ABSTRACT: Assisted reproduction techniques (ART) such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) can help subfertile couples to create a family. It is necessary to induce multiple follicles; this is achieved by follicle stimulating hormone (FSH) injections. Current treatment regimens prescribe daily injections of FSH (urinary FSH with or without luteinizing hormone (LH) injections or recombinant FSH (rFSH)).Recombinant DNA technologies have produced a new recombinant molecule which is a long-acting FSH, named corifollitropin alfa (Elonva) or FSH-CTP. A single dose of long-acting FSH is able to keep the circulating FSH level above the threshold necessary to support multi-follicular growth for an entire week. The optimal dose of long-acting FSH is still being determined. A single injection of long-acting FSH can replace seven daily FSH injections during the first week of controlled ovarian stimulation (COS) and can make assisted reproduction more patient friendly.
To compare the effectiveness of long-acting FSH versus daily FSH in terms of pregnancy and safety outcomes in women undergoing IVF or ICSI treatment cycles.
We searched the following electronic databases, trial registers and websites: the Cochrane Central Register of Controlled Trials (CENTRAL), the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, MEDLINE, EMBASE, PsycINFO, CINAHL, electronic trial registers for ongoing and registered trials, citation indexes, conference abstracts in the ISI Web of Knowledge, LILACS, Clinical Study Results (for clinical trial results of marketed pharmaceuticals), PubMed and OpenSIGLE (10 October 2011). We also carried out handsearches.
All randomised controlled trials (RCTs) comparing long-acting FSH versus daily FSH in women who were part of a couple with subfertility and undertaking IVF or ICSI treatment cycles with a GnRH antagonist or agonist protocol were included.
Data extraction and assessment of risk of bias was independently done by two review authors. Original trial authors were contacted in the case of missing data. We calculated Peto odds ratios for each outcome; our primary outcomes were live birth rate and ovarian hyperstimulation syndrome (OHSS) rate.
We included four RCTs with a total of 2335 participants. A comparison of long-acting FSH versus daily FSH did not show evidence of difference in effect on overall live birth rate (Peto OR 0.92; 95% CI 0.76 to 1.10, 4 RCTs, 2335 women) or OHSS (Peto OR 1.12; 95% CI 0.79 to 1.60, 4 RCTs, 2335 women). We compared subgroups by dose of long-acting FSH. There was evidence of reduced live birth rate in women who received lower doses (60 to 120 μg) of long-acting FSH compared to daily FSH (Peto OR 0.60; 95% CI 0.40 to 0.91, 3 RCTs, 645 women). There was no evidence of effect on live births in the medium dose subgroup (Peto OR 1.03; 95% CI 0.84 to 1.27) and no evidence of effect on clinical pregnancy rate, ongoing pregnancy rate, multiple pregnancy rate, miscarriage rate or ectopic pregnancy rate.
The use of a medium dose of long-acting FSH is a safe treatment option and equally effective compared to daily FSH. Further research is needed to determine if long-acting FSH is safe and effective for use in hyper- or poor responders and in women with all causes of subfertility.
Cochrane database of systematic reviews (Online) 01/2012; 6:CD009577. · 5.72 Impact Factor
ABSTRACT: BACKGROUND: Patient participation is essential in developing high-quality guidelines but faces practical challenges. Evidence on timing, methods, evaluations, and outcomes of methodologies for patient participation in guideline development is lacking. OBJECTIVE: To assess the feasibility of a wiki as a participatory tool for patients in the development of a guideline on infertility determined by (1) use of the wiki (number of page views and visitors), (2) benefits of the wiki (ie, number, content, and eligibility of the recommendations to be integrated into the guideline), and (3) patients' facilitators of and barriers to adoption, and the potential challenges to be overcome in improving this wiki. METHODS: To obtain initial content for the wiki, we conducted in-depth interviews (n = 12) with infertile patients. Transcripts from the interviews were translated into 90 draft recommendations. These were presented on a wiki. Over 7 months, infertile patients were invited through advertisements or mailings to formulate new or modify existing recommendations. After modifying the recommendations, we asked patients to select their top 5 or top 3 recommendations for each of 5 sections on fertility care. Finally, the guideline development group assessed the eligibility of the final set of recommendations within the scope of the guideline. We used a multimethod evaluation strategy to assess the feasibility of the wiki as a participatory tool for patients in guideline development. RESULTS: The wiki attracted 298 unique visitors, yielding 289 recommendations. We assessed the 21 recommendations ranked as the top 5 or top 3 for their eligibility for being integrated into the clinical practice guideline. The evaluation identified some challenges needed to be met to improve the wiki tool, concerning its ease of use, website content and layout, and characteristics of the wiki tool. CONCLUSIONS: The wiki is a promising and feasible participatory tool for patients in guideline development. A modified version of this tool including new modalities (eg, automatically limiting the number and length of recommendations, using a fixed format for recommendations, including a motivation page, and adding a continuous prioritization system) should be developed and evaluated in a patient-centered design.
Journal of Medical Internet Research 01/2012; 14(5):e138. · 4.41 Impact Factor
ABSTRACT: Progesterone prepares the endometrium for pregnancy by stimulating proliferation in response to human chorionic gonadotropin (hCG), which is produced by the corpus luteum. This occurs in the luteal phase of the menstrual cycle. In assisted reproduction techniques (ART) the progesterone or hCG levels, or both, are low and the natural process is insufficient, so the luteal phase is supported with either progesterone, hCG or gonadotropin releasing hormone (GnRH) agonists. Luteal phase support improves implantation rate and thus pregnancy rates but the ideal method is still unclear. This is an update of a Cochrane Review published in 2004 (Daya 2004).
To determine the relative effectiveness and safety of methods of luteal phase support in subfertile women undergoing assisted reproductive technology.
We searched the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, Database of Abstracts of Reviews of Effects (DARE), LILACS, conference abstracts on the ISI Web of Knowledge, OpenSigle for grey literature from Europe, and ongoing clinical trials registered online. The final search was in February 2011.
Randomised controlled trials of luteal phase support in ART investigating progesterone, hCG or GnRH agonist supplementation in in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles. Quasi-randomised trials and trials using frozen transfers or donor oocyte cycles were excluded.
We extracted data per women and three review authors independently assessed risk of bias. We contacted the original authors when data were missing or the risk of bias was unclear. We entered all data in six different comparisons. We calculated the Peto odds ratio (Peto OR) for each comparison.
Sixty-nine studies with a total of 16,327 women were included. We assessed most of the studies as having an unclear risk of bias, which we interpreted as a high risk of bias. Because of the great number of different comparisons, the average number of included studies in a single comparison was only 1.5 for live birth and 6.1 for clinical pregnancy.Five studies (746 women) compared hCG versus placebo or no treatment. There was no evidence of a difference between hCG and placebo or no treatment except for ongoing pregnancy: Peto OR 1.75 (95% CI 1.09 to 2.81), suggesting a benefit from hCG. There was a significantly higher risk of ovarian hyperstimulation syndrome (OHSS) when hCG was used (Peto OR 3.62, 95% CI 1.85 to 7.06).There were eight studies (875 women) in the second comparison, progesterone versus placebo or no treatment. The results suggested a significant effect in favour of progesterone for the live birth rate (Peto OR 2.95, 95% CI 1.02 to 8.56) based on one study. For clinical pregnancy (CPR) the results also suggested a significant result in favour of progesterone (Peto OR 1.83, 95% CI 1.29 to 2.61) based on seven studies. For the other outcomes the results indicated no difference in effect.The third comparison (15 studies, 2117 women) investigated progesterone versus hCG regimens. The hCG regimens were subgrouped into comparisons of progesterone versus hCG and progesterone versus progesterone + hCG. The results did not indicate a difference of effect between the interventions, except for OHSS. Subgroup analysis of progesterone versus progesterone + hCG showed a significant benefit from progesterone (Peto OR 0.45, 95% CI 0.26 to 0.79).The fourth comparison (nine studies, 1571 women) compared progesterone versus progesterone + oestrogen. Outcomes were subgrouped by route of administration. The results for clinical pregnancy rate in the subgroup progesterone versus progesterone + transdermal oestrogen suggested a significant benefit from progesterone + oestrogen. There was no evidence of a difference in effect for other outcomes.Six studies (1646 women) investigated progesterone versus progesterone + GnRH agonist. We subgrouped the studies for single-dose GnRH agonist and multiple-dose GnRH agonist. For the live birth, clinical pregnancy and ongoing pregnancy rate the results suggested a significant effect in favour of progesterone + GnRH agonist. The Peto OR for the live birth rate was 2.44 (95% CI 1.62 to 3.67), for the clinical pregnancy rate was 1.36 (95% CI 1.11 to 1.66) and for the ongoing pregnancy rate was 1.31 (95% CI 1.03 to 1.67). The results for miscarriage and multiple pregnancy did not indicate a difference of effect.The last comparison (32 studies, 9839 women) investigated different progesterone regimens:intramuscular (IM) versus oral administration, IM versus vaginal or rectal administration, vaginal or rectal versus oral administration, low-dose vaginal versus high-dose vaginal progesterone administration, short protocol versus long protocol and micronized progesterone versus synthetic progesterone. The main results of this comparison did not indicate a difference of effect except in some subgroup analyses. For the outcome clinical pregnancy, subgroup analysis of micronized progesterone versus synthetic progesterone showed a significant benefit from synthetic progesterone (Peto OR 0.79, 95% CI 0.65 to 0.96). For the outcome multiple pregnancy, the subgroup analysis of IM progesterone versus oral progesterone suggested a significant benefit from oral progesterone (Peto OR 4.39, 95% CI 1.28 to 15.01).
This review showed a significant effect in favour of progesterone for luteal phase support, favouring synthetic progesterone over micronized progesterone. Overall, the addition of other substances such as estrogen or hCG did not seem to improve outcomes. We also found no evidence favouring a specific route or duration of administration of progesterone. We found that hCG, or hCG plus progesterone, was associated with a higher risk of OHSS. The use of hCG should therefore be avoided. There were significant results showing a benefit from addition of GnRH agonist to progesterone for the outcomes of live birth, clinical pregnancy and ongoing pregnancy. For now, progesterone seems to be the best option as luteal phase support, with better pregnancy results when synthetic progesterone is used.
Cochrane database of systematic reviews (Online) 01/2011; · 5.72 Impact Factor
ABSTRACT: Clinical guidelines are intended to improve healthcare. However, even if guidelines are excellent, their implementation is not assured. In subfertility care, the European Society of Human Reproduction and Embryology (ESHRE) guidelines have been inventoried, and their methodological quality has been assessed. To improve the impact of the ESHRE guidelines and to improve European subfertility care, it is important to optimise the implementability of guidelines. We therefore investigated the implementation barriers of the ESHRE guideline with the best methodological quality and evaluated the used instrument for usability and feasibility.
We reviewed the ESHRE guideline for the diagnosis and treatment of endometriosis to assess its implementability. We used an electronic version of the guideline implementability appraisal (eGLIA) instrument. This eGLIA tool consists of 31 questions grouped into 10 dimensions. Seven items address the guideline as a whole, and 24 items assess the individual recommendations in the guideline. The eGLIA instrument identifies factors that influence the implementability of the guideline recommendations. These factors can be divided into facilitators that promote implementation and barriers that oppose implementation. A panel of 10 experts from three European countries appraised all 36 recommendations of the guideline. They discussed discrepancies in a teleconference and completed a questionnaire to evaluate the ease of use and overall utility of the eGLIA instrument.
Two of the 36 guideline recommendations were straightforward to implement. Five recommendations were considered simply statements because they contained no actions. The remaining 29 recommendations were implementable with some adjustments. We found facilitators of the guideline implementability in the quality of decidability, presentation and formatting, apparent validity, and novelty or innovation of the recommendations. Vaguely defined actions, lack of facilities, immeasurable outcomes, and inflexibility within the recommendations formed barriers to implementation. The eGLIA instrument was generally useful and easy to use. However, assessment with the eGLIA instrument is very time-consuming.
The ESHRE guideline for the diagnosis and treatment of endometriosis could be improved to facilitate its implementation in daily practice. The eGLIA instrument is a helpful tool for identifying obstacles to implementation of a guideline. However, we recommend a concise version of this instrument.
Implementation Science 01/2011; 6:7. · 3.10 Impact Factor
ABSTRACT: For many subfertile women, assisted reproductive techniques (ART) is the only hope for a pregnancy and live birth. The combined oral contraceptive pill (OCP) given prior to the hormone therapy in an IVF cycle may result in better pregnancy outcomes of ART.
To assess whether pre-treatment with combined OCPs, progestogens or estrogens in ovarian stimulation protocols affects outcomes in subfertile couples undergoing ART.
We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, PsycINFO. Other electronic resources on the Internet, reference list of relevant articles were also searched as well as the ESHRE abstracts (2008). All these searches were conducted in November 2008.
Randomised controlled trials of pre-treatment with combined OCP, progestogen or estrogen in subfertile women undergoing IVF/ICSI.
Two authors independently extracted the data and assessed risk of bias. We calculated Peto odds ratios for dichotomous data and weighted mean difference for continuous variables. Authors of trials were contacted in case of missing data.
No evidence of effect was found with regard to the number of live births when using a pre-treatment. However, the combined OCP in GnRH antagonist cycles, compared to no pre-treatment, is associated with fewer clinical pregnancies (Peto OR 0.69, P = 0.03) and more days and a higher amount of gonadotrophin therapy (respectively: MD 1.44, P < 0.00001; and MD 691.69, P < 0.00001). Also compared to placebo or no pre-treatment, a progestogen pre-treatment in GnRH agonist cycles, is associated with more clinical pregnancies (Peto OR 1.95, P = 0.007) and fewer ovarian cysts (Peto OR 0.21, P < 0.00001). At last, in estrogen pre-treated GnRH antagonist cycles, compared to no pre-treatment, more oocytes are retrieved (MD 2.01, P < 0.00001), but a higher amount of gonadotrophin therapy is needed (MD 207.08, P < 0.00001). For the other outcomes no evidence of effect was found or there were not enough studies available in the subgroup for pooling.
There was evidence of improved pregnancy outcomes with progestogen pre-treatment and poorer pregnancy outcomes with a combined OCP pre-treatment. However, we conclude that major changes in ART protocols should not be made at this time, since the number of overall studies in the subgroups is small and reporting of the major outcomes is inadequate.
Cochrane database of systematic reviews (Online) 01/2010; · 5.72 Impact Factor