Risk Of Ovarian Hyperstimulation Syndrome Research Articles

Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze).

Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze).

Dual trigger with gonadotropin-releasing hormone agonist and human chorionic gonadotropin significantly improves oocyte yield in normal responders on GnRH-antagonist cycles.

ObjectiveDuring in vitro fertilization (IVF) cycles, final oocyte maturation is usually triggered by human Chorionic Gonadotropin (hCG) for its known effect in mimicking Luteinizing Hormone (LH) surge; however, with the widespread use of the ‘antagonist protocol’, Gonadotropin Releasing Hormone agonist (GnRHa) is being more commonly employed as a trigger in order to minimize or eliminate the risk of ovarian hyper-stimulation syndrome (OHSS). Many studies proved its efficacy in inducing oocyte maturation and its safety in preventing OHSS in high-risk groups. Moreover, some studies showed that GnRHa trigger may improve oocyte yield. This study aimed to further explore any beneficial effect of adding GnRHa to hCG (dual trigger) on oocyte yield and fertilization rate in normal responder women.MethodsWe retrospectively reviewed and analyzed the data from 127 patients on antagonist protocol (67 dual trigger and 60 HCG trigger).ResultsThe number of total oocytes, the number of MII oocytes and the number of fertilized oocytes were all significantly higher with the dual trigger protocol compared to hCG-only trigger. However, there is no significant difference in clinical pregnancy rate.ConclusionsUsing the dual trigger improved the number and quality of oocytes, and the fertilization rate in normal responders.

Современные тенденции хирургического лечения бесплодия, ассоциированного с синдромом поликистозных яичников

Polycystic ovary syndrome (PCOS) is a common endocrine disorder and one of the main causes of anovulation in women of childbearing age. Surgical procedures for infertility treatment in women with PCOS have been used in clinical practice for a long time. As a rule, they are considered as a second-line therapy after the first-line pharmacological treatment. Since recently the focus has shifted to the comparison of different types of surgical treatment techniques, their effects on the ovarian function, and the development of adhesions. The article reviews the most common surgical options for PCOS treatment in various patient groups and the key results obtained in the top importance studies undertaken in this area. Surgical treatment of PCOS in properly selected patients seems to be a cost-effective therapeutic option that has comparable success rates to ovulation induction with gonadotropins. Laparoscopic ovarian drilling is one of the preferable minimally invasive techniques. This procedure is recommended for patients who have other indications for laparoscopy, or if there is a high risk of ovarian hyperstimulation syndrome and multiple pregnancy, or if there are contraindications to multiple pregnancy. At the same time, it is emphasized that the uniform regimens and standards of PCOS surgical treatment have not been optimized so far. Their outcomes are understudied and the issue is still open for discussion. KEYWORDS: laparoscopic ovarian drilling, polycystic ovary syndrome, ovarian hyperstimulation syndrome, anovulation, infertility, adhesions. FOR CITATION: Grishin I.I., Chirvon T.G., Oguede O.R. Current trends in surgical treatment for infertility associated with polycystic ovary syndrome. Russian Journal of Woman and Child Health. 2022;5(3):209–214 (in Russ.). DOI: 10.32364/2618-8430-2022-5-3-209-214.

Retrospective comparison of pregnancy outcomes of fresh and frozen-warmed single blastocyst transfer: a 5-year single-center experience.

To assess whether live birth rates (LBR) and maternal/neonatal complications differed following single fresh and frozen-warmed blastocyst transfer. The present retrospective observational study analyzed 4,613 single embryo transfers (SET) (646 fresh and 3,967 frozen) from January 1, 2014, to December 31, 2018. Fresh embryo transfer at blastocyst stage was considered according to the age of the patient and her prognosis. In case of the risk of ovarian hyperstimulation syndrome, premature progesterone rise, non-optimal endometrial growth, or supernumerary embryos, cryopreservation with subsequent frozen embryo transfer (FET) was indicated. No differences in LBR were recorded. Fresh embryo transfers yielded an increase both in neonatal complications OR 2.15 (95% CI 1.20-3.86, p 0.010), with a higher prevalence of singletons weighting below the 5th percentile (p 0.013) and of intrauterine growth retardation (p 0.015), as well as maternal complications, with a higher placenta previa occurrence OR 3.58 (95% CI 1.54-8.28, p 0.003), compared to FET. LBR appears not to be affected by the transfer procedure preferred. Fresh embryo transfer is associated with higher risk of neonatal complications (specifically a higher prevalence of singletons weighting below the 5th percentile and of intrauterine growth retardation) and placenta previa. Reflecting on the increased practice of ART procedures, it is imperative to understand whether a transfer procedure yields less complications than the other and if it is time to switch to a "freeze-all" procedure as standard practice. Clinical Trial Registration Number: NCT04310761. Date of registration: March 17, 2020, retrospectively registered.

Assessing couples' preferences for fresh or frozen embryo transfer: a discrete choice experiment.

What are couples' preferences for fresh embryo transfer versus freezing of all embryos followed by frozen embryo transfer and the associated clinical outcomes that may differentiate them? Couples' preferences are driven by anticipated chances of live birth, miscarriage, neonatal complications, and costs but not by the differences in the treatment process (including delay of embryo transfer linked to frozen embryo transfer and risk of ovarian hyperstimulation syndrome (OHSS) associated with fresh embryo transfer). A policy of freezing all embryos followed by transfer of frozen embryos results in livebirth rates which are similar to or higher than those following the transfer of fresh embryos while reducing the risk of OHSS and small for gestational age babies: it can, however, increase the risk of pre-eclampsia and large for gestational age offspring. Hence, the controversy continues over whether to do fresh embryo transfer or freeze all embryos followed by frozen embryo transfer. We used a discrete choice experiment (DCE) technique to survey infertile couples between August 2018 and January 2019. We asked IVF naïve couples attending a tertiary referral centre to independently complete a questionnaire with nine hypothetical choice tasks between fresh and frozen embryo transfer. The alternatives varied across the choice occurrences on several attributes including efficacy (live birth rate), safety (miscarriage rate, neonatal complication rate), and cost of treatment. We assumed that a freeze-all strategy prolonged treatment but reduced the risk of OHSS. An error components mixed logit model was used to estimate the relative value (utility) that couples placed on the alternative treatment approaches and the attributes used to describe them. Willingness to pay and marginal rates of substitution between the non-cost attributes were calculated. A total of 360 individual questionnaires were given to 180 couples who fulfilled the inclusion criteria, of which 212 were completed and returned Our study population included 3 same sex couples (2 females and 1 male) and 101 heterosexual couples. Four questionnaires were filled by one partner only. The response rate was 58.8%. Couples preferred both fresh and frozen embryo transfer (odds ratio 27.93 and 28.06, respectively) compared with no IVF treatment, with no strong preference for fresh over frozen. Couples strongly preferred any IVF technique that offered an increase in live birth rates by 5% (P = 0.006) and 15% (P < 0.0001), reduced miscarriage by 18% (P < 0.0001) and diminished neonatal complications by 10% (P < 0.0001). Respondents were willing to pay an additional £2451 (95% CI 604 - 4299) and £761 (95% CI 5056-9265) for a 5 and 15% increase in the chance of live birth, respectively, regardless of whether this involved fresh or frozen embryos. They required compensation of £5230 (95% CI 3320 - 7141) and £13 245 (95% CI 10 110-16 380) to accept a 10 and 25% increase in the risk of neonatal complications, respectively (P < 0.001). Results indicated that couples would be willing to accept a 1.26% (95% CI 1.001 - 1.706) reduction in the live birth rate for a 1% reduction in the risk of neonatal complications per live birth. Older couples appeared to place less emphasis on the risk of neonatal complications than younger couples. DCEs can elicit intentions which may not reflect actual behaviour. The external validity of this study is limited by the fact that it was conducted in a single centre with generous public funding for IVF. We cannot rule out the potential for selection or responder bias. If a strategy of freeze all was to be implemented it would appear to be acceptable to patients, if either success rates can be improved or neonatal complications reduced. Live birth rates, neonatal complication rates, miscarriage rates, and cost are more likely to drive their preferences than a slight delay in the treatment process. The results of this study have important implications for future economic evaluations of IVF, as they suggest that the appropriate balance needs to be struck between success and safety. A holistic approach incorporating patient preferences for expected clinical outcomes and risks should be taken into consideration for individualized care. No external funding was sought for this study. A.M. is the chief investigator of the randomized controlled trial 'Freeze all'. S.B. is an Editor in Chief of Human Reproduction Open. The other co-authors have no conflicts of interest to declare. Graham Scotland reports non-financial support from Merck KGaA, Darmstadt, Germany, outside the submitted work. N/A.

Clinical outcomes of potential high responders after individualized FSH dosing based on anti-Müllerian hormone and body weight

Research questionHow does the efficacy and safety of individualized follitropin delta dosing compare with conventional dosing for ovarian stimulation in potential high responders? DesignRetrospective analysis of 153 potential high responders identified on the basis of baseline serum anti-Müllerian hormone (AMH) levels above 35 pmol/l, who were originally randomized to an individualized fixed dose of follitropin delta based on AMH and body weight (n = 78) or to a daily starting dose of 150 IU follitropin alfa (n = 75). ResultsAt the end of stimulation, patients treated with individualized follitropin delta or conventional follitropin alfa had 12.1 ± 7.0 and 18.3 ± 7.0 (P < 0.001) follicles measuring 12 mm or wider, and 27.3% and 62.7% had serum progesterone levels higher than 3.18 nmol/l (P < 0.001), respectively. Overall number of oocytes in these two respective arms was 9.3 ± 6.7 and 17.9 ± 8.7 (P < 0.001), and the ongoing pregnancy rate per started cycle after fresh blastocyst transfer was 28.2% and 24.0%. The risk of ovarian hyperstimulation syndrome (OHSS) for all cases was three times higher in the conventional follitropin alfa arm at 16.0% versus 5.1% with individualized follitropin delta treatment (P = 0.025) and 26.7% versus 7.7% (P = 0.001) for early moderate or severe OHSS, preventive interventions for early OHSS, or both. ConclusionsTreatment with individualized follitropin delta provides an improved efficacy–safety balance in women with high ovarian reserve, as it normalizes the ovarian response and decreases the risk of OHSS without compromising the chance of pregnancy.

The role of preimplantation genetic testing for aneuploidy in a good prognosis IVF population across different age groups

ABSTRACT Preimplantation genetic testing for aneuploidy is associated with increased pregnancy success and reduced miscarriage in women 35 years and older when embryos are available for transfer. In this retrospective cohort study our objective was to evaluate if this holds true in good prognosis patients and across all age groups. Data were obtained from the Society for Assisted Reproductive Technology between 2014–2015. We included only the first single frozen embryo transfer where indication for corresponding ‘stimulation/freeze-all cycle’ was for reducing risk of ovarian hyperstimulation syndrome and performance of PGT-A for selecting euploid embryos. Our main outcomes were live birth and miscarriage rates. Among <35 age group, no difference in LBR was observed between cycles who underwent single embryo FET using non-PGT-A tested vs. tested embryos (51.7% vs. 50.9%, aOR 1.03, 95% CI 0.87–1.21). Additionally, the miscarriage rates (8.7% vs. 8.8%, aOR 0.97, 95% CI 0.72–1.30) were not different. Among 35–37 years old, no difference was observed between non-PGT-A tested and tested groups in LBR (50.4% vs. 54.7%, aOR 1.26, 95% CI 0.96–1.67) or miscarriage rates (8.3% vs. 10%; aOR 1.11, 95% CI 0.68–1.82). Similarly, among > 37 year old, no difference was observed between non-PGT-A tested and tested groups in LBR (48.1% vs. 53.2%, aOR 1.27, 95% CI 0.8–2.02) and miscarriage rates (6.2% vs. 8.5%, aOR1.34, 95% CI 0.52–3.43). To conclude, PGT-A tested embryos did not improve LBR and miscarriage rates in a good prognosis IVF population across all age groups. Abbreviations: PGT-A: preimplantation genetic testing for aneuploidy; FET: frozen embryo transfer; LBR: live birth rate; OHSS: ovarian hyperstimulation syndrome; SART: society for assisted reproductive technology

P-622 Prothrombotic biomarkers during controlled ovarian stimulation for assisted reproductive techniques

Abstract Study question Does the evolution of prothrombotic biomarkers over time differ between antagonist and long agonist stimulation protocols for assisted reproductive techniques (ART) ? Summary answer The hypercoagulable state was higher and persistent in the agonist and antagonist with hCG triggering groups compared to the antagonist with GnRH agonist triggering group. What is known already Controlled ovarian stimulation (COS) for ART is associated with supra-physiological serum estradiol levels, a hypercoagulable state and an increased risk of venous thrombosis. Most thromboembolic events associated with COS occur in the context of ovarian hyperstimulation syndrome (OHSS). The use of hCG for final follicular maturation increases the risk of OHSS. In antagonist protocols, GnRH agonist triggering is known to prevent or reduce OHSS and is therefore widely used in women at risk. The impact of the different IVF protocols on pro-thrombotic biomarkers is unknown. Study design, size, duration In this prospective observational cohort study, infertile women undergoing COS for ART in 2017-2019 at the University Hospitals of Geneva and Lausanne (Switzerland) were included. We evaluated changes in key coagulation parameters (D-dimers, factor VIII, fibrinogen activity, protein S and protein C) and thrombin generation, our primary outcome, (using 5 pM of tissue factor) by calibrated automated thrombinography before stimulation (T1), on the day of ovulation triggering (T2) and seven days after triggering (T3). Participants/materials, setting, methods COS was started without hormonal pre-treatment. Protocols were prescribed according to the standards used in each centre taking into account the risk of OHSS (agonist protocol with hCG trigger in women without OHSS risk (Group 1); antagonist protocol in women at risk of OHSS with hCG trigger (Group 2;) or GnRH agonist trigger (Group 3;); variation of endogenous thrombin potential (ETP) was measured and compared among groups using mixed effects linear regression model. Main results and the role of chance A total of 64 women were included: 24 were in group 1, 16 in group 2, and 24 in group 3. The mean age (SD) was 37.8 (2.8), 35.9(5.2) and 34(4.6) years in groups 1, 2 and 3 respectively. As expected, women in group 1 had a statistically lower level of anti-müllerian hormone (p = &amp;lt; 0.001), a lower antral follicular count (p = &amp;lt; 0.001) and lower number of MII oocytes and embryos obtained (p = &amp;lt; 0.001). Mean serum estradiol levels were 1836 (1160), 1628 (815) and 3754 (2165) ng/L at T2, and 945 (471), 1061 (495) and 413 (729) ng/L at T3, in group 1 to 3, respectively. In multivariable regression analysis, the levels in group 3 were statistically higher at T2 and lower at T3 (overall time*group interaction: p &amp;lt; 0.001). The mean ETP was similar between all groups at T1, and increased in all groups at T2 (1442, 1426 and 1486 nM/min in groups 1, 2 and 3, respectively) (p = 0.013). Overall, ETP evolution over time was statistically different between groups, with the lowest increase of ETP between T1 and T3 in group 3. Protein C and protein S levels were stable, while D-dimers, fibrinogen and factor VIII increased at T2 and T3 in all groups. Limitations, reasons for caution Stimulation protocols were prescribed according to the clinical profile and OHSS risks; groups therefore differ substantially in regards to age and ovarian reserve. Thromboembolic events are rare events after COS, we therefore evaluated biological markers of hypercoagulability and not clinical events. Wider implications of the findings Women with GnRH agonist triggering protocol did not increase mean ETP in the week after ovulation, while women with hCG triggering did. This different prothrombotic profile was independent of the variation of the other coagulation parameters investigated. This effect of ovulation triggering should be confirmed by further studies. Trial registration number NCT04188444

P–622 Prothrombotic biomarkers during controlled ovarian stimulation for assisted reproductive techniques

Abstract Study question Does the evolution of prothrombotic biomarkers over time differ between antagonist and long agonist stimulation protocols for assisted reproductive techniques (ART) ? Summary answer The hypercoagulable state was higher and persistent in the agonist and antagonist with hCG triggering groups compared to the antagonist with GnRH agonist triggering group. What is known already Controlled ovarian stimulation (COS) for ART is associated with supra-physiological serum estradiol levels, a hypercoagulable state and an increased risk of venous thrombosis. Most thromboembolic events associated with COS occur in the context of ovarian hyperstimulation syndrome (OHSS). The use of hCG for final follicular maturation increases the risk of OHSS. In antagonist protocols, GnRH agonist triggering is known to prevent or reduce OHSS and is therefore widely used in women at risk. The impact of the different IVF protocols on pro-thrombotic biomarkers is unknown. Study design, size, duration In this prospective observational cohort study, infertile women undergoing COS for ART in 2017–2019 at the University Hospitals of Geneva and Lausanne (Switzerland) were included. We evaluated changes in key coagulation parameters (D-dimers, factor VIII, fibrinogen activity, protein S and protein C) and thrombin generation, our primary outcome, (using 5 pM of tissue factor) by calibrated automated thrombinography before stimulation (T1), on the day of ovulation triggering (T2) and seven days after triggering (T3). Participants/materials, setting, methods COS was started without hormonal pre-treatment. Protocols were prescribed according to the standards used in each centre taking into account the risk of OHSS (agonist protocol with hCG trigger in women without OHSS risk (Group 1); antagonist protocol in women at risk of OHSS with hCG trigger (Group 2;) or GnRH agonist trigger (Group 3;); variation of endogenous thrombin potential (ETP) was measured and compared among groups using mixed effects linear regression model. Main results and the role of chance A total of 64 women were included: 24 were in group 1, 16 in group 2, and 24 in group 3. The mean age (SD) was 37.8 (2.8), 35.9(5.2) and 34(4.6) years in groups 1, 2 and 3 respectively. As expected, women in group 1 had a statistically lower level of anti-müllerian hormone (p = &amp;lt;0.001), a lower antral follicular count (p = &amp;lt;0.001) and lower number of MII oocytes and embryos obtained (p = &amp;lt;0.001). Mean serum estradiol levels were 1836 (1160), 1628 (815) and 3754 (2165) ng/L at T2, and 945 (471), 1061 (495) and 413 (729) ng/L at T3, in group 1 to 3, respectively. In multivariable regression analysis, the levels in group 3 were statistically higher at T2 and lower at T3 (overall time*group interaction: p &amp;lt; 0.001). The mean ETP was similar between all groups at T1, and increased in all groups at T2 (1442, 1426 and 1486 nM/min in groups 1, 2 and 3, respectively) (p = 0.013). Overall, ETP evolution over time was statistically different between groups, with the lowest increase of ETP between T1 and T3 in group 3. Protein C and protein S levels were stable, while D-dimers, fibrinogen and factor VIII increased at T2 and T3 in all groups. Limitations, reasons for caution Stimulation protocols were prescribed according to the clinical profile and OHSS risks; groups therefore differ substantially in regards to age and ovarian reserve. Thromboembolic events are rare events after COS, we therefore evaluated biological markers of hypercoagulability and not clinical events. Wider implications of the findings: Women with GnRH agonist triggering protocol did not increase mean ETP in the week after ovulation, while women with hCG triggering did. This different prothrombotic profile was independent of the variation of the other coagulation parameters investigated. This effect of ovulation triggering should be confirmed by further studies. Trial registration number NCT04188444

P–608 The new standard for ovulation triggering should be GnRH agonist rather than hCG during controlled ovarian stimulation for IVF/ICSI: a systematic review and meta-analysis

Abstract Study question Do Gonadotropin-releasing hormone agonists (GnRHa) triggering improves oocyte maturation, clinical outcomes, and safety compared to human chorionic gonadotropin (hCG) triggering during controlled ovarian stimulation with an antagonist protocol? Summary answer The final triggering using GnRHa allows a higher number of retrieved and mature oocytes to be obtained with comparable clinical outcomes and lower OHSS risk. What is known already GnRHa represent an alternative to hCG for ovulation triggering after controlled ovarian stimulation with an antagonist protocol for IVF/ICSI. GnRHa triggering is thought to be more physiological due to the endogenous surges in LH and FSH levels. However, the benefit of GnRHa over hCG triggering on oocyte maturation remains controversial. Study design, size, duration A systematic review and meta-analysis of randomised controlled clinical trials. Searches were conducted from 01 January 1990 to 15 April 2020 on MEDLINE, EMBASE, the Cochrane Library, ClinicalTrials.gov and EudraCT, using the following search terms: ‘GnRH agonist’, ‘hCG’, ‘triggering’. Two independent reviewers carried out the study selection, the bias assessment using the RoB2 tool, and the data extraction according to Cochrane methods. Participants/materials, setting, methods The primary outcomes were the total number of retrieved oocytes and the number of mature oocytes. The main secondary outcomes were the number of embryos obtained, the clinical pregnancy rate, the early pregnancy loss rate, the live birth rate, and the incidence of ovarian hyperstimulation syndrome (OHSS). Random-effects meta-analysis was performed followed by prespecified sensitivity and subgroup analyses. Main results and the role of chance A total of 29 randomised controlled trials were included. The mean number of retrieved oocytes [difference in means (95% CI) 0.99 (0.21, 1.78); p = 0.01; n = 26] and of mature oocytes [0.68 (0.04, 1.33); p = 0.04; n = 12] were statistically significantly higher after GnRHa than after hCG triggering. A similar difference was observed for the number of embryos [0.94 (0.19, 1.68); p = 0.01; n = 10]. No differences in the clinical pregnancy rate [risk ratio 1.01 (0.90, 1.14); p = 0.83; n = 23], early pregnancy loss [1.27 (0.94, 1.71); p = 0.13; n = 16], and live birth rate [1.00 (0.77, 1.29); p = 0.97; n = 6] were noted. GnRHa was associated with a lower incidence of OHSS [odds ratio 0.25 (0.08, 0.74); p = 0.012; n = 20]. Limitations, reasons for caution The validity of meta-analysis results depends mainly on the quality and the number of the published studies available. Wider implications of the findings: In light of its safety and effectiveness, GnRHa should be the new standard for triggering in antagonist cycles, with dual triggering with hCG when the risk of OHSS is low and a fresh embryo transfer approach is used. Trial registration number NA

P–593 Self-monitoring of hormones via a urine-based hormonal assay — a topical endeavour into telemedicine in medically-assisted reproduction (MAR)

Study questionHow can cycle monitoring using a urine-based hormonal assay device improve current clinical practice in medically assisted reproduction (MAR)?Summary answerA urine-based hormonal assay has the potential to overcome the inconvenience of blood tests and reduce the frequency of appointments, waiting times and patient burden.What is known alreadyCycle monitoring via ultrasound and serum-based hormonal assays during MAR can provide information on the ovarian response and assist in optimising treatment strategies and reducing complications, such as ovarian hyperstimulation syndrome (OHSS). However, blood tests may cause inconvenience to patients due to repeated venepuncture and the need for frequent clinic appointments. Urine-based assays have been historically used by fertility specialists in clinics, but since got replaced by more practical and automated serum-based assays. Novel technology utilising rapid chromatographic immunoassay to test urinary reproductive hormones in a home setting could provide an alternative to current serum-based testing at clinics.Study design, size, durationA questionnaire was disseminated among 24 fertility specialists (2019–2020) on the use of ultrasound and serum-based hormone monitoring in clinical practice. In addition, the literature on the reliability of urine-based hormonal assays compared to serum-based hormonal assays during MAR was reviewed in order to examine if urine-based hormonal monitoring could be re-introduced in clinical practice using novel state-of-the-art technology.Participants/materials, setting, methodsAll 24 surveyed fertility specialists responded, representing 10 countries from across Europe, Asia and Latin America. Questions assessed the frequency and role of hormonal monitoring, the hormones tested and the drawbacks of blood tests. The PubMed search engine was used to search the Medline database for publications between 1960–2020 with (MeSH-) search terms related to cycle monitoring (e.g. fertility monitoring, controlled ovarian stimulation, ovulation confirmation) and hormonal assays (e.g. estrone–3-glucuronide or E1–3G).Main results and the role of chanceThe survey confirmed that many fertility practitioners (n = 22/24) routinely conducted hormone monitoring during MAR, primarily for guiding dose adjustments (n = 20/24) and indicating risk of OHSS (n = 20/24). The reported drawbacks of blood tests included validity of results from different service providers, long waiting times and discomfort to patients due to travelling to clinics for tests and repeated venepunctures. The hormones routinely checked were E2 (n = 22/22), P4 (n = 18/22) and LH (n = 15/22). The literature review revealed a relatively high correlation (correlation coefficients 0.85–0.95) between serum E2 and urinary E1–3G in gonadotrophin stimulated cycles (Lessing 1987, Catalan 1989, Rapi 1992 and Alper 1994). No studies assessed the correlation between serum P4 and urinary PdG or between serum LH and urinary LH in stimulated cycles. In natural cycles, the correlation coefficients between serum P4 and urinary PdG seemed to be slightly higher than those between serum E2 and urinary E1–3G (0.73–0.94 vs. 0.54–0.88) (Denari 1981, Munro 1991, Roos 2015, Stanczyk 1980). One study reported a moderate correlation coefficient (0.72) between serum and urinary LH in natural cycles (Roos 2015).Limitations, reasons for cautionThere is risk of selection-bias for fertility specialists included in survey, however, the 100% response rate is reassuring. The correlation coefficients between serum- and urine-based hormonal assay and the cost-effectiveness and time-efficiency of urinary assay should be confirmed in further clinical studies using a novel state-of-the-art remote urinary monitoring device.Wider implications of the findings: Remote hormonal monitoring can be part of a novel digital health solution that includes remote ultrasound and tele-counselling to link clinics and patients at home. Especially during the unprecedented times of the COVID–19 pandemic, the prospect of remote monitoring system has the potential to improve patient experience during fertility treatment.Trial registration numberNot applicable

P–791 Comparison of the live birth rate after single embryo transfer in fresh versus frozen cycle: no evidence to support routine freeze-all strategy

Abstract Study question Is the treatment outcome compromised after superovulation for fresh IVF/ICSI in comparison to frozen cycle with spontaneous ovulation and luteal support with progesterone? Summary answer Live birth rate (LBR) is dependent on embryo quality both in the fresh and frozen cycles with no sign of harmful effect of the superovulation. What is known already Freeze-all strategy has been advocated in recent years based on the assumption that luteal phase after superovulation is not optimal for embryo implantation. The effects of variable hormonal treatments, given in association with ART, on the endometrium, are still largely unknown. Therefore, more data is needed in order to optimize the treatment policies. Study design, size, duration This is an observational retrospective single-center cohort study. Data were collected from Oulu University Hospital’s ART-database including a total of 5647 single embryo transfer cycles from years 1995–2020. Patients stimulated with long agonist protocol for IVF/ICSI and day 2–3 transfer were included. Frozen embryo transfer was performed in a natural cycle with an ovulation test used for timing of transfer. Luteal support with progesterone was given for two weeks in all cycles. Participants/materials, setting, methods There were 3053 IVF/ICSI fresh cycles (2237 top and 816 N-top) and 2594 frozen cycles (806 top and 1788 N-top). The main outcome measure was LBR compared between fresh and frozen cycles when either a top or a N-top embryo was transferred. As a secondary outcome, clinical pregnancy rate was investigated. Data on the age and body mass index (BMI) of the patients was available. Student’s T-test was used to compare continuous variables. Main results and the role of chance The groups did not differ regarding the age and BMI of the patients. After the transfer of a top quality embryo the clinical pregnancy rate (35.4 vs. 30.8%; p &amp;lt; 0.05) and LBR (29.4 vs. 25.5%; p not significant) was slightly higher in the fresh cycle. After the transfer of a N-top quality embryo the clinical pregnancy rate (19.9 vs. 19.4%) and LBR (15.9 vs. 15.4%) were similar both in the fresh and frozen cycles. Limitations, reasons for caution This study only represents cleavage stage embryo transfers, and all FETs were performed in a natural cycle. In a retrospective study there may also be residual confounding that could not be excluded. Wider implications of the findings: This study provides further evidence that treatment outcome regarding LBR is not affected by superovulation therapy. Hence, the use of freeze-all strategy is warranted only in cases with a risk of ovarian hyperstimulation syndrome. Trial registration number Not applicable

P–586 Clinical outcome in frozen cycles using cryopreserved blastocysts derived from ovarian stimulation with follitropin delta

Abstract Study question To compare the live birth rate using frozen-thawed blastocysts obtained from ovarian stimulation with individualised follitropin delta dosing to conventional follitropin alfa dosing. Summary answer The live birth rate in cryo cycles conducted within 1 year after ovarian stimulation was comparable for individualised follitropin delta and conventional follitropin alfa treatment. What is known already It has been demonstrated that the follitropin delta (Rekovelle, Ferring Pharmaceuticals) in an individualised dosing regimen based on anti-Müllerian hormone (AMH) level and body weight is non-inferior to conventional follitropin alfa (Gonal-f, Merck Serono) dosing with respect to ongoing pregnancy and ongoing implantation rates in fresh cycles. The individualised approach also reduced the risk of ovarian hyperstimulation syndrome (OHSS) versus the conventional approach. Furthermore, treatment with follitropin delta and follitropin alfa gave comparable pregnancy rates in repeated fresh cycles. Study design, size, duration Analysis of frozen cycles using blastocysts obtained from a randomised trial comparing follitropin delta versus follitropin alfa in 1,326 IVF/ICSI patients (18–40 years) and a subsequent trial of up to two additional ovarian stimulation cycles. The clinical outcome includes women with cryopreserved blastocysts following ovarian stimulation and who underwent frozen cycles within 1 year after starting stimulation in their last cycle. Participants/materials, setting, methods A total of 917 women had at least one Day 5 blastocyst which was vitrified and stored following up to three ovarian stimulation cycles. A started cryo cycle was defined as warming of a blastocyst. After warming, 1–2 blastocysts were transferred in cryo cycles, using natural cycle or programmed regimens. Treatment differences and 95% confidence intervals (CI) were calculated with adjustment for age strata and accounting for repeated cycles within patient. Main results and the role of chance The proportion of women with frozen blastocysts was similar in the two treatment groups, with 69.5% in the follitropin delta group and 68.8% in the follitropin alfa group. Similar postwarming blastocyst survival rates were observed for the two groups, with 87.4% of the warmed blastocysts proceeding to transfer in the follitropin delta group and 88.8% in the follitropin alfa group. About half of the women (48.1% in each treatment group) with frozen blastocysts underwent at least one frozen cycle with transfer within the 1-year period, with an average of 1.5 cycles per woman in the follitropin delta group and 1.6 cycles per woman in the follitropin alfa group. The ongoing implantation rate was 27.6% in the follitropin delta group and 27.8% in the follitropin alfa group (adjusted difference 0.5% [95% CI: –7.1%; 8.2%]). The live birth rate per started cryo cycle was 32.0% in the follitropin delta group and 31.3% in the follitropin alfa group (adjusted difference 1.2% [95% CI: –6.8%; 9.3%]), while the live birth rate per cryo cycle with transfer was 33.2% and 31.9% (adjusted difference 1.9% [95% CI: –6.2%; 10.0%]), respectively. Limitations, reasons for caution The number of blastocysts to be transferred in the frozen cycles as well as the protocol for endometrial preparation was based on local centre practices. Wider implications of the findings: These findings suggest that the follitropin delta and follitropin alfa dosing regimens are equally effective in terms of live birth rate in frozen replacement cycles and add reassuring information to the clinical performance of cryopreserved blastocysts derived from ovarian stimulation with follitropin delta. Trial registration number NCT01956110, NCT01956123.

P–761 Can modified luteal support in fresh cycle after agonist trigger “rescue” the cumulative live birth rate (CLBR) in high responders

Abstract Study question Can modified luteal support in fresh cycle “rescue” the cumulative live birth rate (CLBR) in high responders who receive agonist trigger? Summary answer Live birth rate in high responders who had agonist trigger in fresh cycle was significantly reduced despite modified luteal support. What is known already Previous studies, including small randomised controlled trials, claimed that good live birth rate could be achieved at fresh transfer in “high responders” who had GnRHa trigger with modified luteal phase support. However, majority of these studies exclude the true high responders (patients with 20 and above oocytes) and average number of collected eggs reported in many of these studies in the range of 9 to 12. The data on outcome of fresh transfer in true high responders is very limited. Study design, size, duration A prospective observational study was conducted in 407 patients, aged 23–42 years who were expected to be at risk of high response (AFC&amp;gt;18, AMH&amp;gt;20 pmol/l) undergoing controlled ovarian stimulation between 2014–2019 triggered either with HCG or GnRH agonist. Live birth rate (LBR) in a fresh and subsequent 3 frozen transfers were compared in groups with different triggers and freeze all. Participants/materials, setting, methods Patients were stimulated in short antagonist protocol. The trigger was chosen based on the background characteristics, peak oestradiol and clinician discretion. Triggering was achieved either with 0.5 mg buserelin (GnRHa) 0.5mgin 230 patients (A) or with 250 mcg of hCG(H) in 177 patients. Modified luteal support included vaginal progesterone, oral oestrogen and 1500 iu of hCG on the day of egg retrieval. The later was omitted with more than 20 oocytes. Main results and the role of chance The mean age, AFC, number of previous cycles, number of embryos transferred were 33.3, 22.4, 0.26 and 1.2 respectively and did not have significant difference between different triggers. Whereas AMH (53 pmol/l (A) vs 43.1 pmol/l (H), P = 0.003), peak oestradiol (15140.74 (A) vs 9738.59 (H), P = 5.59X10–14), and number of oocytes collected (21 vs.17, P = 5.63X10–7) were significantly higher in GnRHa group. Seventeen patients in buserelin group had elective freeze all. Ovarian Hyperstimulation Syndrome (OHSS) rate was 3.9% in buserelin group (more then half of these cases had a bolus of hCG at egg collection; most were mild/moderate). On the other hand, hCG group had 2.5% of OHSS (all severe). Live birth rate in fresh cycle was 31% in hCG and 21% in GnRHa groups. If freeze all was undertaken in fresh cycle after GnRHa trigger, then LBR in the first frozen cycle of this group was 53% (P = 0.003, fresh vs frozen GnRHa group). CLBR was not different between GnRHa and hCG groups (51%). However, this was significantly lower than CLBR in GnRHa trigger freeze all group 76% (P = 0.03) Limitations, reasons for caution The limitation of this study is its non-randomised nature. However, since it is one of the biggest studies for high responders it has a power to minimise bias by adjusting for multiple variables. Wider implications of the findings: Proceeding with fresh transfer in high responders after GnRHa trigger with modified luteal support not only maintains the risk of OHSS (equivalent to hCG group) but also significantly impairs the LBR not compensated even after 3 subsequent frozen embryo transfers. Therefore, freeze-all approach should be preferred in this group. Trial registration number NA

Comparison of hCG Versus Gonadotropin-Releasing Hormone Agonist to Induce Oocyte Maturation in Assisted Reproductive Technology Cycles: A Retrospective Cohort Study

OBJECTIVE: To compare some cycle characteristics and outcomes using a protocol consisting of a GnRH agonist trigger or hCG trigger after cotreatment with GnRH antagonist.STUDY DESIGN: Thirty-three patients under 35 years of age with polycystic ovarian syndrome, polycystic ovarian morphology, or previous high response who underwent ovulation trigger by GnRH agonist trigger and 132 patients under 35 years of age with the polycystic ovarian syndrome, polycystic ovarian morphology, or previous high response who underwent ovulation trigger by hCG for IVF treatment. Patients were non-randomly assigned to an ovarian stimulation protocol consisting of either GnRH agonist trigger after cotreatment with GnRH antagonist (study group) or hCG trigger after antagonist protocol (control group).RESULTS: The positive pregnancy test was obtained in 70 women in the control group whereas in 13 cases in the study group (p=0.161). No case in the study group needed hospitalization whereas there were 15 cases in the control group who were required to be hospitalized due to ovarian hyperstimulation related symptoms (p=0.04).CONCLUSIONS: The use of a protocol consisting of a GnRH agonist trigger after GnRH antagonist cotreatment and freeze-all strategy reduces the risk of ovarian hyperstimulation syndrome in high-risk patients undergoing IVF without affecting pregnancy rates.

Prednisone combined with letrozole reduced risk of ovarian hyperstimulation syndrome (OHSS) in women undergoing long-term gonadotropin-releasing hormone analog treatment.

Ovarian hyperstimulation syndrome (OHSS) is a severe disease that can lead to serious complication. Letrozole has been applied during controlled ovarian hyperstimulation (COH) to reduce the rate of OHSS in women undergoing long-term Gonadotropin-releasing Hormone Analog (GnRHa) treatment for assisted fertility. Prednisone can prevent vasodilatation and increased vascular permeability, which is common during OHSS. However, few studies have evaluated the combined effect of letrozole and prednisone in preventing severe OHSS and is the aim of our retrospective study of patients receiving GnRHa treatment. A total of 296 women who accepted autologous in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included in this retrospective study. There were three groups: 146 women had letrozole, including letrozole alone (LE group, n=60) and letrozole with prednisone (LE + Pre group, n=86), and 150 women had no treatment (C group). Severe OHSS was diagnosed according to clinical evidence of hydrothorax, severe dyspnea, oliguria/anuria, and intractable nausea/vomiting. The addition of prednisone to letrozole successfully reduced the occurrence rate of severe OHSS than those women administered letrozole alone (55.0% vs. 70.6%, P=0.022). However, the ongoing pregnancy rate was lower in the LE + Pre group than that in the LE-alone group (64.3% vs. 87.0%, P=0.025). Surprisingly, progesterone level on the trigger day (>0.895 ng/mL) is a strong predictor for pregnancy failure with a specificity of 68.3% and sensitivity of 65.7% in the LE-alone group. Treatment with a combination of letrozole and prednisone may lower the rate of severe OHSS in women with prolonged gonadotropin-releasing hormone agonist protocol during assisted fertility treatment. When the progesterone level on trigger day is over 0.895 ng/mL, letrozole treatment may negatively affect clinical pregnancy.

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.

A randomised controlled trial to clinically validate follitropin delta in its individualised dosing regimen for ovarian stimulation in Asian IVF/ICSI patients.

STUDY QUESTIONIs ovarian stimulation with follitropin delta in its individualised fixed-dose regimen at least as efficacious as follitropin alfa in a conventional dosing regimen in Asian population?SUMMARY ANSWEROvarian stimulation with individualised follitropin delta dosing resulted in a non-inferior ongoing pregnancy rate, a significantly higher live birth rate and a significantly lower incidence of early ovarian hyperstimulation syndrome (OHSS) and/or preventive interventions compared to conventional follitropin alfa dosing.WHAT IS KNOWN ALREADYPrevious randomised controlled trials conducted in Japan as well as in Europe, North- and South America have demonstrated that ovarian stimulation with the individualised follitropin delta dosing regimen based on serum anti-Müllerian hormone (AMH) level and body weight modulated the ovarian response and reduced the risk of OHSS without compromising pregnancy and live birth rates.STUDY DESIGN, SIZE, DURATIONRandomised, controlled, multi-centre, assessor-blind trial conducted in 1009 Asian patients from mainland China, South Korea, Vietnam and Taiwan, undergoing their first IVF/ICSI cycle. Randomisation was stratified by age (<35, 35–37, 38–40 years). The primary endpoint was ongoing pregnancy rate assessed 10–11 weeks after embryo transfer in the fresh cycle (non-inferiority limit −10.0%; analysis adjusted for age stratum).PARTICIPANTS/MATERIALS, SETTING, METHODSThe follitropin delta treatment consisted of a fixed daily dose individualised according to each patient’s initial AMH level and body weight (AMH <15 pmol/l: 12 μg; AMH ≥15 pmol/l: 0.19 to 0.10 μg/kg; min-max 6–12 μg). The follitropin alfa dose was 150 IU/day for the first 5 days with subsequent potential dose adjustments according to individual response. A GnRH antagonist protocol was applied. OHSS was classified based on Golan’s system. Women with an ongoing pregnancy were followed until live birth and 4 weeks after.MAIN RESULTS AND THE ROLE OF CHANCEThe number of oocytes retrieved was significantly (P < 0.001) lower with individualised follitropin delta versus conventional follitropin alfa (10.0 ± 6.1 versus 12.4 ± 7.3). Nevertheless, compared to the conventional dosing approach, the individualised follitropin delta dosing regimen resulted in on average 2 more oocytes (9.6 ± 5.3 versus 7.6 ± 3.5) in potential low responders as indicated by AMH <15 pmol/l, and on average 3 fewer oocytes (10.1 ± 6.3 versus 13.8 ± 7.5) in potential high responders as indicated by AMH ≥15 pmol/l. Among women with AMH ≥15 pmol/l, excessive response occurred less frequently with individualised follitropin delta than with follitropin alfa (≥15 oocytes: 20.2% versus 39.1%; ≥20 oocytes: 6.7% versus 18.5%; both P < 0.001). The incidence of early OHSS and/or preventive interventions for early OHSS was significantly (P = 0.004) reduced from 9.6% with follitropin alfa to 5.0% with individualised follitropin delta. The total gonadotropin use was significantly (P < 0.001) reduced from an average of 109.9 ± 32.9 μg (1498 ± 448 IU) follitropin alfa to 77.5 ± 24.4 μg follitropin delta. Non-inferiority of follitropin delta in its individualised dosing regimen to conventional follitropin alfa was established with respect to the primary endpoint of ongoing pregnancy rate which was 31.3% with follitropin delta compared to 25.7% with follitropin alfa (estimated mean difference 5.4% [95% CI: −0.2%; 11.0%]). The live birth rate was significantly higher at 31.3% with individualised follitropin delta compared to 24.7% with follitropin alfa (estimated mean difference 6.4% [95% CI: 0.9%; 11.9%]; P = 0.023). The live birth rate for each stratum were as follows for follitropin delta and follitropin alfa, respectively; <35 years: 31.0% versus 25.0%, 35–37 years: 35.3% versus 26.7%, 38–40 years: 20.0% versus 14.3%.LIMITATIONS, REASONS FOR CAUTIONThe trial only covered the clinical outcome of one treatment cycle with fresh cleavage-stage embryo transfers.WIDER IMPLICATIONS OF THE FINDINGSThe present trial shows that in addition to reducing the early OHSS risk, follitropin delta in its individualised fixed-dose regimen has the potential to improve the success rate in fresh cycles across all ages and with a lower gonadotropin consumption compared to conventional follitropin alfa dosing.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by Ferring Pharmaceuticals. J.Q., Y.Z., X.L., T.H., H.-Y.H. and S.-H.K. have received institutional (not personal) clinical trial fees from Ferring Pharmaceuticals. M.G., B.M. and J.-C.A. are employees of Ferring Pharmaceuticals. J.-C.A. has pending and issued patent applications in the WO 2013/020996 and WO 2019/043143 patent families that comprise allowed and granted patent rights related to follitropin delta.TRIAL REGISTRATION NUMBERNCT03296527 (clinicaltrials.gov).TRIAL REGISTRATION DATE28 September 2017DATE OF FIRST PATIENT’S ENROLMENT1 December 2017

The Effect of Luteinising Hormone Suppression in In Vitro Fertilisation Antagonist Cycles.

Use of GnRH antagonists in IVF stimulation protocols shortens controlled ovarian hyperstimulation (COH) and reduces the risk of ovarian hyperstimulation syndrome (OHSS). However, profound reduction in LH levels has been associated with use of GnRH antagonists. This study aims to determine if LH suppression during GnRH antagonist cycles results in poorer IVF outcomes. This was a prospective pilot longitudinal study where serum LH levels were measured on day 2/3 of the menstrual cycle before COH, 1/2 days following institution of GnRH antagonist and at the day of ovulation trigger. A threshold of LH <0.5 IU/L was used to define profound LH suppression. Data on IVF outcomes was collected. Logistic regression analysis was used to investigate risk factors associated with LH suppression following GnRH antagonist IVF treatment. Ninety-one eligible women were recruited. Women underwent a standard antagonist cycle with Puregon 200u and Ganirelix. No participant had LH <0.5 IU/L prior to GnRH antagonist treatment, and 27 participants (29.7%) had significant LH suppression at either time point. Predictors of profound LH suppression following GnRH antagonist treatment identified (P < 0.20) were age (OR = 0.80, P = 0.013), no previous ovulation induction (OR = 0.26, P = 0.033) and previous GnRH antagonist IVF cycle (OR = 4.32, P = 0.125). Numbers of oocytes, embryos and ongoing pregnancy rates at 12 weeks gestation in patients with and without LH suppression did not differ significantly. We found associations between clinical characteristics and risk of profound LH suppression in women undergoing GnRH antagonist IVF cycles, but no significant differences in IVF and pregnancy outcomes between women with and without significant LH suppression.

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

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