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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.
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Síndrome de Hiperestimulación Ovárica , Femenino , Humanos , Embarazo , Consenso , Técnica Delphi , Hormona Liberadora de Gonadotropina , Gonadotropina Coriónica , Fertilización In Vitro/métodos , Inducción de la Ovulación/métodos , Medición de Riesgo , Índice de EmbarazoRESUMEN
STUDY QUESTION: Does follicular flushing increase the number of cumulus-oocyte complexes (COCs) retrieved compared to single aspiration? SUMMARY ANSWER: Follicular flushing significantly increases the number of COCs retrieved compared to single aspiration. WHAT IS KNOWN ALREADY: On the basis of published meta-analyses, follicular flushing does not seem to increase the number of oocytes retrieved, the probability of clinical pregnancy, or that of live birth and has been associated with an increase in the duration of oocyte retrieval. It should be noted, however, that all the eligible randomized controlled trials (RCTs) in these meta-analyses have randomized patients into either single aspiration or follicular flushing. This study design might not allow the detection of the true effect of follicular flushing. Despite randomization, this might still be obscured, to an extent, by heterogeneity in patients, stimulation characteristics, and differences in the oocyte retrieval procedure. STUDY DESIGN, SIZE, DURATION: A prospective, single centre, RCT, including 105 patients was performed between July and December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible patients were those undergoing oocyte retrieval for ICSI, aged <43 years, with BMI 18-35 kg/m2. Patients with all types of ovarian response (low-normal-high), as assessed on the day of triggering final oocyte maturation, were included. Random allocation of the ovaries of each patient to either single aspiration or follicular flushing was performed on the day of oocyte retrieval, using a computer-generated randomization list. Patients could enter the study only once. All follicles from ovaries allocated to either follicular flushing or single aspiration, were aspirated by the same 16G double lumen needle, with a constant aspiration pressure of 190 mmHg, resulting in flow rate of 0.42 ml/s. In the ovaries allocated to the follicular flushing group, if a COC was not recovered in the initial aspirate of each follicle, follicular flushing was performed until a COC was retrieved, up to a maximum of five times. The primary outcome measure was the number of COCs retrieved. Secondary outcomes were oocyte recovery rate, oocyte maturation rate, fertilization rate, and rate of good quality embryos on Day 2. Values are expressed as a median (inter-quartile range). MAIN RESULTS AND THE ROLE OF CHANCE: Significantly more COCs were retrieved in the follicular flushing as compared to the single aspiration group in all patients [5 (7) vs 2 (3), P < 0.001, respectively], as well as in patients with high [9 (3) vs 5 (4), P < 0.001, respectively], normal [5 (2) vs 2 (3), P < 0.001, respectively] and low [1 (1) vs 1 (1), P < 0.001, respectively] ovarian response. In patients with low ovarian response, no COCs were retrieved in 5.7% of the ovaries in the flushing group vs 42.8% of the ovaries in the single aspiration group (P < 0.001). The oocyte retrieval rate was significantly higher in the follicular flushing vs the single aspiration group, in all patients [88.9% (25.0) vs 45.5% (37.5), P < 0.001, respectively], as well as in patients with high [81.8% (15.9) vs 45.5% (22.2), P < 0.001, respectively], normal [85.7% (28.6) vs 40.0% (30.0), P < 0.001, respectively], and low [100% (0) vs 50.0% (100), P < 0.001, respectively] ovarian response. No significant difference was observed regarding maturation rate [85.2% (30.8) vs 100% (33.3), P = 0.78], fertilization rate [76.4% (50) vs 83.3% (50) P = 0.42], and the proportion of good quality embryos on Day 2 [83.3% (40) vs 100% (50), P = 0.62]. Similarly, no differences in the above variables were observed in patients with different types of ovarian response. Follicular flushing as compared to single aspiration was associated with a significant increase in the duration of oocyte retrieval in all patients [248 s (332) vs 135 s (164), respectively], as well as in patients with high [464 s (225) vs 237 s (89), P < 0.001, respectively], normal [248 s (108) vs 141 s (95), P < 0.001, respectively], and low [64 s (59) vs 48 s (10), P < 0.001, respectively] ovarian response. LIMITATIONS, REASONS FOR CAUTION: Although the current study design allows for a more accurate evaluation of the true effect of follicular flushing on the number of COCs retrieved, it does not permit the evaluation of its role on the probability of pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT to suggest that follicular flushing increases the number of COCs retrieved compared to single aspiration, independently of ovarian response. This implies that follicular flushing plays an important role in the optimization of oocyte retrieval. These results, however, need to be confirmed in future studies, in which an equal flow rate should be used during oocyte retrieval. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT05473455. TRIAL REGISTRATION DATE: 15 July 2022. DATE OF FIRST PATIENT'S ENROLMENT: 27 July 2022.
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Oocitos , Folículo Ovárico , Femenino , Humanos , Embarazo , Fertilización In Vitro/métodos , Recuperación del Oocito/métodos , Oogénesis , Inducción de la Ovulación/métodos , Índice de Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto , Metaanálisis como AsuntoRESUMEN
STUDY QUESTION: How should recurrent implantation failure (RIF) in patients undergoing ART be defined and managed? SUMMARY ANSWER: This is the first ESHRE good practice recommendations paper providing a definition for RIF together with recommendations on how to investigate causes and contributing factors, and how to improve the chances of a pregnancy. WHAT IS KNOWN ALREADY: RIF is a challenge in the ART clinic, with a multitude of investigations and interventions offered and applied in clinical practice, often without biological rationale or with unequivocal evidence of benefit. STUDY DESIGN SIZE DURATION: This document was developed according to a predefined methodology for ESHRE good practice recommendations. Recommendations are supported by data from the literature, if available, and the results of a previously published survey on clinical practice in RIF and the expertise of the working group. A literature search was performed in PubMed and Cochrane focussing on 'recurrent reproductive failure', 'recurrent implantation failure', and 'repeated implantation failure'. PARTICIPANTS/MATERIALS SETTING METHODS: The ESHRE Working Group on Recurrent Implantation Failure included eight members representing the ESHRE Special Interest Groups for Implantation and Early Pregnancy, Reproductive Endocrinology, and Embryology, with an independent chair and an expert in statistics. The recommendations for clinical practice were formulated based on the expert opinion of the working group, while taking into consideration the published data and results of the survey on uptake in clinical practice. The draft document was then open to ESHRE members for online peer review and was revised in light of the comments received. MAIN RESULTS AND THE ROLE OF CHANCE: The working group recommends considering RIF as a secondary phenomenon of ART, as it can only be observed in patients undergoing IVF, and that the following description of RIF be adopted: 'RIF describes the scenario in which the transfer of embryos considered to be viable has failed to result in a positive pregnancy test sufficiently often in a specific patient to warrant consideration of further investigations and/or interventions'. It was agreed that the recommended threshold for the cumulative predicted chance of implantation to identify RIF for the purposes of initiating further investigation is 60%. When a couple have not had a successful implantation by a certain number of embryo transfers and the cumulative predicted chance of implantation associated with that number is greater than 60%, then they should be counselled on further investigation and/or treatment options. This term defines clinical RIF for which further actions should be considered. Nineteen recommendations were formulated on investigations when RIF is suspected, and 13 on interventions. Recommendations were colour-coded based on whether the investigations/interventions were recommended (green), to be considered (orange), or not recommended, i.e. not to be offered routinely (red). LIMITATIONS REASONS FOR CAUTION: While awaiting the results of further studies and trials, the ESHRE Working Group on Recurrent Implantation Failure recommends identifying RIF based on the chance of successful implantation for the individual patient or couple and to restrict investigations and treatments to those supported by a clear rationale and data indicating their likely benefit. WIDER IMPLICATIONS OF THE FINDINGS: This article provides not only good practice advice but also highlights the investigations and interventions that need further research. This research, when well-conducted, will be key to making progress in the clinical management of RIF. STUDY FUNDING/COMPETING INTERESTS: The meetings and technical support for this project were funded by ESHRE. N.M. declared consulting fees from ArtPRED (The Netherlands) and Freya Biosciences (Denmark); Honoraria for lectures from Gedeon Richter, Merck, Abbott, and IBSA; being co-founder of Verso Biosense. He is Co-Chief Editor of Reproductive Biomedicine Online (RBMO). D.C. declared being an Associate Editor of Human Reproduction Update, and declared honoraria for lectures from Merck, Organon, IBSA, and Fairtility; support for attending meetings from Cooper Surgical, Fujifilm Irvine Scientific. G.G. declared that he or his institution received financial or non-financial support for research, lectures, workshops, advisory roles, or travelling from Ferring, Merck, Gedeon-Richter, PregLem, Abbott, Vifor, Organon, MSD, Coopersurgical, ObsEVA, and ReprodWissen. He is an Editor of the journals Archives of Obstetrics and Gynecology and Reproductive Biomedicine Online, and Editor in Chief of Journal Gynäkologische Endokrinologie. He is involved in guideline developments and quality control on national and international level. G.L. declared he or his institution received honoraria for lectures from Merck, Ferring, Vianex/Organon, and MSD. He is an Associate Editor of Human Reproduction Update, immediate past Coordinator of Special Interest Group for Reproductive Endocrinology of ESHRE and has been involved in Guideline Development Groups of ESHRE and national fertility authorities. D.J.M. declared being an Associate Editor for Human Reproduction Open and statistical Advisor for Reproductive Biomedicine Online. B.T. declared being shareholder of Reprognostics and she or her institution received financial or non-financial support for research, clinical trials, lectures, workshops, advisory roles or travelling from support for attending meetings from Ferring, MSD, Exeltis, Merck Serono, Bayer, Teva, Theramex and Novartis, Astropharm, Ferring. The other authors had nothing to disclose. DISCLAIMER: This Good Practice Recommendations (GPR) 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 be deemed inclusive of all proper methods of care, or be exclusive of other methods of care reasonably directed to obtaining the same results. They do 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.
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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.
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Hormona Folículo Estimulante , Síndrome del Ovario Poliquístico , Humanos , Femenino , Técnica Delphi , Fertilización In Vitro , Inducción de la Ovulación , Medición de Riesgo , Fertilización , Hormona AntimüllerianaRESUMEN
STUDY QUESTION: Can the grade of ascites, haematocrit (Ht), white blood cell (WBC) count and maximal ovarian diameter (MOD) measured on Day 3 be used to construct a decision-making algorithm for performing or cancelling embryo transfer in patients at high risk for severe ovarian hyperstimulation syndrome (OHSS) after an hCG trigger? SUMMARY ANSWER: Using cut-offs of ascites grade>2, Ht>39.2%, WBC>12 900/mm3 and MOD>85 mm on Day 3, a decision-making algorithm was constructed that could predict subsequent development of severe OHSS on Day 5 with an AUC of 0.93, a sensitivity of 88.5% and a specificity of 84.2% in high-risk patients triggered with hCG. WHAT IS KNOWN ALREADY: Despite the increasing popularity of GnRH agonist trigger for final oocyte maturation as a way to prevent OHSS, ≥75% of IVF cycles still involve an hCG trigger. Numerous risk factors and predictive models of OHSS have been proposed, but the measurement of these early predictors is restricted either prior to or during the controlled ovarian stimulation. In high-risk patients triggered with hCG, the identification of luteal-phase predictors assessed post-oocyte retrieval, which reflect the pathophysiological changes leading to severe early OHSS, is currently lacking. STUDY DESIGN SIZE DURATION: A retrospective study of 321 patients at high risk for severe OHSS following hCG triggering of final oocyte maturation. High risk for OHSS was defined as the presence of at least 19 follicles ≥11 mm on the day of triggering of final oocyte maturation. PARTICIPANTS/MATERIALS SETTING METHODS: The study includes IVF/ICSI patients at high risk for developing severe OHSS, who administered hCG to trigger final oocyte maturation. Ascites grade, MOD, Ht and WBC were assessed in the luteal phase starting from the day of oocyte retrieval. Outcome measures were the optimal thresholds of ascites grade, MOD, Ht and WBC measured on Day 3 post-oocyte retrieval to predict subsequent severe OHSS development on Day 5. These criteria were used to construct a decision-making algorithm for embryo transfer, based on the estimated probability of severe OHSS development on Day 5. MAIN RESULTS AND THE ROLE OF CHANCE: The optimal Day 3 cutoffs for severe OHSS prediction on Day 5 were ascites grade>2, Ht>39.2%, WBC>12 900/mm3 and MOD>85 mm. The probability of severe OHSS with no criteria fulfilled on Day 3 is 0% (95% CI: 0-5.5); with one criterion, 0.8% (95% CI: 0.15-4.6); with two criteria, 13.3% (95% CI: 7.4-22.8); with three criteria, 37.2% (95% CI: 24.4-52.1); and with four criteria, 88.9% (95% CI, 67.2-98.1). The predictive model of severe OHSS had an AUC of 0.93 with a sensitivity of 88.5% and a specificity of 84.2%. LIMITATIONS REASONS FOR CAUTION: This is a retrospective study, and therefore, it cannot be excluded that non-apparent sources of bias might be present. In addition, we acknowledge the lack of external validation of our model. We have created a web-based calculator (http://ohsspredict.org), for wider access and usage of our tool. By inserting the values of ascites grade, MOD, Ht and WBC of high-risk patients on Day 3 after oocyte retrieval, the clinician instantly receives the predicted probability of severe OHSS development on Day 5. WIDER IMPLICATIONS OF THE FINDINGS: The present study describes a novel decision-making algorithm for embryo transfer based on ascites, Ht, WBC and MOD measurements on Day 3. The algorithm may be useful for the management of high-risk patients triggered with hCG and for helping the clinician's decision to proceed with, or to cancel, embryo transfer. It must be emphasized that the availability of the present decision-making algorithm should in no way encourage the use of hCG trigger in patients at high risk for OHSS. In these patients, the recommended approach is the use of GnRH antagonist protocols, GnRH agonist trigger and elective embryo cryopreservation. In addition, in patients triggered with hCG, freezing all embryos and luteal-phase GnRH antagonist administration should be considered for the outpatient management of severe early OHSS and prevention of late OHSS. STUDY FUNDING/COMPETING INTERESTS: NHMRC Early Career Fellowship (GNT1147154) to C.A.V. No conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
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PURPOSE: The objective of this systematic review and metaanalysis was to examine if the probability of pregnancy after ovarian stimulation for in vitro fertilization (IVF), using GnRH analogues and gonadotrophins is associated with serum estradiol level (Ε2) on the day of triggering final oocyte maturation with human chorionic gonadotrophin (hCG). METHODS: Twenty-one studies were eligible for this systematic review, including 19,598 IVF cycles, whereas three studies were eligible for metaanalysis, including 641 IVF cycles. The main outcome measure was achievement of ongoing pregnancy/live birth and, if not available, clinical pregnancy or biochemical pregnancy. RESULTS: Pooling of data showed no differences in the probability of clinical pregnancy between patients with high and low Ε2 levels on the day of triggering final oocyte maturation. The pooled effect sizes for the Ε2 thresholds groups constructed, regarding clinical pregnancy were 2000-3000 pg/mL-OR 0.91, 95% CI 0.55 to 1.50, (fair quality/moderate risk of bias, n = 1 study), 3000-4000 pg/mL-OR 0.89, 95% CI 0.46 to 1.70, (fair quality/moderate risk of bias, n = 1 study, good quality/no information on which to base a judgement about risk of bias n = 2 studies), 4000-5000 pg/mL-OR 0.74, 95% CI 0.37 to 1.49 fair quality/moderate risk of bias, n = 1 study), 5000-6000 pg/mL-OR 0.62, 95% CI 0.19 to 1.98, (fair quality/moderate risk of bias, n = 1 study). In addition, no difference was observed in the probability of ongoing pregnancy for the Ε2 threshold group of 3000-4000 pg/mL OR 0.85, 95% CI 0.40 to 1.81(good quality/no information on which to base a judgement about risk of bias, n = 1 study). CONCLUSION: Currently, there is insufficient evidence to support or deny the presence of an association between the probability of pregnancy and serum Ε2 levels on the day of triggering final oocyte maturation with hCG in women undergoing ovarian stimulation for IVF.
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Gonadotropina Coriónica/farmacología , Estradiol/sangre , Técnicas de Maduración In Vitro de los Oocitos/métodos , Inducción de la Ovulación/métodos , Gonadotropina Coriónica/análogos & derivados , Transferencia de Embrión , Femenino , Fertilización In Vitro , Humanos , Nacimiento Vivo , Embarazo , Índice de EmbarazoRESUMEN
STUDY QUESTION: Are oocyte maturation rates different among 0.1, 0.2 and 0.4 mg triptorelin used for triggering final oocyte maturation in patients at high risk for ovarian hyperstimulation syndrome (OHSS) undergoing ICSI? SUMMARY ANSWER: A dose of 0.1 mg triptorelin results in similar oocyte maturation rates compared to higher doses of 0.2 and 0.4 mg in patients at high risk for OHSS undergoing ICSI. WHAT IS KNOWN ALREADY: The GnRH agonist triptorelin is widely used instead of hCG for triggering final oocyte maturation, in order to eliminate the risk of severe OHSS in patients undergoing ovarian stimulation for IVF/ICSI. However, limited data are currently available regarding its optimal dose use for this purpose in patients at high risk for OHSS. STUDY DESIGN, SIZE, DURATION: A retrospective study was performed between November 2015 and July 2017 in 131 infertile patients at high risk for severe OHSS undergoing ovarian stimulation for ICSI. High risk for severe OHSS was defined as the presence of at least 19 follicles ≥11 mm in diameter on the day of triggering final oocyte maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian stimulation was performed with recombinant FSH and GnRH antagonists. Patients received 0.1 (n = 42), 0.2 (n = 46) or 0.4 mg (n = 43) triptorelin for triggering final oocyte maturation. Hormonal evaluation of FSH, LH, estradiol (E2) and progesterone (PRG) was carried out on the day of triggering final oocyte maturation, 8 and 36 hours post triggering and 3, 5, 7, and 10 days after triptorelin administration. During this period, all patients were assessed for symptoms and signs indicative of severe OHSS development. Primary outcome measure was oocyte maturation rate, defined as the number of metaphase II (MII) oocytes divided by the number of cumulus-oocyte-complexes retrieved per patient. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences in patient baseline characteristics were observed among the 0.1 mg, the 0.2 mg and the 0.4 mg groups. Regarding the primary outcome measure, no differences were observed in oocyte maturation rate among the three groups compared [82.6% (17.8%) versus 83.3% (18.8%) versus 85.1% (17.2%), respectively, P = 0.686].In addition, no significant differences were present among the 0.1 mg, 0.2 mg and 0.4 mg groups, regarding the number of mature (MII) oocytes [21 (13) versus 20 (6) versus 20 (11), respectively; P = 0.582], the number of oocytes retrieved [25.5 (13) versus 24.5 (11) versus 23 (12), respectively; P = 0.452], oocyte retrieval rate [81.0% (17.7%) versus 76.5% (23.5%) versus 75.0% (22.5), respectively; P = 0.088], the number of fertilized (two pronuclei) oocytes [12.5 (9) versus 14.5 (7) versus 14.0 (8), respectively; P = 0.985], fertilization rate [71.7% (22%) versus 77.1% (19.1%) versus 76.6% (23.3%), respectively; P = 0.525] and duration of luteal phase [7 (1) versus 8 (2) versus 7 (1) days, respectively; P = 0.632]. Moreover, no significant differences were present among the three triptorelin groups regarding serum levels of LH, FSH, E2 and PRG at any of the time points assessed following triggering of final oocyte maturation. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study, and although there were no differences in the baseline characteristics of the three groups compared, the presence of bias cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: Based on the results of the current study, it appears that triggering final oocyte maturation with a lower (0.1 mg) or a higher dose (0.4 mg) of triptorelin, as compared to the most commonly used dose of 0.2 mg, does not confer any benefit in terms of oocyte maturation rate in patients at high risk for severe OHSS. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. There are no conflicts of interest.
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Técnicas de Maduración In Vitro de los Oocitos/métodos , Oocitos/efectos de los fármacos , Síndrome de Hiperestimulación Ovárica/etiología , Pamoato de Triptorelina/efectos adversos , Pamoato de Triptorelina/farmacología , Adulto , Estradiol/sangre , Femenino , Fertilización In Vitro/métodos , Hormona Folículo Estimulante/sangre , Estudios de Seguimiento , Humanos , Hormona Luteinizante/sangre , Oocitos/crecimiento & desarrollo , Oogénesis/efectos de los fármacos , Inducción de la Ovulación/métodos , Embarazo , Índice de Embarazo , Progesterona/sangre , Estudios Retrospectivos , Riesgo , Pamoato de Triptorelina/administración & dosificación , Adulto JovenRESUMEN
OBJECTIVE: To assess ultrasound and hematological changes during the early luteal phase following triggering of final oocyte maturation with human chorionic gonadotropin (hCG) in women at high risk for developing ovarian hyperstimulation syndrome (OHSS). METHODS: This was a retrospective cohort study of 319 women undergoing in-vitro fertilization who were at high risk for OHSS following administration of hCG for the triggering of final oocyte maturation. Patients were treated with a gonadotropin-releasing hormone agonist or antagonist protocol and were monitored for 5 days post-oocyte retrieval (early luteal phase). Severe OHSS was diagnosed in the presence of at least moderate ascites and two or more of the following: maximum ovarian diameter (MOD) > 100 mm, hematocrit (Ht) > 45%, white blood cell count (WBC) > 15 000/mm3 , hydrothorax, dyspnea and oliguria. Outcome measures included change in Ht, ascites grade, WBC and MOD, as well as the association between these changes during the early luteal phase. RESULTS: Ascites grade, Ht and WBC increased significantly (P ≤ 0.001) during the early luteal phase, both in patients who developed and in those who did not develop severe early OHSS. MOD increased significantly (P = 0.001) only in patients who developed severe early OHSS. On multivariable analysis, both time following oocyte retrieval and whether severe early OHSS developed were significantly associated with ascites grade, Ht, WBC and MOD; furthermore, there was also a significant interaction between time and development of severe early OHSS for all four variables (P ≤ 0.001). CONCLUSIONS: In women at high risk of OHSS, ascites grade, Ht and WBC significantly increased with time over the 5-day observation period, in line with the pathophysiology of the syndrome. Our data support the use of MOD in the diagnosis of severe early OHSS, and provide novel evidence for the role of change in Ht as a patient-specific hemoconcentration marker during development of OHSS. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
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Fertilización In Vitro , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Fase Luteínica/fisiología , Síndrome de Hiperestimulación Ovárica/diagnóstico por imagen , Ovario/efectos de los fármacos , Inducción de la Ovulación/efectos adversos , Ultrasonografía , Adulto , Estradiol/uso terapéutico , Femenino , Fertilización In Vitro/efectos adversos , Fertilización In Vitro/métodos , Humanos , Fase Luteínica/efectos de los fármacos , Masculino , Recuperación del Oocito , Evaluación de Resultado en la Atención de Salud , Síndrome de Hiperestimulación Ovárica/sangre , Síndrome de Hiperestimulación Ovárica/fisiopatología , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To investigate the kinetics of serum vascular endothelial growth factor (VEGF) following gonadotrophin-releasing hormone (GnRH) antagonist administration in the luteal phase in women with established severe early ovarian hyperstimulation syndrome (OHSS). DESIGN: Pilot observational cohort study. SETTING: Private in vitro fertilisation (IVF) Unit. POPULATION: Twelve IVF women diagnosed with established severe early OHSS 5 days post oocyte retrieval (POR). METHODS: Women undergoing IVF diagnosed with severe early OHSS 5 days POR were given 0.25 mg GnRH antagonist for 4 days, from day 5 until and including day 8 POR, combined with elective blastocyst cryopreservation. Serum VEGF was measured from the day of oocyte retrieval until day 11 POR. Ovarian volume, ascites, serum estradiol and progesterone, haematocrit and white blood cells were monitored during the same period. MAIN OUTCOME MEASURES: Kinetics of VEGF following luteal GnRH antagonist administration in women with established severe early OHSS. RESULTS: The concentration of VEGF was highest (390.9 ± 137.4 pg/ml) 5 days POR, coinciding with the day of diagnosis of severe OHSS. There was a significant decline of VEGF on day 7 (302.8 ± 104.9 pg/ml; P = 0.026), day 9 (303.3 ± 148.3 pg/ml; P = 0.007), and day 11 (252.6 ± 182.7 pg/ml; P = 0.010) compared with day 5 POR. This decline was associated with an improvement of ultrasound and laboratory parameters, indicating regression of severe OHSS. All women were managed at an outpatient level. CONCLUSIONS: GnRH antagonist administration in the luteal phase is associated with a significant decline of VEGF and with regression of established severe early OHSS.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Síndrome de Hiperestimulación Ovárica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto , Estudios de Cohortes , Femenino , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Fase Luteínica , Proyectos Piloto , Índice de Severidad de la EnfermedadRESUMEN
STUDY QUESTION: Do high-risk patients who develop severe early ovarian hyperstimulation syndrome (OHSS) and receive low-dose GnRH antagonist in the luteal phase have lower live birth rates compared with high-risk patients who do not develop severe early OHSS and do not receive GnRH antagonist in the luteal phase? SUMMARY ANSWER: Low-dose luteal GnRH antagonist administration in women with severe early OHSS is associated with similar live birth rates to that of high-risk patients who do not develop severe early OHSS and do not receive GnRH antagonist in the luteal phase. WHAT IS KNOWN ALREADY: It has been reported that luteal GnRH antagonist administration in patients with established severe early OHSS appears to prevent patient hospitalization and results in quick regression of the syndrome on an outpatient basis. However, the effect of such treatment on pregnancy outcome has been investigated in only a small number of animal studies. STUDY DESIGN, SIZE, DURATION: This is a prospective cohort study of 192 IVF patients who were at high risk for OHSS and who did not wish to cancel embryo transfer and have all embryos cryopreserved. The study was conducted between January 2009 and December 2011 at Eugonia Assisted Reproduction Unit. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were <40 years of age, with polycystic ovaries, at high risk for OHSS (defined by the presence of at least 20 follicles ≥11 mm on the day of triggering of final oocyte maturation) and not willing to cancel embryo transfer and cryopreserve all embryos, if severe early OHSS was diagnosed by Day 5 of embryo culture. Patients who were diagnosed with severe early OHSS on Day 5 post-oocyte retrieval were administered 0.25 mg of ganirelix for 3 days, from Day 5 until and including Day 7 (OHSS + antag group, n = 22). High-risk patients who did not develop the severe early OHSS did not receive GnRH antagonist in the luteal phase (control group, n = 172). All patients underwent embryo transfer on Day 5. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth rates (40.9 versus 43.6%), ongoing pregnancy rates (45.5 versus 48.8%), clinical pregnancy rates (50 versus 65.1%), positive hCG (72.7 versus 75%), duration of gestation (36.86 ± 0.90 weeks versus 36.88 ± 2.38 weeks) and neonatal weight (2392.73 ± 427.04 versus 2646.56 ± 655.74 g) were all similar in the OHSS + antag and control groups, respectively. The incidence of major congenital malformations was 2.9% (3/103) in children born in the control group compared with no cases (0/14) in children born following luteal GnRH antagonist administration. No stillbirths or intrauterine deaths, and no cases of pregnancy-induced late OHSS were recorded in either group. None of the 22 patients with severe early OHSS required hospitalization following luteal antagonist administration. Ovarian volume, ascites, hematocrit, white blood cell count, serum estradiol and progesterone decreased significantly (P < 0.001) by the end of the monitoring period (Day 11 post-oocyte retrieval), indicating rapid resolution of the severe OHSS. LIMITATIONS, REASONS FOR CAUTION: This is a prospective cohort investigation with a very limited number of patients receiving the intervention and a larger number of control patients. Our findings suggest that low-dose luteal GnRH antagonist administration during the peri-implantation period may be safe, although larger studies with follow-up of the children born are required. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests for the first time that low-dose luteal GnRH antagonist administration in women with severe early OHSS is associated with a favourable IVF outcome, comparable to control high-risk patients without severe OHSS and not receiving the intervention. Regarding the wider implications on the concept of an OHSS-free clinic, administration of GnRH antagonist in the luteal phase may present a tertiary management level in patients with established severe OHSS, along with the use of GnRH antagonist protocols for primary prevention and the replacement of hCG with GnRH agonist for triggering final oocyte maturation for secondary prevention. However, at present, fresh embryo transfer combined with antagonist administration should only be used with caution by experienced practitioners, after carefully deciding which patients can have a fresh transfer or embryo cryopreservation, until the current data are confirmed by larger trials.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Síndrome de Hiperestimulación Ovárica/tratamiento farmacológico , Resultado del Embarazo , Adulto , Estudios de Cohortes , Implantación del Embrión , Estradiol/administración & dosificación , Estradiol/uso terapéutico , Femenino , Fertilización In Vitro/métodos , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Fase Luteínica , Síndrome de Hiperestimulación Ovárica/complicaciones , Inducción de la Ovulación/métodos , EmbarazoRESUMEN
Ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovarian stimulation protocols. Currently, no curative therapy exists and the main preventive option is cycle cancellation. Gonadotrophin-releasing hormone (GnRH) antagonist administration in the luteal phase was recently proposed as a new approach for the management of patients with established severe OHSS. Three polycystic ovarian syndrome patients undergoing IVF treatment developed severe OHSS, diagnosed 6 days after oocyte retrieval. On day 6, the patients underwent blastocyst transfer and received GnRH antagonist for 4 days, combined with luteal phase support using exogenous oestradiol and progesterone. Two patients had successful pregnancies that resulted in births of healthy infants, while one patient had a biochemical pregnancy. In all patients, established severe OHSS regressed to a moderate form of the syndrome, no pregnancy-induced life-threatening OHSS was observed, while a short monitoring period was required at an outpatient level, avoiding the need for patient hospitalization. This is the first report in the literature on GnRH antagonist administration in the luteal phase, combined with embryo transfer and exogenous oestradiol and progesterone supplementation. This novel treatment was effective in the regression of established severe OHSS, and resulted in the birth of healthy infants.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Infertilidad Femenina/tratamiento farmacológico , Fase Luteínica/efectos de los fármacos , Síndrome de Hiperestimulación Ovárica/tratamiento farmacológico , Adulto , Transferencia de Embrión/métodos , Femenino , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Recién Nacido , Recuperación del Oocito , Síndrome del Ovario Poliquístico/complicaciones , Embarazo , Resultado del EmbarazoRESUMEN
Despite the fact that many methods have been proposed for the management of severe ovarian hyperstimulation syndrome (OHSS), its prevention is mainly achieved by withholding human chorionic gonadotrophin (HCG) administration and cycle cancellation. Currently no curative therapy is available. Three women diagnosed with polycystic ovarian syndrome underwent ovarian stimulation for IVF using a long gonadotrophin-releasing hormone (GnRH) agonist protocol. Six days after oocyte retrieval, severe early OHSS was diagnosed by analysis of haematocrit, white blood cell (WBC) count, serum urea, and ultrasonographic assessment of ovarian size and ascitic fluid. On the same day, antagonist administration was administrated and continued daily for 1 week, while resulting blastocysts were cryopreserved. Progression of severe early OHSS was inhibited in all three patients. A marked decrease of haematocrit, WBC, ascitic fluid, oestradiol, progesterone and ovarian volume was observed, during 1 week of follow-up suggesting a luteolytic effect of GnRH antagonist. None of the patients required hospitalization. In conclusion, GnRH antagonist administration combined with blastocyst cryopreservation 6 days post retrieval might represent a new approach for the effective management of patients with established severe OHSS. The flexibility of the approach allows the elongation of the monitoring period up to 8 days following HCG administration.
Asunto(s)
Blastocisto , Gonadotropina Coriónica/administración & dosificación , Criopreservación/métodos , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Antagonistas de Hormonas/uso terapéutico , Síndrome de Hiperestimulación Ovárica/terapia , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Adulto , Gonadotropina Coriónica/efectos adversos , Gonadotropina Coriónica/agonistas , Terapia Combinada , Estradiol/sangre , Estudios de Factibilidad , Femenino , Hematócrito , Humanos , Monitoreo Fisiológico , Recuperación del Oocito/métodos , Síndrome de Hiperestimulación Ovárica/sangre , Síndrome de Hiperestimulación Ovárica/etiología , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/complicaciones , Urea/sangreRESUMEN
Several approaches have been proposed for the management of OHSS that reduce, but do not completely eliminate the incidence of human chorionic gonadotrophin (HCG)-induced early severe OHSS. Three women diagnosed with polycystic ovarian syndrome underwent ovarian stimulation for IVF using a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Three days after oocyte retrieval, severe early OHSS was diagnosed by analysis of haematocrit (Ht), white blood cell (WBC) count, serum urea, and ultrasonographic assessment of ovarian size and ascitic fluid. On the same day, antagonist administration was re-initiated and continued daily for a week, while all embryos were cryopreserved. No progression of severe early OHSS was observed in any of the patients. A marked decrease of Ht, WBC count, ovarian volume and ascitic fluid was observed during 1 week of follow-up, and none of the patients required hospitalization. GnRH antagonist re-initiation might represent a new strategy for flexible management of patients with established severe early OHSS. Based on the flexibility of the approach, if severe OHSS does not occur, patients may proceed to embryo transfer, while if severe early OHSS ensues, antagonist administration combined with embryo cryopreservation appear to be associated with prevention of life-threatening OHSS, facilitation of regression of severe OHSS to a moderate form and avoidance of patient hospitalization.