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

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

Introduction: Management for poor response patients is still a challenge for clinician engaged in Assisted Reproductive Technology. Various protocols have been proposed to improve the outcome for patients, though no RCT can provide the evidence based of success rate of one protocol among others. Objective: Our purpose is to find the basic data of poor responder patients in Yasmin Clinic, Jakarta and to assess the IVF cycle outcome after the addition of recombinant Luteinizing Hormones. Material and methods: This is a cohort retrospective study taken from medical records of IVF patients at Yasmin Clinic, Cipto Mangunkusumo Hospital between January 2012 to January 2015. Result :  Two hundreds and eighty-one poor response patients were selected for ART during January 2012 to January 2015, were divided into four main group. Control group received gonadotrophin protocol, while group II received additional recombinant Luteinizing hormones (rLH), Group III received additional Growth hormones (GH) and Group IV received additional rLH and GH both. Discussion: Our study demonstrated the follicle count, the oocyte count and the cleavage rate were statistically significant difference between control group and LH group. Where the oocyte count and follicle count were significantly higher, but the cleavage rate with LH showed negative correlation compare with control group. Conclusion : In this study we found that with adjuvant therapy with recombinant Luteinizing Hormones, produced higher follicles count and oocyte count.

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Characteristic of Poor Responder Patients and the success rate of biochemical pregnancy in the administration of adjuvant recombinant Luteinizing Hormones in Yasmin Clinic, Jakarta

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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Batool Hoseini Rashidi

Papers

GnRHa stop protocol versus long protocol in poor responder IVF patients