Flare Protocol Research Articles

Protocol change improves live birth and recurrent cycle cancellation rates after a previous IVF cycle cancellation: an analysis of 13000 autologous cycles reported to SART CORS.

After an IVF cycle cancellation, does changing the stimulation protocol affect the odds of live birth and recurrent cancellation in the subsequent cycle? After IVF cycle cancellation, compared to those who repeated the same stimulation protocol, those who changed their protocol had higher odds of live birth and lower odds of recurrent cycle cancellation. There is limited data addressing the effect of changing the stimulation protocol after an IVF cycle is cancelled during initial stimulation. The odds of live birth outcomes are not known so far in studies addressing the effect of changing the protocol. Retrospective Cohort Study using the 2014-2017 Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) database. The data included 13135 patients with a first autologous IVF cycle that resulted in a cycle cancellation and was followed by a second autologous cycle within the study period. We excluded fertility preservation cycles, supernumerary cycle attempts after the second IVF cycle attempt, and cycles with more than one stimulation protocol documented per cycle start. Patients who received the same protocol for both cycles (n = 6434) were compared to those who changed their protocol in the second cycle (n = 6701). Multivariable logistic regression analyses were performed to estimate the adjusted odds of live birth and recurrent cancellation. Changing the protocol in the second cycle resulted 14% lower odds of recurrent cycle cancellation (P = 0.01) and 17% higher odds of live birth after fresh transfers (P = 0.04). When stratifying the data by specific combinations of protocol change (agonist flare, agonist suppression, antagonist), there was an increase in live birth when switching from antagonist to agonist suppression (odds ratio (OR) = 1.36, P = 0.03) and from agonist suppression to antagonist (OR = 1.73, P = 0.01) compared to those who repeated their same stimulation protocol. Specifically in poor responders, outcomes were worse when using the agonist flare protocol and significantly improved with the agonist suppression protocol. Comparison of response to stimulation between first and second cycles cannot be made in this study because the index IVF cycle was cancelled during ovarian stimulation, and thus there is no reportable outcome data for that cycle. Additionally, SART only tracks the three stimulation protocols addressed in this study and does not have data on more contemporary protocols that are used in poor responders thus limiting the generalizability of our findings. Using the SART CORS database, which includes >90% of all reported IVF cycles in the USA, provides generalizability to the demographically diverse IVF populations found here. In agreement with prior studies assessing change in IVF protocols, the agonist flare protocol seems to result in worse IVF outcomes, and based on our results, we believe that there is no role for the agonist flare protocol in patients with a prior poor response to stimulation. None declared. N/A.

#182 : Pharmacokinetics of Ovarian Stimulation for Projected Poor Responder Patients in IVF. A Randomised Trial Comparing a Corifollitropin Alfa Agonist Flare Protocol with a Corifollitropin Alfa Antagonist Protocol

Background & Aims: Approximately 10% of patients have a sub-optimal response to controlled ovarian stimulation. Many different protocols for superovulation have been developed for this group of patients but the optimal approach for “poor responder” patients is yet to be determined. Use of corifollitropin alfa (Elonva) in a flare (EF) protocol is a novel approach to ovarian stimulation for predicted poor responder patients. We hypothesised that the unique pharmacokinetic and pharmacodynamic profiles of corifollitropin alfa would maximise FSH exposure and follicular recruitment in the critical early follicular phase due to the initial suprathreshold release of bioactive FSH in the initial 2-3 days of exposure to Elonva, in combination with the ‘flare’ of endogenous FSH release. Method: Twenty-one women aged 31-41 were identified as predicted poor responder patients according to the Poseidon criteria. Each participant was randomised to treatment with Elonva/Synarel flare or Elonva/Orgalutran antagonist. Serum FSH and E2 were measured daily for five days following injection of Elonva. The study was approved by the Southeastern Sydney HREC. Results: Serum FSH concentrations were significantly higher at each time point in the EF group when compared with the antagonist group (p=0.022). Peak FSH two days after injection of Elonva, was also significantly higher 27 vs 11 IU/L. Serum E2 concentrations were also significantly higher in the EF group at each time point (p=0.039). On day seven of stimulation, E2 concentrations were 3000 vs 1850 pmol/L. Conclusion: The corifollitropin alfa agonist flare protocol produces significantly higher FSH and E2 concentrations than a standard corifollitropin alfa antagonist protocol for projected poor responder patients, with reduced patient burden for a group who may need multiple ovarian stimulation cycles to achieve a pregnancy. A larger RCT is required to study embryology and pregnancy outcomes, costs and patient burden.

Editorial Expression of Concern: A comparative study of luteal estradiol pre-treatment in GnRH antagonist protocols and in micro dose flare protocols for poor-responding patients.

Editorial Expression of Concern: A comparative study of luteal estradiol pre-treatment in GnRH antagonist protocols and in micro dose flare protocols for poor-responding patients.

P-646 The effect of profound LH suppression in GnRH antagonist cycles on IVF/ICSI outcomes-A retrospective study of 400 cycles

Abstract Study question Does low pretrigger LH in GnRH antagonist cycles affect the blastulation rates and cumulative live birth rates? Summary answer Low pretrigger LH in GnRH antagonist cycles does not affect the blastulation rates and cumulative live birth rates in frozen embryo transfer cycles. What is known already • There is conflicting evidence that in GnRH antagonist cycles stimulated with recombinant FSH, low serum LH may effect negatively the pregnancy outcomes in fresh embryo transfer.(Benmachiche et al 2019). • Whether the observed effect of low LH is on the embryo or on the endometrial receptivity is not clear. Study design, size, duration • Retrospective observational single centre study with a study population of 400 undergoing IVF/ICSI in between December 2018- December 2021. • Controlled ovarian stimulation in GnRH Antagonist protocol in unselected population > 21yrs old undergoing IVF/ICSI. • Exclusion Criteria- • Long protocol • Flare protocol • Oocyte cryopreservation cycle • Donor oocyte cycle Participants/materials, setting, methods • Controlled ovarian stimulation is done according to the hospital’s standard operations of practice in flexible antagonist cycle with human menopausal gonadotropins and recombinant/urinary follicle stimulating hormone. • When 3 or more follicles >/=17mm, triggered with GnRH Agonist or dual trigger. • Oocyte pick up scheduled at 35-36hrs following trigger. • Serum LH measured at baseline and at trigger. • Clinical and embryological outcomes are assessed in between low serum LH i.e., <1.5MIU/ML and normal serum LH >/= 1.5 MIU/ML. Main results and the role of chance Demographic variables were comparable between both the arms, except that baseline LH is low in subjects with low pretrigger LH. Mean dose of gonadotropins although not statistically significant, is slightly higher in the low pretrigger LH group. Mean duration of stimulation is higher in low pretrigger LH group and is statistically significant. Mean number of oocytes retrieved, mature oocytes, fertilisation rate, number of blastocysts, day5 and day6 blastocyts, good quality blastocysts and cumulative live birth rates are similar between low pretrigger LH and normal pretrigger LH group. Outcomes between low pretrigger LH and normal pretrigger LH- Mean number of blastocysts- 5.02 +/-3.84 vs 4.72 +/-3.82 (p = 0.44) Mean number of day5 blastocysts- 4 (0-14) vs 3.5(0-20) (p = 0.86) Mean number of day6 blastocysts- 1 (0-8) vs 1 (0-9) (p = 0.4) Mean number of good quality blastocysts- 2(0-19) vs 2 (0-17) (p = 0.68 ) Number of cycles with no blastocysts- 11.1 vs 16.1% (p = 0.35) Cumulative live birth rate 47 vs 48% (p = 0.99) SECONDARY OUTCOMES- Mean dose of gonadotropins- 3282+/- 913 iu vs 3119 vs 926iu (p = 0.07) Mean duration of stimulation- 11.67 +/- 1.87days vs 11.09 +/- 2days (p = 0.01) Mean number of oocytes retrieved-14.98+/- 7.14 vs 13.9+/-7.9 (p = 0.15) Mean number of mature oocytes-11.19+/- 5.64 vs 10.43+/-6.44 (p + 0.21) Mean fertilisation rate-10.7+/- 5.47 vs 9.81+/-6.08 (p = 0.12) Limitations, reasons for caution Retrospective design. Outcomes are assessed in frozen embryo transfer cycles, bur are not compared with fresh embryo transfer cycles. Wider implications of the findings The study provides reassuring data that low serum LH on the day of trigger does not affect the blastulation rates, quality of blastocysts and cumulative live birth rates in frozen embryo transfer cycles. Whether frozen embryo transfer can negate the effect of low pretrigger LH, further studies are needed. Trial registration number Not applicable

P-671 Comparing clomiphene citrate/ flexible GnRH antagonist vs ultrashort flare GnRH agonist protocols for controlled ovarian stimulation in poor ovarian reserve patients

Abstract Study question How do Clomiphene citrate (CC)/ flexible GnRH antagonist and ultrashort flare GnRH agonist protocols compare in poor ovarian reserve patients (POSEIDON groups 3 & 4)? Summary answer In poor ovarian reserve patients, irrespective of age, use of CC / flexible antagonist vs ultrashort flare protocol significantly reduces gonadotrophin consumption and stimulation duration. What is known already Poor responders constitute 47% of ART patients and up to 65% of these have diminished ovarian reserve. Despite the various treatment options available, lack of good quality evidence to enable recommendation of a particular protocol or adjuvant continues to pose a challenge to their effective management. The need for multiple stimulations for pooling up embryos also makes effective cost of treatment an added concern in them. Study design, size, duration An open label, multi centric, randomized controlled study was conducted over a period of 1 year recruiting 116 women having AMH <1.2ng/dl and antral follicle count (AFC) <5 who were further analysed in POSEIDON 3 and 4 subgroups. Patients were randomized to 1 of 2 groups for controlled ovarian stimulation. Those with severe endometriosis, adenomyosis, autoimmune or metabolic disorders, sustained hyperprolactinaemia, congenital uterine malformations and with male partners having severe oligoasthenoteratozoospermia were excluded. Participants/materials, setting, methods Group A (55 women) received CC 100mg from D1-D5 with 300 IU human menopausal gonadotrophin (hMG) in a flexible GnRH antagonist protocol. Group B (61 women) underwent ultrashort flare protocol. 1mg leuprolide was administered from D1-D4 and 300 IU hMG given D2 onwards followed by flexible GnRH antagonist administration. Dual trigger with triptorelin and recombinant hCG was administered 35-36 hours before oocyte retrieval. Embryos cultured till D5 were vitrified for transfer at a later stage. Main results and the role of chance The two groups were well matched for baseline characteristics like age, BMI, AMH, duration of infertility, D2 AFC, estradiol and FSH levels. The mean total gonadotrophin consumption (3387.29 + 1082.5 vs 4407 + 1224.2, p value <0.01) and the duration of stimulation (10.71 + 2.52 vs 11.95 + 2.43, p value <0.01) were significantly lower in group A vs group B. The primary outcomes of median number of oocytes retrieved (4 vs 4, p value- 0.71) , M2 rate (3 vs 3, p value-0.91), fertilisation rate were similar in the two groups. The secondary outcomes of oocyte retrieval rate (103.05 + 42.97 vs 97.14 + 42.96, p value- 0.63), FORT (0.81 +0.68 vs 0.96 + 0.48, p value- 0.37) FOI (0.91 + 0.55 vs 0.92+ 0.54, p value 0.92), top quality embryo rate (0.53 + 1.1 vs 0.41 + 0.84, p value 0.61), cycle cancellation rate (26.22% vs 29.09%), implantation rate (23.63% vs 24.59%) and clinical pregnancy rate (21.31% vs 20%) were also similar in group A vs B respectively. A subgroup analysis of POSEIDON 3 versus POSEIDON 4 patients revealed similar outcomes with both the protocols in the two groups. Limitations, reasons for caution Small sample size of the cases limits the current statistical power of the study. Wider implications of the findings CC /flexible GnRH antagonist protocol is an effective alternative to ultrashort flare protocol in patients with poor ovarian reserve irrespective of their age. The lower gonadotrophin dosage required and shorter duration of stimulation observed make it a viable option in patients who might need multiple stimulations for pooling up embryos. Trial registration number Not applicable

Causal inference indicates that poor responders have similar outcomes with the antagonist protocol compared with flare

To use causal inference to investigate whether the flare or antagonist protocol is better for poor responders going through controlled ovarian stimulation. A retrospective study. Retrieval cycles from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. Patients in the United States underwent autologous invitro fertilization cycles from 2014 to 2019 using either the flare or antagonist protocol. Not applicable. Primary outcomes included oocytes retrieved, fertilized oocytes (2PNs), blastocysts, the cumulative live birth rate (CLBR), and cycle cancelation rate. After propensity score matching, patients with a predicted poor response (antimüllerian hormone, <0.5) on their first invitro fertilization cycle had similar outcomes on the antagonist protocol (CLBR of 14.2%, 95% confidence intervals [CIs]: 13.6%, 14.8%) compared with flare (CLBR of 13.6%, 95% CIs: 12.4%, 14.8%). We evaluated patients undergoing a second cycle after having a poor response (<4 oocytes retrieved) on their first cycle. Patients in the antagonist-to-antagonist group had a similar change in outcomes between the first and second cycles (average CLBR improvement of 13.9%, 95% CIs: 12.1%, 15.6%) compared with the antagonist-to-flare group (average CLBR improvement of 14.4%, 95% CIs: 10.9%, 18.3%). In addition, patients in the flare-to-antagonist group had a similar change in outcomes between the first and second cycles (average CLBR improvement of 10.4%, 95% CIs: 6.6%, 14.5%) compared with the flare-to-flare group (average CLBR improvement of 9.0%, 95% CIs: 5.1%, 13.4%). Poor responders have similar outcomes on an antagonist protocol compared with a flare protocol for both the first and second cycles.

THE NEW FOLLICULAR WAVE: DUOSTIM VS MICRODOSE FLARE CYCLE OUTCOMES IN DIMINISHED OVARIAN RESERVE

To optimize ovarian stimulation in patients with diminished ovarian reserve (DOR), by comparing IVF cycle outcomes in DOR patients who underwent DuoStim protocol compared to those who underwent Microdose Lupron Flare (MDF) protocol.

The effect of androgen administration on in vitro fertilization outcome in poor responders undergoing ovarian stimulation with microdose protocol: A randomized clinical trial

Objective(s)Patients with poor ovarian response who have reduced ovarian reserve sometimes despite the maximum dose of gonadotropins do not respond properly. Androgens have been shown to play an important role in the early follicular development and proliferation of granulosa cells. This study aimed to evaluate the effect of androgen administration on IVF outcome in poor responders. Study DesignIn this randomized clinical trial, 60 poor responder women candidate for controlled ovarian stimulation were randomly enrolled in two groups (n = 30/each). In the intervention group testosterone gel added to the interrupted microdose flare protocol. The control group received the conventional microdose flare protocol. ResultsThe main outcome was clinical and chemical pregnancy; and the second outcomes were the number of mature oocytes, duration of cycle and total dose of gonadotropins. Basic clinical and demographic features were comparable between the groups. The total gonadotropin consumption were significantly higher in the control group than the intervention group (p = 0.047). In addition, the number of MII oocytes was higher (but not significant) in the intervention group than the control group (p = 0.16). The mean total duration of the cycle was equal in both groups. There were no significant differences in chemical and clinical pregnancy rates between the two groups (p = 0.41, p = 0.67). Conclusion(s)The results of the current study showed that androgen administration in poor responders in in vitro fertilization reduces the total dose of gonadotropin, but it does not improve the pregnancy outcomes.

Flexible Antagonist versus Agonist Flare Protocol in Women above 40 Undergoing IVF, A retrospective Cohort Study.

Several strategies have been proposed for ovarian stimulation in older women, such as using an increased daily dose of gonadotropins (300-450 IU per day) with GnRH agonist (long or micro dose flare protocols), or using GnRH antagonist protocols. The objective of this study is to compare the efficacy of flexible GnRH antagonist protocol and GnRH agonist flare - pituitary block protocols for ovarian stimulation in women above 40 years old undergoing IVF. This study was performed between January 2016 and February 2019. One hundred and fourteen women aged between 40 and 42 years who underwent IVF were divided into two groups; group I were treated by Flexible GnRH antagonist protocol (Antagonist group, n=68); and group II were treated by Flare GnRH agonist protocol (Flare group, n=46). Patients treated with the antagonist protocol had a significantly lower cancellation rate when compared with patients treated with flare agonist protocol (10.3% vs. 21.7%, p value 0.049). The other parameters evaluated did not show statistically significant differences. Our finding showed that both Flexible antagonist and Flare agonist protocols had comparable outcomes, with lower cycle cancellation rates for older patients treated with the antagonist protocol.

COST ANALYSIS OF ESTROGEN PRIMING VS MICRODOSE LEUPROLIDE FLARE PROTOCOLS FOR WOMEN WITH DIMINISHED OVARIAN RESERVE UNDERGOING IVF

Previous studies comparing E2 priming and leuprolide flare IVF protocols report that E2 priming protocols result in longer cycles and higher total gonadotropin dose with similar oocyte yield, fertilization, and pregnancy rates; though, one report suggests a trend toward higher quality embryos in E2 priming cycles. We aimed to compare cost effectiveness between these two cycle types in women with DOR and hypothesized that a leuprolide flare protocol would be more cost effective.

MON-348 Surgical Management of Bilateral Hip Fracture in a Patient with Fibrodysplasia Ossificans Progressiva Treated with Palovarotene

Background: Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder marked by painful, recurrent flare-ups and progressive heterotopic ossification (HO) in soft tissues. The bone formation can be idiopathic or provoked by trauma, illness, or inflammation. There are limited treatment options, with glucocorticoids and non-steroidal anti-inflammatory agents being used for palliative treatment. Palovarotene (PVO), an investigational retinoic acid receptor gamma agonist, offers a potential avenue to prevent HO development. Clinical Case: The patient was a 29 year-old male, diagnosed with FOP at age 9, who enrolled in a study evaluating chronic PVO (5mg/day) for the treatment of FOP. Major joints affected at enrollment were his spine, jaw, shoulders, right hip and ankles. One year after starting PVO, he had a fall that resulted in a left intertrochanteric fracture. He underwent intramedullary nailing of the femur shaft with screw placement at the distal femur. After surgery, he received flare-dosing PVO at 20 mg/day for 4 weeks, then 10 mg/day for 8 weeks. Post-surgical imaging 12 weeks after the surgery showed new bridging HO at the site of intramedullary rod insertion and around the distal screw.Nine months after the fracture the patient had a second fall resulting in a right intertrochanteric fracture. He underwent intramedullary nailing of the right hip, in a modified procedure which did not require distal screw placement. PVO was increased similarly to the above flare protocol, but, at the time of fracture occurrence rather than post-surgery. He had no skin or healing complications with either treatment regimen.After each fracture the patient had prolonged recurrent flare-ups at the injury sites, significantly increasing his number of flare-ups per year. After the fractures there was new Brooker class D HO at the left hip, originating at the insertion of the intramedullary rod, and new class B HO at the right greater trochanter, again near the insertion site of the intramedullary rod compared to his pre-surgery baseline. In contrast, there was no new HO at the right distal intramedullary rod whereas HO occurred around the screw placement site at the left distal rod. Conclusion: This case suggests that PVO in the dosing regimen received by this patient can be tolerated in an individual with FOP following major surgery. HO still occurred in this patient, particularly along the rod insertion track, suggesting that the PVO regimen may need to be optimized for surgical cases or that poly-trauma events may not be adequately blocked by the dosing regimen received by this patient. However, PVO did not negatively impact fracture healing or osteointegration, and no major skin healing effects were identified. Further investigation is needed to assess whether PVO can lead to a dose-dependent reduction in HO in the setting of trauma and surgery.

Practices and Attitudes Regarding Women Undergoing Fertility Preservation: A Survey of the National Physicians Cooperative.

To describe physician attitudes and variations in oncofertility treatment strategies. An exploratory online survey administered between December 1, 2014 and January 27, 2015 to 185 members of the National Physicians Cooperative (NPC). Twenty-eight percent (52 of 185) of NPC members responded to the online survey. Fifty percent of respondents were obstetrician-gynecologists working largely in academic medical centers. Thirty-eight percent stated that 14 was the youngest age they felt comfortable performing oocyte retrievals with 35% stating that any age was acceptable as long as they were postpubertal. Short stimulation protocols, utilizing a gonadotropin-releasing hormone (GnRH) antagonist (86%), were more common than long stimulation or microdose Lupron flare protocols (23% and 18%), respectively, which utilize a GnRH agonist. Random start protocols were used by 77% and over 90% perform luteal phase starts. When using random start protocols, 64% use gonadotropins only and 32% start GnRH antagonists alone for several days before starting gonadotropins. Fifty-five percent of physicians were comfortable stimulating ovarian cancer patients only after clearance from an oncologist. Aromatase inhibitors (77%) were significantly more common than tamoxifen (24%) for stimulation in breast cancer patients (p = 0.0006). When considering ovarian stimulation after chemotherapy, 24% expressed comfort only if blood counts are normal, 38% tend to wait 3 months. Regarding experimental treatment, 83% report discussing the use of GnRH agonists alone and 64% of clinics offer ovarian tissue cryopreservation. This study underlines the wide variation that exists in stimulation and phase start techniques, patient selection, comfort levels, and cancer type-specific decision making.

A comparison of microdose flare versus antagonist protocol in poor responders chosen according to the Bologna criteria

Background: Uncertainty exists in deciding the optimal stimulation protocol in poor responders undergoing in-vitro fertilization (IVF). Our study aims to compare microdose flare and antagonist protocols in the management of patients considered to be poor responders, chosen according to Bologna criteria. Materials and Methods: In a prospective observational study, 66 poor responders as per the Bologna criteria were recruited to undergo IVF-ICSI cycles using either microdose flare protocol (Group I; n = 28) or the flexible antagonist (Group II; n = 38). Pregnancy rate per cycle was taken as the primary outcome. Total days of stimulation, total dose of gonadotropins, estradiol (E2) and progesterone levels on the day of human chorionic gonadotropin (hCG) trigger, cycle cancellation rate, total oocytes retrieved, total Metaphase II (MII) oocytes, number of embryos formed, number of Grade I embryos, fertilization and cleavage failure, total number of cycles that did not reach embryo transfer were taken as secondary outcome measures. Results: There was no significant difference in the pregnancy rates between the two groups. The microdose flare group (Group I) had higher levels of E2 on the day of hCG trigger (P = 0.03) and more number of MII oocytes (P = 0.04). Conclusion: Patients stimulated with the microdose flare protocol had significantly more E2 levels with the recovery of more MII oocytes, but this did not transform to higher pregnancy rates. A large multicentered randomized trial would be required to draw definite conclusion to achieve significant difference between the cycle cancellation and pregnancy rates between these two protocols for poor responders.

The duration of gonadotropin stimulation does not alter the clinical pregnancy rate in IVF or ICSI cycles.

Ovarian stimulation is an essential part of assisted reproduction treatments. Research on whether the duration of stimulation alters the success in assisted reproduction has not been conclusive. The purpose of the study was to establish whether the duration of ovarian stimulation alters the success in assisted reproduction treatments. All fresh (non-donor) stimulation cycles performed in an academic tertiary referral ART centre over a period of 18years, between 1st January 1997 and 31st December 2014, were identified. Data were prospectively and electronically collected. IVF and ICSI cycles were analysed independently. Each category was then subdivided into assisted reproduction cycles where the antagonist, long (down regulation) and flare protocol were used. Clinical pregnancy was the main outcome measured. A total of 10,478 stimulation cycles (6011 fresh IVF and 4467 fresh ICSI) reaching egg collection were included. We showed no significant difference in CP rates in IVF cycles for the long (p=0.082), antagonist (p=0.217) or flare (p=0.741) protocol cycles or in ICSI cycles with the long (p=0.223), antagonist (p=0.766) or the flare (p=0.690) protocol with regards the duration of stimulation. The duration of stimulation does not alter the CP rate in ICSI or IVF cycles using the long, antagonist or flare stimulation protocol.

Is the type of gonadotropin-releasing hormone suppression protocol for ovarian hyperstimulation associated with ectopic pregnancy in fresh autologous cycles for in vitro fertilization?

To evaluate the association between different ovarian hyperstimulation protocols and ectopic pregnancy (EP) in invitro fertilization (IVF) cycles in fresh autologous embryo transfer cycles in the United States between 2008 and 2011 as reported to the Society of Assisted Reproductive Technology (SART). Historical cohort study. Not applicable. None. None. All autologous cycles that resulted in a clinical pregnancy after a fresh, intrauterine embryo transfer and described characteristics of cycles according to protocol were included: luteal GnRH agonist, GnRH agonist flare, or GnRH antagonist. Multivariate logistic regression was conducted to investigate the association between type of protocol and EP. Among 136,605 clinical pregnancies, 2,645 (1.94%) were EP. Ectopic pregnancy was more frequent with GnRH antagonist (2.4%) cycles than with GnRH agonist flare (2.1%) or luteal GnRH agonist (1.6%) cycles. After adjusting for maternal and treatment characteristics, the GnRH antagonist and the GnRH agonist flare protocols were associated with increased odds of EP (adjusted odds ratio [aOR] 1.52; 95% confidence interval [CI], 1.39-1.65; and aOR 1.25; 95% CI, 1.09-1.44, respectively) compared with luteal GnRH agonist. Analysis of differences in the factors related to EP in luteal GnRH agonist versus GnRH antagonist protocols indicated that diminished ovarian reserve was associated with an increased risk of EP in luteal GnRH agonist but not in GnRH antagonist cycles. The type of protocol used during ovarian hyperstimulation in fresh autologous cycles was associated with EP. This finding suggests a role for extrapituitary GnRH on the tubal and uterine environment during ovarian hyperstimulation treatment for IVF.

Trends in 'poor responder' research: lessons learned from RCTs in assisted conception.

A substantial minority of women undergoing IVF will under-respond to controlled ovarian hyperstimulation. These women-so-called 'poor responders'-suffer persistently reduced success rates after IVF. Currently, no single intervention is unanimously accepted as beneficial in overcoming poor ovarian response (POR). This has been supported by the available research on POR, which consists mainly of randomized controlled trials (RCTs) with an inherent high-risk of bias. The aim of this review was to critically appraise the available experimental trials on POR and provide guidance towards more useful-less wasteful-future research. A comprehensive review was undertaken of RCTs on 'poor responders' published in the last 15 years. Data on various methodological traits as well as important clinical characteristics were extracted from the included studies and summarized, with a view to identifying deficiencies from which lessons can be learned. Based on this analysis, recommendations were provided for further research in this field of assisted conception. We selected and analysed 75 RCTs. A valid, 'low-risk' randomization method was reported in three out of four RCTs. An improving trend in reporting concealment of patient allocation was also evident over the 15-year period. In contrast, <1 in 10 RCTs 'blinded' patients and <1 in 5 RCTs 'blinded' staff to the proposed intervention. Only 1 in 10 RCTs 'blinded' ultrasound practitioners to patient allocation, when assessing the outcome of early pregnancy. The majority of trials reported an intention-to-treat analysis for at least one of their outcomes, with an improving trend in the recent years. Substantial variation was noted in the definitions used for 'poor responders', the most popular being 'low ovarian response at previous stimulation'. The preferred cut-off value for defining previous low response has been 'less or equal to three retrieved oocytes'. The most popular tests used for diagnosing diminished ovarian reserve have been antral follicle count and FSH. Although the Bologna criteria for POR were only recently introduced, they are expected to become a popular definition in future 'poor responder' trials. Numerous interventions have been studied on 'poor responders'. Most of these have been applied before/during controlled ovarian hyperstimulation. The antagonist protocol, the microdose flare protocol and the long down-regulation protocol have been among the most popular interventions. The analysis of outcomes revealed a clear improving trend in reporting live birth. In contrast, only 10% of RCTs reported significant improvement in reproductive outcomes among tested interventions. Twelve 'significant' interventions were reported, each supported by a single 'positive' RCT. Finally, trials of higher methodological quality were more likely to have been published in a high-impact journal. Overall, the majority of published trials on POR suffer from methodological flaws and are, thus, regarded as being high-risk for bias. The same trials have used a variety of definitions for their poor responders and a variety of interventions for their head-to-head comparisons. Not surprisingly, discrepancies are also evident in the findings of trials comparing similar interventions. Based on the identified deficiencies, this novel type of 'methodology and clinical' review has introduced custom recommendations on how to improve future experimental research in the 'poor responder' population.

Comparison of The Effectiveness of Clomiphene Citrate versus Letrozole in Mild IVF in Poor Prognosis Subfertile Women with Failed IVF Cycles.

Our objective was to evaluate the effectiveness of clomiphene citrate (CC) vs. letrozole (L) plus human menopausal gonadotropin (hMG) in gonadotropin releasing hormone (GnRH) antagonist protocol in poor prognosis women with previous failed ovarian stimulation undergoing intracytoplasmic sperm injection (ICSI). This retrospective cohort study included cycles with CC and L plus hMG/GnRH antagonist protocols of 32 poor responders who had failed to have ideal follicles to be retrieved during oocyte pick-up (OPU) or embryo transfer (ET) at least for 2 previous in vitro fertilization (IVF) cycles with microdose flare protocol or GnRH antagonist protocol from January 2006 to December 2009. Main outcome measures were implantation, clinical pregnancy and live birth rates per cycle. Duration of stimulation, mean gonadotropin dose used, endometrial thickness, number of mature follicles, serum estradiol (E2) and progesterone (P) levels on the day of human chorionic gonadotropin (hCG) administration, number of retrieved oocytes and fertilization rates were also evaluated. A total number of 42 cycles of 32 severe poor responders were evaluated. Total gonadotropin consumption was significantly lower (1491 ± 873 vs. 2808 ± 1581 IU, P=0.005) and mean E2 level on the day of hCG injection were significantly higher in CC group than L group (443.3 ± 255.2 vs. 255.4 ± 285.2 pg/mL, P=0.03). ET, overall pregnancy and live birth rates per cycle were significantly higher in CC than L protocol (27.2 vs. 15%, 13.6 vs. 0% and 4.5 vs. 0%, respectively, P<0.05). Severe poor responders who had previously failed to respond to microdose or GnRH antagonist protocols may benefit from CC plus hMG/GnRH antagonist protocol despite high cancellation rate.

Microdose flare protocol with interrupted follicle stimulating hormone and added androgen for poor responders—an observational pilot study

To investigate whether temporarily withholding FSH and adding androgen could improve follicular response during a microdose flare protocol in women with slow follicular growth or asynchronous follicular development. Observational pilot study. University-affiliated private fertility center. Twenty-six women aged 34-47 years with poor response to stimulation or a previous cancelled IVF cycle and with slow or asynchronous follicular growth during a microdose flare cycle. For 13 women, after initiation of ovarian stimulation using the microdose flare protocol, gonadotropin administration was interrupted and transdermal testosterone gel was added for several days (4.4 ± 1.2 d) starting after cycle day 7 (mean cycle day 10 ± 2.6). FSH, E2, follicular growth, and total number of mature oocytes retrieved were determined for all of the patients. Cycle cancellation rate as well as pregnancy rate following embryo transfer were also documented when applicable. FSH levels declined (25.2 ± 6.5 to 6.8 ± 3.2 IU/L), E2 levels increased (896 ± 687 to 2,163 ± 1,667 pmol/L), and follicular growth improved significantly during gonadotropin interruption and were tracked for 2 days during this time frame. The average number of oocytes retrieved was 5.3 ± 2.6, and the ratio of mature to total oocytes was 4:5. Four of the 13 women in the interruption group conceived following frozen embryo transfer, whereas none in the control group did. The androgen-interrupted FSH protocol may improve follicular response to gonadotropins in cycles that might otherwise be cancelled.

Growth Hormone Supplementation in the Luteal Phase Before Microdose GnRH Agonist Flare Protocol for In Vitro Fertilization

Growth hormone (GH) acts in both early and late follicular development to stimulate the proliferation and differentiation of granulosa cells and to increase the production of estradiol in animal and human ovaries. Investigators have therefore explored GH supplementation to improve outcomes in women undergoing in vitro fertilization, with the greatest interest in women with diminished ovarian reserve. Recent meta-analyses indicate that GH supplementation can be beneficial for poor responders undergoing IVF. In most studies, GH has been given concomitantly with gonadotropins during the follicular phase; this may not be optimal, since follicular recruitment begins during the preceding luteal phase. We therefore wished to examine the effect of GH supplementation in the luteal phase before controlled ovarian stimulation (COH) with a microdose GnRH agonist flare (MDF) protocol in women undergoing in vitro fertilization. We performed a retrospective matched case-control study of patients undergoing treatment at a private IVF facility between June 2012 and July 2013. Patients identified as poor responders to COH were offered adjuvant GH treatment as part of their ovarian stimulation regimen. The patients in the experimental group chose to take GH, 3.33 mg daily by subcutaneous injection for 14 days, before starting COH. All patients had an MDF stimulation protocol using 450 IU of follicle stimulating hormone (FSH) daily. A total of 42 women were included in the study. There were 14 women in the experimental group (GH) and 28 controls (C) matched for age, BMI, and day 3 FSH level. There was no difference between the groups in clinical pregnancy rate (GH = 29%, C = 32%, P = 0.99), number of mature oocytes retrieved (GH = 2.5, C = 5.0, P = 0.13), cycle cancellation rate (GH = 21%, C = 14%, P = 0.88), duration of COH (GH = 10.1, C = 10.1, P = 0.93), or mean peak estradiol level (GH = 4174 pmol/L, C = 5105 pmol/L, P = 0.44). The administration of growth hormone during the luteal phase before a microdose GnRH agonist flare protocol for in vitro fertilization did not improve outcomes in "poor responder" patients.

In Search of a Cost-Effective Flare Protocol for Poor Responders

In Search of a Cost-Effective Flare Protocol for Poor Responders