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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, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71–2.07) and RR 0.73 (95% CI 0.38–1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between −1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports ‘other’ from Ferring BV, personal fees from Up to date Hyperthecosis, ‘other’ from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work. TRIAL REGISTRATION NUMBER Registered in the Netherlands Trial Register (NL5193/NTR 5342). TRIAL REGISTRATION DATE 31 July 2015. DATE OF FIRST PATIENT’S ENROLMENT 26 January 2016.

STUDY QUESTION The objective of this trial is to compare the effectiveness and costs of true natural cycle (true NC-) frozen embryo transfer (FET) using urinary LH tests to modified NC-FET using repeated ultrasound monitoring and ovulation trigger to time FET in the NC. Secondary outcomes are the cancellation rates of FET (ovulation before hCG or no dominant follicle, no ovulation by LH urine test, poor embryo survival), pregnancy outcomes (miscarriage rate, clinical pregnancy rates, multiple ongoing pregnancy rates, live birth rates, costs) and neonatal outcomes (including gestational age, birthweight and sex, congenital abnormalities or diseases of babies born). WHAT IS KNOWN ALREADY FET is at the heart of modern IVF. To allow implantation of the thawed embryo, the endometrium must be prepared either by exogenous oestrogen and progesterone supplementation (artificial cycle (AC)-FET) or by using the NC to produce endogenous oestradiol before and progesterone after ovulation to time the transfer of the thawed embryo (NC-FET). During an NC-FET, women visit the hospital repeatedly and receive an ovulation trigger to time FET (i.e. modified (m)NC-FET or hospital-based monitoring). From the woman’s point of view, a more natural approach using home-based monitoring of the ovulation with LH urine tests to allow a natural ovulation to time FET may be desired (true NC-FET or home-based monitoring). STUDY DESIGN, SIZE, DURATION This is a multicentre, non-inferiority prospective randomised controlled trial design. Consenting women will undergo one FET cycle using either true NC-FET or mNC-FET based on randomisation. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on our sample size calculation, the study group will consist of 1464 women between 18 and 45 years old who are scheduled for FET. Women with anovulatory cycles, women who need ovulation induction and women with a contra indication for pregnancy will be excluded. The primary outcome is ongoing pregnancy. Secondary outcomes are cancellation rates of FET, pregnancy outcomes (including miscarriage rate, clinical pregnancy, multiple pregnancy rate and live birth rate). Costs will be estimated by counting resource use and calculating unit prices. STUDY FUNDING/COMPETING INTEREST(S) The study received a grant from the Dutch Organisation for Health Research and Development (ZonMw 843002807; www.zonmw.nl). ZonMw has no role in the design of the study, collection, analysis, and interpretation of data or writing of the manuscript. F.B. reports personal fees from member of the external advisory board for Merck Serono, grants from Research support grant Merck Serono, outside the submitted work. A.E.P.C. reports and Unrestricted grant of Ferring B.V. to the Center for Reproductive medicine, no personal fee. Author up-to-date on Hyperthecosis. Congress meetings 2019 with Ferring B.V. and Theramex B.V. M.G. reports Department research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the submitted work. E.R.G. reports personal fees from Titus Health Care, outside the submitted work. C.B.L. reports grants from Ferring, grants from Merck, from Guerbet, outside the submitted work. The other authors have none to declare. TRIAL REGISTRATION NUMBER Dutch Trial Register (Trial NL6414 (NTR6590), https://www.trialregister.nl/). TRIAL REGISTRATION DATE 23 July 2017 DATE OF FIRST PATIENT’S ENROLMENT 10 April 2018

Objective Sexual problems among cervical cancer survivors may in part be caused by reduced vaginal blood flow due to damaged hypogastric nerves during radical hysterectomy with pelvic lymphadenectomy and/or by radiation-induced vaginal changes after pelvic radiotherapy. A nerve-sparing modification of radical hysterectomy (NSRH) may preserve vaginal blood flow. Vaginal blood flow during sexual arousal was compared between different treatment modalities. Methods We investigated premenopausal women treated for early-stage cervical cancer with radical hysterectomy (n = 29), NSRH (n = 28), NSRH with radiotherapy (n = 14), and controls (n = 31). Genital arousal and subjective sexual arousal in response to sexual stimuli were measured using vaginal photoplethysmography and a questionnaire. Results were compared by using a between-study (treatment groups) by within-study (stimulus) design. Results Participants were aged 29 to 51 years (mean, 42 years) and at 1 to 14 years (mean, 5 years) after treatment. Measured vaginal blood flow in women treated with NSRH was similar to controls. Women treated with radical hysterectomy had a significantly lower vaginal blood flow compared with controls overall and lower compared with the NSRH group during sexual stimulation. Women treated with radiotherapy had a vaginal blood flow intermediate between the other groups without significant differences. The erotic films were equally effective in enhancing subjective sexual arousal among treatment groups. Conclusions Cervical cancer treatment with radical hysterectomy disrupts the vaginal blood flow response, and this may be prevented by conducting an NSRH. Treatment with radiotherapy did not significantly impact vaginal blood flow, but further investigation is needed with a larger sample.

Contains fulltext : 177721.pdf (Publisher’s version ) (Open Access) 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 12 months 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.

The objective of this study was to evaluate the problems with miction, defecation, and sexuality after a radical hysterectomy with or without adjuvant radiotherapy for the treatment of cervical cancer stage I–IIA. This study included an observational longitudinal study of self-reported bladder, defecation, and sexual problems with a baseline score. Ninety-four women were included in the study. An age-matched control group consisted of 224 women. The patients showed significantly more negative effects on sexual function compared with both the controls and their situation before the treatment throughout 24 months of follow-up. The problems included less lubrication, a narrow and short vagina, senseless areas around the labia, dyspareunia, and sexual dissatisfaction. Up to 12 months after the treatment, the patients complained significantly more of little or no urge to urinate and diarrhea as compared with the controls. Adjuvant radiotherapy did not increase the risk of bladder dysfunction, colorectal motility disorders, and sexual functions. We conclude that a radical hysterectomy for the treatment of early-stage cervical carcinoma is associated with adverse effects mainly on sexual functioning.

The objective of this study was to assess the role of postoperative radiotherapy (RT) in early-stage cervical carcinoma with risk factors other than positive nodes, parametrial invasion, or positive margins and to compare outcomes using the Leiden University Medical Center (LUMC) modification of the Gynecologic Oncology Group (GOG) system with the GOG prognostic scoring system itself. Between January 1984 and April 2005, 402 patients with early-stage cervical cancer underwent radical hysterectomy. A total of 51 patients (13%) had two of the three risk factors and had pathologic tumor size (≥40 mm), invasion (≥15 mm), and capillary lymphatic space involvement, and were identified as the so-called high-risk (HR). We compared 34 patients who received RT based on the LUMC risk profile (67%) with 17 who did not (33%). The GOG score was calculated as well. We compared the GOG scores within the LUMC risk groups: HR+ (two out of three risk factors) and HR− (less than two out of three risk factors). Differences in 5-year cancer-specific survival (CSS) and 5-year disease-free survival (DFS) between the HR group treated with RT (86%, 85%) and without RT (57%; 43%) were statistically significant. The LUMC criteria did not significantly differ from the GOG risk profile, concerning recurrence, CSS, and DFS. HR patients benefit from adjuvant RT. The LUMC modification of the GOG system seems to be simpler and has a slightly higher threshold for the indication for RT but without a difference in outcome.

ObjectiveConventional radical hysterectomy with pelvic lymphadenectomy (RHL) for early-stage cervical cancer is associated with significant bladder, anorectal, and sexual dysfunction. Nerve-sparing modification of RHL (NS-RHL) has been developed with the aim to reduce surgical treatment-related morbidity. Postoperative radiation therapy (RT) is offered to patients with unfavorable prognostic features to improve local control. The aim of the study was to assess self-reported morbidity of various types of treatment in cervical cancer patients.MethodsSelf-reported symptoms were prospectively assessed before and 1 and 2 years after treatment by the Dutch Gynaecologic Leiden Questionnaire.ResultsIncluded were 229 women (123 NS-RHL and 106 conventional RHL). Ninety-four (41%) received RT. Up to 2 years (response rate, 81%), women reported significantly more bowel, bladder, and sexual symptoms compared with the pretreatment situation. No significant difference was found between the conventional RHL and NS-RHL with the exception of the unexpected finding that a smaller percentage in the NS-RHL group (34% vs 68%) complained about numbness of the labia and/ or thigh. Radiation therapy had a negative impact on diarrhea, urine incontinence, lymphedema, and sexual symptoms (especially a narrow/short vagina).ConclusionsIn the current longitudinal cohort study, treatment for early-stage cervical cancer was associated with worse subjective bladder, anorectal, and sexual functioning, irrespective of the surgical procedure used. Postoperative RT resulted in a significant deterioration of these functions. The results have to be interpreted with caution in view of the study design and method used.

Background: The aim of this study was to investigate the psychometric properties of the items concerning sexual functioning of the Gynaecologic Leiden Questionnaire (LQ), which consists of items for post operative morbidity for women with cancer. Methods: The total study sample consisted of 198 subjects: 66 patients treated for cervical cancer, 66 patients with sexual complaints and 66 subjects from the general population. Results: By means of factor analysis three subscales were derived: Female Sexual Complaints, Female Sexual Function and Female Orgasm. The reliability of the subscales appeared to be satisfactory. The scores on the three subscales differentiated well between the patients treated for cervical cancer, patients with sexual complaints and the subjects from the general population. Furthermore, the subscales were sensitive to changes within the patients treated for cervical cancer. The convergent and divergent construct validities of the LQ were investigated using other instruments measuring sexual functioning, sexual dissatisfaction, marital distress, general life distress and psychological distress. The LQ subscales were found to represent relatively independent constructs. Conclusion: The results support the reliability and psychometric validity of the LQ in the assessment of sexual functioning and vaginal changes in gynaecological cancer patients. Copyright © 2007 John Wiley & Sons, Ltd.

To evaluate the possibility to give a prediction of the future (disease-free) survival, given the fact that a patient with a history of early-stage cervical cancer has been disease free for a specific period after treatment. Between January 1984 and April 2005, 615 patients with cervical cancer stages I–IIA underwent radical hysterectomy with or without adjuvant radiotherapy. The Kaplan–Meier method was used to detect statistical significance and multistate risk models to estimate the influence of covariates and to generate predicted survival curves by simulation. Simulations were done for patients with positive lymph nodes (n= 123), patients with negative lymph nodes (n= 492), and 4 hypothetical patients. The 5-year cancer-specific survival and disease-free survival of the entire group was 84% and 76%, respectively. The probability of death of the two lymph node groups and the four hypothetical patients was demonstrated in predicted cumulative probability plots. It is possible with multistate risk models to give a detailed prediction of the future (disease-free) survival, given the fact that a patient has been disease free for a specific period after treatment. This possibility is an important step forward to improve the quality of cancer care.

Radical hysterectomy with pelvic lymphadenectomy (RHL) for cervical cancer causes damage to the autonomic nerves, which are responsible for increased vaginal blood flow during sexual arousal. The aim of the study of which we now report preliminary data was to determine whether a nerve-sparing technique leads to an objectively less disturbed vaginal blood flow response during sexual stimulation. Photoplethysmographic assessment of vaginal pulse amplitude (VPA) during sexual stimulation by erotic films was performed. Subjective sexual arousal was assessed after each stimulus. Thirteen women after conventional RHL, 10 women after nerve-sparing RHL, and 14 healthy premenopausal women participated. Data were collected between January and August 2006. The main outcome measure was the logarithmically transformed mean VPA. To detect statistically significant differences in mean VPA levels between the three groups, a univariate analysis of variance was used. Mean VPA differed between the three groups (P= 0.014). The conventional group had a lower vaginal blood flow response than the control group (P= 0.016), which tended also to be lower than that of the nerve-sparing group (P= 0.097). These differences were critically dependent on baseline vaginal blood flow differences between the groups. The conventional group follows a vaginal blood flow pattern similar to postmenopausal women. Conventional RHL is associated with an overall disturbed vaginal blood flow response compared with healthy controls. Because it is not observed to the same extent after nerve-sparing RHL, it seems that the nerve-sparing technique leads to a better overall vaginal blood flow caused by less denervation of the vagina.

Aims To determine if the number of removed lymph nodes in radical hysterectomy with lymphadenectomy (RHL) influences survival of patients with early stage cervical cancer and to analyze the relation of different factors like patient age, tumour size and infiltration depth with the number of nodes examined in node-negative early stage cervical cancer patients. Methods Of consecutive patients, who underwent RHL between January 1984 and April 2005, 331 had negative nodes (group A) without adjuvant therapy and 136 had positive nodes (group B). The Kaplan–Meier method and Cox regression model were used to detect statistical significance. Factors associated with excision of nodes were confirmed with linear regression models. Results The median number of removed nodes was 19 and 18 for group A and group B, respectively. There was no significant relationship between the number of removed nodes and the cancer specific survival (CSS) or disease free survival (DSF) for patients of group A ( p =0.625 and p =0.877, respectively). The number of removed nodes in group B was not significantly associated with the CSS ( p =0.084) but it was for the DSF ( p =0.014). Factors like patient age, tumour size and infiltration depth were not associated with the number of nodes. Conclusions No relation was found between the number of negative nodes examined after RHL for the treatment of early stage cervical cancer and CSS or DFS. However, a higher amount of removed lymph nodes leaded to a better DFS for patients with positive nodes. It is suggested that patients with positive nodes benefit from a complete pelvic lymphadenectomy and a sufficient yield of removed nodes.