Instruments to Identify Menstrual Complaints and Their Impact on Adolescents: A Systematic Review.

STUDY OBJECTIVE: The aim of this review was to create an overview of available instruments used to evaluate the menstrual complaints of dysmenorrhea and heavy menstrual bleeding (HMB) in adolescents. METHODS: The search was conducted in PubMed, Web of Science, Embase, and PsycINFO on December 1, 2022. Studies published in English reporting on menstrual complaints among girls aged 10-19 were included. The quality and bias risk was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. RESULTS: Of 8994 identified studies, 57 were included. In these studies, 19 instruments were described, of which 8 were validated in adolescents. One was difficult to use in daily practice, 1 had low sensitivity and specificity in the detection of HMB, 2 were validated by face validity, and 2 were not specifically developed to evaluate (the impact of) menstrual complaints. Therefore, only 2 were validated and feasible to measure adolescent menstrual complaints: the Period ImPact and Pain Assessment (PIPPA) and the Adolescent Menstrual Bleeding Questionnaire (aMBQ). Remarkably, the Pictorial Blood Loss Assessment Chart (PBAC) was the most frequently used instrument in adolescents. There was one modified version of the PBAC for adolescents, which had a lower cutoff value for HMB and low sensitivity and specificity. CONCLUSION: We found that the PIPPA and aMBQ are suitable for assessing menstrual complaints and their impact on daily activities and health-related quality of life in adolescents. The PBAC, which is used frequently in adults, needs to be further assessed specifically for adolescents. In particular, the clinical relevance of the PBAC cutoff value for HMB should be determined for this age group. Considering the different interpretations, experiences, and limited knowledge of menstrual complaints, instruments suitable for adults may not be suitable for adolescents.

Home-based monitoring of ovulation to time frozen embryo transfers in the Netherlands (Antarctica-2): an open-label, nationwide, randomised, non-inferiority trial.

BACKGROUND: The growing field of assisted reproductive techniques, including frozen-thawed embryo transfer (FET), should lead the way to the best sustainable health care without compromising pregnancy chances. Correct timing of FET is crucial to allow implantation of the thawed embryo. Nowadays, timing based on hospital-controlled monitoring of ovulation in the natural cycle of a woman is the preferred strategy because of the assumption of favourable fertility prospects. However, home-based monitoring is a simple method to prevent patient travel and any associated environmental concerns. We compared ongoing pregnancy rates after home-based monitoring versus hospital-controlled monitoring with ovulation triggering. METHODS: This open-label, multicentre, randomised, non-inferiority trial was undertaken in 23 hospitals and clinics in the Netherlands. Women aged between 18 and 44 years with a regular ovulatory menstrual cycle were randomly assigned in a 1:1 ratio via a web-based randomisation program to home-based monitoring or hospital-controlled monitoring. Those who analysed the data were masked to the groups; those collecting the data were not. All endpoints were analysed by intention to treat and per protocol. Non-inferiority was established when the lower limit of the 90% CI exceeded -4%. This study was registered at the Dutch Trial Register (Trial NL6414). FINDINGS: 1464 women were randomly assigned between April 10, 2018, and April 13, 2022, with 732 allocated to home-based monitoring and 732 to hospital-controlled monitoring. Ongoing pregnancy occurred in 152 (20·8%) of 732 in the home-based monitoring group and in 153 (20·9%) of 732 in the hospital-controlled monitoring group (risk ratio [RR] 0·99 [90% CI 0·81 to 1·22]; risk difference [RD] -0·14 [90% CI -3·63 to 3·36]). The per-protocol analysis confirmed non-inferiority (152 [21·0%] of 725 vs 153 [21·0%] of 727; RR 1·00 (90% CI 0·81 to 1·23); RD -0·08 [90% CI -3·60 to 3·44]). INTERPRETATION: Home-based monitoring of ovulation is non-inferior to hospital-controlled monitoring of ovulation to time FET. FUNDING: The Dutch Organisation for Health Research and Development.

Levonorgestrel-releasing intrauterine system versus endometrial ablation for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding affects the physical functioning and social well-being of many women. The levonorgestrel-releasing intrauterine system and endometrial ablation are 2 frequently applied treatments in women with heavy menstrual bleeding. OBJECTIVE: This study aimed to compare the effectiveness of the levonorgestrel-releasing intrauterine system with endometrial ablation in women with heavy menstrual bleeding. STUDY DESIGN: This multicenter, randomized controlled, noninferiority trial was performed in 26 hospitals and in a network of general practices in the Netherlands. Women with heavy menstrual bleeding, aged 34 years and older, without a pregnancy wish or intracavitary pathology were randomly allocated to treatment with either the levonorgestrel-releasing intrauterine system (Mirena) or endometrial ablation, performed with a bipolar radiofrequency device (NovaSure). The primary outcome was blood loss at 24 months, measured with a Pictorial Blood Loss Assessment Chart score. Secondary outcomes included reintervention rates, patient satisfaction, quality of life, and sexual function. RESULTS: We registered 645 women as eligible, of whom 270 women provided informed consent. Of these, 132 women were allocated to the levonorgestrel-releasing intrauterine system (baseline Pictorial Blood Loss Assessment Chart score, 616) and 138 women to endometrial ablation (baseline Pictorial Blood Loss Assessment Chart score, 630). At 24 months, mean Pictorial Blood Loss Assessment Chart scores were 64.8 in the levonorgestrel-releasing intrauterine system group and 14.2 in the endometrial ablation group (difference, 50.5 points; 95% confidence interval, 4.3-96.7; noninferiority, P=.87 [25 Pictorial Blood Loss Assessment Chart point margin]). Compared with 14 women (10%) in the endometrial ablation group, 34 women (27%) underwent a surgical reintervention in the levonorgestrel-releasing intrauterine system group (relative risk, 2.64; 95% confidence interval, 1.49-4.68). There was no significant difference in patient satisfaction and quality of life between the groups. CONCLUSION: Both the levonorgestrel-releasing intrauterine system and endometrial ablation strategies lead to a large decrease in menstrual blood loss in women with heavy menstrual bleeding, with comparable quality of life scores after treatment. Nevertheless, there was a significant difference in menstrual blood loss in favor of endometrial ablation, and we could not demonstrate noninferiority of starting with the levonorgestrel-releasing intrauterine system. Women who start with the levonorgestrel-releasing intrauterine system, a reversible and less invasive treatment, are at an increased risk of needing additional treatment compared with women who start with endometrial ablation. The results of this study will enable physicians to provide women with heavy menstrual bleeding with the evidence to make a well-informed decision between the 2 treatments.

Ulipristal acetate versus gonadotropin-releasing hormone agonists prior to laparoscopic myomectomy (MYOMEX trial): Long term results of a double-blind randomized controlled trial.

OBJECTIVE: The aim of this study was to compare the effect of ulipristal acetate (UPA) and gonadotropin-releasing hormone agonists (GnRHa) before laparoscopic myomectomy on long term secondary outcomes of the MYOMEX-trial, regarding quality of life, ultrasound characteristics, hemoglobin levels 6 weeks post-operative, sexual function and menstrual bleeding control. A cost-analysis was also performed. Short-term primary and secondary outcomes are reported elsewhere. STUDY DESIGN: A double-blind, randomized, controlled, non-inferiority trial in nine hospitals in the Netherlands. Participants were randomized in a 1:1 ratio (block size of four, stratified per hospital) to either UPA or GnRHa pre-treatment. Additional placebo injections containing saline, respectively daily placebo tablets were given to both groups to ensure double-blinding. Surgery was performed within a month after the last tablet. Women were followed up until six months post-surgery. RESULTS: A total of 55 participants were randomized: 30 to the UPA- and 25 to the GnRHa-group between May 2015 and July 2017. Uterine volume at six weeks post-operative did not differ significantly between both pre-treatment groups with 170.1 cm3 (106.8-243.5; N = 29) vs. 152.8 cm3 (92.3-205.6; N = 23) for the UPA- and GnRHa-group respectively (p = 0.423). Hemoglobin levels six weeks post-operatively recovered back to baseline and were not significantly different between groups with 7.7 mmol/L for the UPA- vs. 8.1 mmol/L for the GnRHa-group (p = 0.157; mean difference -0.4 (CI -0.9, 0.2). Menstrual bleeding pattern, quality of life, effects on general and sexual health showed a significant improvement compared to baseline in both groups without any differences between the treatment groups. Symptom severity scores also decreased significantly at 6 week post-operatively compared to baseline, but did not differ between the treatment groups. Fibroid characteristics at baseline (e.g. mean diameter of largest fibroid) appeared not to be a confounding factor. An exploratory cost analysis showed no significant differences in absenteeism costs, total healthcare and societal costs, after adjustment for confounding factors. CONCLUSION: Pre-treatment prior to laparoscopic myomectomy with UPA compared to GnRHa has similar effects on bleeding pattern, menopausal symptoms, sexual functioning, symptom severity and quality of life from baseline up to six months post-operative. Due to the small sample size, these findings should be interpreted with caution. Also, no firm conclusions on costs could be made.

Role of FAM19A4/miR124-2 methylation analysis in predicting regression or non-regression of CIN2/3 lesions: a protocol of an observational longitudinal cohort study.

INTRODUCTION: The clinical course of high-grade cervical intraepithelial neoplasia (CIN2/3) is characterised by a high spontaneous regression rate. Histological assessment is unable to differentiate between CIN2/3 lesions likely to regress and those likely to persist or progress. Most CIN2/3 lesions are treated by surgical excision, leading to overtreatment of a substantial proportion. In this prospective study, we evaluate the value of DNA methylation of host cell genes, which has shown to be particularly sensitive for the detection of advanced CIN2/3 and cervical cancer, in the prediction of regression or non-regression of CIN2/3 lesions. METHODS AND ANALYSIS: This is a multicentre observational longitudinal study with 24-month follow-up. Women referred for colposcopy with an abnormal cervical scrape, who have been diagnosed with CIN2/3 and a small cervical lesion (≤50% of cervix) will be asked to participate. Participants will be monitored by 6-monthly cytological and colposcopic examination. In case of clinical progression, participants will receive treatment and exit the study protocol. At baseline and during follow-up, self-sampled cervicovaginal brushes and cervical scrapes will be collected for high-risk human papillomavirus (HPV) testing and FAM19A4/miR124-2 methylation analysis. A colposcopy-directed biopsy will be taken from all participants at the last follow-up visit. The primary study endpoint is regression or non-regression at the end of the study based on the histological diagnosis. Regression is defined as CIN1 or less. Non-regression is defined as CIN2 or worse. The secondary study endpoint is defined as HPV clearance (double-negative HPV test at two consecutive time-points). The association between methylation status and regression probability will be evaluated by means of χ2 testing. ETHICS AND DISSEMINATION: Ethics approval was obtained in all participating clinics. Results of the main study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NTR6069; Pre-results.

Reproducibility of three-dimensional gel installation sonohysterography in the assessment and classification of intrauterine abnormalities.

OBJECTIVE: Purpose of this study is to determine the interobserver and intraobserver variability of 3D GIS in the assessment of intrauterine abnormalities. STUDY DESIGN: Forty five 3D volumes were randomly selected from a larger prospective cohort study that studied the diagnostic accuracy of 3D GIS in addition to 2D GIS. To study interobserver agreement volumes were reviewed by two independent examiners. One examiner reviewed these samples twice with an interval of 1 month in a random order. Interobserver and intraobserver agreement were tested with Cohen's kappa coefficient and shown in Bland and Altman plots. Quality of the 3D volumes was evaluated. RESULTS: Cohen's kappa for interobserver variability for type of abnormalities (none, polyp, fibroid, other) was 0.64 and for presence of a fibroid (fibroid yes/no) 0.77. Agreement on type of fibroid was 0.59. Intraobserver agreement was almost perfect for type of abnormality (Cohen's kappa of 1.0) and good for fibroid diameter. Quality of the 3D volumes was poor in 11 out of 45 cases. Reproducibility increased when poor quality images were excluded. CONCLUSION: Substantial interobserver and intraobserver agreement for 3D GIS in the diagnoses of intrauterine abnormalities was found. 3D GIS interobserver and intraobserver agreement are good for fibroid diameter and moderate for volume and protrusion.

Diagnostic and clinical value of 3D gel installation sonohysterography in addition to 2D gel installation sonohysterography in the assessment of intrauterine abnormalities.

OBJECTIVE: To study the diagnostic value of three-dimensional gel instillation sonography (3D GIS) in addition to two-dimensional (2D) GIS in the assessment of intrauterine abnormalities. Secondly, the clinical value of 3D GIS in the planning for hysteroscopic procedures was evaluated. STUDY DESIGN: A prospective cohort study was performed from 2008 till 2010. All women with a suspected intrauterine abnormality on 2D GIS suitable for hysteroscopic resection or with recurrent postmenstrual bleeding were planned for a hysteroscopic procedure. Diagnostic accuracy tests were calculated for the detection of fibroids and polyps with both histology and hysteroscopy as the reference standard. For the assessment of type and size of fibroids hysteroscopy was used as the reference standard. We compared the planning for type of hysteroscopy based on 2D GIS findings with the combined 2D-3D GIS findings. RESULTS: In total 110 patients were analysed. In comparison to histology, addition of 3D GIS did not change sensitivity or specificity substantially in the discrimination between fibroids and polyps. In comparison to hysteroscopy, sensitivity increased for detecting fibroids and polyps, without major interference with the specificity. Despite an improved accuracy after the addition of 3D GIS, the planning for hysteroscopic procedures did not improve substantially. CONCLUSION: In daily practice, the addition of 3D GIS to 2D GIS improved the accuracy for the detection of polyps and fibroids compared to hysteroscopy, but only marginally improved the planning of hysteroscopic procedures, and therefore the clinical relevance seems to be limited.

Increasing experience in laparoscopic staging of early ovarian cancer.

We assessed the effect of increasing experience of a single surgeon (learning curve) in the laparoscopic staging procedure for women with early ovarian cancer and compared the results with the literature. We retrospectively analysed a total of 25 women with apparent early-stage ovarian cancer who underwent a laparoscopic staging procedure by the same surgeon. Three time periods, based on date of surgery, were compared with respect to operating time, amount of lymph nodes harvested and surgical outcome. There was no significant difference in operation time, estimated blood loss and hospital stay between the three periods. There was, however, a significant increase in the median number of pelvic and para-aortal lymph nodes harvested (group1 = 6.5, group 2 = 8.0 and group 3 = 21.0; P < 0.005). For the total period, median operation time was 235 min and median estimated blood loss was 100 ml. The median length of hospital stay was 4.0 days. Two intraoperative and two postoperative complications occurred. The upstaging rate was 32%. The mean interval between initial surgery and laparoscopic staging was 51.2 days. Mean duration of follow-up was 43 months, range (1-116 months). Five (20%) patients had recurrences, and two (8%) patients died of the disease. In conclusion, there is a significant learning curve for the laparoscopic full staging procedure in ovarian cancer. In our study this is mainly reflected in the amount of lymph nodes harvested and not in the total operating time.

Clarifying the diagnosis of clinically suspected recurrence of cervical cancer: impact of 18F-FDG PET.

UNLABELLED: Clarifying the diagnosis of clinically suspected recurrence of cervical cancer can be challenging. The aim of this study was to investigate the clinical value of (18)F-FDG PET in this context. METHODS: The medical records of a cohort of 40 (18)F-FDG PET referrals in whom recurrence of cervical cancer was clinically suspected were reviewed. Two expert gynecologic oncologists assessed the level of pre-PET clinical doubt, quality of pre-PET work-up, and impact of (18)F-FDG PET on diagnostic understanding and management using questionnaires. RESULTS: In patients with clinically equivocal recurrence, (18)F-FDG PET had a sensitivity of 92% and a specificity of 93% (prevalence, 65%). Before (18)F-FDG PET, there was high disagreement about the adequacy of the conventional work-up (intraclass correlation coefficient [ICC], 0.25) and the presence of recurrence (ICC, 0.24). (18)F-FDG PET increased experts' confidence (median increase, 14% and 25%; P < 0.0001) and diagnostic agreement (from 68% to 98%; ICC, from 0.24 to 0.95). When (18)F-FDG PET was positive for recurrence, the median overall survival was 13 mo. For patients with negative (18)F-FDG PET findings, the median survival was not reached (log rank, 15.50, P = 0.0001). When the treatment plan was categorized as local therapy, systemic therapy, and expectative management, (18)F-FDG PET changed the treatment plan in half of all cases. The 2 experts reported that (18)F-FDG PET led to a better diagnosis and a beneficial change in management in, respectively, 60% and 65% of cases. CONCLUSION: (18)F-FDG PET can help to clarify the diagnosis of clinically suspected recurrence of cervical cancer. In this patient population, (18)F-FDG PET had significant value in diagnostic understanding and management of recurrent cervical cancer, facilitating decision making and treatment planning. Therefore, (18)F-FDG PET should be part of the diagnostic work-up in detection of recurrent cervical cancer. The high positive predictive value of (18)F-FDG PET in these patients suggests that inclusion in intervention trials might be based on a positive (18)F-FDG PET scan.

Sentinel lymph node detection in early stage uterine cervix carcinoma: a systematic review.

OBJECTIVE: The aim of this study was to systematically review the diagnostic performance of Sentinel Node (SN) detection for assessing the nodal status in early stage cervical carcinoma, and to determine which technique (using blue dye, Technetium-99m colloid (99mTc), or the combined method) had the highest success rate in terms of detection rate and sensitivity. METHODS: A comprehensive computer literature search of English language studies in human subjects on Sentinel Node procedures was performed in MEDLINE and EMBASE databases up to July 2006. For each article two reviewers independently performed a methodological qualitative analysis and data extraction using a standard form. Pooled values of the SN detection rate and pooled sensitivity values of the SN procedure are presented with a 95% confidence interval (95% CI) for the three different SN detection techniques. RESULTS: We identified 98 articles, and 23 met the inclusion criteria, comprising a total of 842 patients. Ultimately, 12 studies used the combined technique with a sensitivity of 92% (95% CI: 84-98%). Five studies used 99mTc-colloid, with a pooled sensitivity of 92% (95% CI: 79-98%; p=0.71 vs. combined technique), and four used blue dye with a pooled sensitivity of 81% (67-92%, p=0.17 vs. combined technique). The SN detection rate was highest for the combined technique: 97% (95% CI: 95-98%), vs. 84% for blue dye (95% CI: 79-89%; p<0.0001), and 88% (95% CI: 82-92%, p=0.0018) for 99mTc colloid. CONCLUSION: SN biopsy has the highest SN detection rate when 99mTc is used in combination with blue dye (97%), and a sensitivity of 92%. Hence, according to the present evidence in literature the combination of 99mTc and a blue dye for SN biopsy in patients with early stage cervical cancer is a reliable method to detect lymph node metastases in early stage cervical cancer.