ABSTRACT
STUDY QUESTION: Does double stimulation, followed by a fresh embryo transfer (DUOSTIM fresh) give a higher number of good-quality blastocysts as compared with a single stimulation in young low prognosis patients? SUMMARY ANSWER: Compared to single stimulation, DUOSTIM fresh leads to a significantly higher number of good quality blastocysts, without hindering fresh embryo transfer outcomes. WHAT IS KNOWN ALREADY: DUOSTIM (ovarian stimulation both in the follicular and luteal phase of the same cycle) is an innovative strategy to retrieve a higher number of oocytes in a shorter time frame, thus it is particularly appealing for poor ovarian responders. Three current limitations of dual stimulation are: (i) it is unclear whether outcomes of the second (luteal) wave result from the second stimulation, or a carry-over effect from previous follicular stimulation; (ii) the desynchronization between endometrium and ovaries and, (iii) lack of robust evidence. No previous studies explored DUOSTIM starting from the luteal phase, and with a fresh embryo transfer (DUOSTIM fresh). STUDY DESIGN, SIZE, DURATION: This study is a randomized, controlled, single-center, superiority clinical trial comparing two different ovarian stimulation protocols: a double stimulation cycle versus a single stimulation cycle followed by fresh embryo transfer. The primary outcome was the number of good quality blastocysts obtained, while secondary outcomes included results from fresh embryo transfer (clinical pregnancy, miscarriage). A total of 120 women were enrolled in this study between October 2020 and October 2022, with a 1:1 allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Only young (<40 years old) low prognosis (anti-Müllerian hormone <1.2 ng/ml) patients were recruited in the Reproductive Medicine Department of Dexeus University Hospital. In the investigational group, DUOSTIM fresh, the first stimulation was initiated in the luteal phase (Day 18-21 cycle) followed by a second stimulation 5 days post first oocyte retrieval, initiated in the follicular phase and a fresh embryo transfer of the best blastocyst generated (first or second cycle). The control group performed a follicular phase single stimulation cycle with a fresh embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 107 patients were analyzed, 53 in the investigational (DUOSTIM fresh) and 54 in the control arm (single stimulation). DUOSTIM fresh resulted in a significantly higher number of good quality blastocysts as compared to single stimulation (difference of mean 0.81, 95% CI 0.12-1.49). The mean percentage of cycles with embryo transfer was comparable (62.3% and 51.9%, respectively for double versus single stimulation). No significant differences were found for clinical outcomes following fresh embryo transfer with an ongoing pregnancy rate of 24.5% for DUOSTIM fresh versus 22.2%, for conventional IVF. Of interest comparisons between different stimulation cycles (A: luteal-phase DUOSTIM fresh, B: follicular-phase DUOSTIM fresh, and C: single stimulation) did not demonstrate any significant difference in terms of ovarian response with the mean (SD) number of mature oocytes being (A: 3.3 (2.9), B: 3.4 (3.4), and C: 3.5 (2.9), respectively). LIMITATIONS, REASONS FOR CAUTION: Study sample size was calculated to detect differences on the mean number of good quality blastocysts. Therefore, results for secondary outcomes (embryo transfer rates and clinical pregnancy rates) should be interpreted with caution as exploratory findings that deserve future investigations. WIDER IMPLICATIONS OF THE FINDINGS: Although DUOSTIM fresh results in a higher number of blastocysts as compared with a single stimulation in young low prognosis patients, the decision of performing dual stim should be evaluated with caution, considering that whether this may improve embryo transfers rate and pregnancy outcomes is still unclear. Results on cumulative-live-birth-rate are warranted. STUDY FUNDING/COMPETING INTEREST(S): The study was an investigator-initiated study supported by an unrestricted grant by Organon. N.P.P. has received grants from Merck Serono, Organon, Ferring Pharmaceutical, Theramex, and Besins Healthcare. N.P.P. has received consulting fees from Merck Serono, Organon, Besins Healthcare, and IBSA. N.P.P. has received honoraria for lectures from Merck Serono, Organon, Theramex, Roche Diagnostics, IBSA, Besins Healthcare, and Ferring. A.R. has received Research grants, honoraria for lectures from Merck Serono, MSD/Organon, Ferring Pharmaceuticals, Besins International, IBSA, Guerbet. The other authors declare that there is no conflict of interest to disclose with respect to the content of this article. TRIAL REGISTRATIO NUMBER: NCT04446845. TRIAL REGISTRATION DATE: 25 June 2020. DATE OF FIRST PATIENT'S ENROLMENT: 30 October 2020.
ABSTRACT
Endometriosis is a complex and chronic gynaecological disorder that affects millions of women worldwide, leading to significant morbidity and impacting reproductive health. This condition affects up to 10% of women of reproductive age and is characterised by the presence of endometrial-like tissue outside the uterus, potentially leading to symptoms such as chronic pelvic pain, dysmenorrhoea, dyspareunia, and infertility. The Montreux summit brought a number of experts in this field together to provide a platform for discussion and exchange of ideas. These proceedings summarise the six main topics that were discussed at this summit to shed light on future directions of endometriosis classification, diagnosis, and therapeutical management. The first question addressed the possibility of preventing endometriosis in the future by identifying risk factors, genetic predispositions, and further understanding of the pathophysiology of the condition to develop targeted interventions. The clinical presentation of endometriosis is varied, and the correlation between symptoms severity and disease extent is unclear. While there is currently no universally accepted optimal classification system for endometriosis, several attempts striving towards its optimisation - each with its own advantages and limitations - were discussed. The ideal classification should be able to reconcile disease status based on the various diagnostic tools, and prognosis to guide proper patient tailored management. Regarding diagnosis, we focused on future tools and critically discussed emerging approaches aimed at reducing diagnostic delay. Preserving fertility in endometriosis patients was another debatable aspect of management that was reviewed. Moreover, besides current treatment modalities, potential novel medical therapies that can target underlying mechanisms, provide effective symptom relief, and minimise side effects in endometriotic patients were considered, including hormonal therapies, immunomodulation, and regenerative medicine. Finally, the question of hormonal substitution therapy after radical treatment for endometriosis was debated, weighing the benefits of hormone replacement.
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STUDY QUESTION: Which add-ons are safe and effective to be used in ART treatment? SUMMARY ANSWER: Forty-two recommendations were formulated on the use of add-ons in the diagnosis of fertility problems, the IVF laboratory and clinical management of IVF treatment. WHAT IS KNOWN ALREADY: The innovative nature of ART combined with the extremely high motivation of the patients has opened the door to the wide application of what has become known as 'add-ons' in reproductive medicine. These supplementary options are available to patients in addition to standard fertility procedures, typically incurring an additional cost. A diverse array of supplementary options is made available, encompassing tests, drugs, equipment, complementary or alternative therapies, laboratory procedures, and surgical interventions. These options share the common aim of stating to enhance pregnancy or live birth rates, mitigate the risk of miscarriage, or expedite the time to achieving pregnancy. STUDY DESIGN, SIZE, DURATION: ESHRE aimed to develop clinically relevant and evidence-based recommendations focusing on the safety and efficacy of add-ons currently used in fertility procedures in order to improve the quality of care for patients with infertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: ESHRE appointed a European multidisciplinary working group consisting of practising clinicians, embryologists, and researchers who have demonstrated leadership and expertise in the care and research of infertility. Patient representatives were included in the working group. To ensure that the guidelines are evidence-based, the literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, recommendations were based on the professional experience and consensus of the working group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 46 independent international reviewers. A total of 272 comments were received and incorporated where relevant. MAIN RESULTS AND THE ROLE OF CHANCE: The multidisciplinary working group formulated 42 recommendations in three sections; diagnosis and diagnostic tests, laboratory tests and interventions, and clinical management. LIMITATIONS, REASONS FOR CAUTION: Of the 42 recommendations, none could be based on high-quality evidence and only four could be based on moderate-quality evidence, implicating that 95% of the recommendations are supported only by low-quality randomized controlled trials, observational data, professional experience, or consensus of the development group. WIDER IMPLICATIONS OF THE FINDINGS: These guidelines offer valuable direction for healthcare professionals who are responsible for the care of patients undergoing ART treatment for infertility. Their purpose is to promote safe and effective ART treatment, enabling patients to make informed decisions based on realistic expectations. The guidelines aim to ensure that patients are fully informed about the various treatment options available to them and the likelihood of any additional treatment or test to improve the chance of achieving a live birth. STUDY FUNDING/COMPETING INTEREST(S): All costs relating to the development process were covered from ESHRE funds. There was no external funding of the development process or manuscript production. K.L. reports speakers fees from Merck and was part of a research study by Vitrolife (unpaid). T.E. reports consulting fees from Gynemed, speakers fees from Gynemed and is part of the scientific advisory board of Hamilton Thorne. N.P.P. reports grants from Merck Serono, Ferring Pharmaceutical, Theramex, Gedeon Richter, Organon, Roche, IBSA and Besins Healthcare, speakers fees from Merck Serono, Ferring Pharmaceutical, Theramex, Gedeon Richter, Organon, Roche, IBSA and Besins Healthcare. S.R.H. declares being managing director of Fertility Europe, a not-for-profit organization receiving financial support from ESHRE. I.S. is a scientific advisor for and has stock options from Alife Health, is co-founder of IVFvision LTD (unpaid) and received speakers' fee from the 2023 ART Young Leader Prestige workshop in China. A.P. reports grants from Gedeon Richter, Ferring Pharmaceuticals and Merck A/S, consulting fees from Preglem, Novo Nordisk, Ferring Pharmaceuticals, Gedeon Richter, Cryos and Merck A/S, speakers fees from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S, Theramex and Organon, travel fees from Gedeon Richter. The other authors disclosed no conflicts of interest. DISCLAIMER: This Good Practice Recommendations (GPRs) document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and are based on the scientific evidence available at the time of preparation.ESHRE GPRs should be used for information and educational purposes. They should not be interpreted as setting a standard of care or bedeemedinclusive of all proper methods of care, or be exclusive of other methods of care reasonably directed to obtaining the same results.Theydo not replace the need for application of clinical judgement to each individual presentation, or variations based on locality and facility type.Furthermore, ESHRE GPRs do not constitute or imply the endorsement, or favouring, of any of the included technologies by ESHRE.
Subject(s)
Infertility , Reproductive Medicine , Pregnancy , Female , Humans , Infertility/therapy , Birth Rate , Treatment Outcome , Pharmaceutical PreparationsABSTRACT
PURPOSE: To provide agreed-upon guidelines on the management of a hyper-responsive patient undergoing ovarian stimulation (OS) METHODS: A literature search was performed regarding the management of hyper-response to OS for assisted reproductive technology. A scientific committee consisting of 4 experts discussed, amended, and selected the final statements. A priori, it was decided that consensus would be reached when ≥66% of the participants agreed, and ≤3 rounds would be used to obtain this consensus. A total of 28/31 experts responded (selected for global coverage), anonymous to each other. RESULTS: A total of 26/28 statements reached consensus. The most relevant are summarized here. The target number of oocytes to be collected in a stimulation cycle for IVF in an anticipated hyper-responder is 15-19 (89.3% consensus). For a potential hyper-responder, it is preferable to achieve a hyper-response and freeze all than aim for a fresh transfer (71.4% consensus). GnRH agonists should be avoided for pituitary suppression in anticipated hyper-responders performing IVF (96.4% consensus). The preferred starting dose in the first IVF stimulation cycle of an anticipated hyper-responder of average weight is 150 IU/day (82.1% consensus). ICoasting in order to decrease the risk of OHSS should not be used (89.7% consensus). Metformin should be added before/during ovarian stimulation to anticipated hyper-responders only if the patient has PCOS and is insulin resistant (82.1% consensus). In the case of a hyper-response, a dopaminergic agent should be used only if hCG will be used as a trigger (including dual/double trigger) with or without a fresh transfer (67.9% consensus). After using a GnRH agonist trigger due to a perceived risk of OHSS, luteal phase rescue with hCG and an attempt of a fresh transfer is discouraged regardless of the number of oocytes collected (72.4% consensus). The choice of the FET protocol is not influenced by the fact that the patient is a hyper-responder (82.8% consensus). In the cases of freeze all due to OHSS risk, a FET cycle can be performed in the immediate first menstrual cycle (92.9% consensus). CONCLUSION: These guidelines for the management of hyper-response can be useful for tailoring patient care and for harmonizing future research.
Subject(s)
Ovarian Hyperstimulation Syndrome , Female , Humans , Pregnancy , Consensus , Delphi Technique , Gonadotropin-Releasing Hormone , Chorionic Gonadotropin , Fertilization in Vitro/methods , Ovulation Induction/methods , Risk Assessment , Pregnancy RateABSTRACT
PURPOSE: To provide an agreed upon definition of hyper-response for women undergoing ovarian stimulation (OS)? METHODS: A literature search was performed regarding hyper-response to ovarian stimulation for assisted reproductive technology. A scientific committee consisting of 5 experts discussed, amended, and selected the final statements in the questionnaire for the first round of the Delphi consensus. The questionnaire was distributed to 31 experts, 22 of whom responded (with representation selected for global coverage), each anonymous to the others. A priori, it was decided that consensus would be reached when ≥ 66% of the participants agreed and ≤ 3 rounds would be used to obtain this consensus. RESULTS: 17/18 statements reached consensus. The most relevant are summarized here. (I) Definition of a hyper-response: Collection of ≥ 15 oocytes is characterized as a hyper-response (72.7% agreement). OHSS is not relevant for the definition of hyper-response if the number of collected oocytes is above a threshold (≥ 15) (77.3% agreement). The most important factor in defining a hyper-response during stimulation is the number of follicles ≥ 10 mm in mean diameter (86.4% agreement). (II) Risk factors for hyper-response: AMH values (95.5% agreement), AFC (95.5% agreement), patient's age (77.3% agreement) but not ovarian volume (72.7% agreement). In a patient without previous ovarian stimulation, the most important risk factor for a hyper-response is the antral follicular count (AFC) (68.2% agreement). In a patient without previous ovarian stimulation, when AMH and AFC are discordant, one suggesting a hyper-response and the other not, AFC is the more reliable marker (68.2% agreement). The lowest serum AMH value that would place one at risk for a hyper-response is ≥ 2 ng/ml (14.3 pmol/L) (72.7% agreement). The lowest AFC that would place one at risk for a hyper-response is ≥ 18 (81.8% agreement). Women with polycystic ovarian syndrome (PCOS) as per Rotterdam criteria are at a higher risk of hyper-response than women without PCOS with equivalent follicle counts and gonadotropin doses during ovarian stimulation for IVF (86.4% agreement). No consensus was reached regarding the number of growing follicles ≥ 10 mm that would define a hyper-response. CONCLUSION: The definition of hyper-response and its risk factors can be useful for harmonizing research, improving understanding of the subject, and tailoring patient care.
Subject(s)
Follicle Stimulating Hormone , Polycystic Ovary Syndrome , Humans , Female , Delphi Technique , Fertilization in Vitro , Ovulation Induction , Risk Assessment , Fertilization , Anti-Mullerian HormoneABSTRACT
Research question: The main objective of the study is to define the optimal trade-off progesterone (P4) values on the day of embryo transfer (ET), to identify low P4-human chorionic gonadotropin (hCG), and to establish whether P4 supplementation started on the hCG day can increase the success rate of the frozen embryo transfer (FET) cycle. Design: A single-center, cohort, retrospective study with 664 hormone replacement therapy (HRT)-FET cycles analyzed female patients who received vaginal 600 mg/day of P4 starting from 6 days before the FET, had normal P4 values on the day before ET, and whose P4 on the day of the pregnancy test was assessed. Results: Of the 664 cycles, 69.6% of cycles showed P4 ≥ 10.6 ng/ml, while 30.4% showed P4 < 10.6 ng/ml on the day of the hCG. Of the 411 chemical pregnancies detected, 71.8% had P4-hCG ≥ 10.6 ng/ml (group A), while 28.2% had P4-hCG < 10.6 ng/ml. Of the cycles with P4-hCG < 10.6 ng/ml, 64.7% (group B) were supplemented with a higher dose of vaginal P4 (1,000 mg/day), while 35.3% (group C) were maintained on the same dose of vaginal micronized P4. The live birth rate was 71.9%, 96%, and 7.3% for groups A, B, and C, respectively. Conclusion: The likelihood to detect P4-hCG < 10.6 ng/ml decreased as the level of serum P4 the day before ET increased. The live birth rate (LBR) was shown to be significantly lower when P4 was low and not supplemented.
Subject(s)
Pregnancy Tests , Progesterone , Pregnancy , Female , Humans , Pregnancy Rate , Luteal Phase , Retrospective Studies , Chorionic Gonadotropin/therapeutic useABSTRACT
STUDY QUESTION: Does the presence of FSHR single-nucleotide polymorphisms (SNPs) affect late follicular phase progesterone and estradiol serum levels in predicted normoresponders treated with rFSH? SUMMARY ANSWER: The presence of FSHR SNPs (rs6165, rs6166, rs1394205) had no clinically significant impact on late follicular phase serum progesterone and estradiol levels in predicted normoresponders undergoing a GnRH antagonist protocol with a fixed daily dose of 150 IU rFSH. WHAT IS KNOWN ALREADY: Previous studies have shown that late follicular phase serum progesterone and estradiol levels are significantly correlated with the magnitude of ovarian response. Several authors have proposed that individual variability in the response to ovarian stimulation (OS) could be explained by variants in FSHR. However, so far, the literature is scarce on the influence of this genetic variability on late follicular phase steroidogenic response. Our aim is to determine whether genetic variants in the FSHR gene could modulate late follicular phase serum progesterone and estradiol levels. STUDY DESIGN, SIZE, DURATION: In this multicenter multinational prospective study conducted from November 2016 to June 2019, 366 patients from Vietnam, Belgium and Spain (166 from Europe and 200 from Asia) underwent OS followed by oocyte retrieval in a GnRH antagonist protocol with a fixed daily dose of 150 IU rFSH. All patients were genotyped for 3 FSHR SNPs (rs6165, rs6166, rs1394205) and had a serum progesterone and estradiol measurement on the day of trigger. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included patients were predicted normal responder women <38 years old undergoing their first or second OS cycle. The prevalence of late follicular phase progesterone elevation (PE), as well as mean serum progesterone and estradiol levels on the day of trigger were compared between the different FSHR SNPs genotypes. PE was defined as >1.50 ng/ml. MAIN RESULTS AND THE ROLE OF CHANCE: The overall prevalence of PE was 15.8% (n = 58). No significant difference was found in the prevalence of PE in Caucasian and Asian patients (17.5% versus 14.5%). Estradiol levels on the day of trigger and the number of retrieved oocytes were significantly higher in patients with PE (4779 ± 6236.2 versus 3261 ± 3974.5 pg/ml, P = 0.003, and 16.1 ± 8.02 versus 13.5 ± 6.66, P = 0.011, respectively). Genetic model analysis, adjusted for patient age, body mass index, number of retrieved oocytes and continent (Asia versus Europe), revealed a similar prevalence of PE in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. No statistically significant difference was observed in the mean late follicular phase progesterone serum levels according to the genotypes of FSHR rs6166 (P = 0.941), rs6165 (P = 0.637) and rs1394205 (P = 0.114) in the bivariate analysis. Also, no difference was found in the genetic model analysis regarding mean late follicular phase progesterone levels across the different genotypes. Genetic model analysis has also revealed no statistically significant difference regarding mean estradiol levels on the day of trigger in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. Haplotype analysis revealed a statistically significant lower estradiol level on the day of trigger for rs6166/rs6165 haplotypes GA, AA and GG when compared to AG (respectively, estimated mean difference (EMD) -441.46 pg/ml (95% CI -442.47; -440.45), EMD -673.46 pg/ml (95% CI -674.26; -672.67) and EMD -582.10 pg/ml (95% CI -584.92; -579.28)). No statistically significant differences were found regarding the prevalence of PE nor late follicular phase progesterone levels according to rs6166/rs6165 haplotypes. LIMITATIONS, REASONS FOR CAUTION: Results refer to a population of predicted normal responders treated with a normal/low fixed dose of 150 IU rFSH throughout the whole OS. Consequently, caution is needed before generalizing our results to all patient categories. WIDER IMPLICATIONS OF THE FINDINGS: Based on our results, FSHR SNPs rs6165, rs6166 and rs1394205 do not have any clinically significant impact neither on late follicular phase serum progesterone nor on estradiol levels in predicted normal responders. These findings add to the controversy in the literature regarding the impact of individual genetic susceptibility in response to OS in this population. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD, IISP56222). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Organon, Theramex and Institut Biochimique SA (IBSA). C.A. reports conference fees from Merck Serono, Medea and Event Planet. A.R.N., C.B., C.S., P.Q.M.M., H.T., C.B., N.L.V., M.T.H. and S.G. report no conflict of interests related to the content of this article. TRIAL REGISTRATION NUMBER: NCT03007043.
Subject(s)
Follicular Phase , Progesterone , Female , Humans , Pregnancy , Estradiol , Fertilization in Vitro/methods , Gonadotropin-Releasing Hormone , Hormone Antagonists , Ovulation Induction/methods , Pregnancy Rate , Prospective StudiesABSTRACT
BACKGROUND: The performance of the public hospitals of the National Health System (NHS) of Greece, as reflected in their financial and operational results, is related to their strategic planning and the factors that influence the accomplishment of their objectives. METHOD: The organizational performance of NHS hospitals was assessed by analyzing their operational and financial data for the period 2010-2020 (recorded by the "BI-Health" system of the Ministry of Health). Based on internationally accepted factors that influence the successful implementation of strategic planning and the achievement of its objectives, a structured questionnaire consisting of 11 demographic and 93 (on a scale of 1 to 7) factor-related questions was developed and addressed to 56 managers and senior executives. Their response was analyzed using descriptive statistical methods and inference, and "significant" factors were extracted using Principal Components Analysis. RESULTS: Hospitals reduced their expenditure from 2010 to 2015 by 34.6 %, while the number of inpatients increased by 5.9 %. However, expenditure increased by 41.2 % in the period 2016-2020, while concurrently, inpatients rose by 14.7 %. Outpatient and emergency department visits remained almost stable (6.5 and 4.8 million/year, respectively), during 2010-2015, while increased by 14.5 % till 2020. The average length of stay decreased from 4.1 in 2010 to 3.8 in 2015 and 3.4 in 2020. The survey data showed that NHS hospitals' strategic plan is well "documented", but its "actual implementation" is moderate; The "achievement of the objectives" related to clinical work, quality improvement of services, human resources development, financial strategy, asset strategy, digital strategy, communication and engagement strategy, and research might be good; chief executive officers, nurses, laboratory physicians, and administrators receive a positive grade of participation while the Board of Directors, physicians, employee representatives and the School of Medicine/University receive a moderate grade. The factors: "elements of strategic planning" (33.6 %), "evaluation of services and staff" (20.5 %), "employees' commitment and involvement" (20.1 %), and "operational outcomes and performance" (8.9 %), as derived from the principal component analysis, had the highest impact on achieving their financial and operational objectives, as assessed by the views of the managers of the 35 NHS hospitals. CONCLUSION: The NHS hospitals increased their efficiency from 2010 to 2020 but failed to maintain control over their expenditure. Through their clinical managers and other employees' representatives, chief executive officers and the Board of Directors need to improve planning formulation, staff involvement and utilization, financial performance, and outcomes as their primary commitment among health policy and management sectors in the Greek NHS. HIPPOKRATIA 2022, 26 (3):91-97.
Subject(s)
Follicular Phase , Luteal Phase , Blastocyst , Female , Humans , Ovulation Induction , PregnancyABSTRACT
Over the last 25 years, a vast body of literature has been published evaluating different treatment modalities for the management of poor ovarian responders. Despite the evidence that maximizing ovarian response can improve the chances of live born babies in poor responders, there are still voices suggesting that all poor responders are the same, irrespective of their age and their actual ovarian reserve. This has resulted in the suggestion of adopting a mild ovarian stimulation approach for all poor responders, based on the results of several trials which failed to identity differences when comparing mild and more intense stimulation in predicted poor responders. The current article analyzes in detail these studies and discusses the shortcomings in terms of type of population included, outcomes and settings performed, which may actually be responsible for the belief that only mild stimulation should be used. In the era of individualization in medicine, it must be realized that there are subgroups of predicted poor responders who will benefit from an individual rather than 'one fits all' mild stimulation approach and thus we should provide the same standard of treatment for all our poor responder patients.
Subject(s)
Fertilization in Vitro , Ovarian Reserve , Birth Rate , Female , Humans , Ovulation Induction , Pregnancy , Pregnancy RateABSTRACT
The article "EStradiol and PRogesterone in In vitro ferTilization (ESPRIT): a multicenter study evaluating third versus secondgeneration estradiol and progesterone immunoassays.
ABSTRACT
PURPOSE: To assess estradiol (E2) and progesterone levels during ovarian stimulation determined by third-generation (Gen III) and second-generation (Gen II) Elecsys® immunoassays. METHODS: E2 and progesterone concentrations were measured using Elecsys® Gen III and Gen II immunoassays, and progesterone concentrations on the day of ovulation triggering were determined by LC-MS/MS. This was a retrospective, non-interventional study conducted at European tertiary referral infertility clinics in women aged 18-45 years, with a body mass index 18-35 kg/m2, regular menses, and both ovaries. RESULTS: Serum samples were obtained from 230 women classified by oocyte retrieval as poor (33.0%; 0-3 oocytes), normal (40.9%; 4-15 oocytes), or high (26.1%; > 15 oocytes) responders. E2 and progesterone levels increased during ovarian stimulation, with greatest increases observed in high responders. Elecsys® Gen III and Gen II assay results were highly correlated for E2 (Pearson's r = 0.99) and progesterone (r = 0.89); Gen III results were lower than Gen II for both E2 and progesterone. On the day of triggering, Gen III E2 and progesterone levels showed a difference of - 15.0% and - 27.9%, respectively. Progesterone levels (on day of triggering) measured by LC-MS/MS correlated better with Gen III (0.98) than Gen II (0.90). Mean relative differences for Gen III and Gen II assays versus LC-MS/MS were 14.6% and 62.8%, respectively. CONCLUSION: E2 and progesterone levels determined with Elecsys® Gen II and III assays were highly correlated; results were lower for Gen III versus Gen II. Differences observed for progesterone on the day of triggering may be clinically relevant.
Subject(s)
Blood Chemical Analysis/methods , Estradiol/blood , Fertilization in Vitro , Ovulation Induction , Progesterone/blood , Adolescent , Adult , Chromatography, Liquid , Estradiol/analysis , Female , Humans , Immunoassay/methods , Middle Aged , Monitoring, Physiologic/methods , Progesterone/analysis , Retrospective Studies , Tandem Mass Spectrometry , Young AdultABSTRACT
Research question: Do live birth rates (LBRs) differ in frozen cycles of women who received single versus double embryo transfer?Design: Retrospective cohort study including women who underwent their first frozen embryo transfer (FET) in a tertiary referral University Hospital between 2009-2014.Results: 3601 patients were included in the analysis with 1936 (53.8%) having a single embryo transfer (SET) and 1665 (46.2%) having a double embryo transfer (DET). Overall, 657/3601 (18.24%) had a live birth. LBR were similar between SET and DET either for cleavage [100/757 (13.1%) versus 153/1032 (14.8%), p = .33] or blastocyst stage FET [256/1179 (21.7%) versus 148/633 (23.4%), p = .4). Ongoing pregnancy rates were comparable between DET and SET [316/1665 (18.9%) versus 359/1936 (18.5%)]. Multiple delivery rates were significantly higher in women with DET compared to SET [53/316 (16.7%) versus 7/359 (1.9%), p < .001]. Multivariate logistic regression analysis allowing adjustment for relevant confounders showed that the number of embryos transferred in the frozen cycle was not related to LBR.Conclusions: This is the largest study providing evidence that both SET and DET may result in similar LBR, albeit multiple pregnancy rates are significantly lower in case of SET. Therefore, SET should be the main strategy in women undergoing FET.
Subject(s)
Embryo Transfer , Fertilization in Vitro , Live Birth/epidemiology , Adult , Birth Rate , Blastocyst , Cryopreservation , Embryo Transfer/methods , Embryo Transfer/statistics & numerical data , Female , Fertilization in Vitro/methods , Fertilization in Vitro/statistics & numerical data , Humans , Infant, Newborn , Infertility/epidemiology , Infertility/therapy , Male , Pregnancy , Pregnancy Outcome/epidemiology , Pregnancy Rate , Retrospective Studies , Single Embryo Transfer/methods , Single Embryo Transfer/statistics & numerical data , Treatment OutcomeABSTRACT
STUDY QUESTION: Is there significant variability in progesterone levels during the final day of oocyte maturation in women undergoing ovarian stimulation? SUMMARY ANSWER: Progesterone levels drop from the basal level up to 44% during the final day of oocyte maturation in women undergoing ovarian stimulation. WHAT IS KNOWN ALREADY: It has been suggested that elevated progesterone levels on the final day of ovarian stimulation may be related to poorer outcomes in in vitro fertilization fresh cycles due to a negative impact on the endometrium. However, despite conflicting results regarding the actual effect of progesterone on pregnancy rates and the lack of a well-established cut off, currently many IVF patients have their embryo transfer deferred when progesterone values surpass a threshold of 1.5 ng/ml on the day of ovulation triggering. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study conducted in 22 oocyte donors of a university-affiliated fertility centre between November 2017 and January 2018. We calculated the sample size to detect a difference of 15% between the first and last progesterone measurements with a 5% false-positive rate in a two-sided test with 80% statistical power and a 95% confidence interval (CI). PARTICIPANTS/MATERIALS, SETTING, METHODS: Progesterone circulating levels were evaluated at four different times during the final day of oocyte maturation (08:00, 12:00, 16:00 and 20:00) before ovulation triggering in healthy oocyte donors. A flexible antagonist protocol was used, and ovarian stimulation was achieved with recombinant follicle-stimulating hormone (FSH) in all cases. The pairwise percentage differences in progesterone levels for each patient were calculated. Univariate linear regression analysis was adopted in order to evaluate variables associated with progesterone levels on the first measurement. The intra-day variability of progesterone was analysed using mixed models. MAIN RESULTS AND THE ROLE OF CHANCE: Mean serum progesterone values at 08:00, 12:00, 16:00 and 20:00 were 1.75 ng/ml, 1.40 ng/ml, 1.06 ng/ml and 0.97 ng/ml. The progesterone difference between 08:00 and 20:00 was 0.77 (95% CI, 0.56-0.99), which is equivalent to a 44% decline in the mean progesterone values between the first (08:00) and the last determination (20:00; P < 0.001). Among those patients with basal (08:00) progesterone levels >1.5 ng/ml (n = 10), 70% (n = 7) showed levels reduced to <1.5 ng/ml on the last determination of the day (20:00). A mixed model analysis revealed that the progesterone reduction during the day was significantly associated with time and total recombinant FSH dose administered. LIMITATIONS, REASONS FOR CAUTION: Only young healthy oocyte donors stimulated with an antagonist protocol using recombinant FSH were included. Extrapolation to the general IVF population, with different stimulation protocols and gonadotropins, needs to be confirmed. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that a single progesterone determination on the final day of oocyte maturation is not reliable enough to make clinical decisions due to the enormous variation in progesterone during the day. Further studies are needed to better define the impact of the follicular progesterone rise on the endometrium of IVF cycles. STUDY FUNDING/COMPETING INTEREST(S): Funding was granted from Fundació Santiago Dexeus Font. N.P.P. received unrestricted grants and/or lectures fees from Roche Diagnostics, MSD, Merck, Ferring Pharmaceuticals, IBSA, Theramex and BESINS International, not associated with the current study. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT03366025.
Subject(s)
Fertilization in Vitro/methods , Oocytes/growth & development , Ovulation Induction/methods , Progesterone/blood , Adult , Female , Humans , Live Birth , Pregnancy , Pregnancy Rate , Prospective Studies , Young AdultABSTRACT
A retrospective cohort study was performed to examine whether, in artificial endometrial preparation for frozen embryo transfer (FET) cycles, progesterone (P) levels the day prior to embryo transfer of euploid embryos have an impact on pregnancy outcomes. In a private university clinic, 244 FETs between January 2016 and June 2017 were analyzed. Endometrial preparation was achieved with estradiol valerate and vaginal micronized progesterone. Serum P and estradiol levels the day prior to embryo transfer were measured. A multivariable analysis to assess the relationship between serum P level and pregnancy outcomes was performed, adjusted for confounding variables. Mean P value was 11.3 ± 5.1 ng/ml. Progesterone levels were split in quartiles: Q1: ≤ 8.06 ng/ml; Q2: 8.07-10.64 ng/ml; Q3: 10.65-13.13 ng/ml; Q4: > 13.13 ng/ml. Patients included in the lower P quartile had a significantly higher miscarriage rate and significantly lower live birth rate (LBR) compared to the higher ones. A low serum P level (≤ 10.64 ng/ml) one day before FET is associated with a lower pregnancy and LBR following FET of euploid embryos.
Subject(s)
Embryo Transfer/methods , Fertilization in Vitro , Pregnancy Outcome , Progesterone/blood , Adult , Birth Rate , Cryopreservation , Female , Humans , Live Birth , Pregnancy , Retrospective Studies , Risk FactorsABSTRACT
Prospective studies comparing different durations of progesterone supplementation before transfer of vitrified-warmed blastocysts in an artificial cycle are lacking. However, in oocyte donation programmes, the sporadic available evidence demonstrates considerable differences in clinical pregnancy rates according to the duration of progesterone administration. This randomised controlled trial (RCT), included 303 patients undergoing a frozen-thawed embryo transfer (FET) of one or two vitrified-warmed blastocyst(s) in an artificial cycle. Randomisation was performed when the endometrial thickness reached ≥7 mm after oestrogen supplementation. One hundred and fifty two patients in group A received 7 d of vaginal micronised progesterone tablets and 151 patients in group B received 5 d of micronised vaginal progesterone before FET. No differences were seen in clinical pregnancy rate between both groups: 42/152 (27.6%) in group A versus 49/151 (32.5%) in group B. Although no statistically significant difference was observed in clinical pregnancy rates, our study was powered to detect an absolute difference of 16%. In this regard, we cannot exclude that smaller, clinically relevant differences might exist and our study did not have the power to detect this. Patients were also not blinded for the intervention, causing a potential bias.
Subject(s)
Blastocyst , Embryo Transfer/methods , Progesterone/therapeutic use , Vitrification , Adult , Embryo Implantation/drug effects , Female , Humans , Infant, Newborn , Menstrual Cycle/drug effects , Menstrual Cycle/physiology , Pregnancy , Pregnancy RateABSTRACT
BACKGROUND: This study is an initial effort to examine the dynamics of efficiency and productivity in Greek public hospitals during the first phase of the crisis 2009-2012. Data were collected by the Ministry of Health after several quality controls ensuring comparability and validity of hospital inputs and outputs. Productivity is estimated using the Malmquist Indicator, decomposing the estimated values into efficiency and technological change. METHODS: Hospital efficiency and productivity growth are calculated by bootstrapping the non-parametric Malmquist analysis. The advantage of this method is the estimation efficiency and productivity through the corresponding confidence intervals. Additionally, a Random-effects Tobit model is explored to investigate the impact of contextual factors on the magnitude of efficiency. RESULTS: Findings reveal substantial variations in hospital productivity over the period from 2009 to 2012. The economic crisis of 2009 had a negative impact in productivity. The average Malmquist Productivity Indicator (MPI) score is 0.72 with unity signifying stable production. Approximately 91% of the hospitals score lower than unity. Substantial increase is observed between 2010 and 2011, as indicated by the average MPI score which fluctuates to 1.52. Moreover, technology change scored more than unity in more than 75% of hospitals. The last period (2011-2012) has shown stabilization in the expansionary process of productivity. The main factors contributing to overall productivity gains are increases in occupancy rates, type and size of the hospital. CONCLUSIONS: This paper attempts to offer insights in efficiency and productivity growth for public hospitals in Greece. The results suggest that the average hospital experienced substantial productivity growth between 2009 and 2012 as indicated by variations in MPI. Almost all of the productivity increase was due to technology change which could be explained by the concurrent managerial and financing healthcare reforms. Hospitals operating under decreasing returns to scale could achieve higher efficiency rates by reducing their capacity. However, certain social objectives should also be considered. Emphasis perhaps should be placed in utilizing and advancing managerial and organizational reforms, so that the benefits of technological improvements will have a continuing positive impact in the future.