Association between body mass index and oocyte maturation in patients triggered with GnRH agonist who are at high risk for severe ovarian hyperstimulation syndrome: an observational cohort study.

RESEARCH QUESTION: Is body-mass index (BMI) associated with oocyte maturation in women at high risk for developing severe ovarian hyperstimulation syndrome (OHSS) who are triggered with gonadotrophin releasing hormone (GnRH) agonist? DESIGN: Prospective observational cohort study. A total of 113 patients at high risk for severe OHSS (presence of at least 19 follicles ≥11 mm) pre-treated with gonadotrophin releasing hormone (GnRH) antagonists and recombinant FSH were administered 0.2 mg triptorelin to trigger final oocyte maturation. Patients were classified in two groups depending on their BMI: ΒΜΙ less than 25 kg/m2 (n = 72) and ΒΜΙ 25 kg/m2 or over (n = 41). Baseline, ovarian stimulation and embryological characteristics, as well as luteal-phase hormone profiles, were compared in patients classified into the two BMI groups. The main outcome measure was the number of mature oocytes. RESULTS: A significantly higher number of mature (metaphase II) oocytes (19 [18-21] versus 16 [13-20], P = 0.029) was present in women with BMI less than 25 kg/m2 compared with those with BMI 25 kg/m2 or greater. The number of retrieved oocytes, the number of fertilized oocytes, oocyte retrieval, maturation and fertilization rates were similar in the two groups. A significantly higher dose of recombinant FSH was required for patients with BMI 25 kg/m2 or greater compared with patients with BMI less than 25 kg/m2 (1875 [1650-2150] IU versus 1650 [1600-1750] IU, P = 0.003) and the two groups displayed different luteal phase hormonal profiles. CONCLUSIONS: Among women at high risk for developing severe OHSS who are triggered with a standard dose (0.2 mg) of the GnRH agonist triptorelin, women with BMI 25 kg/m2 or greater had significantly fewer mature oocytes, required a higher total dose of recombinant FSH compared with women with BMI less than 25 kg/m2.

Basal serum progesterone and history of elevated progesterone on the day of hCG administration are significant predictors of late follicular progesterone elevation in GnRH antagonist IVF cycles.

STUDY QUESTION: Are there any baseline predictors of progesterone elevation (PE) on the day of human chorionic gonadotrophin (hCG) which are not associated with the intensity of ovarian stimulation in women undergoing in vitro fertilization (IVF) using follicle stimulating hormone (FSH) and gonadotrophin-releasing hormone (GnRH) antagonists? SUMMARY ANSWER: Basal (Day 2 of the menstrual cycle) serum progesterone concentration and history of PE are baseline variables that can predict the occurrence of PE on the day of hCG independently of the intensity of ovarian stimulation. WHAT IS KNOWN ALREADY: PE on the day of hCG is associated with the magnitude of the ovarian response to stimulation. For this reason, it has been hypothesized that milder ovarian stimulation might reduce the probability of PE. However, given the fact that the number of oocytes retrieved is associated with the probability of live birth, such a strategy should be considered only in patients that are at high risk of PE on the day of hCG. STUDY DESIGN, SIZE, DURATION: This is a retrospective analysis of a cohort of fresh IVF/ICSI cycles (n = 1702) performed in a single IVF centre during the period 2001-2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients in whom ovarian stimulation was performed with FSH and GnRH antagonists and with basal FSH <14.0 mIU/ml, progesterone (P) ≤1.6 ng/ml and estradiol (E2) ≤80 pg/ml on the same day (prior to the initiation of stimulation) were considered eligible. PE was defined as serum progesterone concentration >1.5 ng/ml. Pre-stimulation characteristics of patients and basal hormonal profile were assessed for their ability to predict the occurrence of PE after ovarian stimulation through generalized estimating equation univariable and multivariable regression analyses, controlling for the effect of ovarian stimulation. Furthermore, a secondary analysis in a subset of patients with multiple IVF cycles explored whether the occurrence of PE in one of the previous cycles included in this study is associated with a significantly higher occurrence of PE elevation in subsequent cycles. MAIN RESULTS AND THE ROLE OF CHANCE: Univariable regression analyses showed that female age (OR: 0.97; 95% CI: 0.94-0.99), basal FSH (OR: 0.85; 95% CI: 0.79-0.92) and basal P (OR: 4.20; 95% CI: 2.47-7.12) were baseline variables that could significantly predict PE on the day of hCG. When these variables were entered in the same model as covariates, only basal FSH (OR: 0.86; 95% CI: 0.80-0.94) and basal P (OR: 3.83; 95% CI: 2.24-6.56) could still predict the occurrence of PE. Basal P (OR: 6.30; 95% CI: 3.35-11.82) was the only variable that could significantly predict the occurrence of PE on the day of hCG after adjusting for the intensity of ovarian stimulation. The secondary analysis revealed that history of PE on the day of hCG in a previous cycle was also strongly associated with an increased risk of PE in a subsequent cycle. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective analysis and although the effect of the most important confounders was controlled for in the multivariable analysis, the presence of residual bias cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study might help clinicians identify patients at high risk for late follicular PE and alter the management of their cycle. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.

Live birth rates after modified natural cycle compared with high-dose FSH stimulation using GnRH antagonists in poor responders.

STUDY QUESTION: Do live birth rates differ between modified natural cycles (MNCs) and cycles using high-dose follicle stimulating hormone (HDFSH) with gonadotrophin-releasing hormone (GnRH) antagonist in poor responder patients? SUMMARY ANSWER: Live birth rates are significantly higher in MNC compared with HDFSH GnRH antagonist cycles in poor responder patients. WHAT IS KNOWN ALREADY: Previous data on the efficiency of MNC in poor responders are very limited and suggest that MNC in vitro fertilization (IVF) does not offer a realistic solution for parenthood in these patients, since live birth rates are disappointingly low. To date, no studies exist comparing MNC with HDFSH stimulation protocols in poor responders. STUDY DESIGN, SIZE, DURATION: The present retrospective study included 161 MNCs (106 women in the MNC group) and 164 HDFSH antagonist cycles (136 women in the HDFSH group) performed between January 2008 and December 2013 at Eugonia Assisted Reproduction Unit. The patients included in the study had to fulfill the Bologna criteria for the definition of poor ovarian response. PARTICIPANTS/MATERIALS, SETTING, METHODS: Irrespective of their age, poor responder patients should have a diminished ovarian reserve as shown by low antral follicle count (≤5) and increased basal FSH (>12 IU/l), and one or more previous failed IVF cycles in which ≤3 oocytes were retrieved using a high gonadotrophin dose. Analysis was performed by adjusting for the non-independence of the data. MAIN RESULTS AND THE ROLE OF CHANCE: The probability of live birth was significantly higher in the MNC when compared with the HDFSH group (OR: 4.01, 95% CI: 1.14-14.09), after adjusting for basal FSH, female age and cause of infertility, variables which were shown to be associated with the probability of live birth in univariable analysis. MNCs were characterized by significantly lower total gonadotrophin dose (490.0 ± 35.2 IU versus 2826.1 ± 93.4 IU, P < 0.001), lower estradiol concentrations (237.5 ± 12.3 pg/ml versus 487.3 ± 29.8 pg/ml, P < 0.001), fewer follicles present on the day of hCG (1.9 ± 0.1 versus 3.2 ± 0.2, P < 0.001), fewer oocytes retrieved (1.1 ± 0.01 versus 2.4 ± 0.1, P < 0.001), fewer oocytes fertilized (0.7 ± 0.1 versus 1.4 ± 0.1, P < 0.001), fewer embryos transferred (0.7 ± 0.1 versus 1.4 ± 0.1, P < 0.001), fewer good-quality embryos available (0.5 ± 0.1 versus 0.8 ± 0.1, P < 0.001) and fewer good-quality embryos transferred (0.5 ± 0.05 versus 0.8 ± 0.1, P < 0.001) compared with the HDFSH group. However, the proportion of cycles with at least one good-quality embryo transferred per started cycle was similar between the two groups compared (62.5, 95% CI: 52.7-72.3 versus 62.7, 95% CI: 53.0-72.5, respectively). LIMITATIONS, REASONS FOR CAUTION: This is a retrospective comparison between MNC and HDFSH GnRH antagonist protocols in a large group of poor responder patients according to the Bologna criteria. Although the two groups compared were not imbalanced for all basic characteristics and multivariate analysis were performed to adjust for all known confounders, it cannot be excluded that non-apparent sources of bias might still be present. Future randomized controlled trials are necessary to verify the present findings. WIDER IMPLICATIONS OF THE FINDINGS: Both MNC and HDFSH antagonist protocols offer very low chances of live birth in poor responder patients who fulfill the Bologna criteria. However, MNC-IVF is a more patient-friendly approach, with a higher probability of live birth compared with the HDFSH antagonist protocol. In this respect, the current data might be of help in counseling such patients, who do not wish to undergo oocyte donation, prior to abandoning treatment altogether and/or proceeding to adoption. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained. C.A.V. reports personal fees and non-financial support from Merck, Sharp and Dome, personal fees and non-financial support from Merck Serono, personal fees and non-financial support from IPSEN Hellas S.A. outside the submitted work. B.C.T. reports grants from Merck Serono, grants from Merck Sharp & Dohme, personal fees from IBSA, personal fees from Merck Sharp & Dohme and personal fees from Ovascience outside the submitted work .

Estimating the net effect of progesterone elevation on the day of hCG on live birth rates after IVF: a cohort analysis of 3296 IVF cycles.

STUDY QUESTION: What is the proper way of assessing the effect of progesterone elevation (PE) on the day of hCG on live birth in women undergoing fresh embryo transfer after in vitro fertilization (IVF) using GnRH analogues and gonadotrophins? SUMMARY ANSWER: This study indicates that a multivariable approach, where the effect of the most important confounders is controlled for, can lead to markedly different results regarding the association between PE on the day of hCG and live birth rates after IVF when compared with the bivariate analysis that has been typically used in the relevant literature up to date. WHAT IS KNOWN ALREADY: PE on the day of hCG is associated with decreased pregnancy rates in fresh IVF cycles. Evidence for this comes from observational studies that mostly failed to control for potential confounders. STUDY DESIGN, SIZE, DURATION: This is a retrospective analysis of a cohort of fresh IVF/intracytoplasmic sperm injection cycles (n = 3296) performed in a single IVF centre during the period 2001-2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients in whom ovarian stimulation was performed with gonadotrophins and GnRH analogues. Natural cycles and cycles where stimulation involved the administration of clomiphene were excluded. In order to reflect routine clinical practice, no other exclusion criteria were imposed on this dataset. The primary outcome measure for this study was live birth defined as the delivery of a live infant after 24 weeks of gestation. We compared the association between PE on the day of hCG (defined as P > 1.5 ng/ml) and live birth rates calculated by simple bivariate analyses with that derived from multivariable logistic regression. The multivariable analysis controlled for female age, number of oocytes retrieved, number of embryos transferred, developmental stage of embryos at transfer (cleavage versus blastocyst), whether at least one good-quality embryo was transferred, the woman's body mass index, the total dose of FSH administered during ovarian stimulation and the type of GnRH analogues used (agonists versus antagonists) during ovarian stimulation. In addition, an interaction analysis was performed in order to assess whether the ovarian response (<6, 6-18, >18 oocytes) has a moderating effect on the association of PE on the day of hCG with live birth rates after IVF. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth rates were not significantly different between cycles with and those without PE when a bivariate analysis was performed [odds ratio (OR): 0.78, 95% confidence interval (CI): 0.56-1.09]. However, when a multivariable analysis was performed, controlling for the effect of the aforementioned confounders, live birth rates (OR: 0.68, 95% CI: 0.48-0.97) were significantly decreased in the group with PE on the day of hCG. The number of oocytes retrieved was the most potent confounder, causing a 29.4% reduction in the OR for live birth between the two groups compared. Furthermore, a moderating effect of ovarian response on the association between PE and live birth rates was not supported in the present analysis since no interaction was detected between PE and the type of ovarian response (<6, 6-18, >18 oocytes). LIMITATIONS, REASONS FOR CAUTION: This is a retrospective analysis of data collected during a 12-year period, and although the effect of the most important confounders was controlled for in the multivariable analysis, the presence of residual bias cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: This analysis highlights the need for a multivariable approach when researchers or clinicians aim to evaluate the impact of PE on pregnancy rates in their own clinical setting. Failure to do so might explain why many past studies have failed to identify the detrimental effect of PE in fresh IVF cycles. STUDY FUNDING/COMPETING INTERESTS: None.

Non-invasive metabolomic analysis using a commercial NIR instrument for embryo selection.

CONTEXT: Metabolomics was introduced in human in vitro fertilization (IVF) for noninvasive identification of viable embryos with the highest developmental competence. AIMS: To determine whether embryo selection using a commercial version of metabolomic analysis leads to increased implantation rates (IRs) with fetal cardiac activity (FCA) compared with morphology evaluation alone. SETTING AND DESIGN: Randomized controlled trial from April to December 2010 at a private IVF unit. The study was terminated prematurely due to the market withdrawal of the instrument. MATERIALS AND METHODS: IVF patients ≥18 and ≤43 years with ≥4 × 2PN were randomly allocated to metabolomic analysis combined with embryo morphology (ViaMetrics-E; metabolomics + morphology group) or embryo morphology alone (morphology group). Cycles with frozen embryos, oocyte donations, or testicular biopsy were excluded. STATISTICAL ANALYSIS: Categorical and continuous data were analyzed for statistical significance using 2-tailed Fisher's exact test and t-test, respectively. Statistical significance was accepted when P > 0.05. RESULTS: A total of 125 patients were included in the study; 39 patients were allocated to metabolomics + morphology group and 86 patients to morphology group. Patients were stratified according to the day of embryo transfer (Days 2, 3, or 5). IRs with FCA were similar for Days 2 and 3 transfers in both groups. For Day 5 transfers, IRs with FCA were significantly higher in the metabolomics + morphology group (46.8% vs. 28.9%; P = 0.041; 95% confidence intervalp [CI]: 1.09-34.18). Pregnancy and live births rates were similar for Days 2, 3, and 5 in both groups. The study was terminated early following the voluntary market withdrawal of ViaMetrics-E in December 2010. CONCLUSIONS: Metabolomic analysis using the commercial near-infrared (NIR) instrument does not appear to have a beneficial effect on pregnancy and live births, with improvement in IR with FCA for Day 5 transfers. However, no solid conclusions can be reached due to the lack of adequate study power.ClinicalTrials.gov Identifier: NCT01490515.

Outpatient management of severe early OHSS by administration of GnRH antagonist in the luteal phase: an observational cohort study.

BACKGROUND: Management of established severe OHSS requires prolonged hospitalization, occasionally in intensive care units, accompanied by multiple ascites punctures, correction of intravascular fluid volume and electrolyte imbalance. The aim of the present study was to evaluate whether it is feasible to manage women with severe OHSS as outpatients by treating them with GnRH antagonists in the luteal phase. METHODS: This is a single-centre, prospective, observational, cohort study. Forty patients diagnosed with severe OHSS, five days post oocyte retrieval, were managed as outpatients after administration of GnRH antagonist (0.25 mg) daily from days 5 to 8 post oocyte retrieval, combined with cryopreservation of all embryos. The primary outcome measure was the proportion of patients with severe OHSS, in whom outpatient management was not feasible. RESULTS: 11.3% (95% CI 8.3%-15.0%) of patients (40/353) developed severe early OHSS. None of the 40 patients required hospitalization following luteal antagonist administration and embryo cryopreservation. Ovarian volume, ascites, hematocrit, WBC, serum oestradiol and progesterone decreased significantly (P < 0.001) by the end of the monitoring period, indicating rapid resolution of severe OHSS. CONCLUSIONS: The current study suggests, for the first time, that successful outpatient management of severe OHSS with antagonist treatment in the luteal phase is feasible and is associated with rapid regression of the syndrome, challenging the dogma of inpatient management. The proposed management is a flexible approach that minimizes unnecessary embryo transfer cancellations in the majority (88.7%) of high risk for OHSS patients.

Flexible GnRH antagonist protocol versus GnRH agonist long protocol in patients with polycystic ovary syndrome treated for IVF: a prospective randomised controlled trial (RCT).

BACKGROUND: Women with polycystic ovary syndrome (PCOS) are at risk of developing ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation. Use of GnRH antagonist in the general subfertile population is associated with lower incidence of OHSS than agonists and similar probability of live birth but it is unclear if this is true for patients with PCOS. Our aim was to compare the flexible GnRH antagonist and GnRH agonist long protocols in patients with PCOS undergoing IVF (primary end-point: ongoing pregnancy rate per patient randomized). METHODS: In this randomised controlled trial (RCT), 220 patients with PCOS were randomly allocated in two groups: long GnRH agonist down-regulation protocol (n = 110) and flexible GnRH antagonist protocol (n = 110). RESULTS: No differences were observed in ongoing pregnancy rates [50.9 versus 47.3%, difference 3.6%, 95% confidence interval (CI): -9.6 to +16.8%] in the agonist and antagonist protocols, respectively. Incidence of OHSS Grade II was lower in the antagonist compared with agonist group (40.0 versus 60.0%, difference -20.0%, 95% CI: -7.1 to -32.9%, P < 0.01). Duration of stimulation (10 versus 12 days, difference 2 days, 95% CI: +1 to +2, P < 0.001) and total gonadotrophin required (1575 versus 1850 IU, difference -275 IU, 95% CI: -25 to -400, P < 0.05) were also lower in the antagonist compared with agonist protocol. CONCLUSIONS: The current RCT suggests that the flexible GnRH antagonist protocol is associated with a similar ongoing pregnancy rate, lower incidence of OHSS grade II, lower gonadotrophin requirement and shorter duration of stimulation, compared with GnRH agonist. The GnRH antagonist might be the treatment choice for patients with PCOS undergoing IVF. The study was registered at clinicaltrials.gov. ID: NCT00417144.

Flexible GnRH antagonist versus flare-up GnRH agonist protocol in poor responders treated by IVF: a randomized controlled trial.

BACKGROUND: Although initial studies in poor responders using GnRH antagonists have reported encouraging results, they are limited in number, only a few of them are prospective, while the majority is characterized by limited power to detect a clinically important difference. METHODS: A randomized controlled trial was performed in patients with one or more previous failed IVF cycles in which five or less oocytes were retrieved, using > or =300 IU of gonadotrophins/day. Patients were randomized by computer-generated list and treated by either the flare-up GnRH agonist protocol (n = 90) or a flexible GnRH antagonist protocol (n = 180). RESULTS: Ongoing pregnancy rate, the primary outcome measure, was significantly higher in the antagonist group compared with the agonist group (12.2 versus 4.4%, P< 0.048; difference 7.8%, 95% CI: 0.2 to 14.0). Estradiol levels on the day of hCG administration were lower in the antagonist protocol [median (interquartile range): 572 (325-839) versus 727 (439-1029) pg/ml, P = 0.018]. Clinical and biochemical pregnancy rates, fertilization and implantation rates, as well as the number of oocytes retrieved, the number of mature oocytes present, the stimulation period and the gonadotrophin dosage were not significantly different between the two groups compared. CONCLUSIONS: The flexible GnRH antagonist protocol is associated with significantly higher ongoing pregnancy rates compared with the flare-up GnRH agonist protocol in poor responders.