Background The success of in-vitro fertilisation (IVF) treatment depends on adequate follicle recruitment by using controlled ovarian stimulation with gonadotrophins. Failure to recruit adequate follicles is called 'poor response'. Various treatment protocols have been proposed that are targeted at this cohort of women, aiming to increase their ovarian response. Objectives To compare the effectiveness of different treatment interventions in women who have poor response to controlled ovarian hyperstimulation (are poor responders) in the context of in vitro fertilisation. Search strategy We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials (MDSG), the Cochrane Central Register of Controlled trials (CENTRAL) (The Cochrane Library 2003, Issue 1), MEDLINE (1966 to August 2006), EMBASE (1980 to August 2006) and The National Research Register (NRR). The citation lists of relevant publications, review articles, abstracts of scientific meetings and included studies were also searched. The authors were contacted to identify or clarify data that were unclear from the trial reports. Selection criteria Only randomised controlled trials (RCTs) comparing one type of intervention versus another for controlled ovarian stimulation of poor responders to a previous IVF treatment, using a standard long protocol were included. Data collection and analysis Two review authors independently scanned the abstracts, identified relevant papers, assessed inclusion and trial quality and extracted relevant data. Validity was assessed in terms of method of randomisation, completeness of treatment cycle and co-intervention. Where possible, data were pooled for analysis. Main results Nine trials involving six different comparison groups have been included in this review. Only one trial reported live birth rates. Four groups compared the long protocol with another intervention. Only one comparison group (bromocryptine versus long protocol) reported a higher clinical pregnancy rate per cycle, in the bromocryptine arm (OR 5.60, 95% CI 1.40 to 22.47). Two comparison groups showed a lower number of oocytes in the long protocol group (versus stop and gonadotrophin releasing hormone (GnRH) antagonist protocols). However, two comparison groups also showed lower cancellation rates in the long protocol treatment group (versus stop and GnRHa flare-up protocols). None reported any evident difference in the adverse effects. Authors' conclusions There is insufficient evidence to support the routine use of any particular intervention either for pituitary downregulation, ovarian stimulation or adjuvant therapy in the management of poor responders to controlled ovarian stimulation in IVF. More robust data from good quality RCTs with relevant outcomes are needed.

Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF).

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

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Trends in ‘poor responder’ research: lessons learned from RCTs in assisted conception

Objective : To evaluate the reproductive outcome following hysteroscopic septum resection in patients with primary and secondary (recurrent pregnancy loss [RPL] and bad obstetric history [BOH]) infertility. Study Design : Retrospective study. Materials and Methods : Hysteroscopic septum resection was performed on 26 patients with a history of either recurrent pregnancy loss, BOH or infertility. The septum resection was performed using a bipolar versapoint system. Reproductive performance of these patients after septum resection was analyzed. The main outcome measures were clinical pregnancy and live birth rates. Results : Hysteroscopic septum resection was performed on seven patients with the history of secondary infertility. Post operatively, the pregnancy rate was 86% (n=6), and the live birth rate was 67% (n=4). After septum resection in 19 primary infertile patients, 6 (32%) patients conceived which resulted in live birth rates of 67% (n=4). Conclusion : Hysteroscopic septum resection using bipolar versapoint system is an effective and safe approach for the removal of septum. Hysteroscopic septum resection in women with septate uterus significantly improves the live birth rates and future fertility is not impaired.

Reproductive outcome of septate uterus following hysteroscopic septum resection.

Different steroid pre-treatments have been used to schedule the start of the ovarian stimulation in IVF cycles. Currently, there is controversy about their effects on gestational outcomes. We designed a three-armed randomised controlled trial (RCT). Eighty-six normoresponder patients undergoing IVF treatment with antagonist GnRH protocol were allocated to three different groups. In the group 1, 34 patients received oral contraceptive pill (OCP) from the first day of the cycle to five days before starting ovarian stimulation, in the group 2, 25 patients received 2 mg/12 hours of oral E2 valerate from day 25 of the previous cycle until the day before starting stimulation, and finally, in the group 3, 27 patients did not receive any treatment. There are no statistically significant differences neither in clinical pregnancy rate (CPR) (40.9% OCP vs. 28.6% E2 vs. 53.3% no treatment group, p=.388) nor live birth rate (LBR) (31.8% OCP vs. 28.6% E2 vs. 46.7% no treatment group, p=.537) between groups in fresh embryo transfer. Likewise, no differences were found in the cumulative CPR, nor in cumulative LBR. However, there is a tendency to worst outcomes in the E2 group. In this E2 group, we observed better results with longer exposition, although no significant differences are reached (E2 mean days in the pregnant group 8.29 vs. 6.83 in the non-pregnant group, p=.08). Our study shows no significant differences in pregnancy rates between groups, but the E2 group is trending at worse gestational results. Trial registration number: Eudra-CT registration number is 2014-001809-40.Impact StatementWhat is already known on this subject? Nowadays, there is much controversy about how pregnancy rates could be affected by the selection of steroid pre-treatments used in order to schedule IVF cycles. However, these treatments are widely utilised in clinical practice.What the results of this study add? The results support the clinical findings of most of the studies previously published. No significant differences in gestational outcomes were found between the groups treated with steroid pre-treatments and the control group. Additionally, oestrogen pre-treatment seems to be related to better pregnancy outcomes when the exposition is longer. Thus, an earlier start of this treatment in the luteal phase could be the optimal approach.What the implications are of these findings for clinical practice and/or further research? This study pretends to provide clarity about the treatment guidelines of steroid pre-treatments to schedule the clinical work without impact on gestational outcomes.

Use of steroid pre-treatments in IVF-ICSI cycles with GnRH antagonist protocol and their impact on gestational outcomes.

This thesis examines the various interventions proposed for the management of poor responders undergoing IVF treatment. I began by performing a systematic review and metaanalysis to identify the ideal controlled ovarian hyperstimulation (COH) regimen for women with poor ovarian response undergoing IVF. The systematic review found the evidence to be inconsistent and inconclusive. The poor responders intervention trial (PRINT) was thus conceived. PRINT is an RCT comparing the gonadotrophin releasing hormone (GnRH) agonist long versus the GnRH agonist short versus the GnRH antagonist regimens for poor responders undergoing IVF. Results of PRINT showed the GnRH agonist long regimen to be efficacious. The relationship between egg numbers and live birth following IVF is poorly understood. I set out to investigate this by examining a large cohort of IVF cycles. I was able to demonstrate a strong association between egg numbers and live birth following IVF and justify the use of egg numbers as a primary outcome for PRINT. A frequent scenario faced in the management of women who have a poor response is whether to continue with their current IVF cycle or to cancel and start again on the assumption that there could be intercycle variability. I examined this hypothesis by comparing two consecutive IVF cycles with identical COH regimens. There was no significant intercycle variability in poor responders suggesting that the more cost effective option would be to continue with the IVF cycle.

Interventions for poor responders undergoing in vitro fertilisation treatment

Background Both oral contraceptive pills (OCPs) and estradiol valerate (E2) have been used to schedule a gonadotropin-releasing hormone antagonist in vitro fertilization (IVF) cycles. Since the suppression of follicle-stimulating hormone by OCPs can stay 5-7 days after stopping the pills, it seems that starting the gonadotropin-releasing hormone (GnRH) after 6 days of pre-treatment discontinuation may be important in IVF outcomes. Objective The aim of the present study was to determine the number of mature oocyte and pregnancy rate of three pretreatment methods for fresh embryo transfer cycles. Materials and methods In this randomized controlled trial, two-hundred ten women (18-35 yr and less than 2 previous IVF attempts) undergoing IVF with the GnRH antagonist protocol were randomized to the OCP, E2, and no pretreatment arms. OCP group (n=53) received OCP (ethinyl estradiol30 μg and levonorgestrel150 μg), E2 group (n=63) received 4 mg/day oral E2 (17β-E2) for 10 days from day 20 of the previous cycle and GnRH antagonist stimulation was started 6 days after the interruption of OCP and E2. The control group (n =70) did not receive any pretreatment. Results No significant difference was observed in the mean number of the mature oocyte, endometrial thickness, and embryo quality. The pregnancy rate in E2 group was higher than the two other groups (42.9% vs 39.6% and 34.3% in OCP and control group, respectively), but the difference was not statistically significant (p=0.59). Conclusion It seems OCP or E2 pretreatment could not improve the fresh IVF-embryo transfer outcomes.

https://journals.ssu.ac.ir/ijrmnew/article-1-1180-en.pdf

Comparison of pre-treatment with OCPs or estradiol valerate vs. no pre-treatment prior to GnRH antagonist used for IVF cycles: An RCT

Background: Recently different studies suggested that discontinuation of gonadotrophin releasing hormone analogue (GnRHa) at beginning of ovarian stimulation (improvement of ovarian response to gonadotrophins) may have some benefit to poor responder patients in invitro fertilization (IVF) cycles. Objective:The efficacy of GnRHa stop protocol in poor responder patients in IVF cycles was assessed. Materials and Methods: This study was a prospective, randomized controlled trial that 40 poor responder patients (less than three mature follicles in a previous cycle) with normal basal follicle stimulating hormone (FSH) were randomly allocated into two protocols: 1) Non-stop protocol: long GnRHa suppression, and start gonadotrophins from day 3 of mense. 2) Stop-protocol: GnRHa is stopped with the onset of menses, and gonadotrophin doses remained similar to group 1. Results: A significantly higher number of follicles, oocytes, embryos and fertilization rate also shorter stimulation days and lower human menopausal gonadotropins (HMG) ampoules were recorded in the stop protocol compared to the control group. Both protocols resulted in a similar cancellation rate, pregnancy rate, estradiol level and LH level. Conclusion: Early follicular cessation of GnRHa permitted the retrieval of a significantly higher number of follicles, oocytes and embryos, and can reduce the number of HMG and stimulation days.

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GnRHa stop protocol versus long protocol in poor responder IVF patients

Background: Mullerian disorders are present in 5-25% of infertile women. Myoma, polyp and endometrial adhesions are among other involved factors in infertility. Objective: The aim of this study was to determine the frequency distribution of pregnancy occurrence in infertile women after the diagnostic-surgical hysteroscopy on selected infertile cases including those with abnormal uterine. Materials and Methods: One hundred and fifteen women with at least 12 months infertility who had abnormal uterine cavity and patients who had at least 4 unsuccessful ART cycles with no confirmed diagnosis of uterine cavity problem, underwent diagnostic hysteroscopy and if required hysteroscopic surgery. Follow up sonography and HSG performed 2-3 months later and all subjects were followed for pregnancy occurrence for 12 months. Results: Mean age of subjects was 32.65 ± 6.2 years and mean of infertility duration was 8.33 ± 5.25 years. Based on the sonography and HSG performed prior to the hysteroscopy, respectively 69.6% and 41.8% of the subjects had abnormality. In 65.2% of the cases, hysteroscopy showed septum, myoma, endometrial adhesion and irregularity and all of them underwent hysteroscopic operation. Among the operated cases, in 27 cases pregnancy occurred during the first 6 postoperative months and in 2 cases during the second 6 postoperative months of whom one case was EP. Conclusion: There was no significant difference in the rate of pregnancy occurrence between those who had abnormal hysteroscopy and those who were normal (p= 0.63). This can show the variation of infertility causes and the fact that infertility is not just due to uterine problems. Therefore, the repetition of therapeutic measures and longer follow up of infertile cases are necessary.

Ensieh Shahrokh Tehrani Nejad

Papers

Comparison of pre-treatment with OCPs or estradiol valerate vs. no pre-treatment prior to GnRH antagonist used for IVF cycles: An RCT

GnRHa stop protocol versus long protocol in poor responder IVF patients

Frequency distribution of pregnancy occurrence in infertile women after diagnostic-surgical hysteroscopy