implantation, and clinical pregnancy rates. ConclusionThis study showed that MPA could sequentially replace GnRHant and effectively prevent premature LH surge after several days of GnRHant administration in patients being at high risk of OHSS during controlled ovarian stimulation. Switch protocol could individualize freeze-all policy and reduce the injection burden of GnRHant.

Secondary predictors of ovarian hyperstimulation syndrome development

In the treatment of infertility by the method of fertilization in vitro , such a serious complication as ovarian hyperstimulation syndrome (OHSS) can occur. Primary predictors of OHSS development are widely used in practice while selecting controlled ovarian stimulation patterns. The identification and evaluation of secondary predictors of OHSS development is relevant. Aim. To identify and evaluate secondary predictors of OHSS in women at high risk of OHSS. Materials and methods. The study included 240 women at high risk of developing ovarian hyperstimulation syndrome, 63 of these women subsequently developed ovarian hyperstimulation syndrome, and 177 did not. To identify secondary predictors, a number of preovulatory follicles and oocytes was evaluated, estradiol levels, vascular endothelial growth factor (VEGF) and interleukin‑6 (IL‑6) were defined in the blood serum and follicular fluid. Results . Compared to women without OHSS, there was a statistically significant increase in the number of preovulatory follicles, oocytes, estradiol, VEGF, IL‑6 in the blood serum and follicular fluid in OHSS patients. There was a direct correlation between the serum and follicular fluid levels of estradiol (r s = 0.85; 95 % CI 0.80–0.89; P < 0.001), VEGF (r s = 0.76; 95 % CI 0.69–0.81; P < 0.001) and IL‑6 (r s = 0.67; 95 % CI 0.58–0.74; P < 0.001). Secondary predictors of OHSS was the number of preovulatory follicles ≥30 for two ovary (sensitivity – 46.0 %, specificity – 91.0 %), the number of oocytes ≥19 (sensitivity – 87.3 %, specificity – 97.7 %), serum estradiol levels ≥4800 pg/ml (sensitivity – 74.6 %, specificity – 96.6 %) and estradiol in follicular fluid – ≥725000 pg/ml (sensitivity – 98.4 %, specificity – 97.7 %), serum VEGF ≥ 30 pg/ml (sensitivity – 76.2 %, specificity – 98.3 %) and VEGF in follicular fluid ≥500 pg/ml (sensitivity – 87.3 %, specificity – 97.2 %), IL‑6 in serum ≥4 pg/ml (sensitivity – 65.1 %, specificity – 98.9 %) and IL‑6 in follicular fluid ≥8.5 pg/ml (sensitivity – 90.5 %, specificity – 98.3 %), respectively. Conclusions. The predictors of OHSS should be taken into account to reduce the risk of its development. In identifying secondary predictors of OHSS development, it is necessary to use preventive measures consisting in discontinuation of luteal phase support, vitrification of all embryos and their transfer in subsequent thawed cycles.

The role of Letrozole (LE) in controlled ovarian stimulation (COS) in patients at high risk to develop ovarian hyper stimulation syndrome (OHSS). A prospective randomized controlled pilot study

BackgroundRecently, it has been shown that PCOS patients with extremely high anti-Mullerian hormone (AMH) level are more likely to experience OHSS during IVF, compared to PCOS patients with lower AMH level. While recent data questioned the effect of Letrozole (LE) on the occurrence of OHSS in non-PCOS patients, it role in PCOS patients with very high AMH level was never investigated in a prospective manners. Hence, our main objective was to evaluate the clinical outcome of PCOS patients at very high risk for OHSS undergoing two different COS protocols (with or without LE). MethodsA prospective randomized controlled study (RCT) of 51 patients with specifically high levels of AMH undergoing one of two COS protocols. The control group (group A) consisted of 24 PCOS women who received low-dose gonadotropins using the multiple-dose GnRH-antagonist protocol, GnRH agonist-triggered and “freeze all”. The study group (group B) consisted of 24 women with PCOS who received the same protocol combined with LE. High risk criteria for OHSS were: PCOS patients with low BMI, young age, and extremely high level of serum AMH (inclusion criteria for AMH > 50 pmol/L). ResultsCumulative live birth rates per retrieval were similar in both groups. While no single case of severe OHSS was observed in, in the study group (group B), the rate of moderate and mild OHSS was 5 times lower compared to the control group (P < 0.05). ConclusionIn PCOS patients with extremely high AMH levels the LE co-administration to GnRH-Ant protocols results in reduced incidence of OHSS than conventional GnRH-Ant protocols. LE co-administration may prove to be highly effective in preventing OHSS, even in the women who are at high risk to these dangerous complications.

Fresh versus freeze-all strategy in assisted reproductive technology – a cochrane review

In vitro fertilisation (IVF) treatments imply a fresh embryo transfer, possibly followed by one or more frozen-thawed embryo transfers in subsequent cycles. Alternatively, one can opt to freeze all suitable embryos and transfer frozen-thawed embryos in subsequent cycles only, which is also known as the freeze-all strategy. We compared the effectiveness and safety of these treatment strategies. We searched the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Studies (CRSO), MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials in February 2019 for relevant studies, and checked references and contacted study authors in the field to obtain additional data. We used standard methodological procedures as recommended by Cochrane for our search, data extraction, and analyses. The primary outcome was cumulative live birth rate (cLBR). Secondary outcomes included ovarian hyper stimulation syndrome (OHSS), pregnancy complications, and time to pregnancy. We included six RCTs in our meta-analyses, that together reported on 4324 women. The studies compared the freeze-all strategy to IVF with fresh transfer in women with a high risk of OHSS, in ‘good prognosis' women based on the number of follicles, in women with PCOS, and in young women without PCOS. The evidence was of moderate to low quality due to serious risk of bias, serious imprecision for four studies, and serious unexplained heterogeneity for one study. For cLBR we found an OR of 1.10 (95% CI 0.97 to 1.24; 6 RCTs; 4324 women; I2 = 0%, moderate quality of evidence) for the freeze-all strategy versus IVF with fresh transfer of embryos. These data suggest that for a cLBR of 63% following IVF with fresh transfer of embryos, the cLBR following the freeze-all strategy would be between 62% and 67%. Women developed less OHSS after the freeze-all strategy compared to IVF with fresh transfer of embryos (OR 0.29, 95% CI 0.19 to 0.44; 4 RCTs; 4065 women; I2 = 5%, low quality evidence). These data suggest that for an OHSS rate of 4% following the conventional strategy, the rate following the freeze-all strategy would be between 1% and 2%. The risk of maternal hypertensive disorders and having a large for gestational age baby was increased following the freeze-all strategy (OR 2.15, 95% CI 1.42 to 3.25; 3 trials; 3940 women; I2 = 29% and OR 1.87, 95% CI 1.43 to 2.44; 3 trials; 3119 women; I2 = 0%, respectively, both low-quality evidence). The risk of having a small for gestational age baby was lowered following the freeze-all strategy (OR 0.68, 95% CI 0.53 to 0.89; 3 trials; 3119 women; I2 = 56%, low-quality evidence). One trial reported on time to conception and one trial reported on time to live birth which were both longer in the freeze all strategy. We did not find a clear difference in cLBR between the two strategies. The freeze-all strategy lowered the risk of OHSS, increased the risk of maternal hypertensive disorders of pregnancy, increased the risk of a large for gestational age baby, and lowered the risk of a small for gestational age baby. The time to pregnancy was longer in the freeze-all strategy.