A multicentre double-blinded randomized controlled trial on the efficacy of laser-assisted hatching in patients with repeated implantation failure undergoing IVF or ICSI.

STUDY QUESTION: Does assisted hatching increase the cumulative live birth rate in subfertile couples with repeated implantation failure? SUMMARY ANSWER: This study showed no evidence of effect for assisted hatching as an add-on in subfertile couples with repeated implantation failure. WHAT IS KNOWN ALREADY: The efficacy of assisted hatching, with regard to the live birth rate has not been convincingly demonstrated in randomized trials nor meta-analyses. It is suggested though that especially poor prognosis women, e.g. women with repeated implantation failure, might benefit most from assisted hatching. STUDY DESIGN, SIZE, DURATION: The study was designed as a double-blinded, multicentre randomized controlled superiority trial. In order to demonstrate a statistically significant absolute increase in live birth rate of 10% after assisted hatching, 294 participants needed to be included per treatment arm, being a total of 588 subfertile couples. Participants were included and randomized from November 2012 until November 2017, 297 were allocated to the assisted hatching arm of the study and 295 to the control arm. Block randomization in blocks of 20 participants was applied and randomization was concealed from participants, treating physicians, and laboratory staff involved in the embryo transfer procedure. Ovarian hyperstimulation, oocyte retrieval, laboratory procedures, embryo selection for transfer and cryopreservation, the transfer itself, and luteal support were performed according to local protocols and were identical in both the intervention and control arm of the study with the exception of the assisted hatching procedure which was only performed in the intervention group. The laboratory staff performing the assisted hatching procedure was not involved in the embryo transfer itself. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were eligible for inclusion in the study after having had either at least two consecutive fresh IVF or ICSI embryo transfers, including the transfer of frozen and thawed embryos originating from those fresh cycles, and which did not result in a pregnancy or as having had at least one fresh IVF or ICSI transfer and at least two frozen embryo transfers with embryos originating from that fresh cycle which did not result in a pregnancy. The study was performed at the laboratory sites of three tertiary referral hospitals and two university medical centres in the Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE: The cumulative live birth rate per started cycle, including the transfer of fresh and subsequent frozen/thawed embryos if applicable, resulted in 77 live births in the assisted hatching group (n = 297, 25.9%) and 68 live births in the control group (n = 295, 23.1%). This proved to be statistically not significantly different (relative risk: 1.125, 95% CI: 0.847 to 1.494, P = 0.416). LIMITATIONS, REASONS FOR CAUTION: There was a small cohort of subfertile couples that after not achieving an ongoing pregnancy, still had cryopreserved embryos in storage at the endpoint of the trial, i.e. 1 year after the last randomization. It cannot be excluded that the future transfer of these frozen/thawed embryos increases the cumulative live birth rate in either or both study arms. Next, at the start of this study, there was no international consensus on the definition of repeated implantation failure. Therefore, it cannot be excluded that assisted hatching might be effective in higher order repeated implantation failures. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated no evidence of a statistically significant effect for assisted hatching by increasing live birth rates in subfertile couples with repeated implantation failure, i.e. the couples which, based on meta-analyses, are suggested to benefit most from assisted hatching. It is therefore suggested that assisted hatching should only be offered if information on the absence of evidence of effect is provided, at no extra costs and preferably only in the setting of a clinical trial taking cost-effectiveness into account. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR 3387, NL 3235, https://www.clinicaltrialregister.nl/nl/trial/26138). TRIAL REGISTRATION DATE: 6 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: 28 November 2012.

Increased amplitude of subendometrial contractions identified by ultrasound speckle tracking in women with a caesarean scar defect.

RESEARCH QUESTION: What is the effect of a caesarean scar defect on subendometrial contractions? DESIGN: Prospective cohort study in a Dutch medical centre including women with a niche in the uterine caesarean section scar. Data were compared with controls without a caesarean section scar. All women underwent a 5-min recording by transvaginal ultrasound at four phases in the menstrual cycle: during menses; late follicular; early luteal; or late luteal phase. Uterine motion analysis was evaluated by dedicated speckle tracking using two-dimensional optical flow. MAIN OUTCOME: amplitude of the subendometrial contractions. RESULTS: Thirty-one women with a niche in the uterine scar and 11 controls, matched for menstrual cycle phase, were included. The amplitude of the subendometrial contractions was significantly higher in women with a niche compared with controls during all phases of the menstrual cycle (menses P < 0.001; late follicular P < 0.001; early luteal P = 0.028; late luteal P = 0.003). Velocity was lower in women with a niche during late follicular phase only (P = 0.012). A positive correlation between niche sizes (depth, length) and amplitude of subendometrial contractions was found. CONCLUSION: Subendometrial contractions were affected in women with a niche in the caesarean section scar compared with women who had not undergone a previous caesarean section. Contraction amplitude was higher and independent of the menstrual phase. These findings may cause postmenstrual spotting, dysmenorrhoea and lower implantation rates in women with a niche. Future studies should investigate this association and the underlying pathways.

Characterization of Uterine Peristaltic Waves by Ultrasound Strain Analysis.

Uterine peristalsis (UP) is a wavelike uterine motion that plays an important role in the generation of intrauterine streams for menstrual emptying and to support embryo implantation. Our understanding of uterine mechanical behavior is hampered by a lack of quantitative analysis. Here, we propose a spatiotemporal analysis of UP by ultrasound speckle tracking and dedicated strain analysis. We aim at characterizing UP propagating around the endometrial cavity through the anterior and posterior walls of the uterus. To this end, velocity and coordination features are proposed in this study. We investigated a total of 11 healthy volunteers during their natural menstrual cycle and 81 patients undergoing in vitro fertilization (IVF) treatment. They all received multiple 4-min 2-D transvaginal ultrasound scans. Significant differences in propagation velocity were found among different phases of the menstrual cycle, which are in line with the expected uterine behavior. A significant difference in coordination was found between the group of women with successful (pregnancy at 11 weeks) and unsuccessful IVF. This result suggests that the ability to generate coordinated UP represents an important factor for IVF success. The proposed UP quantification may represent a valuable clinical tool for improved understanding of UP and improved decision-making in the context of IVF procedures.

External validation of Risk of Malignancy Index compared to IOTA Simple Rules.

BACKGROUND: Mathematical predictive models for ovarian tumors have an advantage over subjective assessment due to their relative simplicity, and therefore usefulness for less experienced sonographers. It is currently unclear which predictive model is best at predicting the nature of an ovarian tumor. PURPOSE: To compare the diagnostic predictive accuracy of the International Ovarian Tumour Analysis Simple Rules (IOTA SR) with Risk of Malignancy Index (RMI), to differentiate between benign and malignant ovarian tumors. MATERIAL AND METHODS: A total of 202 women diagnosed with ovarian tumor(s) were included. Preoperatively, patients were examined through transvaginal ultrasonography and CA-125 (U/mL) levels were measured. RMI and IOTA SR were determined, and where possible compared to definitive histopathological diagnosis. RESULTS: Of the 202 women with ovarian tumors, 168 women were included in this cohort study. Of these tumors, 118 (70.2%) were benign, 17 (10.1%) were borderline, and 33 (19.7%) were malignant. The sensitivity, specificity, and area under the curve for the RMI were 72.0%, 90.7%, and 0.896, respectively. For the IOTA SR, these were 90.0%, 68.6%, and 0.793, respectively. CONCLUSION: This cohort study shows that the RMI is a relatively useful diagnostic model in characterizing ovarian tumors, compared to the IOTA SR. However, due to the relatively low sensitivity of the RMI and high rate of inconclusive results of the IOTA SR, both diagnostic tests do not seem discriminative enough. Therefore, alternative diagnostic models are necessary.

Machine learning for classification of uterine activity outside pregnancy.

The objective of this study was to investigate the use of classification methods by a machine-learning approach for discriminating the uterine activity during the four phases of the menstrual cycle. Four different classifiers, including support vector machine (SVM), K-nearest neighbors (KNN), Gaussian mixture model (GMM) and naïve Bayes are here proposed. A set of amplitude- and frequency-features were extracted from signals measured by two different quantitative and noninvasive methods, such as electrohysterography and ultrasound speckle tracking. The proposed classifiers were trained using all possible feature combinations. The method was applied on a database (24 measurements) collected in different phases of the menstrual cycle, comprising uterine active and quiescent phases. The SVM classifier showed the best performance for discrimination between the different menstrual phases. The classification accuracy, sensitivity, and specificity were 90%, 79%, 93%, respectively. Similar methods can in the future contribute to the diagnosis of infertility or other common uterine diseases such as endometriosis.

Prevalence and predictors of depression and well-being after hysterectomy: An observational study.

OBJECTIVES: To assess risk and predictive factors for depression and well-being, 3 and 12 months after elective hysterectomy. Secondary objectives were to assess the incidence of depression, level of well-being, and feelings of femininity. STUDY DESIGN: A prospective multicenter cohort study was performed among 419 women, undergoing hysterectomy for benign indication. Data were collected in the week prior to surgery, and in the per- and postoperative period up to the fourth postoperative day and 3 and 12 months after surgery. Sociodemographic variables, baseline health status, psychosocial predictors, and surgery data were assessed. Outcome measures were Center for Epidemiological Studies-Depression scale (CES-D, range 0-60), the 12-item well-being questionnaire energy and positive well-being subscales (range 0-12), and feelings of femininity. Predictor analyses were performed using linear mixed model analyses. RESULTS: Levels of depression, energy, and positive well-being after hysterectomy were predicted by their corresponding baseline levels (estimate 0.62 p<0.001, 0.39 p<0.001, 0.37 p<0.001, respectively) and baseline pain (0.31 p=0.003, -0.09 p=0.026, -0.10 p=0.008). Postoperative infection reported at 12 months affected CES-D and energy level. Several other gynaecological, psychosocial, or perioperative factors were also predictive for one of the outcomes. Prevalence of depression at baseline, 3 and 12 months was 24%, 19%, and 21%, respectively. In general, well-being scores were slightly higher 3 and 12 months after hysterectomy than at baseline. Feelings of femininity were not negatively affected in 92% of the patients. CONCLUSIONS: Preoperative psychosocial status, perioperative pain, and postoperative infection were found as predictors of psychological outcome after hysterectomy. In the majority of patients we observed small but significant improvements with regard to postoperative depression and well-being, while feelings of femininity were unaffected.

Outcomes of pregnancies in women with hysteroscopically placed micro-inserts in situ.

This was a retrospective review of all pregnancies reported after Essure in situ in the Netherlands. Pregnancies included those that were unintentional (resulting from lack of protocol adherence and/or misread confirmation tests) and those that were intentional (resulting from off-label use of Essure micro-inserts for hydrosalpinx closure before in vitro fertilization/intracytoplasmic sperm injection with embryo transfer or in vitro fertilization with embryo transfer after regret of sterilization). The outcomes of 50 pregnancies in women with 1 or 2 micro-inserts in situ were evaluated. Eight unintended pregnancies and 18 intended pregnancies resulted in birth of a full-term healthy baby. Seven infants were delivered via cesarean-section. Two women delivered prematurely by C-section, (singleton after 34 weeks 1 day, twins after 35 weeks 3 days). All babies are healthy and without any congenital anomalies. There were 2 stillbirths after 20 weeks; however, it is unlikely that this was related to the presence of the micro-inserts. In conclusion, it is unlikely that the presence of intratubal micro-inserts interferes with implantation and the developing amniotic sac and fetus.

First report of transvaginal endoscopic microsurgery in a patient with squamous cell carcinoma of the vagina.

Transanal endoscopic microsurgery has been used by surgeons since 1983. All these years of experience and research have shown that this is a safe and successful approach for rectal neoplasms, both benign and malignant. The advantage of this procedure is the excellent view and hence precise surgical margins in an operative field that is otherwise difficult to reach. Furthermore, selected patients who used to require major rectal surgery now may be treated using this minimally invasive technique. These advantages may also be favorable for the gynecological field, especially in intravaginal surgery. Our case report describes the first successfully performed transvaginal endoscopic microsurgery in a woman with residual disease after treatment with chemoradiation for squamous cell carcinoma of the vagina. Despite the difficulty of operating in tissue with post-radiation effect, the rest of the tumor was excised with clear surgical margins without damage to the rectum. The patient was discharged from the hospital 2 days after the procedure and recovered without complications.

The inSIGHT study: costs and effects of routine hysteroscopy prior to a first IVF treatment cycle. A randomised controlled trial.

BACKGROUND: In in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI) treatment a large drop is present between embryo transfer and occurrence of pregnancy. The implantation rate per embryo transferred is only 30%. Studies have shown that minor intrauterine abnormalities can be found in 11-45% of infertile women with a normal transvaginal sonography or hysterosalpingography. Two randomised controlled trials have indicated that detection and treatment of these abnormalities by office hysteroscopy after two failed IVF cycles leads to a 9-13% increase in pregnancy rate. Therefore, screening of all infertile women for intracavitary pathology prior to the start of IVF/ICSI is increasingly advocated. In absence of a scientific basis for such a policy, this study will assess the effects and costs of screening for and treatment of unsuspected intrauterine abnormalities by routine office hysteroscopy, with or without saline infusion sonography (SIS), prior to a first IVF/ICSI cycle. METHODS/DESIGN: Multicenter randomised controlled trial in asymptomatic subfertile women, indicated for a first IVF/ICSI treatment cycle, with normal findings at transvaginal sonography. Women with recurrent miscarriages, prior hysteroscopy treatment and intermenstrual blood loss will not be included. Participants will be randomised for a routine fertility work-up with additional (SIS and) hysteroscopy with on-the-spot-treatment of predefined intrauterine abnormalities versus the regular fertility work-up without additional diagnostic tests. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months of IVF/ICSI treatment after randomisation. Secondary study outcome parameters are the cumulative implantation rate; cumulative miscarriage rate; patient preference and patient tolerance of a SIS and hysteroscopy procedure. All data will be analysed according to the intention-to-treat principle, using univariate and multivariate logistic regression and cox regression. Cost-effectiveness analysis will be performed to evaluate the costs of the additional tests as routine procedure. In total 700 patients will be included in this study. DISCUSSION: The results of this study will help to clarify the significance of hysteroscopy prior to IVF treatment. TRIAL REGISTRATION: NCT01242852.

Teaching diagnostic and therapeutic procedures of bladder pathology using a newly developed pig bladder model.

PURPOSE: To present a newly developed, low-cost, easy-to-use training model for diagnostic and therapeutic procedures in bladder pathology with real-time haptics. MATERIALS AND METHODS: The model consists of a white plastic box in which a removable unit is placed and has been constructed to accommodate a prepared pig bladder on a metal plate. Small and large bladder tumors can be created in the bladder enabling diagnostics and treatment. Also, foreign bodies, such as bladder stones, can be inserted for training in cystolitholapaxy. RESULTS: This training model provides a realistic environment for training with the same instruments that are used in clinical practice. Numerous procedures can be performed, such as flexible and rigid urethrocystoscopy, biopsy taking, transurethral tumor resection, and cystolitholapaxy. The model is cheap and simple to create and install. Its practical usefulness has been proven during several training courses. Validation studies are under way. CONCLUSIONS: Training in diagnostic and therapeutic procedures in bladder pathology can be performed using this novel pig bladder model. The model offers a nonpressurized environment in which residents can acquire practical as well as procedural skills and material knowledge of urethrocystoscopy, transurethral resection of bladder tumor, biopsy taking, and cystolitholapaxy.