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Background: In vitro fertilisation is a widely used reproductive technique that can be undertaken with or without intracytoplasmic sperm injection. The endometrial scratch procedure is an in vitro fertilisation 'add-on' that is sometimes provided prior to the first in vitro fertilisation cycle, but there is a lack of evidence to support its use., Objectives: (1) To assess the clinical effectiveness, safety and cost-effectiveness of endometrial scratch compared with treatment as usual in women undergoing their first in vitro fertilisation cycle (the 'Endometrial Scratch Trial') and (2) to undertake a systematic review to combine the results of the Endometrial Scratch Trial with those of previous trials in which endometrial scratch was provided prior to the first in vitro fertilisation cycle., Design: A pragmatic, multicentre, superiority, open-label, parallel-group, individually randomised controlled trial. Participants were randomised (1 : 1) via a web-based system to receive endometrial scratch or treatment as usual using stratified block randomisation. The systematic review involved searching electronic databases (undertaken in January 2020) and clinicaltrials.gov (undertaken in September 2020) for relevant trials., Setting: Sixteen UK fertility units., Participants: Women aged 18-37 years, inclusive, undergoing their first in vitro fertilisation cycle. The exclusion criteria included severe endometriosis, body mass index ≥ 35 kg/m 2 and previous trauma to the endometrium., Interventions: Endometrial scratch was undertaken in the mid-luteal phase of the menstrual cycle prior to in vitro fertilisation, and involved inserting a pipelle into the cavity of the uterus and rotating and withdrawing it three or four times. The endometrial scratch group then received usual in vitro fertilisation treatment. The treatment-as-usual group received usual in vitro fertilisation only., Main Outcome Measures: The primary outcome was live birth after completion of 24 weeks' gestation within 10.5 months of egg collection. Secondary outcomes included implantation, pregnancy, ectopic pregnancy, miscarriage, pain and tolerability of the procedure, adverse events and treatment costs., Results: One thousand and forty-eight (30.3%) women were randomised to treatment as usual ( n  = 525) or endometrial scratch ( n  = 523) and were followed up between July 2016 and October 2019 and included in the intention-to-treat analysis. In the endometrial scratch group, 453 (86.6%) women received the endometrial scratch procedure. A total of 494 (94.1%) women in the treatment-as-usual group and 497 (95.0%) women in the endometrial scratch group underwent in vitro fertilisation. The live birth rate was 37.1% (195/525) in the treatment-as-usual group and 38.6% (202/523) in the endometrial scratch group: an unadjusted absolute difference of 1.5% (95% confidence interval -4.4% to 7.4%; p  = 0.621). There were no statistically significant differences in secondary outcomes. Safety events were comparable across groups. No neonatal deaths were recorded. The cost per successful live birth was £11.90 per woman (95% confidence interval -£134 to £127). The pooled results of this trial and of eight similar trials found no evidence of a significant effect of endometrial scratch in increasing live birth rate (odds ratio 1.03, 95% confidence interval 0.87 to 1.22)., Limitations: A sham endometrial scratch procedure was not undertaken, but it is unlikely that doing so would have influenced the results, as objective fertility outcomes were used. A total of 9.2% of women randomised to receive endometrial scratch did not undergo the procedure, which may have slightly diluted the treatment effect., Conclusions: We found no evidence to support the theory that performing endometrial scratch in the mid-luteal phase in women undergoing their first in vitro fertilisation cycle significantly improves live birth rate, although the procedure was well tolerated and safe. We recommend that endometrial scratch is not undertaken in this population., Trial Registration: This trial is registered as ISRCTN23800982., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 10. See the NIHR Journals Library website for further project information.

Study Question: What is the clinical-effectiveness and safety of the endometrial scratch (ES) procedure compared to no ES, prior to usual first time in vitro fertilisation (IVF) treatment?, Summary Answer: ES was safe but did not improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF cycle, with or without intracytoplasmic sperm injection (ICSI)., What Is Known Already: ES is an 'add-on' treatment that is available to women undergoing a first cycle of IVF, with or without ICSI, despite a lack of evidence to support its use., Study Design, Size, Duration: This pragmatic, superiority, open-label, multi-centre, parallel-group randomised controlled trial involving 1048 women assessed the clinical effectiveness and safety of the ES procedure prior to first time IVF, with or without ICSI, between July 2016 and October 2019., Participants/materials, Setting, Methods: Participants aged 18-37 years undergoing their first cycle of IVF, with or without ICSI, were recruited from 16 UK fertility clinics and randomised (1:1) by a web-based system with restricted access rights that concealed allocation. Stratified block randomisation was used to allocate participants to TAU or ES in the mid-luteal phase followed by usual IVF with or without ICSI treatment. The primary outcome was live birth after completing 24 weeks gestation within 10.5 months of egg collection., Main Results and the Role of Chance: In total, 1048 women randomised to TAU (n = 525) and ES (n = 523) were available for intention to treat analysis. In the ES group, 453 (86.6%) received the ES procedure. IVF, with or without ICSI, was received in 494 (94.1%) and 497 (95.0%) of ES and TAU participants respectively. Live birth rate was 37.1% (195/525) in the TAU and 38.6% (202/523) in the ES: an unadjusted absolute difference of 1.5% (95% CI -4.4% to 7.4%, P = 0.621). There were no statistical differences in secondary outcomes. Adverse events were comparable across groups., Limitations, Reasons for Caution: A sham ES procedure was not undertaken in the control group, however, we do not believe this would have influenced the results as objective fertility outcomes were used., Wider Implications of the Findings: This is the largest trial that is adequately powered to assess the impact of ES on women undergoing their first cycle of IVF. ES was safe, but did not significantly improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF or ICSI cycle. We recommend that ES is not undertaken in this population., Study Funding/competing Interest(s): Funded by the National Institute of Health Research. Stephen Walters is an National Institute for Health Research (NIHR) Senior Investigator (2018 to present) and was a member of the following during the project: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Clinical Trials and Evaluation Committee (2011-2017), NIHR HTA Commissioning Strategy Group (2012 to 2017); NIHR Programme Grants for Applied Research Committee (2020 to present); NIHR Pre doctoral Fellowship Committee (2019 to present). Dr. Martins da Silva reports grants from AstraZeneca, during the conduct of the study; and is Associate editor of Human Reproduction and Editorial Board member of Reproduction and Fertility. Dr. Bhide reports grants from Bart's Charity and grants and non-financial support from Pharmasure Pharmaceuticals outside the submitted work., Trial Registration Number: ISRCTN number: ISRCTN23800982., Trial Registration Date: 31 May 2016., Date of First Patient’s Enrolment: 04 July 2016., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Objective: To assess the role of the variant p.Asn680Ser in the follicle-stimulating hormone receptor (FSHR) gene in determining ovarian response in patients undergoing in vitro fertilization (IVF) treatment., Design: Prospective observational study., Setting: Tertiary referral center for reproductive medicine., Patient(s): Women (n = 421) undergoing their first cycle of controlled ovarian stimulation for IVF and 83 healthy, ethnically matched controls., Intervention(s): Baseline pelvic ultrasound and blood tests taken on days 2 to 3 of the cycle for assessment of baseline hormones and for DNA extraction., Main Outcome Measure(s): Genotypes for FSHR p.Asn680Ser determined using TaqMan allelic discrimination assay, and ovarian response to gonadotropin treatment classified as normal, poor, or overresponse based on the number of oocytes retrieved., Result(s): The FSHR p.Asn680Ser genotype frequencies were similar in IVF patients and controls. The number of oocytes retrieved was comparable between patients with different FSHR receptor genotypes. The total amount of gonadotropin used was also similar in all the genotype groups. A logistic regression analysis showed nonstatistically significant twofold difference in the distribution of genotypes between the groups with poor and normal ovarian response., Conclusion(s): The variant FSHR p.Asn680Ser was not shown to be predictive of ovarian response, but clinically relevant differences cannot be ruled out., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: In an effort to improve outcomes of in-vitro fertilisation cycles the use of growth hormone has been considered. Improving the outcomes of in-vitro fertilisation is especially important for subfertile women who are considered 'poor responders'., Objectives: To assess the effectiveness of adjuvant growth hormone in in-vitro fertilisation protocols., Search Strategy: We searched the Cochrane Menstrual Disorders and Subfertility Groups trials register (June 2009), the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 2, 2009), MEDLINE (1966 to June 2009), EMBASE (1988 to June 2009) and Biological Abstracts (1969 to June 2009)., Selection Criteria: All randomised controlled trials were included if they addressed the research question and provided outcome data for intervention and control participants., Data Collection and Analysis: Assessment of trial risk of bias and extraction of relevant data was performed independently by two reviewers., Main Results: Ten studies (440 subfertile couples) were included. Results of the meta-analysis demonstrated no difference in outcome measures and adverse events in the routine use of adjuvant growth hormone in in-vitro fertilisation protocols. However, meta-analysis demonstrated a statistically significant difference in both live birth rates and pregnancy rates favouring the use of adjuvant growth hormone in in-vitro fertilisation protocols in women who are considered poor responders without increasing adverse events, OR 5.39, 95% CI 1.89 to 15.35 and OR 3.28, 95% CI 1.74 to 6.20 respectively., Authors' Conclusions: Although the use of growth hormone in poor responders has been found to show a significant improvement in live birth rates, we were unable to identify which sub-group of poor responders would benefit the most from adjuvant growth hormone. The result needs to be interpreted with caution, the included trials were few in number and small sample size. Therefore, before recommending growth hormone adjuvant in in-vitro fertilisation further research is necessary to fully define its role.

The ovarian response to follicle stimulating hormone (FSH) stimulation in assisted conception cycles is variable. Although it would be beneficial to predict accurately the response of patients to FSH, to date no absolute predictors of ovarian performance have been identified. Recently, there have been a number of studies on the effect of single-nucleotide polymorphisms (SNPs) in the FSH receptor gene and its predictability in ovarian response to FSH stimulation. Several reports have shown that two very common SNPs at positions 307 and 680 in exon 10 of the FSH receptor gene are associated with ovarian response in IVF. The SNPs in exon 10 result in four discrete allelic variants characterised by the amino acid combinations Thr(307)-Asn(680), Ala(307)-Ser(680), Ala(307)-Asn(680) and Thr(307)-Ser(680). Because Thr(307) is almost always in linkage disequilibrium with Asn(680), and Ala(307) almost always with Ser(680), most studies are focussed solely on position 680. Some authors have shown predictability of ovarian response to FSH stimulation in patients with different alleles, while others have refuted this finding. In vitro models have not shown any difference in response among various alleles. Most of the available studies are retrospective, observational. Until now, there is no clear clinical benefit in the screening for SNP before IVF treatment. However, there is the prospect of devising mathematical models using a group of polymorphisms to provide an important tool for improving ovulation induction, especially in poor responders.