Mild Ovarian Hyperstimulation Syndrome Research Articles

Efficacy analysis of letrozole combined with gonadotropin-releasing hormone antagonists in patients with high risk of ovarian hyperstimulation syndrome undergoing total embryo freezing

Objective: To investigate the clinical efficacy of letrozole combined with gonadotropin-releasing hormone antagonists (GnRH-ant) in patients at high risk of ovarian hyperstimulation syndrome (OHSS) who underwent total embryo freezing after oocyte retrieval. Methods: A retrospective analysis was conducted on 348 female patients who underwent in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) at the Reproductive and Genetic Hospital of the First Affiliated Hospital of Zhengzhou University between January and July 2023. Due to their high risk of OHSS, these patients canceled fresh embryo transfer and opted for total embryo freezing. Based on patients' preferences, those who received GnRH-ant and letrozole after oocyte retrieval were categorized as the intervention group (164 cases), while those who did not receive these medications were categorized as the control group (184 cases). The first luteal phase after oocyte retrieval, OHSS grading, ovarian volume, and estradiol (E2) levels were evaluated in both groups. A multivariate logistic regression model was used to analyze factors related to moderate-to-severe OHSS among patients at high risk of OHSS who underwent total embryo freezing after oocyte retrieval. Results: The age of the intervention and control groups was (29.3±3.8) and (29.4±4.1) years, respectively (P=0.821). The duration of the first luteal phase post-oocyte retrieval was shorter in the intervention group [(7.16±1.39) days] compared to that in the control group [(13.88±2.11) days] (P<0.001). The incidences of mild, moderate, and severe OHSS in the intervention group were 75.0% (123 cases), 23.8% (39 cases), and 1.2% (2 cases), respectively, whereas in the control group they were 12.5% (23 cases), 60.9% (112 cases), and 26.6% (49 cases) (P<0.001). E2 levels on the 2nd and 6th days after oocyte retrieval [M(Q1,Q3)] in the intervention group were 1 520.0 (1 213.8, 1 884.8) and 108.5 (45.6, 218.0) ng/L, respectively, which were statistically significantly lower than those in the control group [1 666.0 (508.8, 1 702.0) ng/L] and [1 761.0 (826.0, 2 546.5) ng/L] (P<0.001). The abdominal cavity effusion in the intervention group [M(Q1,Q3)] were 19.5 (0, 30) and 0 mm, statistically significantly less than those in the control group [46.0 (0, 61.0) mm] and [54.5 (0, 69.5) mm] (P<0.001). On the 6th day after oocyte retrieval, the bilateral ovarian volumes in the intervention group were smaller than those in the control group (P<0.001). Multivariate logistic regression analysis indicated that no combined treatment with letrozole and GnRH-ant was a risk factor of moderate to severe OHSS. The risk of developing moderate to severe OHSS in the control group was 35.312 times higher than that in the intervention group (OR=35.312, 95%CI: 17.488-71.300). Conclusions: The administration of letrozole combined with GnRH-ant post-oocyte retrieval in patients at high risk of OHSS can prevent the occurrence of moderate-to-severe OHSS, shorten the first luteal phase, accelerate the reduction of serum E2 levels, and promote the recovery of ovarian volume and absorption of abdominal fluid.

Progestin-Primed Ovarian Stimulation versus GnRH Antagonist Protocol for Ovarian Stimulation in IVF: A Prospective Pilot Study

Background: Progestin-primed ovarian stimulation (PPOS) has been proposed as an alternative to conventional gonadotropin-releasing hormone (GnRH) antagonist protocol for ovarian stimulation in in vitro fertilization (IVF). The aim of PPOS is to provide an effective, patient-friendly treatment. However, studies comparing outcomes after the use of PPOS and GnRH antagonist protocol in IVF have shown mixed results. This study compared ongoing pregnancy rates after the use of PPOS versus GnRH antagonist protocol for ovarian stimulation in IVF. Methods: This prospective pilot study was conducted at a single IVF center. Women aged 18–35 years old with an anti-Müllerian hormone (AMH) level greater than or equal to 1.2[Formula: see text]ng/mL or an antral follicle count (AFC) greater than or equal to 5 who were undergoing their first IVF cycle were allocated to undergoing ovarian stimulation using PPOS (dydrogesterone 20[Formula: see text]mg/day started on the day of gonadotropin) or a GnRH antagonist protocol (fixed regimen from stimulation day 5). The primary outcome was the ongoing pregnancy rate (at 12 weeks’ gestation). Results: The study included 30 women (15 in each treatment group). Baseline characteristics were similar between groups. The ongoing pregnancy rate was 7/15 (46.7%) in the PPOS group and 8/15 (53.3%) in the GnRH antagonist group ([Formula: see text]); the number of oocytes retrieved and fertilization rates were also comparable between groups. One case of mild ovarian hyperstimulation syndrome (OHSS) occurred in the GnRH antagonist group. Conclusions: This pilot study showed similar ongoing pregnancy rates after the use of a PPOS protocol and a conventional GnRH antagonist protocol for ovarian stimulation in IVF. Additional studies with larger sample sizes are needed to confirm these findings.

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

Incidence and severity of ovarian hyperstimulation syndrome (OHSS) in high responders after gonadotropin-releasing hormone (GnRH) agonist trigger in “freeze-all” approach

Objective To determine the incidence and severity of ovarian hyperstimulation syndrome (OHSS) in high responders (25–35 follicles with a diameter of ≥12 mm on day of triggering) who received a gonadotropin-releasing hormone (GnRH) agonist to trigger final follicular maturation. Methods We used individual data from women who participated in four different clinical trials and were high responders to ovarian stimulation in a GnRH antagonist protocol in this retrospective combined analysis. All women were evaluated for signs and symptoms of OHSS using identical criteria based on Golan’s system (1989). Results High responders (n = 77) were of different ethnicities. There were no differences in baseline characteristics between women with or without signs and symptoms of OHSS. Mean ± standard deviation baseline data were: age, 32.3 ± 3.5 years; anti-Müllerian hormone, 42.4 ± 20.7 pmol/L; antral follicle count, 21.5 ± 9.2. Before triggering, duration of stimulation was 9.5 ± 1.6 days and the mean number of follicles with a diameter of ≥12 mm and ≥17 mm was 26.5 ± 4.4 and 8.8 ± 4.7, respectively. Mean serum estradiol (17,159 pmol/l) and progesterone (5.1 nmol/l) levels were high at 36 h after triggering. Overall, 17/77 high responders (22%) developed signs and symptoms of mild OHSS which lasted 6–21 days. The most frequently prescribed medication was cabergoline to prevent worsening of OHSS. No severe OHSS occurred and no OHSS cases were reported as serious adverse events. Conclusions High responders receiving GnRH agonist for triggering should be informed that they may experience signs and symptoms of mild OHSS.

Differences in Follicle Development and Hormone Dynamics Between Controlled Ovarian Stimulation (COS) Using Follitropin Delta and that Using Follitropin Alfa

Background: We compared the performance of follitropin delta and follitropin alfa in the gonadotropin-releasing hormone (GnRH) antagonist protocol for controlled ovarian stimulation (COS) and discussed the distinctive features of follitropin delta in COS. Methods: Patients underwent COS using the GnRH antagonist protocol with either recombinant follicle-stimulating hormone (FSH) and oocytes were retrieved. We compared the results of COS, oocyte pick up, fertilization, embryo culture, and clinical pregnancy between the follitropin alfa group and the follitropin delta group. Results: The serum estrogen level at trigger was significantly lower in the delta than in the alfa group (3,576.69 ± 1,775.60 vs. 2,833.19 ± 1,567.88) as was serum P4 level (2.14 ± 1.26 vs. 1.19 ± 0.85). The stimulation duration (in days) were longer (12.97 ± 2.38 vs. 13.96 ± 2.26) and total gonadotropin dose significantly lower (199.69 ± 54.47 vs. 114.27 ± 39.92), respectively, in the delta group than in the alfa group. The ovarian hyperstimulation syndrome (OHSS) rate was significantly lower in the delta than in the alfa group (48.1% vs. 58.6%). Fertilization, good blastocyst, and clinical pregnancy rates were not significantly different. COS using follitropin delta is characterized by significantly slower follicle development than COS using follitropin alfa. A comparison of developing follicles showed that the minimum follicle was significantly smaller in the delta group on days 6–8 of COS. The maximum follicle was significantly smaller in the delta group on days 6–8 and 11–13 of COS. The number of follicles larger than 14 mm was significantly lower in the delta group on days 6–8 of COS. Conclusions: Using follitropin delta is associated with slow follicular development, slow serum E2 elevation, and longer stimulation duration; however, excessive elevation of serum estrogen levels during COS is reduced and so is the incidence of mild OHSS.

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.

Assisted reproduction in patients with cardiac disease: A retrospective review

ObjectiveTo assess risks of assisted reproduction in patients with cardiac disease. Study designRetrospective case note review of patients with cardiac disease undergoing ART over a 10 year period in the obstetric cardiac services of three UK tertiary centres. Assessment of maternal, obstetric and fetal complications during ART and resultant pregnancies. Results34 patients with cardiac disease underwent 51 cycles of assisted reproduction. 24 patients (71%) received pre-pregnancy counselling. Mean age at the start of an assisted reproduction cycle was 32 years. Modified WHO (mWHO) risk category for the 34 patients was mWHO I, n = 3; mWHO II, n = 13; mWHO II- III, n = 10; mWHO III, n = 7; mWHO IV, n = 1. The 51 assisted reproduction cycles resulted in 31 pregnancies in 29 patients, and 31 live births, including two sets of twins. Live birth rate per cycle was 60.8%. Twin pregnancy rate per cycle was 5.8%. Four patients experienced complications during assisted reproduction treatment (7.8% per cycle); one major intra-abdominal haemorrhage following egg collection in a patient with a mechanical aortic valve, one endocarditis, one mild ovarian hyperstimulation syndrome and one vagal syncope during egg collection. Four other patients experienced cardiac complications during resultant pregnancies (12.9%). 43% of mWHO class III patients experienced cardiac, obstetric or neonatal complications. Five babies were delivered pre-term (<37/40). ConclusionsThis small study demonstrates that assisted reproduction carries increased risks of complications in patients with cardiac disease, but can be undertaken without major complication in the majority, as long as appropriate adjustments to treatment pathways are made, and they are managed through a multi-disciplinary team.

P-698 Pituitary functioning gonadotroph adenomas (FGA)-induced ovarian hyperstimulation syndrome (OHSS): results from tertiary neuroendocrine centres in the UK

Abstract Study question There are no published series of OHSS due to FGA. What FGA features should clinicians look for during OHSS, and what treatments are effective? Summary answer FGA tumour size is always &amp;gt;10mm. Other pituitary hormones may be deficient. Surgical resection of FGA is an effective treatment for OHSS. What is known already Pituitary adenomas affect 1:1000 adults and are classified as functioning or non-functioning. Non-functioning pituitary adenomas do not secrete hormones, but most commonly stain histologically gonadotroph cells. Functional pituitary adenomas secrete hormones such as prolactin causing prolactinoma. However, it is rare for a pituitary tumour to cause clinical features of excessive gonadotrophins (functioning gonadotroph adenoma; FGA). Single case reports, but no case series, have been published on the presentation of FGA-induced OHSS in women. Surgical excision of adenomas has been reported to cause remission of symptoms, though systematic data are lacking owing to rarity of these tumours. Study design, size, duration National case series from tertiary neuroendocrine units in England, Wales and Scotland. Participants/materials, setting, methods Eight high-volume pituitary endocrine tertiary units within England, Wales and Scotland audited their records for any cases of FGA-induced OHSS; only seven patients have been identified to date. In all cases, there had been no recent exposure to assisted reproductive technologies (ART) or drugs known to induce OHSS including gonadotrophins or selective oestrogen receptor modulators (SERMS). Main results and the role of chance Seven cases of FGA were identified with mean age 31.6 years (range 16-48) at diagnosis. Two-of-seven women presented acutely unwell with abdominal pain, distention and palpable mass requiring oophorectomy for ovarian torsion/ruptured ovarian cyst. The remaining five women presented with abdominal pain (n = 2), thyrotoxicosis (n = 1), menstrual irregularities/galactorrhoea (n = 1) and visual disturbances (n = 1). All women experienced intermittent pelvic pain during medical attendance. Pelvic ultrasound demonstrated enlarged multiseptated ovaries (volume ranging 27-442cm3). Ascites was noted in one woman. Six women had visual field defects due to optic chiasm compression on formal assessment. Median FSH was 26.10 u/L (8.3-33), but LH was &amp;lt;2.5 u/L in all cases. Estradiol (E2) far exceeded the reference range in 5/7 women (2990 to &amp;gt; 18000pmol/L);E2 was at the upper limit of normal in the remaining 2/7 women (960-1450pmol/L). Hyperprolactinaemia, hyperthyroidism and other pituitary hormones deficiency were noted in 6/7, 1/7 and 4/7 women respectively. All FGAs were macroadenomas with diameters ranging 16-48mm. Two patients were administered a somatostatin analogue prior to surgery, but FSH, E2 and tumour size did not change. Transsphenoidal surgery was performed in 6/7 women, and always improved symptomatic and biochemical features of OHSS; however, residual FGA tumour was present post-operatively in all cases studied. Limitations, reasons for caution It is possible that some ‘non-functioning’ gonadotroph adenomas cause subclinical problems including menstrual irregularity and mild OHSS which were never diagnosed. We have insufficient data to determine the prognosis for future pregnancy after FGA-induced OHSS. This study utilised historical case-notes, so some data is missing. Wider implications of the findings The ‘spontaneous’ presentation of OHSS may be confusing for clinicians. We report that FGA is an important cause of spontaneous OHSS which has well-defined biochemical and radiological characteristics, which may be treated effectively in the short-to-medium with pituitary surgery. Results of this study may provide greater awareness of FGA-induced OHSS. Trial registration number N/A

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.

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.

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

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

Ovarian Hyperstimulation Syndrome Is Associated with a High Secondary Sex Ratio in Fresh IVF Cycles with Cleavage-Stage Embryo Transfer: Results for a Cohort Study.

The sex ratio at birth is defined as the secondary sex ratio (SSR). Ovarian hyperstimulation syndrome (OHSS) is a serious and iatrogenic complication associated with controlled ovarian stimulation (COS) during assisted reproductive technology (ART) treatments. It has been hypothesized that the human SSR is partially controlled by parental hormone levels around the time of conception. Given the aberrant hormonal profiles observed in patients with OHSS, this retrospective study was designed to evaluate the impact of OHSS on the SSR. In this study, all included patients were divided into 3 groups: non-OHSS (n=2777), mild OHSS (n=644), and moderate OHSS (n=334). Our results showed that the overall SSR for the study population was 1.033. The SSR was significantly increased in patients with moderate OHSS (1.336) compared to non-OHSS patients (1.002) (p=0.048). Subgroup analyses showed that increases in the SSR in patients with moderate OHSS were observed in the IVF group (1.323 vs 1.052; p=0.043), but not in the ICSI groups (1.021 vs 0.866; p=0.732). In addition, the elevated serum estradiol (E2) and progesterone (P4) levels in OHSS patients were not associated with SSR. In this study, for the first time, we report that a high SSR is associated with OHSS in patients who received fresh IVF treatments. The increases in SSR in OHSS patients are not attributed to the high serum E2 and P4 levels. Our findings may make both ART clinicians and patients more aware of the influences of ART treatments on the SSR and allow clinicians to counsel patients more appropriately.

Luteal Support with very Low Daily Dose of Human Chorionic Gonadotropin after Fresh Embryo Transfer as an Alternative to Cycle Segmentation for High Responders Patients Undergoing Gonadotropin-Releasing Hormone Agonist-Triggered IVF.

The segmentation of the in vitro fertilization (IVF) cycle, consisting of the freezing of all embryos and the postponement of embryo transfer (ET), has become popular in recent years, with the main purpose of preventing ovarian hyperstimulation syndrome (OHSS) in patients with high response to controlled ovarian stimulation (COS). Indeed cycle segmentation (CS), especially when coupled to a GnRH-agonist trigger, was shown to reduce the incidence of OHSS in high-risk patients. However, CS increases the economic costs and the work amount for IVF laboratories. An alternative strategy is to perform a fresh ET in association with intensive luteal phase pharmacological support, able to overcome the negative effects of the GnRH-agonist trigger on the luteal phase and on endometrial receptivity. In order to compare these two strategies, we performed a retrospective, real-life cohort study including 240 non-polycystic ovarian syndrome (PCO) women with expected high responsiveness to COS (AMH >2.5 ng/mL), who received either fresh ET plus 100 IU daily human chorionic gonadotropin (hCG) as luteal support (FRESH group, n = 133), or cycle segmentation with freezing of all embryos and postponed ET (CS group, n = 107). The primary outcomes were: implantation rate (IR), live birth rate (LBR) after the first ET, and incidence of OHSS. Overall, significantly higher IR and LBR were observed in the CS group than in the FRESH group (42.9% vs. 27.8%, p < 0.05 and 32.7% vs. 19.5%, p < 0.05, respectively); the superiority of CS strategy was particularly evident when 16–19 oocytes were retrieved (LBR 42.2% vs. 9.5%, p = 0.01). Mild OHSS appeared with the same incidence in the two groups, whereas moderate and severe OHSS forms were observed only in the FRESH group (1.5% and 0.8%, respectively). In conclusion, in non-PCO women, high responders submitted to COS with the GnRH-antagonist protocol and GnRH-agonist trigger, CS strategy was associated with higher IR and LBR than the strategy including fresh ET followed by luteal phase support with a low daily hCG dose. CS appears to be advisable, especially when >15 oocytes are retrieved.

Factors Associated with Ovarian Hyperstimulation Syndrome (OHSS) Severity in Women With Polycystic Ovary Syndrome Undergoing IVF/ICSI.

IntroductionAge, polycystic ovary syndrome (PCOS), low body mass index (BMI), high antral follicle count (AFC), increased anti-Muller hormone (AMH) levels, and elevated serum estradiol (E2) concentrations are risk factors for ovarian hyperstimulation syndrome (OHSS). However, data on the relationship between risk factors and OHSS severity in patients with PCOS are rare.ObjectiveThis retrospective study examined the risk factors for OHSS and their effect on OHSS severity in patients with PCOS undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).MethodThe records of 2,699 women were reviewed and included in this study. These women were diagnosed with PCOS during their first IVF/ICSI cycle between January 2010 and December 2017. We analyzed the association between each of the interrogated risk factors (including female age, BMI, AFC, basal serum E2, and the number of oocytes retrieved) and OHSS. The effects of each risk factor on OHSS severity were further explored. Logistic regression was performed as part of the above analysis.ResultsOf the 2,699 women with PCOS who underwent assisted reproductive technology (ART), 75.2% had a normal response to controlled ovarian hyperstimulation (COH), while 24.8% developed OHSS. All OHSS patients were younger and had lower BMIs and basal serum follicle-stimulating hormone (FSH) and E2 levels but higher AFCs than those in the normal group. AFC demonstrated a strong correlation with OHSS, with a cutoff value of 24 in patients with PCOS. A total of 19.5% of the patients had mild OHSS, while 80.5% had moderate OHSS. Compared with those in the moderate OHSS group, those in the mild OHSS group were older and had higher basal serum FSH levels and lower serum E2 and T levels. However, BMI and AFC were not different between the mild and moderate OHSS groups. Basal serum E2 showed a strong correlation with OHSS severity, with a cutoff value of 37.94 pg/ml.ConclusionsAFC is a strong marker of OHSS, and basal serum E2 is the best predictor of OHSS severity in women with PCOS undergoing IVF treatment.

Efficacy, safety, and immunogenicity of a biosimilar recombinant human follicle-stimulating hormone (Folitime®) vs. Gonal-f® in women undergoing ovarian stimulation for IVF: A randomized, multicenter, evaluator-blinded, non-inferiority study.

ObjectiveWe compared the efficacy, safety, and immunogenicity of a biosimilar recombinant human follicle-stimulating hormone (Folitime®) with Gonal-f® in women undergoing ovarian stimulation for in-vitro fertilization.MethodsThis randomized (1:1), multicenter, assessor-blinded, non-inferiority, parallel-group, controlled study conducted at four infertility clinics in Argentina included infertile normogonadotropic women with ages below 39 years, with menstrual cycles of 25/35 days and a body mass index of 18-32 kg/m2 undergoing assisted reproductive technology therapy. During a 5-day fixed-dose phase, the women received 225 IU/day of Folitime® (n=49) or Gonal-f® (n=44), followed by a dose-adaptation phase up to a maximum of 450 IU/day. The non-inferiority margin for oocyte retrieval was estimated at -4 oocytes (one-sided test). Immunogenicity was investigated on days 9 and 84, following the start of treatment.ResultsThe mean number of oocytes retrieved was 12.6 (SD 7.4) in the Folitime® group and 13.4 (SD 6.9) in the Gonal-f® group (per protocol analysis, 95% confidence interval = -3.82; 2.33), within the non-inferiority margin. Pregnancy rate at week 10 was 24.4% among subjects treated with Folitime® and 19.5% for subjects treated with Gonal-f®. One serious adverse drug reaction-late mild ovarian hyper stimulation syndrome and deep venous thrombosis in the left deep jugular vein-occurred in a subject treated with Folitime®. None of the subjects developed antibodies against the study drugs. There were no unexpected safety findings.ConclusionsFolitime® is non-inferior to Gonal-f®, with no differences in the safety profile and has been approved as a biosimilar in Argentina.

Individualized ovarian stimulation for in vitro fertilization: a multicenter, open label, exploratory study with a mixed protocol of follitropin delta and highly purified human menopausal gonadotropin

To evaluate the safety profile and the number of usable blastocysts on day 5 and on day 6 after treatment with an individualized dosing regimen of a follitropin delta and highly purified human menopausal gonadotropin (HP-hMG) for controlled ovarian stimulation. Multicenter, open label, exploratory study. Reproductive medicine clinics. A total of 110 patients (aged 18-40 years). Follitropin delta coadministered with HP-hMG, with follitropin delta dose fixed according to an established algorithm and HP-hMG dose at 75 IU when the follitropin delta starting dosage was <12 μg; 150 IU when follitropin delta dosage was 12 μg and weight <100 kg, and 225 IU when follitropin delta dosage was 12 μg and weight ≥100 kg (dosage adjustments confined to HP-hMG only). Mean number of good-quality blastocysts obtained at day 5 and day 6 as well as the proportion of women with ovarian hyperstimulation syndrome (OHSS). A cohort study was compared with the follitropin delta group from the Evidence-based Stimulation Trial with Human Recombinant Follicle-Stimulating Hormone in Europe and Rest of World 1 (ESTHER-1) study. Even when stratified by age, a statistically significantly higher mean in the number of oocytes retrieved and number of good-quality blastocysts was observed in this study compared with the ESTHER-1 trial in which follitropin delta was used alone. The rate of patients triggered with a gonadotropin-releasing hormone agonist was statistically significantly higher in our Menopur and Rekovelle Combined Study (MARCS) cohort (43%) when compared with the rates reported in the follitropin delta cohort in the ESTHER-1 study (2.3%). Incidence of any grade of OHSS was 9.3% in the present study compared to 2.6% in follitropin delta group from ESTHER-1 trial. No cases of moderate or severe OHSS were observed in our study compared with 1.4% in the follitropin delta group of ESTHER-1. Optimizing the ovarian response during invitro fertilization employing a mixed protocol of individualized dosing of follitropin delta and HP-hMG resulted in a statistically significant number of usable blastocysts on days 5 and 6 with an increased risk of mild OHSS, which did not require medical intervention or hospitalization. NCT03483545.

Assessing the Usefulness of Severity Markers in Women with Ovarian Hyperstimulation Syndrome.

The present study aims to assess the usefulness of severity markers in women with ovarian hyperstimulation syndrome (OHSS). An observational study was designed including 76 women with varying degrees of severity of OHSS. Clinical history, physical examination, laboratory tests, and ultrasound measurement of the ovarian size and ascites index were carried out in all patients. Intra-abdominal pressure (IAP) was measured using an intravesical Foley Manometer catheter. Ascites index and ovarian volume increased progressively being highest in the most severe stage of OHSS. The median IAP in mild OHSS was found to be lower than that in the moderate and severe OHSS (4.0mm, 12mm, and 16.0mm, respectively). Critical cases of OHSS presented the highest IAP (25.0mm). IAP did not reach the level of intra-abdominal hypertension in mild OHSS, whereas moderate and severe OHSS was associated with intra-abdominal hypertension grade I and grade II-III, respectively. Values of IAP in critical OHSS were found similar to those observed in abdominal compartment syndrome patients. The IAP showed a strong positive correlation with ovarian volume and ascites index. The reduction of IAP after paracentesis was greater among critical OHSS patients. The ovarian volume and the level of intra-abdominal hypertension are related to the severity of OHSS and are of particular importance in the initialization of the syndrome. Ascites index is simple and convenient and can serve as an indirect marker of the abdominal reserve volume. In conjunction with clinical and laboratory data, ascites index and IAP values might be indicators for paracentesis.

Ovarian hyperstimulation syndrome in a spontaneous pregnancy after cessation of a long-term combined oral contraceptive use: A case report

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovulation induction or controlled ovarian hyperstimulation. The OHSS frequently occurs due to the administration of human chorionic gonadotropin (hCG) in controlled ovarian hyperstimulation cycles. However, OHSS has been reported rarely in normal spontaneous pregnancy cases. In this paper, a case of mild OHSS at 10 weeks 5 days of gestation in a woman with singleton gestation, who conceived naturally after cessation of a long-term combined oral contraceptive use was reported. Patients using long-term oral contraceptive should be informed about the symptoms of OHSS for early diagnosis. Early diagnosis and appropriate supportive therapy are essential to avoid the potentially life-threatening complications of OHSS.

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.

Gonadotropin-Releasing Hormone Agonist Versus Human Chorionic Gonadotropin for Ovulation Induction in Polycystic Ovary Syndrome Patients Undergoing Intrauterine Insemination: A Randomised Controlled Trial

Background: Gonadotropins have been recommended to improve ovulation, pregnancy and live birth rates in polycystic ovary syndrome (PCOS) patients with anovulatory infertility and clomiphene citrate (CC) resistance. However, this could increase the risk of ovarian hyperstimulation syndrome (OHSS). Gonadotropin-releasing hormone agonist (GnRHa) triggering could significantly reduce the risk of OHSS in patients undergoing in vitro fertilisation. However, data on the use of GnRHa in intrauterine insemination (IUI) is limited. This study compared the effectiveness of GnRHa and human chorionic gonadotropin (hCG) for ovulation induction in PCOS patients undergoing IUI. Methods: This non-inferiority, single-centre, randomised controlled trial was conducted at IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam between April 2016 and May 2018. PCOS patients aged 18–37 years with CC resistance and [Formula: see text] 3 developing ([Formula: see text] 16 mm) follicles on trigger day after stimulation with gonadotropins were eligible. Those with uterine abnormalities or tubal damage or inseminated with frozen semen were excluded. Triptorelin 0.1 mg or hCG 5000 IU was used when there was [Formula: see text] 1 follicle of [Formula: see text] 17 mm. IUI was performed at 36 hours after triggering. Primary outcome was ongoing pregnancy. Secondary outcomes were clinical pregnancy, multiple pregnancy, miscarriage and OHSS. Results: A total of 380 patients were randomised (190 per group). Treatment groups had similar characteristics at baseline. Ongoing pregnancy rate was 23.7% in the GnRHa group versus 25.3% in the hCG group (Relative risk 0.94; 95% confidence interval, 0.66–1.34; p [Formula: see text] 0.81). Secondary outcome parameters were also not significantly different between the two groups. There were two cases of mild OHSS in the hCG group and none in the GnRHa group. Conclusion: 0.1 mg triptorelin was non-inferior to 5000 IU hCG IU in PCOS patients undergoing ovulation induction by hMG followed by IUI with respect to pregnancy outcomes.