Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH)

STUDY QUESTION: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratchin

Mild strategies for IVF: from theory to practice

Over the last 25 years, ovarian stimulation for IVF treatment has gradually become more complex, time consuming and expensive. Recently, the downsides of ovarian stimulation have attracted increasing attention. Currently, a shift in the focus of IVF is occurring from striving for maximizing instant success 'at all costs' to developing safer and more patient friendly protocols in which the risks of treatment are minimized while optimizing the chance of a singleton live birth. Strategies involving single embryo transfer and milder ovarian stimulation protocols) have been proposed to provide such a patient friendly strategy. An important concern regarding the use of mild treatment strategies remains the reduction in the per cycle chance of pregnancy. The principle aim of this thesis was to identify means of improving the efficacy and therefore the uptake of milder treatment strategies for IVF such as mild ovarian stimulation and SET. In this thesis it was shown that fear regarding the use of mild stimulation for a reduction in ovarian response or an increase of drop-outs (when the number of treatment cycles needed is increased) is unjustified. Indeed, the retrieval of a modest number of oocytes following mild ovarian stimulation was, in contrast to following conventional ovarian stimulation, associated with optimal pregnancy outcomes. Additionally, patients were found to be willing to undergo an increased number of treatment cycles as long as a mild ovarian stimulation protocol was applied. Furthermore, prediction models were developed to reduce the chance of cancellation following mild stimulation and to provide an evidence based method to identify women who may qualify for the transfer of a single versus two embryos. After external validation the first model should be able to reduce the chance of cancellation following mild stimulation to an average level, the second should lead to an increase the overall pregnancy rate per transfer while maintaining a low number of multiple pregnancies. These interventions could increase the efficacy and implementation of mild treatment strategies

Mild strategies for IVF: from theory to practice

Over the last 25 years, ovarian stimulation for IVF treatment has gradually become more complex, time consuming and expensive. Recently, the downsides of ovarian stimulation have attracted increasing attention. Currently, a shift in the focus of IVF is occurring from striving for maximizing instant success 'at all costs' to developing safer and more patient friendly protocols in which the risks of treatment are minimized while optimizing the chance of a singleton live birth. Strategies involving single embryo transfer and milder ovarian stimulation protocols) have been proposed to provide such a patient friendly strategy. An important concern regarding the use of mild treatment strategies remains the reduction in the per cycle chance of pregnancy. The principle aim of this thesis was to identify means of improving the efficacy and therefore the uptake of milder treatment strategies for IVF such as mild ovarian stimulation and SET. In this thesis it was shown that fear regarding the use of mild stimulation for a reduction in ovarian response or an increase of drop-outs (when the number of treatment cycles needed is increased) is unjustified. Indeed, the retrieval of a modest number of oocytes following mild ovarian stimulation was, in contrast to following conventional ovarian stimulation, associated with optimal pregnancy outcomes. Additionally, patients were found to be willing to undergo an increased number of treatment cycles as long as a mild ovarian stimulation protocol was applied. Furthermore, prediction models were developed to reduce the chance of cancellation following mild stimulation and to provide an evidence based method to identify women who may qualify for the transfer of a single versus two embryos. After external validation the first model should be able to reduce the chance of cancellation following mild stimulation to an average level, the second should lead to an increase the overall pregnancy rate per transfer while maintaining a low number of multiple pregnancies. These interventions could increase the efficacy and implementation of mild treatment strategies

Predictors of low response to mild ovarian stimulation initiated on cycle day 5 for IVF.

Background: Milder stimulation protocols are being developed to minimize adverse effects of ovarian stimulation in in vitro fertilization (IVF) programs. A drawback is the possibility of an increased rate of insufficient ovarian response. This study aimed to develop a prognostic model for the prediction of cycle cancellation due to insufficient response to mild stimulation. Methods: A total of 174 IVF patients aged &lt;38 years and with a body mass index (BMI) &lt;28 Kg/m2 were treated with mild ovarian stimulation using a fixed daily dose (150 IU) of recombinant follicle-stimulating hormone (rFSH) from cycle day 5 and GnRH antagonist from the late follicular phase. In women with mono- or bifollicular growth (17%), the cycle was cancelled and the treatment was adjusted in a second treatment cycle by starting rFSH on cycle day 2. Results: In a multivariable logistic regression analysis, duration of infertility, menstrual cycle length, secondary infertility and BMI were included in the prediction model. The area under the receiver-operating characteristics curve of the model was 0.69. A probability cut-off for cancellation of 0.3 yielded an expected sensitivity of 33% and specificity of 92%. Analysis of ovarian response in the subsequent treatment cycle showed an improved ovarian response and a significant reduction in the cancellation rate. Conclusions: With the presented model, it is possible to identify patients at risk for cycle cancellation, during mild ovarian stimulation, due to insufficient response. The contributing factors of the model suggest that ovarian aging and BMI are related to insufficient response to mild stimulation. <br/

The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis

Background: milder ovarian stimulation protocols for in vitro fertilization (IVF) are being developed to minimize adverse effects. Mild stimulation regimens result in a decreased number of oocytes at retrieval. After conventional ovarian stimulation for IVF, a low number of oocytes are believed to represent poor ovarian reserve resulting in reduced success rates. Recent studies suggest that a similar response following mild stimulation is associated with better outcomes. Methods: this review investigates whether the retrieval of a low number of oocytes following mild ovarian stimulation is associated with impaired implantation rates. Three randomized controlled trials comparing the efficacy of the mild ovarian stimulation regimen (involving midfollicular phase initiation of FSH and GnRH co-treatment) for IVF with a conventional long GnRH agonist co-treatment stimulation protocol could be identified by means of a systematic literature search. Results: these studies comprised a total of 592 first treatment cycles. Individual patient data analysis showed that the mild stimulation protocol results in a significant reduction of retrieved oocytes compared with conventional ovarian stimulation (median 6 versus 9, respectively, P &lt; 0.001). Optimal embryo implantation rates were observed with 5 oocytes retrieved following mild stimulation (31%) versus 10 oocytes following conventional stimulation (29%) (P = 0.045). Conclusions: the optimal number of retrieved oocytes depends on the ovarian stimulation regimen. After mild ovarian stimulation, a modest number of oocytes is associated with optimal implantation rates and does not reflect a poor ovarian response. Therefore, the fear of reducing the number of oocytes retrieved following mild ovarian stimulation appears to be unjustified

Randomized Trial of a Lifestyle Program in Obese Infertile Women

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Endometrial scratching in women with implantation failure after a first IVF/ICSI cycle; does it lead to a higher live birth rate? The SCRaTCH study : A randomized controlled trial (NTR 5342)

Background: Success rates of assisted reproductive techniques (ART) are approximately 30%, with the most important limiting factor being embryo implantation. Mechanical endometrial injury, also called 'scratching', has been proposed to positively affect the chance of implantation after embryo transfer, but the currently available evidence is not yet conclusive. The primary aim of this study is to determine the effect of endometrial scratching prior to a second fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle on live birth rates in women with a failed first IVF/ICSI cycle. Method: Multicenter randomized controlled trial in Dutch academic and non-academic hospitals. A total of 900 women will be included of whom half will undergo an endometrial scratch in the luteal phase of the cycle prior to controlled ovarian hyperstimulation using an endometrial biopsy catheter. The primary endpoint is the live birth rate after the 2nd fresh IVF/ICSI cycle. Secondary endpoints are costs, cumulative live birth rate (after the full 2nd IVF/ICSI cycle and over 12months of follow-up); clinical and ongoing pregnancy rate; multiple pregnancy rate; miscarriage rate and endometrial tissue parameters associated with implantation failure. Discussion: Multiple studies have been performed to investigate the effect of endometrial scratching on live birth rates in women undergoing IVF/ICSI cycles. Due to heterogeneity in both the method and population being scratched, it remains unclear which group of women will benefit from the procedure. The SCRaTCH trial proposed here aims to investigate the effect of endometrial scratching prior to controlled ovarian hyperstimulation in a large group of women undergoing a second IVF/ICSI cycle. Trial registration: NTR 5342 , registered July 31st, 2015. Protocol version: Version 4.10, January 4th, 2017