Prevention Of Ovarian Hyperstimulation Syndrome Research Articles

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.

#140 : Combined Use of Letrozole, Cabergoline and GnRH Antagonist to Prevent Ovarian Hyperstimulation Syndrome Completely in Polycystic Ovarian Syndrome Treatment

Background and Aims: The main difficulty to treat polycystic ovarian syndrome (PCOS) is the possibility of ovarian hyperstimulation syndrome (OHSS). There are several clinical approaches to avoid dangerous complications of OHSS: laparoscopic ovarian drilling (LOD), in vitro maturation (IVM), and GnRH antagonist-GnRH agonist based controlled ovarian stimulation (COS) with low dose of gonadotrophin. However, clinical outcomes after using these methods are less satisfactory than COS in normal ovarian function. We started a new approach combining the use of three kinds of medicine, Letrozole, Cabergoline and GnRH antagonist from just after the oocyte pick up and continue for five consecutive days to prevent the occurrence of OHSS in the PCOS treatment. Method: We compared the severity of OHSS after using a new treatment (the novel COS) in 53 women (55 cycles) with the severity of OHSS in a group of 37 women (37 cycles) who received the most widely used conventional GnRH antagonist-GnRH agonist- based COS for PCOS in retrospective cohort study. Results: This table shows the comparison of clinical outcomes between two groups. Conclusion: PCOS patients have been treated with hypostimulation methods and IVM to prevent OHSS. However, our method is considered to be more effective, safer and more versatile than any other treatment method. It seems to be an important alternative treatment method for PCOS patients. We believe this new treatment is highly recommended for the complete prevention of OHSS.

Real-world practices of hormone monitoring during ovarian stimulation in assisted reproductive technology: a global online survey.

The aim of this study is to understand the global practice of routine hormonal monitoring (HM) during ovarian stimulation (OS) in the context of assisted reproductive technique (ART) treatment. An open-access questionnaire was available to 3,845 members of IVF-Worldwide.com from September 8 to October 13, 2021. The survey comprised 25 multiple-choice questions on when and how ultrasound (US) and hormone tests were conducted during ovarian stimulation OS. For most questions, respondents were required to select a single option. Some questions allowed the selection of multiple options. In all, 528 (13.7%) members from 88 countries responded to the questionnaire. Most respondents (98.9%) reported using US to monitor OS cycles. HM was used by 79.5% of respondents during any of the cycle monitoring visits and was most commonly performed on the day of, or a day prior to final oocyte maturation. Overall, 87% of respondents claimed adjusting the dose of gonadotropin during OS, with 61.7% adjusting the dose based on hormonal levels. Oestradiol (E2) was the most frequently monitored hormone during all visits and was used by 74% of respondents for the prediction of ovarian hyperstimulation syndrome (OHSS). On or a day prior to ovulation triggering (OT), the number of respondents who measured progesterone increased from 34.3% in the second/third visit to 67.7%. Approximately one-third of respondents measured luteinizing hormone during all visits. Globally, most ART specialists (~80%) use HM, along with US, for monitoring OS, especially for the prevention of OHSS.

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.

Guideline No. 315: Prevention of Ovarian Hyperstimulation Syndrome

Summary Statements1.The particular follicle-stimulating hormone formulation used for ovarian stimulation does not affect the incidence of ovarian hyperstimulation syndrome. (I)2.Coasting may reduce the incidence of severe ovarian hyperstimulation syndrome. (III)3.Coasting for longer than 3 days reduces in vitro fertilization pregnancy rates. (II-2)4.The use of either luteinizing hormone or human chorionic gonadotropin for final oocyte maturation does not influence the incidence of ovarian hyperstimulation syndrome. (I)5.There is no clear published evidence that lowering the human chorionic gonadotropin dose will result in a decrease in the rate of ovarian hyperstimulation syndrome. (III)6.Cabergoline starting from the day of human chorionic gonadotropin reduces the incidence of ovarian hyperstimulation syndrome in patients at higher risk and does not appear to lower in vitro fertilization pregnancy rates. (II-2)7.Avoiding pregnancy by freezing all embryos will prevent severe prolonged ovarian hyperstimulation syndrome in patients at high risk. (II-2)8.Pregnancy rates are not affected when using gonadotropin-releasing hormone (GnRH) agonists in GnRH antagonist protocols for final egg maturation when embryos are frozen by vitrification for later transfer. (II-2) Recommendations1.The addition of metformin should be considered in patients with polycystic ovarian syndrome who are undergoing in vitro fertilization because it may reduce the incidence of ovarian hyperstimulation syndrome. (I-A)2.Gonadotropin dosing should be carefully individualized, taking into account the patient’s age, body mass, antral follicle count, and previous response to gonadotropins. (II-3B)3.Cycle cancellation before administration of human chorionic gonadatropin is an effective strategy for the prevention of ovarian hyperstimulation syndrome, but the emotional and financial burden it imposes on patients should be considered before the cycle is cancelled. (III-C)4.Gonadotropin-releasing hormone (GnRH) antagonist stimulation protocols are recommended in patients at high risk for ovarian hyperstimulation syndrome (OHSS). The risk of severe OHSS in patients on GnRH antagonist protocols who have a very robust ovarian stimulation response can be reduced by using a GnRH agonist as a substitute for human chorionic gonadotropin to trigger final oocyte maturation. (I-B)5.A gonadotropin-releasing hormone (GnRH) antagonist protocol with a GnRH agonist trigger for final oocyte maturation is recommended for donor oocyte and fertility preservation cycles. (III-C)6.Albumin or other plasma expanders at the time of egg retrieval are not recommended for the prevention of ovarian hyperstimulation syndrome. (I-E)7.Elective single embryo transfer is recommended in patients at high risk for ovarian hyperstimulation syndrome. (III-C)8.Progesterone, rather than human chorionic gonadotropin, should be used for luteal phase support. (I-A)9.Outpatient culdocentesis should be considered for the prevention of disease progression in severe ovarian hyperstimulation syndrome. (II-2B)

The investigation of cholinergic receptor muscarinic 1 activity in the rat ovary with induced ovarian hyperstimulation.

We look at the immunoreactivity of cholinergic receptor muscarinic 1 (CHRM1) in the ovarian tissues of rats with ovarian hyperstimulation syndrome (OHSS) considering the possibility that the muscarinic activity may contribute to the pathophysiology of OHSS. In this study, 14 immature female Wistar Albino rats were divided into two groups at random. The rats were 22 days old. Rats in the control group (n=7) were 22 days old, while those in the OHSS group (n=7) received 10 IU follicle-stimulating hormone subcutaneously over the course of four days and 30 IU human chorionic gonadotropin (hCG) on the fifth day to induce ovarian hyperstimulation. All the rats were sacrificed after all the groups' ovaries and blood samples were collected at the conclusion of the experiment. The left ovarian tissues were kept in aluminum foil at -80 °C, while the right ovarian tissues were kept in 10% formalin. Tissue vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α and malondialdehyde (MDA) levels were measured by The Enzyme Linked Immunosorbent Assay technique in the ovarian tissues. CHRM1 immunoreactivity was scored immunohistochemically. Ovarian weight, tissue IL-10, TNF-α, VEGF and MDA levels, and CHRM1 immunoreactivity were significantly increased in the OHSS group. Increased levels of CHRM1 activity may play a role in the pathophysiology of OHSS. With further studies, the effect of luteinizing hormone and hCG on the ovarian and hypothalamic cholinergic system can be further investigated, and useful information can be obtained in determining OHSS prevention strategies.

Letrozole and Ovarian Hyperstimulation Syndrome (OHSS): A Promising Prevention Strategy.

Ovarian Hyperstimulation Syndrome (OHSS) is an uncommon but serious complication occurring in patients undergoing ovarian stimulation. It is characterized by ovarian enlargement, nausea, vomiting, abdominal pain/distension, and reduction in urine output. However, OHSS may rarely evolve into a life-threatening condition with ascites, hemoconcentration and hypercoagulability. Prevention of OHSS consists of an integrated approach that associates behavioral aspects with administration of pharmacological compounds. Among drugs used to manage OHSS, Letrozole has recently been proposed as an effective option for prevention of the syndrome. However, despite the promising findings reported by several studies, to date Letrozole is not yet officially mentioned in the guidelines for "Prevention and Treatment of moderate and severe ovarian hyperstimulation syndrome". In this scenario, the current study discusses Letrozole approaches scientifically available to prevent OHSS.

Cryopreservation as a strategy for prevention of ovarian hyperstimulation syndrome in a public assisted reproduction service in São Paulo - Brazil.

This study aimed to evaluate the prevalence of ovarian hyperstimulation syndrome (OHSS) and associated risk factors in patients undergoing fertilization cycles at risk of OHSS (≥15 antral follicles or ≥15 oocytes aspirated) and submitted to cryopreservation of all embryos in the Human Reproduction Service of the Pérola Byington Hospital (Referral Center for Women's Health) in São Paulo, SP, Brazil. This cross-sectional, institutional, descriptive study of secondary data from patients' charts enrolled in the Assisted Reproduction Service of the Pérola Byington Hospital at risk of OHSS after controlled ovarian stimulation and submitted to cryopreservation of all embryos was conducted between January 2015 and September 2017. OHSS occurred in 47.5% of cycles, all with mild severity, and there were no moderate or severe cases of OHSS. The cryopreservation of all embryos is associated with a reduction in moderate and severe forms of OHSS. Risk factors for OHSS should be evaluated prior to initiation of treatment, with less intense stimulation protocols accordingly.

Evaluation of The Effect of Letrozole in the Ovarian Hyperstimulation Syndrome Prevention in Participants at Risk of Treatment with Ovulation-Stimulating Drugs:A Randomized Controlled Trial.

This study aims to evaluate the effect of Letrozole (LE) in reducing ovarian hyperstimulation syndrome (OHSS) in high-risk participants with polycystic ovary syndrome (PCOS) treated with In vitro fertilization (IVF). This study was a randomized clinical trial in which participants were randomly divided into two groups (n= 25 per group). Based on GnRH-antagonist protocol, recombinant follicle-stimulating hormone 150 units/day subcutaneously and human menopausal gonadotropin 75 units/ day intramuscularly used from day 2 of the menstrual cycle. In the study group, Letrozole 5 mg daily was added simultaneously with gonadotropin during the first five days of the IVF cycle and in the control group placebo was added. There were statistically significant differences among the groups in terms of Estradiol level on Trigger Day (p= 0.04). The total days of stimulation and cumulative Gonadotropin dose were significantly lower in the Letrozole group (p= 0.00). There were no significant differences between the groups in terms of the number of oocytes retrieved, numbers of implanted embryos, and clinical pregnancy rates (p-value> 0.05). There was only one moderate case in the intervention group and 9 moderate symptoms in the control group (p= 0.04). Administration of Letrozole with GnRH antagonist protocol, conventional protocol in PCOS cases in IVF cycle, had a significant effect on reducing the incidence of OHSS. So, if the future studies prove LE co-administration may lessen the incidence of OHSS, LE will be a highly potent drug for preventing OHSS in PCOS cases.

P-641 Physicians’ practices towards hormone monitoring during ovarian stimulation in context of treatment with Assisted Reproductive Technology (ART). A global Survey conducted through IVFworldwide.com

Abstract Study question What is the practice of routine hormone monitoring (HM) during ovarian stimulation (OS) in the context of ART treatment? Summary answer The majority of ART specialists (∼80%) use HM, along with ultrasound, for monitoring OS, especially for the prevention of ovarian hyperstimulation syndrome (OHSS). What is known already Ovarian stimulation (OS) is an essential part of ART and optimal monitoring is essential in order to optimize final outcome and ensure safety. Monitoring of OS can be either done with ultrasound (US) and/or hormonal monitoring in order to adjust gonadotropin dose, to trigger ovulation and to maximize success while avoiding the risk of OHSS. Clinical practice guidelines typically propose US monitoring as the cornerstone of OS monitoring during ART treatment. Although HM is practiced widely, the current attitude and practice of clinicians regarding HM has not been evaluated on a global scale. Study design, size, duration In a cross-sectional study carried out using a survey on current practice of blood HM, we evaluated physicians’ attitudes towards blood HM during OS in context of ART treatment. An open-access questionnaire was accessible to the members of IVF-Worldwide.com, from September 8 to October 13,2021 on IVF-Worldwide.com and was completed by 528 participants. Data analysis was performed using Excel (Microsoft Inc., USA), statistics were calculated once giving all survey entries an equal representation. Participants/materials, setting, methods An initial invitation and one reminder were sent to all 3845 registered members of IVF-Worldwide.com by email. In total, 528 participants answered the survey (13.7%). The survey was composed of 25 multiple-choice questions with mainly single answers. These questions asked about tests performed during any cycle monitoring visits during OS for ART treatment (blood hormone monitoring, ultrasound, timing, and frequency of prescribed tests), about monitoring to prevent OHSS as well as to adjust gonadotropin dose. Main results and the role of chance A total of 528 members from 88 countries responded to this web-based survey. Most participants (87.9%) were clinicians and practiced reproductive medicine for more than 15 years (56.7%). Nearly half (46.2%) performed more than 500 oocyte aspiration cycles in their clinic annually. Of the 528 respondents, the vast majority (98.9%) used US to monitor OS cycles during ART treatment. Hormone monitoring (HM) was widely accepted and performed by 420 (79.5%) of participants during any of the cycle monitoring visits for OS (from stimulation day 1 until the day before ovulation triggering (OT)). Among different visits, participants most frequently monitored hormones on the day on or before the final oocyte maturation (71%) as compared with 57% on the first visit and 61% on the second and third visit during OS. The most frequent reason for HM was for prediction of OHSS (74%) and for adjusting gonadotropin dose (50%), whereas 45% of physicians considered HM for timing of OT. Most respondents (60.7%) considered that hormones play an important role in monitoring ovarian response during OS and a 58% considered that blood hormone tests are important to guiding decision-making in preventing OHSS. Limitations, reasons for caution The survey was designed to represent self-reported statistics and opinions from experts in the field. It did not capture actual clinician performance or patient data. Wider implications of the findings Although several guidelines consider US monitoring as the cornerstone for monitoring ovarian response during OS for ART, the majority of ART specialists consider HM as essential. Good quality studies are needed to document the value of HM during OS, with respect to dose adjustment, ovulation triggering and prevention of OHSS. Trial registration number not applicable

P-664 The effect of LH levels on the day of trigger on the oocyte retrieval and maturation rates in GnRH-antagonist cycles with an agonist trigger

Abstract Study question Are LH levels on day of trigger correlated with the number of oocytes retrieved and oocyte maturation rate in GnRH-antagonist cycles with an agonist trigger? Summary answer Low LH levels on the day of trigger were associated with a lower oocyte retrieval rate yet no correlation with oocyte maturation rates was found. What is known already The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. GnRHa trigger offers important advantages including the prevention of ovarian hyperstimulation syndrome (OHSS) with the elicitation of an endogenous LH and FSH surge. Therefore, we sought to evaluate whether LH levels on the day of the trigger are associated with the efficacy of the trigger in eliciting endogenous LH surge and thereby influencing oocyte retrieval and oocyte maturation rates. Study design, size, duration This retrospective single center study included all GnRH antagonist cycles triggered with GnRHa trigger (Decapeptyl 0.2mg) performed at our IVF unit between July 2013 and December 2020. We studied the association between LH levels on the day of trigger and the number of oocytes retrieved. Additionally, we studied the effect of LH levels on oocyte maturation rates. Participants/materials, setting, methods All GnRH antagonist cycles triggered with GnRHa trigger were included. Data was acquired through individual review of medical records. Linear regression was used to study the correlation between LH levels and oocyte retrieval and maturation rates. Moreover, LH levels on day of trigger were divided ≤1 IU/L and > 1 IU/L to further investigate this correlation. The ratio between Basal LH and LH on day of trigger was investigated as well. Main results and the role of chance There were 211 GnRH antagonist cycles triggered with GnRH agonist trigger during the study period. The mean age of patients in the study group was 30.1±4.8 y/o, mean basal LH levels were - 6.8±3.4 IU/L, mean Basal FSH levels were - 6.7±1.9IU/L and the mean total dose of gonadotropin administered was 1633.4±680.6 Units. The mean E2 levels were 11,444±7018.5 pmol/L and the mean number of oocytes retrieved was 19.8±10.2. A correlation was found between lower LH levels on the day of trigger and the number of oocytes retrieved (p < 0.001). No correlation was found between LH levels on the day of trigger and oocyte maturation rates (p = 0.82). The ratio between Basal LH and LH on day of trigger was not found to be a significant factor influencing either the number of oocytes retrieved or oocyte maturation rate. When dividing the group by LH on day of trigger to below and above 1, a borderline difference was found relating to oocyte retrieval rate between the two groups (p = 0.06). Limitations, reasons for caution The retrospective nature of the study is the main limitation. Patients receiving GnRHa trigger are mainly a selective population of either high responders or patients for fertility preservation stimulated to retrieve many oocytes, therefore findings may not be applicable to normal or poor responders. Wider implications of the findings Low LH levels on day of trigger were found associated with lower oocyte retrieval rates. GnRHa has become an alternative to standard hCG triggering in certain situations. These are preliminary findings of an ongoing study designed to investigate the efficacy of GnRHa trigger according to cycle parameters including LH levels. Trial registration number not applicable

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.

A patient and physician friendly stimulation protocol using long acting FSH and progestin priming should be the future of IVF

Objective: Needle phobias and concern about the discomfort remain significant disincentives for many women contemplating in vitro fertilization (IVF). The number of injections required in an IVF cycle is increased by the use of most medications which prevent premature ovulation. Mechanism: long-acting follicular stimulation hormone (LA-FSH) that was developed 15 years ago has the ability to stimulate folliculogenesis in a patient for seven days with a single injection, with comparable outcomes to daily injections in assisted reproduction. Many clinicians were hesitated to use it in their patients, fearing an inability to decrease levels of FSH stimulation for 7 days and the resultant increased risks of ovarian hyperstimulation syndrome (OHSS). This occurred prior to the widespread adoption of Gonadotropin-releasing hormone (GnRH)-agonist triggering and freeze all embryos for the prevention of OHSS. Conclusions: We suggest LA-FSH protocol with the use of progestins to prevent ovulation, which could be an alternative way to treat IVF patients without any compromise of the effectiveness of the treatments or the safety of the patients.

Ovarian hyperstimulation syndrome and its relation to pregnancy

Vytautas Abraitis1, Saulė Kržčonavičiūtė1, Marija Vaitkevičiūtė2 1 Department of Obstetrics and Gynecology, Medical Academy, Lithuanian University of Health Sciences, Eivenių g. 2, LT-50161 Kaunas, Lithuania 2 Medical Academy, Lithuanian University of Health Sciences, A. Mickevičiaus g. 9, LT-44307 Kaunas, Lithuania Abstract Introduction: Ovarian Hyperstimulation Syndrome (OHSS) is an iatrogenic complication manifested by suprafysiological ovarian stimulation. This syndrome is commonly related to assisted reproduction. OHSS has been associated with an increased risk of miscarriage, multiple pregnancies, and more severe clinical course of the syndrome. However, there are few studies examining the relationship between OHSS and pregnancy, and more consistent studies are needed. The aim – to discuss the characteristics of OHSS and it‘s possible links with pregnancy. Research method: systematic literature review was conducted. Articles, describing OHSS and its links to pregnancy, were selected. The review was done using the electronic database Pub-Med (Medline). Results: OHSS prevention is selected individually based on risk factors, anti-müllerian hormone concentration, and number of tertiary follicles. Mild to moderate OHSS may regress spontaneously and treatment is not always necessary. Patients who develop signs of severe OHSS should be hospitalized and treated with medication and (or) surgery. In case of unclear pathogenesis of the disease, only symptomatic treatment is possible. A correlation was observed between OHSS and an increased risk of miscarriage, preterm birth, gestational hypertension and low birth weight. Conclusions: OHSS is an iatrogenic complication that can occur at different stages and degrees due to variety of risk factors and prevention. Mild to moderate OHSS is often a transient condition, however, severe OHSS can be potentially life-threatening. The complications associated with OHSS are miscarriage and preterm birth, although there are also associations between this syndrome and gestational hypertension as well as low birth weight. Keywords: ovarian hyperstimulation syndrome, OHSS treatment, pregnancy.

Calcium gluconate infusion is not as effective as dopamine agonists in preventing ovarian hyperstimulation syndrome.

The aim of the study was to compare the effectiveness of calcium gluconate and cabergoline therapy in the prevention of ovarian hyperstimulation syndrome (OHSS). Eight hundred and forty-five women who underwent GnRH antagonist protocol and at high risk for developing OHSS were divided into two groups, those given cabergoline (n=435) or calcium gluconate (n=410). In cabergoline group, 0.5 mg of cabergoline was administered once daily p.o. starting on the day of ovulation trigger and continued until the following 8 days. In calcium gluconate group, intravenous calcium gluconate was administered daily for four days starting on the day of oocyte pickup (OPU). 10 ml of 10% calcium gluconate solution was dissolved in 200 ml of physiological saline and administered by intravenous route within 40 minutes. Infusion was started within the first 30 minutes following the OPU and continued on the 1st, 2nd and 3rd days after OPU. Mild OHSS was developed in 367 (89%) patients receiving calcium gluconate infusion, while 251 patients (57%) in the cabergoline group developed mild OHSS. The frequency of mild OHSS in the calcium group was significantly higher than the cabergoline group (p<.001). Moderate OHSS was observed in 32 people (7.8%) in the calcium gluconate group, while it was observed in 184 people in the cabergoline group (42.3%). Calcium gluconate infusion significantly reduced the development of moderate OHSS compared to cabergoline therapy (p<.001). Severe OHSS developed in 11 patients (2.7%) in the calcium gluconate group, while severe OHSS did not develop in those given cabergoline (0%, p<.001). Clinical pregnancy, live birth and abortion rates were similar in the two groups. When logistic regression analysis was performed, a significant correlation was found between age, BMI, AMH, the number of antral follicle count, OHSS history, paracentesis, progesterone on the day of hCG, 2 PN zygotes, and HbA1c levels and the development of OHSS. No correlation was found between the use of metformin or cetrotide and the development of OHSS. Calcium gluconate treatment is not effective in the prevention of OHSS.

Nintedanib Treatment After Ovulation is an Effective Therapeutic Strategy for the Alleviation of Ovarian Hyperstimulation Syndrome (OHSS) in a Mouse Model.

PurposeOvarian hyperstimulation syndrome (OHSS) is a serious complication of controlled ovarian hyperstimulation. In this study, we hope to explore whether nintedanib, a tyrosine kinase inhibitor, can inhibit OHSS by blocking signaling of vascular endothelial growth factor in a mouse model. Considering that nintedanib been approved for the treatment of some diseases. We believe that nintedanib has important potential in the treatment of OHSS.MethodsFemale ICR mice aged 6–8 weeks with similar initial weights were used to establish the OHSS model. At 12 and 24 hours after human chorionic gonadotropin (hCG) trigger, we administered nintedanib by subcutaneous injection and analyzed the OHSS-related physiological characteristics and biochemical indices of the model mice within 48 hours after hCG-trigger.ResultsNintedanib significantly alleviated the symptoms of OHSS after hCG-trigger compared with those of OHSS group (weight change, P < 0.0001; ovarian weight, P < 0.0001, peritoneal exudation level, P < 0.01). Further investigation proved that the corpus luteum (number, P < 0.001; diameter, P < 0.0001) and luteal vessel (P < 0.0001) development were inhibited in the nintedanib administration group. Then, the vascular permeability test showed that the capillary bleeding points (P < 0.0001) were also significantly reduced in nintedanib administration group. Gene expression tests demonstrated that the intercellular connection-related genes expression in the nintedanib administration group was similar to that in the no-OHSS induced group. Further detection of coagulation and thrombosis indices indicated that the nintedanib administration in the OHSS model did not increase the risk of thrombosis or bleeding.ConclusionOur study demonstrated that nintedanib can alleviate and manage the symptoms of OHSS in a mouse model. These findings identify a feasible scheme for the prevention and treatment of OHSS in clinical practice in the future. Moreover, since the scheme can be implemented after ovulation, it will not cause potential adverse effects on gametogenesis, fertilization or embryonic development.

Comparison of the Effectiveness of Various Medicines in the Prevention of Ovarian Hyperstimulation Syndrome: A Network Meta-Analysis of Randomized Controlled Trials.

BackgroundPrevious studies have described the effects of different drugs in preventing ovarian hyperstimulation syndrome (OHSS). However, the efficacies of those drugs in preventing OHSS remain inconclusive.MethodsWe searched the PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. A network meta-analysis of randomized controlled trials (RCTs) was performed up to August 2021. We investigated the following drugs in our study: aspirin, albumin, metformin, calcium, cabergoline, quinagolide, letrozole, hydroxyethyl starch (HES), and glucocorticoids. The primary outcome was the incidence rate of moderate-to-severe OHSS, with the results presented as risk ratios (RRs) with 95% confidence intervals (CIs).ResultsThe incidence of moderate-to-severe OHSS was significantly reduced by calcium administration (risk ratios [RR] 0.14, 95% confidence interval [CI]: 0.04, 0.46) (grade: high), HES (RR 0.25, 95% CI 0.07, 0.73) (grade: high), and cabergoline (RR 0.43, 95% CI 0.24, 0.71) (grade: moderate). The surface under the cumulative ranking curve (SUCRA) indicated that calcium (SUCRA, 92.4%) was the most effective intervention for preventing moderate-to-severe OHSS. These drugs were safe and did not affect clinical pregnancy, miscarriage, or live birth rates.ConclusionCalcium, HES, and cabergoline could effectively and safely prevent moderate-to-severe OHSS, with calcium as the most effective intervention.

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.

Current possibilities in the prevention and therapy of ovarian hyperstimulation syndrome.

To present current possibilities of the prevention and therapy of ovarian hyperstimulation syndrome (OHSS). Literature and guidelines were researched. From the view of safety and prevention of OHSS, antagonistic protocol is suitable. Patients with syndrome of polycystic ovaries benefit from the use of metformin or letrozole that can be sufficient to induce ovulation. As atreatment of imminent OHSS, it is recommended to administer 0.5 mg of cabergoline per os daily as well as low molecular weight heparin subcutaneously in prophylactic dose and to maintain sufficient fluid intake. Diuretics are strongly discouraged to use. To maintain intravascular volume, drained ascites can be reintroduced. We present areview of current literature and recommendations.

A Prospective Randomised Comparative Clinical Trial Study of Luteal PhaseLetrozole versus Ganirelix Acetate Administration to Prevent Severity of Early Onset OHSS in ARTs.

BackgroundOvarian hyperstimulation syndrome (OHSS) is the most notable complication in ovulation induction for assisted reproductive techniques (ARTs) like in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Hence, we decided to evaluate the effect of the aromatase inhibitor, letrozole, versus gonadotrophin-releasing hormone (GnRH)-antagonist (ganirelix acetate) on prevention of severity of OHSS and reduction in serum estradiol (E2) levels when administered during the luteal phase after oocyte retrieval in IVF/ICSI cycles.Materials and MethodsIn this prospective single-centred, randomized, parallel-arm study, 122 patients were rand- omized to receive oral letrozole (n=61, 2.5 mg twice daily) or ganirelix acetate (n=61, 0.25 mg subcutaneously daily) from the day of egg retrieval for the next 7 days. Incidence and severity of early OHSS were the primary endpoints assessed by the signs, symptoms, and laboratory findings of OHSS (e.g., serum E2 levels). The secondary endpoints were patient satisfaction and the additional cost of therapy to prevent the severity of OHSS.ResultsLetrozole group had lower incidence of OHSS (13.1%) compared to 19.6% in ganirelix acetate group (P=0.32). Serum E2 levels on post-pick up days 5 and 7 were significantly lower in the letrozole group when com- pared to the ganirelix acetate group (P=0.001). The majority of the patients in both groups had no major complica- tions. No significant difference was found between the study groups with respect to the incidence of OHSS (P=0.33). The additional cost per IVF cycle for prevention of severity of early-onset OHSS in the letrozole group was 5.32 USD compared to 267.26 USD in the ganirelix acetate group, which was almost fifty times costlier.ConclusionLetrozole and ganirelix acetate have the same efficiency for the overall prevention of OHSS, whereas letrozole was more effective in preventing moderate OHSS. Letrozole had better patient satisfaction and is cheaper compared to GnRH antagonists (Registration number: CTRI/2020/10/028674).