Risk Of Ovarian Hyperstimulation Syndrome Research Articles

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.

Psychosocial wellbeing shortly after allocation to a freeze-all strategy compared with a fresh transfer strategy in women and men: a sub-study of a randomized controlled trial.

Psychosocial wellbeing shortly after allocation to a freeze-all strategy compared with a fresh transfer strategy in women and men: a sub-study of a randomized controlled trial.

Efficacy of progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing in vitro fertilization: a systematic review and meta-analysis.

NPLASY (202340059). https://inplasy.com/inplasy-2023-4-0059/.

Recent Advances in InVitro Maturation (IVM): A Systematic Literature Review

In Vitro Maturation (IVM) is one of the Assisted Reproductive Technologies (ART) that involves the retrieval of immature oocytes from antral follicles in the ovaries, either in a non-stimulated or minimally stimulated state. IVM has drawn the attention of fertility specialists due to its reliability, cost-effectiveness, low risk of Ovarian Hyperstimulation Syndrome (OHSS), and acceptable clinical pregnancy rates Objective: Understanding the Process and Factors Influencing In Vitro Maturation of Human Oocytes (IVM) Method: The research methodology employed in this study is the Systematic Literature Review (SLR) method. Data was collected by documenting all articles based on predetermined inclusion and exclusion criteria. A total of 10 national and international journal articles were utilized for this study, obtained from databases such as Google Scholar, PubMed, and Science Direct, using specific keywords including "In Vitro Maturation" and "human oocyte maturation". The literature search and study selection process followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Results: There were no instances of moderate-severe OHSS (ovarian hyperstimulation syndrome) in the IVM group. The fertilization rate in the group receiving growth hormone (GH) was 12.8% higher compared to the control group. Additionally, the blastocyst rate in the GH group was 9.5% higher than that of the control group. Treatment with a concentration of 50 µmol/L ALA (alpha-lipoic acid) significantly accelerated oocyte maturation. It resulted in a significantly higher mitochondrial DNA (mtDNA) copy number in mature oocytes compared to the control group (0 µmol/L ALA). The highest maturation rates were observed in human umbilical cord mesenchymal cells (hUCM) in the in vitro maturation (fIVM) of germinal vesicle (GV) oocytes, while the lowest maturation rates were observed using alpha-Minimum Essential Medium (α-MEM) in the in vitro maturation (vIVM) of GV oocytes. When AMH (anti-Müllerian hormone) was added to the IVM medium, a maturation rate of 100% was achieved in mature oocytes. The inclusion of 50 mmol/L CoQ10 in IVM media was found to reduce the level of oocyte aneuploidy by nearly 50%. The formation rate of metaphase II (MII) stage oocytes was higher in culture medium containing 1.0 mm resveratrol compared to the control group. Subsequently, a total of eight cleavage-stage embryos were frozen after intracytoplasmic sperm injection (ICSI). One year later, when the patient returned for the transfer of cryopreserved embryos, two embryos were thawed and transferred into the uterus. The patient successfully became pregnant, and the twin pregnancy progressed without complications, delivering two healthy full-term baby boys. Conclusion: The occurrence of OHSS was not observed in any of the IVM intervention groups. Supplementation with growth hormone (GH), alpha-lipoic acid (ALA), umbilical cord-derived mesenchymal stem cells (CM-MSC), anti-Müllerian hormone (AMH), and resveratrol in the culture media each demonstrated a significant improvement in human oocyte maturation. Furthermore, resveratrol and coenzyme Q10 were effective in addressing abnormal spindle morphology, irregular chromosome arrangement, and high postmeiotic aneuploidy. It is worth noting that IVM is not exclusively limited to patients with polycystic ovary syndrome (PCOS), as it can yield satisfactory outcomes in patients with autoimmune premature ovarian insufficiency (POI).

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.

Outcomes of the Next In Vitro Fertilization Cycle in Women with Polycystic Ovary Syndrome after a Failed In Vitro Maturation Attempt.

In vitro maturation (IVM) is indicated in women with polycystic ovary syndrome (PCOS) who have a very good ovarian response during in vitro fertilization (IVF) and are therefore at high risk of ovarian hyperstimulation syndrome (OHSS). According to the latest practice committee document, IVM could be a major advance in assisted reproductive technology (ART) procedures (reduced cost and simplified treatment); nevertheless, retrospective studies of IVM versus IVF still demonstrate lower chances of a live birth with IVM. Could IVM prove to be an optimal first-line treatment approach? And limited information is available concerning the success of the subsequent IVF cycle after the failure of an IVM cycle. Does IVM treatment adversely affect the subsequent IVF cycle, and is this worth considering before performing the IVF cycle for women with PCOS? This prospective nested case-control study at the Peking University Reproductive Medicine center in China was performed between March 2018 and September 2020. Women aged 20-38 years with PCOS and infertility and who were scheduled for their first IVF attempt were eligible. A total of 351 women were randomly allocated to receive one cycle of unstimulated natural IVM (n = 175) or one cycle of standard IVF with a flexible GnRH antagonist protocol followed by hCG as an ovulation trigger (n = 176). This study involved 234 women (58 women with no blastocysts in the first IVM cycle and 158 women who underwent the first IVF cycle). Cumulative live birth rate at 12 months after oocyte retrieval and OHSS of a standard controlled ovarian stimulation (COS) IVF cycle were compared between 58 women in an IVF cycle following a failed IVM cycle and 158 women who underwent the first IVF cycle. No significant differences were found in the cumulative live birth rate (CLBR), ongoing pregnancy rate, or clinical pregnancy rate at 12 months after oocyte retrieval between the two groups (56.9% vs. 58.9%, p = 0.795; 58.6% vs. 60.8%, p = 0.776; and 84.5% vs. 76.0%, p = 0.178). The incidence of moderate-to-severe OHSS was not significantly different between the groups (6.9% vs. 5.7%, p = 0.742). Additionally, there were no significant differences in the total gonadotropin dose, stimulation duration, number of retrieved oocytes, number of retrieved mature oocytes, or fertilization rates. Even if the first IVM attempt failed in subfertile women with PCOS, comparable cumulative live birth rates were observed in the subsequent IVF cycle. IVM treatment does not adversely affect the subsequent IVF cycle.

Effect of Metformin (MTF) Intervention During Pregnancy in Women With Polycystic Ovarian Syndrome (PCOS): A Systematic Review.

Metformin (MTF) is a commonly prescribed medication for women with polycystic ovarian syndrome (PCOS), but its impact on pregnancy outcomes in women with PCOS remains controversial. This systematic review aims to evaluate the effects of MTF intervention on pregnancy outcomes in women with PCOS and the impact of MTF on offspring. A comprehensive search is conducted in PubMed, Google Scholar, and ScienceDirect databases from 2019 up to May 16, 2023. Only review articles and meta-analyses are included, focusing on women with PCOS who received MTF during pregnancy or as part of infertility treatment. The primary outcomes of interest are clinical pregnancy rate (CPR), miscarriage rate, preterm birth rate, and live birth rate. Secondary outcomes are the safety profile of MTF.Data extraction and quality assessment are performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the assessment using the multiple systematic reviews (AMSTAR) 2 tool, respectively. The initial search produced 1877 studies. Thirteen studies were included in the review. While the use of MTF during pregnancy in women with PCOS may have some benefits in reducing certain pregnancy complications such as pregnancy-induced hypertension (PIH), gestational diabetes mellitus (GDM), preeclampsia, preterm delivery, reducing the risk of ovarian hyperstimulation syndrome (OHSS) in women with PCOS undergoing in vitro fertilization (IVF); however, there is no significant difference in clinical pregnancy and live birth rates overall, but subgroup analysis suggests potential benefits for women with a higher body mass index (BMI). MTF is associated with a larger fetal head circumference and potential long-term effects on offspring's BMI and obesity. Further research is needed to better understand the optimal dosing of MTF, long-term effects, and effects in specific subgroups. The heterogeneity of the included studies limited the ability to analyze the data effectively, leading to challenges in drawing definitive conclusions.

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.

Long-acting gonadotropin-releasing hormone agonist trigger in fertility preservation cycles before chemotherapy

Oocytes/embryo cryopreservation and ovarian function suppression with gonadotropin-releasing hormone (GnRH) agonists (GnRHas) are two established strategies for preserving fertility in patients with cancer, frequently both being offered to the same woman. As the first injection of GnRHa should be administered before chemotherapy, it is usually performed in the luteal phase of the urgent controlled ovarian stimulation (COS) cycle. The GnRHa flare-up effect on recently stimulated ovaries may cause ovarian hyperstimulation syndrome (OHSS) and this risk may discourage some oncologists to offer an ovarian function preservation method with proven efficacy. We suggest the long-acting GnRHa as an option to trigger ovulation for egg retrieval in oncological patients, whenever ovarian suppression during chemotherapy is planned. We retrospectively analyzed prospectively collected data from all consecutive ovarian stimulation cases in oncological patients for oocyte cryopreservation from 2016 to 2021 in a single academic referral center. The COS was performed according to good clinical practice standards. Since 2020 long-acting GnRHa trigger was offered to all patients for whom ovarian suppression after cryopreservation was planned. All other patients served as controls, stratified for the triggering method used: highly purified chorionic gonadotrophin 10 000 UI or short-acting GnRHa 0.2 mg. Mature oocytes were collected, with the expected maturation rate, in all the 22 cycles triggered with GnRHa. The mean number of cryopreserved oocytes was 11.1 ± 4, with a maturation rate of 80% (57%-100%), versus 8.8 ± 5.8, 74% (33%-100%) with highly purified chorionic gonadotrophin and 14 ± 8.4, 80% (44%-100%) with short-acting GnRHa. No case of OHSS was observed after long-acting GnRHa triggering and by 5 days after egg retrieval most patients had reached luteinizing hormone levels showing suppression. Our preliminary data show that long-acting GnRHa is efficacious in inducing the final oocytes' maturation, reducing OHSS risk and suppressing ovarian function by the start of chemotherapy.

Dose Nomogram of Individualization of the Initial Follicle-Stimulating Hormone Dosage for Patients with Polycystic Ovary Syndrome Undergoing IVF/ICSI with the GnRH-Ant Protocol: A Retrospective Cohort Study.

For high responders with polycystic ovary syndrome (PCOS), there is no clear recommendation for the initial follicle-stimulating hormone (FSH) dosage to ensure an optimal number of retrieved oocytes and avoid ovarian hyperstimulation syndrome (OHSS). The aim of this study was to determine the ideal initial FSH dosage of in patients with PCOS undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) using the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol to obtain the optimal number of retrieved oocytes and minimize the risk of OHSS. The data of 1898 patients with PCOS aged 20-40years from January 2017 to December 2020 were retrospectively analyzed to explore the factors related to the number of retrieved oocytes. Statistically significant variables were used to construct a dose nomogram and it was then validated using an independent cohort of patients with PCOS from January 2021 to December 2021. Multivariate analyses demonstrated that body mass index (BMI) was the most significant factor to predict the number of retrieved oocytes compared to body weight (BW) and body surface area (BSA). Among patients with PCOS aged 20-40years undergoing their first IVF cycles with the GnRH-ant protocol, age was not a significant predictor of the initial FSH dosage. We developed a nomogram based on BMI, basal FSH, basal luteinizing hormone (bLH), anti-Müllerian hormone (AMH), and antral follicle count (AFC) to calculate the ideal initial FSH dosage for patients with PCOS undergoing IVF/ICSI using the GnRH-ant protocol. In addition, low BMI and high bLH and AMH levels and AFC appear to be risk factors for OHSS. We clearly demonstrated that the initial FSH dosage for patients with PCOS undergoing IVF/ICSI with the GnRH-ant protocol may be calculated on the basis of the woman's BMI and ovarian reserve markers. The nomogram will help guide clinicians in the selection of the most appropriate initial FSH dose in the future.

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)

O-186 The implementation of a novel algorithm for monitoring ovulation in an IVF mixed protocol may simplify stimulation monitoring

Abstract Study question Which patients are eligible to skip ovulation monitoring before day 10 in In Vitro Fertilization (IVF) and what are the financial implications? Summary answer Thanks to our innovative gonadotropin prescription algorithm, patients with low ovarian reserve and maximum ovarian stimulation may not require monitoring until day 10 of IVF. What is known already In most fertility clinics, the standard procedure for IVF is early monitoring on day 6 of ovarian stimulation. Our focus is on personalizing the stimulation protocol by identifying the optimal dose of gonadotropin. With the aid of our unique algorithm, we aim to streamline monitoring. Frequent ultrasound examinations required for IVF can impose restrictions and create a burden for patients, resulting in increased costs for both patients and physicians. Study design, size, duration In a retrospective study conducted from April 2021 to August 2022 at the OVO clinic in Montreal (Canada), participants included all patients over 18 years old who underwent an IVF stimulation cycle utilizing an antagonist protocol and a customized mixed protocol prescription consisting of follitrophin delta and human menopausal gonadotropin, based on the patient's weight and anti-Mullerian hormone level. The sudy was approved by Veritas IRB, an independent ethic committee. Tracking number of study :2023-3189-13659-2 Participants/materials, setting, methods In the study, gonadotropin dosages were assigned either based on our algorithm (group 1) or at the physician's discretion (group 2). Ultrasound and hormonal analysis were performed on day 6. Following the physician's evaluation, adjustments to the gonadotropin dosage were made if necessary. The common trigger criteria was the presence of at least three follicles measuring between 16 and 22mm. Main results and the role of chance The study included 714 patients meeting the inclusion criteria. In group 1, there was a high percentage of patients stimulated with the maximum doses (80.3% compared to 22.5% in group 2). No dosage modifications or incidents of ovarian hyperstimulation syndrome were observed in group 1. Only 4.5% of patients (n = 16) triggered ovulation before day 10 (on day 9). In the non-maximal dose population, patients treated according to the algorithm (group A) experienced significantly fewer changes to the gonadotropin dosage at day 6 compared to patients treated based on the physician's discretion only (group B) (24.6% vs 46.9%, p &amp;lt; 0.001). The dosage of gonadotropins was notably more frequent adjusted in group B (46.9% vs 24.6%, p &amp;lt; 0.001). A higher risk of ovarian hyperstimulation syndrome was significantly more frequent in the non-maximal dose population compared to the maximal dose population (64.6% vs 27.5%, p &amp;lt; 0.01). These findings suggest that ovulation monitoring may not be necessary in the population stimulated to the maximum dose. This could result in 478 ultrasound and blood tests being avoided in the context of this study. Limitations, reasons for caution The data was obtained through a retrospective analysis. However, not monitoring before day 10 could pose a risk of delaying the cancellation of the IVF cycle, resulting in unnecessary treatment continuation. Wider implications of the findings This significant study indicates that, thanks to our algorithm, monitoring only on day 10 would be adequate for patients with low ovarian reserve who are stimulated to the maximum dose. Further validation of this strategy can be conducted through a randomized prospective study or with the use of different gonadotropins. Trial registration number non applicable

P-630 Comparison of follitropin delta versus follitropin alfa in progestin-primed ovarian stimulation in IVF

Abstract Study question Is there a difference in a clinical outcome between using follitropin delta and follitropin alfa undergoing a progestin primed ovarian stimulation (PPOS) protocol? Summary answer There was no difference between follitropin delta and follitropin alfa in terms of pregnancy rates. What is known already Follitropin delta (REKOVELLE, Ferring Pharmaceuticals, Switzerland) is the first recombinant human follicle-stimulating hormone (FSH) using the algorithm-based individualized dosing regimen while reducing the risk of ovarian hyperstimulation syndrome (OHSS) as compared with conventional dosing strategies. The efficacy and safety of follitropin delta has been demonstrated in randomized controlled trials (RCTs). Study design, size, duration We performed a retrospective analysis of 645 patients who underwent ovarian stimulation by a PPOS protocol using follitropin delta or follitropin alfa between April 2022 and August 2022. (325 patients using follitropin delta and 320 patients using follitropin alfa, respectively.) Participants/materials, setting, methods 325 cycles of women who used follitropin delta were compared to 320 cycles of women who used follitropin alfa. The following outcomes were analysed; fertilized rate, 2 pronuclear embryo rate, good quality embryo rate, blastocyst rate, good quality blastocyst rate. A total of 499 women who underwent embryo transfer in cryo cycles using natural cycle or hormone replacement cycle were analysed about biochemical pregnancy rate, clinical pregnancy rate. Main results and the role of chance Baseline demographics for 325 women in follitropin delta group and 320 women in follitropin alfa were: age, 35.1±4.3 years and 35.2±4.3 years; number of previous IVF cycles, 1.6±1.6 and 1.7±1.7, respectively. The laboratory data were: fertilization rate, 81.4% and 80.1%, 2 pronuclear embryo rate, 73.9% and 71.5%, good quality cleavage stage embryo rate, 59.4% and 55.9%, blastocyst rate, 58.9% and 55.7%, good quality blastocyst rate, 41.3% and 38.7%, respectively. Only good quality cleavage stage embryo rate and good quality blastocyst rate were significantly higher (P &amp;lt; 0.05) in follitropin delta group. A vitrified-warmed embryo transfer was performed for 257/325 women (79.1%) and 242/320 women (75.6%) and subsequent positive β-human chorionic gonadotropin (βhCG) reported for 218/621 cycles (35.1%) and 194/570 cycles (34.0%), respectively. Ongoing pregnancy rate after embryo transfer were 19.2% (n = 119) and 19.6% (n = 112) and cumulative ongoing pregnancy rate were both 46.3%. Mild OHSS was reported for 131 women (40.3%) and 170 women (53.1%), respectively (P = 0.07). Limitations, reasons for caution This is a non-controlled, retrospective study. Wider implications of the findings The present study shows that in addition to reducing the OHSS risk, follitropin delta in its individualised fixed-dose regimen has the potential to improve the quality of embryos although there was no significant difference in clinical outcomes. Trial registration number not applicable

P-119 Relation of graphical follicle models to the cumulative live birth rate in GnRH-antagonist stimulation treatment cycles

Abstract Study question Is it possible to create a model that combines follicle number and size to help physicians visualize the trigger requirements to predict oocyte utilization? Summary answer Findings support graphical follicle model as an innovative, simple, and practiced parameter for predicting clinical results in ovary stimulation treatment and facilitating personalized protocol adjustment. What is known already Previous studies have observed the number and size of follicles are two independent indicators of whether the oocyte is adequate and mature and are used to predict the trigger time in routine clinical practice. However, due to individualized differences, it currently relies mainly on physician experience. Study design, size, duration This retrospective study included 8405 patients started their first in vitro fertilization cycle with a GnRH-ant protocol including fresh and subsequent frozen-thawed cycles during 2016–2020. Participants/materials, setting, methods We classified follicles recorded on the HCG day by size. We then produced graphical models, and classified into Inverted-trapezoid (large follicles in dominant proportion), Polygon (moderate follicles in dominant proportion), Trapezoid (small follicles in dominant proportion), Rectangle (equivalent proportions of the three size categories). The Cochran–Mantel–Haenszel and Generalized Linear Model(GLM) were used to evaluate the difference among models in relation to maturity, fertilization, and number of viable embryos, as well as cumulative live birth rate. Main results and the role of chance In GLM analysis, after adjusting the confounders, there are differences between models of CLBR. The CLBR of the different models was higher in the Polygon and Inverted-trapezoid model than Trapezoid and Rectangle model (42.75%, 39.56%, vs. 37.38%, 28.57%, respectively; all P&amp;lt;0.05). For oocytes derived from very large follicles ( &amp;gt; 20 mm), the CLBR was lower than that of patients with ≤ 20 mm follicles [26.10% vs. 42.10%, OR = 1.74 (95% confidence interval 1.52–2.00), P&amp;lt;0.01] in Inverted-trapezoid model, but there was no difference between models. And the risk of ovarian hyperstimulation syndrome (OHSS) rate of patients with ≤ 20 mm follicles was lower than that of patients with &amp;gt; 20 mm follicles [8.64% vs. 17.89%, OR = 0.57 (95%CI: 0.49−0.65), P&amp;lt;0.01] in Inverted-trapezoid model. Patients who received an adjusted Gn dose(whether Decreased or Increased-dose protocol) showed no difference in CLBR among models (Polygon vs Inverted-trapezoid vs Trapezoid vs Rectangle model: 47.07% vs. 49.21% vs. 47.69% vs. 42.42%, P &amp;gt; 0.05); but when patients continued with the same starting dose in Fixed-dose protocol, the CLBR of the Polygon model was higher than that of other models (40.43% vs. 34.32, 31.13% vs. 26.46%, respectively; all P value &amp;lt;0.05). Limitations, reasons for caution This study is retrospective. Due to analysis of real-world data, the follicular corresponding outcome following measurement was not obtained. Besides, the majority of patients received 2 cleavage stage embryos transfer, this approach may impact the external validity of follicle model. Wider implications of the findings The follicle models can demonstrate ovarian response of patients. It is better for patients to reach the Inverted-trapezoid model with dominate follicles &amp;gt; 18 mm and &amp;lt;20 mm. Adjusting the protocol is critical to the outcome. But how to improve follicle models by regulating stimulation remains to be further studied. Trial registration number not applicable

O-185 A clinically robust machine learning model for selecting the first FSH dose during controlled ovarian hyperstimulation: incorporating clinical knowledge to the learning process

Abstract Study question Can we improve the selection of the first dose of follicle stimulating hormone (FSH) for IVF patients by incorporating clinical evidence with machine learning? Summary answer A significant improvement in correct dose prescription is achieved when using a FSH dosing model that integrates a novel machine learning methodology with clinical knowledge. What is known already The appropriate selection of the initial FSH dose during controlled ovarian hyperstimulation (COH) is key for ART success. An optimal number of oocytes should be obtained for achieving pregnancy, while also avoiding complications for the patient. While clinical protocols achieve good results for the majority of patients, further refinements in individualized FSH dosing may improve safety while reducing the risk of poor response. Machine learning techniques have been applied to dose/response problems with promising results. However, the observational datasets used to train the models are often incomplete and biased, leading to less clinically robust predictions. Study design, size, duration We used a database of 2713 first cycles performed between January 2011 and December 2019, across five clinics to train the model. Predictors included age, body mass index (BMI), anti-Müllerian hormone (AMH) levels and antral follicle count (AFC). First FSH dose and number of mature oocytes retrieved were also recorded. Another 273 cycles performed between January 2020 and September 2021 were used for validation. Dosing was performed by 41 clinicians (mean 12 years of experience). Participants/materials, setting, methods The model was developed in Python and trained while incorporating available clinical evidence. The relationship between FSH dose and response (number of mature oocytes) was specified by assuming a positive linear function. Rules were incorporated to penalize dose changes that resulted in poorer outcomes compared to the clinician, and to discourage large dose modifications by the model. These same rules were applied during the validation phase. Comparisons were assessed by Chi-squared test with Bonferroni correction. Main results and the role of chance Mean maternal age was 37.1 ± 4.9 years. Patients had a mean BMI of 23.8 ± 4.2, AFC of 11.9 ± 7.7 and AMH of 2.4 ± 2.3. They were prescribed a first dose of 247.0 ± 59.0 IU of FSH and obtained 7.3 ± 5.3 mature oocytes after pick-up. An optimal outcome was defined as 10-15 mature oocytes retrieved, and 300 IU was the maximum FSH dose allowed. In the validation dataset, we observed that 22.9% patients could have received a higher FSH dose (&amp;lt;10 mature oocytes collected), 69.3% were correctly prescribed (10-15 mature oocytes or no change in dose was required), while 7.9% needed a decrease in FSH dose (&amp;gt;15 mature oocytes). In the machine learning model 9.4% of patients required a dose increase, 80.5% were correctly prescribed and 7.9% needed a decrease in dose. Accordingly, the model rescued 11.6% of patients that would have otherwise achieved suboptimal outcomes. Ultimately, when compared to the clinicians, the model significantly reduced the number of patients that required a dose increase, and significantly improved the number of patients that were prescribed a correct dose (p &amp;lt; 0.05). Limitations, reasons for caution The model assigned a non-conservative dose increase to 2.3% of patients, potentially leading to a risk of ovarian hyperstimulation syndrome. Moreover, hyper-responders were underrepresented in the database, resulting in no significant improvements in the dose/outcome relationship for this subgroup. Wider implications of the findings Coding clinical knowledge into the training of clinically relevant machine learning models ensured adherence to scientific evidence, and improved model performance while making conservative changes. This approach is critical for the safe and robust clinical implementation of interventional models. Trial registration number not applicable

O-132 Comparison of pregnancy rates in antagonist cycles after luteal support with GnRH-agonist versus progesterone – prospective randomized study

Abstract Study question Are pregnancy rates in GnRH-antagonist cycles triggered with hCG and luteal phase support (LPS) with intranasal GnRH-agonist or vaginal progesterone comparable? Summary answer Nasal GnRH-agonist for LPS is associated with higher pregnancy rates compared with standard progesterone support in antagonist-based cycles triggered with hCG What is known already Regardless of its mechanism of action, the use of GnRH-a during the luteal phase in addition to progesterone, either in a single or multiple doses, has become a common practice as a part of ART protocols, based on its association with higher pregnancy and live birth rates . Its use as a sole agent for LPS has not gained the same popularity although studies supporting non-inferiority and even higher live birth rates with GnRH-a as a sole LPS agent have been published. Study design, size, duration A single-center, prospective, randomized study. A total of 150 patients underwent 164 GnRH-antagonist-based IVF cycles triggered with hCG and fresh embryo transfer. The study was conducted between June 9th, 2020, and May 5th, 2022. Participants/materials, setting, methods The study was conducted in the IVF clinic at University-affiliated tertiary medical center. Patients meeting the inclusion criteria who underwent antagonist-based IVF cycles and hCG triggering were enrolled. Computer-based randomization (1:1 ratio) was performed on the day of oocyte pickup (OPU). In both groups LPS was initiated on the evening of the OPU day with either GnRH-agonist nasal spray (Nafareline, nasal spray 200 mcg twice daily)or vaginal micronized progesterone (Utrogestan 300 mg, 3 times daily). Main results and the role of chance A total of 150 patients underwent 164 cycles, 127 cycles of which were included in the study cohort. Of them, 64 (50.4%) and 63 (49.6%) cycles were treated with GnRH-agonist or progesterone respectively as sole luteal phase support. A significantly higher pregnancy rate was found in the GnRH-a group compared with the progesterone group (43.8% versus 25.4% respectively; P = 0.030). After adjustment of several potential confounders such as age, body mass index (BMI), past obstetric history, number of IVF cycles, oocytes retrieved and embryos transferred, GnRH-agonist was still associated with a higher pregnancy rate (odds ratio 3.4, 95% confidence interval 1.4-8.3). Ovarian hyperstimulation syndrome (OHSS) rates were similar between the groups. Significantly higher progesterone levels were measured at β-hCG testing day in the GnRH-a group, both for the cleavage stage embryos (129.1±23.7 nmol/L vs. 97.7±48.9 nmol/L, P = 0.024) and for the blastocysts (127.2±0.1 nmol/L vs. 75.3±49.1 nmol/L, P = 0.034). Limitations, reasons for caution This study is not powered for analysis of clinical pregnancy rates, live birth rates and pregnancy outcomes. Larger studies are needed for research of these outcomes. All patients participating were at low risk for OHSS, therefore the study is underpowered to find significant differences in early or late OHSS.Wider implications of the findings Our findings suggest that intranasal GnRH-agonist administration as a sole luteal support in antagonist-based IVF cycles triggered with hCG results in higher pregnancy rates in comparison with traditional irritating vaginal preparations while not mandating additional support in the first weeks of pregnancy. Trial registration number Clinicaltrials.gov - NCT05484193

Lights and shadows on the use of metformin in pregnancy: from the preconception phase to breastfeeding and beyond.

During pregnancy, the complex hormonal changes lead to a progressive decrease of insulin sensitivity that can drive the onset of gestational diabetes (GDM) or worsen an already-known condition of insulin resistance like type 2 diabetes, polycystic ovarian syndrome (PCOS), and obesity, with complications for the mother and the fetus. Metformin during pregnancy is proving to be safe in a growing number of studies, although it freely crosses the placenta, leading to a fetal level similar to maternal concentration. The aim of this literature review is to analyze the main available evidence on the use of metformin during, throughout, and beyond pregnancy, including fertilization, lactation, and medium-term effects on offspring. Analyzed studies support the safety and efficacy of metformin during pregnancy. In pregnant women with GDM and type 2 diabetes, metformin improves obstetric and perinatal outcomes. There is no evidence that it prevents GDM in women with pregestational insulin resistance or improves lipid profile and risk of GDM in pregnant women with PCOS or obesity. Metformin could have a role in reducing the risk of preeclampsia in pregnant women with severe obesity, the risk of late miscarriages and preterm delivery in women with PCOS, and the risk of ovarian hyperstimulation syndrome, increasing the clinical pregnancy rate in women with PCOS undergoing in vitro fertilization (IVF/FIVET). Offspring of mothers with GDM exposed to metformin have no significant differences in body composition compared with insulin treatment, while it appears to be protective for metabolic and cardiovascular risk.

The ovarian hyperstimulation that truly matters: Admissions, severity and prevention strategies.

Ovarian hyperstimulation syndrome (OHSS) is a common but serious complication of in vitro fertilisation. Despite available strategies to reduce OHSS incidence, a small proportion of patients will develop the clinically significant disease with substantial morbidity. Efforts toward better understanding and the prevention of severe disease are required to improve patient outcomes. The aims are to: (1) formulate clinically relevant OHSS classification for inpatient settings and data collection/reporting; (2) estimate OHSS prevalence requiring hospital admission in Victoria; and (3) determine the extent of OHSS preventability with clinical strategies. This retrospective cohort study included all OHSS admissions in a tertiary referral centre, January 2016-December 2021, which included approximately 40% of all cases of hospitalisation for OHSS in the State of Victoria. Patient characteristics, treatment regimes, fertility treatment outcomes, timing classification, and clinical markers of disease severity were studied. Patients were classified as having mild, moderate, or severe OHSS with a novel inpatient classification system. Of 199 OHSS cases presenting to the tertiary institution, 107 were classified as moderate/severe, with no significant difference between age, body mass index, length of stimulation and follicle number between mild/moderate and severe groups. There were more cases of early hyperstimulation (137) compared to late (62) presentation, of which 53% were severe. The average length of stay overall was 3.1 days, and 5.2 days for severe presentations. In 15% of severe cases, an agonist trigger was used. The overall prevalence of OHSS requiring hospital admission appears to be low (approximately 0.6% of all stimulated cycles). Established risk factors may not accurately predict clinically relevant OHSS risk. Further monitoring, clinician and patient education are required to minimise the risk of significant OHSS that results in hospital admissions.

Spontaneous dichorionic diamniotic twin pregnancy following a leuprolide acetate trigger and freeze all cycle for OHSS risk: A case report

Introduction: Gonadotropin-releasing hormone (GnRH) agonist triggers are increasingly used in antagonist in vitro fertilization (IVF) cycles to prevent ovarian hyperstimulation syndrome (OHSS) following a robust ovarian response. The luteolytic effects of GnRH agonists inhibit implantation or spontaneous pregnancy, warranting freezing available blastocysts for future transfer after the risk of OHSS subsides. Case Report: A 33-year-old G1P1 with secondary infertility due to polycystic ovarian syndrome underwent IVF with a GnRH antagonist cycle. A leuprolide acetate trigger for final oocyte maturation was prescribed given her risk of OHSS. A spontaneous dichorionic/diamniotic twin pregnancy ensued. Conclusion: This case reinforces the importance of advising abstinence during the stimulation phase of an IVF cycle and that, although rare, the endometrium may allow for spontaneous conception following a leuprolide acetate trigger, which may further potentiate the risk of late OHSS.

Ganirelix and the prevention of premature luteinizing hormone surges

Ganirelix is a gonadotropin-releasing hormone (GnRH) antagonist with high antagonistic activity that blocks the GnRH receptor by competitive binding. A daily dose of 0.25 mg of ganirelix was sel5ected after a phase II study because it was the minimal, effective daily dose to prevent premature luteinizing hormone surges and this dose yielded the highest ongoing pregnancy rate per started cycle. After subcutaneous administration, ganirelix is rapidly absorbed, reaching peak levels within 1-2 hours (tmax), and has a high absolute bioavailability (>90%). Prospective, comparative studies have demonstrated the advantages of GnRH antagonists over long GnRH agonist treatment in assisted reproduction, including the immediate reversibility of drug effects, a requirement for less follicle-stimulating hormone, a shortened duration of stimulation, a reduced incidence of ovarian hyperstimulation syndrome, and reduced patient burden. Combined analyses concluded that in the general invitro fertilization population, there is a trend for a slightly lower ongoing pregnancy rate and a lower risk of ovarian hyperstimulation syndrome that is largely eliminated when considering triggering with GnRH agonist instead of human chorionic gonadotropin. Regardless of all the research, it is still not fully elucidated why the long GnRH agonist protocol has a trend for higher pregnancy rates after fresh transfer of the same number of good-quality embryos.