Regional practice variation in hysterectomy and the implementation of less invasive surgical procedures: A register-based study in the Netherlands.

INTRODUCTION: Many women experience bleeding disorders that may have an anatomical or unexplained origin. Although hysterectomy is the most definitive and common treatment, it is highly invasive and resource-intensive. Less invasive therapies are therefore advised before hysterectomy for women with fibroids or bleeding disorders. This study has two aims related to treating bleeding disorders and uterine fibroids in the Netherlands: (1) to evaluate the regional variations in prevalence and surgical approaches; and (2) to assess the associations between regional rates of hysterectomies and less invasive surgical techniques to analyze whether hysterectomy can be replaced in routine practice. MATERIAL AND METHODS: We completed a register-based study of claims data for bleeding disorders and fibroids in women between 2016 and 2020 using data from Statistics Netherlands for case-mix adjustment. Crude and case-mix adjusted regional hysterectomy rates were examined overall and by surgical approach. Coefficients of variation were used to measure regional variation and regression analyses were used to evaluate the association between hysterectomy and less invasive procedure rates across regions. RESULTS: Overall, 14 186 and 8821 hysterectomies were performed for bleeding disorders and fibroids, respectively. Laparoscopic approaches predominated (bleeding disorders 65%, fibroids 49%), followed by vaginal (bleeding disorders 24%, fibroids 5%) and abdominal (bleeding disorders 11%, fibroids 46%) approaches. Substantial regional differences were noted in both hysterectomy rates and the surgical approaches. For bleeding disorders, regional hysterectomy rates were positively associated with endometrial ablation rates (ß = 0.11; P = 0.21) and therapeutic hysteroscopy rates (ß = 0.14; P = 0.31). For fibroids, regional hysterectomy rates were positively associated with therapeutic hysteroscopy rates (ß = 0.10; P = 0.34) and negatively associated with both embolization rates (ß = -0.08; P = 0.08) and myomectomy rates (ß = -0.03; P = 0.82). CONCLUSIONS: Regional variation exists in the rates of hysterectomy and minimally invasive techniques. The absence of a significant substitution effect provides no clear evidence that minimally invasive techniques have replaced hysterectomy in clinical practice. However, although the result was not significant, embolization could be an exception based on its stronger negative association.

Waste analysis and energy use estimation during MR-HIFU treatment: first steps towards calculating total environmental impact.

OBJECTIVES: To assess the environmental impact of the non-invasive Magnetic Resonance image-guided High-Intensity Focused Ultrasound (MR-HIFU) treatment of uterine fibroids, we aimed to perform a full Life Cycle Assessment (LCA). However, as a full LCA was not feasible at this time, we evaluated the CO2 (carbon dioxide) emission from the MRI scanner, MR-HIFU device, and the medication used, and analyzed solid waste produced during treatment. METHODS: Our functional unit was one uterine fibroid MR-HIFU treatment. The moment the patient entered the day care-unit until she left, defined our boundaries of investigation. We retrospectively collected data from 25 treatments to assess the CO2 emission based on the energy used by the MRI scanner and MR-HIFU device and the amount and type of medication administered. Solid waste was prospectively collected from five treatments. RESULTS: During an MR-HIFU treatment, the MRI scanner and MR-HIFU device produced 33.2 ± 8.7 kg of CO2 emission and medication administered 0.13 ± 0.04 kg. A uterine fibroid MR-HIFU treatment produced 1.2 kg (range 1.1-1.4) of solid waste. CONCLUSIONS: Environmental impact should ideally be analyzed for all (new) medical treatments. By assessing part of the CO2 emission and solid waste produced, we have taken the first steps towards analyzing the total environmental impact of the MR-HIFU treatment of uterine fibroids. These data can contribute to future studies comparing the results of MR-HIFU LCAs with LCAs of other uterine fibroid therapies. CRITICAL RELEVANCE STATEMENT: In addition to (cost-) effectiveness, the environmental impact of new treatments should be assessed. We took the first steps towards analyzing the total environmental impact of uterine fibroid MR-HIFU. KEY POINTS: • Life Cycle Assessments (LCAs) should be performed for all (new) medical treatments. • We took the first steps towards analyzing the environmental impact of uterine fibroid MR-HIFU. • Energy used by the MRI scanner and MR-HIFU device corresponded to 33.2 ± 8.7 kg of CO2 emission.

Considerations on implementation of the newest treatment for symptomatic uterine fibroids: Oral GnRH antagonists.

Novel gonadotrophin releasing hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix and linzagolix have assessed treatment efficacy for fibroid-related heavy menstrual blood loss in comparison to placebo. Marketing authorization has been granted by several agencies including those in Europe, the United Kingdom and the United States. While the registration trials report a robust effect on the reduction of heavy menstrual blood loss and improvement in quality of life scores, reticence is advised before widespread prescription. In this review, we demonstrate limitations in the trial data, namely a lack of generalizability due to the restricted study population, the lack of transparency in the distribution of disease-level characteristics limiting the predictability of treatment success in the real-world diverse population, and the absence of any comparison to current alternative treatment methods. Importantly, no clinically meaningful volume reductions were found with GnRH antagonist combination preparations, and long-term safety data, particularly concerning modest but stable bone mineral density decline, need further addressing. Symptoms related to uterine fibroids adversely affect many women's quality of life and effective medical treatments are lacking. However, despite the urgent need for conservative treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness and cost-effectiveness in a representative population and are compared with alternative treatment methods before introduction into mainstream clinical practice.

Environmental sustainability in obstetrics and gynaecology: A systematic review.

BACKGROUND: The healthcare sector is responsible for 4%-10% of global greenhouse gas emissions. Considering the broad range of care that obstetricians and gynaecologists provide, mitigation strategies within this specialty could result in significant reductions of the environmental footprint across the whole healthcare industry. OBJECTIVES: The aim of this review was to identify for what services, procedures and products within obstetric and gynaecological care the environmental impact has been studied, to assess the magnitude of such impact and to identify mitigation strategies to diminish it. SEARCH STRATEGY: The search strategy combined terms related to environmental impact, sustainability, climate change or carbon footprint, with the field of obstetrics and gynaecology. SELECTION CRITERIA: Articles reporting on the environmental impact of any service, procedure or product within the field of obstetrics and gynaecology were included. Included outcomes covered midpoint impact categories, CO2 emissions, waste generation and energy consumption. DATA COLLECTION AND ANALYSIS: A systematic literature search was conducted in the databases of MEDLINE (Ovid), Embase (Ovid) and Scopus, and a grey literature search was performed on Google Scholar and two websites of gynaecological associations. MAIN RESULTS: The scope of the investigated studies encompassed vaginal births, obstetric and gynaecological surgical procedures, menstrual products, vaginal specula and transportation to gynaecological oncologic consultations. Among the highest yielding mitigation strategies were displacing disposable with reusable materials and minimising content of surgical custom packs. The lowest yielding mitigation strategy was waste optimisation, including recycling. CONCLUSIONS: This systematic review highlights opportunities for obstetricians and gynaecologists to decrease their environmental footprint in many ways. More high-quality studies are needed to investigate the environmental impact of other aspects of women's and reproductive health care.

Favorable surgical and obstetrical outcomes in pre- and postconceptional laparoscopic abdominal cerclage: a large multicenter cohort study.

BACKGROUND: Cervical incompetence is an important cause of extremely preterm delivery. Without specialized treatment, cervical incompetence has a 30% chance of recurrence in a subsequent pregnancy. Recently, the first randomized controlled trial showed significant superiority of abdominal cerclage compared with both high and low vaginal cerclage in preventing preterm delivery at <32 weeks of gestation and fetal loss in patients with a previous failed vaginal cerclage. OBJECTIVE: This study aimed to assess surgical and obstetrical outcomes in patients with pre- and postconceptional laparoscopic abdominal cerclage placement. Furthermore, it also aimed to perform subgroup analysis based on the indication for cerclage placement in order to identify patients who benefit the most from an abdominal cerclage. STUDY DESIGN: A retrospective multicenter cohort study with consecutive inclusion of all eligible patients from 1997 onward in the Dutch cohort (104 patients) and from 2007 onward in the Boston cohort (169 patients) was conducted. Eligible patients had at least 1 second- or third-trimester fetal loss due to cervical incompetence and/or a short or absent cervix after cervical surgery. This includes loop electrosurgical excision procedure, conization, or trachelectomy. Patients were divided into the following subgroups based on the indication for cerclage placement: (1) previous failed vaginal cerclage, (2) previous cervical surgery, and (3) other indications. The third group consisted of patients with a history of multiple second- or early third-trimester fetal losses due to cervical incompetence (without a failed vaginal cerclage) and/or multiple dilation and curettage procedures. The primary outcome measure was delivery at ≥34 weeks of gestation with neonatal survival at hospital discharge. Secondary outcome measures included surgical and obstetrical outcomes, such as pregnancy rates after preconceptional surgery, obstetrical complications, and fetal survival rates. RESULTS: A total of 273 patients were included (250 in the preconceptional and 23 in the postconceptional cohort). Surgical outcomes of 273 patients were favorable, with 6 minor complications (2.2%). In the postconceptional cohort, 1 patient (0.4%) had hemorrhage of 650 mL, resulting in conversion to laparotomy. After preconceptional laparoscopic abdominal cerclage (n=250), the pregnancy rate was 74.1% (n=137) with a minimal follow-up of 12 months. Delivery at ³34 weeks of gestation occurred in 90.5% of all ongoing pregnancies. Four patients (3.3%) had a second-trimester fetal loss. The indication for cerclage in all 4 patients was a previous failed vaginal cerclage. The other subgroups showed fetal survival rates of 100% in ongoing pregnancies, with a total fetal survival rate of 96%. After postconceptional placement, 94.1% of all patients with an ongoing pregnancy delivered at ³34 weeks of gestation, with a total fetal survival rate of 100%. Thus, second-trimester fetal losses did not occur in this group. CONCLUSION: Pre- and postconceptional laparoscopic abdominal cerclage is a safe procedure with favorable obstetrical outcomes in patients with increased risk of cervical incompetence. All subgroups showed high fetal survival rates. Second-trimester fetal loss only occurred in the group of patients with a cerclage placed for the indication of previous failed vaginal cerclage, but was nevertheless rare even in this group.

Modifiable prognostic factors in uterine fibroid development: a systematic review of literature.

BACKGROUND: Many risk factors in uterine fibroid development have been identified, but women and their physicians are less aware of the influence of lifestyle on uterine fibroid development. The objective of this systematic review is to investigate and summarize modifiable prognostic factors associated with uterine fibroid development. METHODS: Pubmed and Embase were searched for relevant articles according to PRISMA guidelines. References from included articles were screened and when relevant also included. Human in vivo studies on modifiable factors in fibroid development were included. Studies on non-modifiable factors and treatment, in vitro studies and animal studies were excluded. 607 articles were screened and 33 articles were included. Two independent investigators collected data from the report. RESULTS: The strongest risk factor for fibroid development was a high BMI, while the strongest protective factors were a high fruit and vegetable intake and high vitamin D intake. CONCLUSION: More high-quality studies are necessary to better understand the impact of the abovementioned factors as well as the role they play in the growth of already existing fibroids.

Uterine fibroid development is multifactorial. Various non-modifiable and modifiable factors have been linked to uterine fibroid development. Modifiable factors are controllable by patients themselves. We performed a systematic review to investigate these modifiable factors. We screened 607 articles from 2 databases (PubMed and Embase) of which 33 were included in the review. We only included clinical studies on humans. A high body mass index (BMI) is found to be a modifiable risk factor for uterine fibroid development. Protective of uterine fibroid development are high fruit and vegetable intake and high vitamin D intake or sun exposure. More research is needed to investigate the applicability of these findings in clinical practice and to investigate the influence on the growth of already existing uterine fibroids.

Procedural sedation and analgesia versus general anesthesia for hysteroscopic myomectomy (PROSECCO trial): A multicenter randomized controlled trial.

BACKGROUND: Hysteroscopic resection is the first-choice treatment for symptomatic type 0 and 1 fibroids. Traditionally, this was performed under general anesthesia. Over the last decade, surgical procedures are increasingly being performed in an outpatient setting under procedural sedation and analgesia. However, studies evaluating safety and effectiveness of hysteroscopic myomectomy under procedural sedation are lacking. This study aims to investigate whether hysteroscopic myomectomy under procedural sedation and analgesia with propofol is noninferior to hysteroscopic myomectomy under general anesthesia. METHODS AND FINDINGS: This was a multicenter, randomized controlled noninferiority trial conducted in 14 university and teaching hospitals in the Netherlands between 2016 and 2021. Inclusion criteria were age ≥18 years, maximum number of 3 type 0 or 1 fibroids, maximum fibroid diameter 3.5 cm, American Society of Anesthesiologists class 1 or 2, and having sufficient knowledge of the Dutch or English language. Women with clotting disorders or with severe anemia (Hb < 5.0 mmol/L) were excluded. Women were randomized using block randomization with variable block sizes of 2, 4, and 6, between hysteroscopic myomectomy under procedural sedation and analgesia (PSA) with propofol or under general anesthesia (GA). Primary outcome was the percentage of complete resections, assessed on transvaginal ultrasonography 6 weeks postoperatively by a sonographer blinded for the treatment arm and surgical outcome. Secondary outcomes were the surgeon's judgment of completeness of procedure, menstrual blood loss, uterine fibroid related and general quality of life, pain, recovery, hospitalization, complications, and surgical reinterventions. Follow-up period was 1 year. The risk difference between both treatment arms was estimated, and a Farrington-Manning test was used to determine the p-value for noninferiority (noninferiority margin 7.5% of incomplete resections). Data were analyzed according to the intention-to-treat principle, including a per-protocol analysis for the primary outcome. A total of 209 women participated in the study and underwent hysteroscopic myomectomy with PSA (n = 106) or GA (n = 103). Mean age was 45.1 [SD 6.4] years in the PSA group versus 45.0 [7.7] years in the GA group. For 98/106 women in the PSA group and 89/103 women in the GA group, data were available for analysis of the primary outcome. Hysteroscopic resection was complete in 86/98 women (87.8%) in the PSA group and 79/89 women (88.8%) in the GA group (risk difference -1.01%; 95% confidence interval (CI) -10.36 to 8.34; noninferiority, P = 0.09). No serious anesthesiologic complications occurred, and conversion from PSA to GA was not required. During the follow-up period, 15 serious adverse events occurred (overnight admissions). All were unrelated to the intervention studied. Main limitations were the choice of primary outcome and the fact that our study proved to be underpowered. CONCLUSIONS: Noninferiority of PSA for completeness of resection was not shown, though there were no significant differences in clinical outcomes and quality of life. In this study, hysteroscopic myomectomy for type 0 and 1 fibroids with PSA compared to GA was safe and led to shorter hospitalization. These results can be used for counseling patients by gynecologists and anesthesiologists. Based on these findings, we suggest that hysteroscopic myomectomies can be performed under PSA in an outpatient setting. TRIAL REGISTRATION: The study was registered prospectively in the Dutch Trial Register (NTR 5357; registration date: 11 August 2015; Date of initial participant enrollment: 18 February 2016).

Environmental Impact Assessment of Reusable and Disposable Surgical Head Covers.

This life cycle assessment compares the environmental footprint of reusable surgical head covers with single-use disposable surgical head covers.

Reproductive outcomes after laparoscopic resection of symptomatic niches in uterine cesarean scars: Long-term follow-up on the prospective LAPNICHE study.

INTRODUCTION: After incomplete healing of the uterine cesarean section scar, a niche can be observed; 24% of the women develop large niches with a residual myometrial thickness <3 mm. In these cases a laparoscopic resection is possible. The effect of this new treatment on fertility outcome is not known yet. This paper describes reproductive outcomes 2 years after a laparoscopic niche resection and compares women with or without secondary infertility at baseline. MATERIAL AND METHODS: A prospective cohort study was performed, with consecutive inclusion of women between 2011 and 2019. Women with a niche in the uterine cesarean scar, with a residual myometrial thickness of <3 mm and with a desire to become pregnant, were scheduled to undergo a laparoscopic niche resection because of one or more of the following problems (1) postmenstrual spotting; (2) midcycle intrauterine fluid accumulation diagnosed during the fertility workup or (3) difficulties with a previous embryo transfer and preferring a surgical therapy. The study is registered in the ISRCTN register (ref. no. ISRCTN02271575) on April 23, 2013. RESULTS: There were 133 (62%) women included with a desire to become pregnant, 88 with secondary infertility. In all, 83 had an ongoing pregnancy at the 2-year follow-up. The ongoing pregnancy rate in patients with previous fertility problems was 60.2% compared with 66.7% in patients without infertility (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.32-1.7). The OR for live births was 0.57 (95% CI 0.02-1.2). Overall, 8.3% of the pregnancies resulted in miscarriages by the 2-year follow-up. CONCLUSIONS: The reproductive outcomes in women with and without previous fertility problems undergoing resection of a large niche are very promising and quite comparable in both groups. These results suggest, but do not prove, a beneficial effect of this therapy for these indications. The results support the design of future randomized controlled trials to evaluate the effect of niche resection vs expectant management to assess its additional value in women with or without fertility problems who desire pregnancy.

The Effect of a Myomectomy on Myoma-related Symptoms and Quality of Life: A Retrospective Cohort Study.

STUDY OBJECTIVE: Although it is assumed that myomectomy improves uterine myoma-related symptoms such as pelvic pain and heavy menstrual bleeding (HMB), validated measures are rarely reported. This study aimed to verify the effect of myomectomy on myoma-related symptoms. DESIGN: A retrospective cohort study. SETTING: A university-affiliated hospital. PATIENTS: Our study included 241 patients with a myoma diagnosis and received a myomectomy between 2004 and 2018. Data were collected from the patient medical file and patients responded in 1 questionnaire. INTERVENTIONS: Transcervical resection of myoma (TCRM) and laparoscopic or abdominal myomectomy (LAM). MEASUREMENTS AND MAIN RESULTS: One year after TCRM, a significant number of women experienced symptom improvement for pelvic pain (79% [19/24, p = .01]) and HMB (89% [46/52, p <.001]). For other myoma-related symptoms, abdominal pressure (43%, 10/23), sexual complaints (67%, 2/3), infertility (56%, 10/18), and other complaints (83%, 5/6), improvements were not statistically significant. One year after LAM, a significant number of women experienced symptom improvement for pelvic pain (80%, 74/93), HMB (83%, 94/113), abdominal pressure (85%, 79/93), sexual complaints (77%, 36/47), and other complaints (91%, 40/44). One year after myomectomy, 47% (30/64) (TCRM) and 44% of women (78/177) (LAM) described no myoma-related symptoms. Most women (82% [172/217]) were satisfied with the postoperative result after 1 year and 53% (114/217) would have liked to receive the myomectomy earlier in life. Average quality of life (measured on a 10-point Likert scale) increased from 6.3 at baseline to 8.0 at 1 year after TCRM and from 6.2 to 8.0 1 year after LAM, resulting in a difference of 1.7 points (p <.001; 95% confidence interval, 1.1-2.3) and 1.9 points (p <.001; 95% confidence interval, 1.4-2.3), respectively. CONCLUSION: One year after myomectomy, most women have benefited from myomectomy, concluded by a significant number of women who experienced myoma-related symptom improvement, positive patient satisfaction, and a significant improvement in reported quality of life. Validation of results after conventional treatment such as myomectomy is essential in counseling patients for surgical treatment in today's evidence based practice. In addition, it is necessary to make an adequate comparison with new treatment options for myomas. To provide this, further research should preferably be conducted prospectively or by randomization.

Effectiveness of laparoscopic niche resection versus expectant management in patients with unexplained infertility and a large uterine caesarean scar defect (uterine niche): protocol for a randomised controlled trial (the LAPRES study).

INTRODUCTION: A uterine niche is a defect at the site of the uterine caesarean scar that is associated with gynaecological symptoms and infertility. Promising results are reported in cohort studies after a laparoscopic niche resection concerning reduction of gynaecological symptoms in relation to baseline and concerning pregnancy outcomes. However, randomised controlled trials to study the effect of a laparoscopic niche resection on reproductive outcomes in infertile women are lacking. This study will answer the question if laparoscopic niche resection in comparison to expectant management improves reproductive outcomes in infertile women with a large uterine niche. METHODS AND ANALYSIS: The LAPRES study is a randomised, non-blinded, controlled trial, including 200 infertile women with a total follow-up of 2 years. Women with the presence of a large niche in the uterine caesarean scar and unexplained infertility of at least 1 year or failed IVF will be randomly allocated to a laparoscopic niche resection within 6 weeks or to expectant management for at least 9 months. A large niche is defined as a niche with a depth of >50% of the myometrial thickness and a residual myometrium of ≤3 mm on transvaginal ultrasound. Those receiving expectant management will be allowed to receive fertility therapies, including assisted reproductive techniques, if indicated. The primary outcome is time to ongoing pregnancy, defined as a viable intrauterine pregnancy at 12 weeks' gestation. Secondary outcome measures are time to conception leading to a live birth, other pregnancy outcomes, received fertility therapies after randomisation, menstruation characteristics, patient satisfaction, quality of life, additional interventions, and surgical and ultrasound outcomes (intervention group). Questionnaires will be filled out at baseline, 6, 12 and 24 months after randomisation. Ultrasound evaluation will be performed at baseline and at 3 months after surgery. ETHICS AND DISSEMINATION: The study protocol was approved by the medical ethics committee of the Amsterdam University Medical Centre. (Ref. No. 2017.030). Participants will sign a written informed consent before participation. The results of this study will be submitted to a peer-reviewed journal for publication. TRIAL REGISTRATION NUMBER DUTCH TRIAL REGISTER REF NO NL6350 : http://www.trialregister.nl.

['Is there a doctor on board?' Reducing air travel associated with international medical conferences]. / 'Is er een dokter aan boord?'.

International medical conferences aim to improve health outcomes, but the associated air travel-related carbon emissions are a significant contributor to the environmental impact of medical scientific activities. The COVID-19 pandemic has urged the medical world to shift towards virtual conferences, decreasing associated carbon emissions by 94% to 99%. However, virtual conferences are still not the norm and doctors are returning to business as usual. Various stakeholders need to be mobilized to minimize carbon-intensive flights to conferences. Doctors, (academic) hospitals, conference organizers and universities all hold a responsibility to incorporate every effort to decarbonize and build climate mitigation into their decisions. These efforts include sustainable travel policies, selecting accessible venues, decentralizing host locations, encouraging low carbon alternatives to air travel, increasing virtual attendance and increasing awareness.

Endometrial Angiogenesis of Abnormal Uterine Bleeding and Infertility in Patients with Uterine Fibroids-A Systematic Review.

Uterine fibroids are the most common benign tumors in women, with abnormal uterine bleeding (AUB) as the main reported symptom. Additionally, an association between fibroids and infertility has been established, especially if the fibroid protrudes in the uterine cavity. Hormonal therapy is associated with side-effects and as well as hysterectomy, which is incompatible with a desire to conceive. To improve treatment, it is essential to unravel the etiology of fibroid-related symptoms. We aim to evaluate endometrial angiogenesis in women with fibroids, with and without AUB, and the influence of pharmaceutical therapies in these patients. Furthermore, we explore the possible role of altered angiogenesis in patients with fibroids and infertility. We performed a systematic review according to PRISMA-guidelines (PROSPERO: CRD42020169061), and included 15 eligible studies. Endometrial expression of vascular endothelial growth factor (VEGF) and adrenomedullin was increased in patients with fibroids. This suggests aberrant angiogenesis, potentially involving disturbed vessel maturation, resulting in immature and fragile vessels. Treatment with gonadotropin-releasing hormone agonist, ulipristal acetate, and continuous oral contraception pills reduced several angiogenic parameters, including VEGF. If infertile and fertile patients with fibroids were compared, a significant decreased expression of the bone morphogenetic protein/Smad-protein pathway was found, possibly caused by the increased expression of transforming growth factor-beta. For future therapeutic development, these different angiogenic pathways could be of interest as possible targets to treat fibroid-related symptoms.

Angiogenesis in abnormal uterine bleeding: a narrative review.

BACKGROUND: Abnormal uterine bleeding (AUB) has a significant socioeconomic impact since it considerably impacts quality of life. Therapeutic options are frequently based on trial and error and do not target disease aetiology. Pathophysiological insight in this disease is required for the development of novel treatment options. If no underlying cause is found for the AUB (e.g. fibroids, adenomyosis, polyps), endometrial-AUB (AUB-E) is usually caused by a primary endometrium disorder. When AUB is induced by prescribed (exogenous) hormones, it is classified as iatrogenic-AUB (AUB-I). Considering vascular modulation and function, AUB-E and AUB-I both could potentially result from abnormal vascularization in the endometrium due to alterations in the process of angiogenesis and vascular maturation. OBJECTIVE AND RATIONALE: We aim to investigate the fundamental role of angiogenesis and vascular maturation in patients with AUB and hypothesize that aberrant endometrial angiogenesis has an important role in the aetiology of both AUB-E and AUB-I, possibly through different mechanisms. SEARCH METHODS: A systematic literature search was performed until September 2021 in the Cochrane Library Databases, Embase, PubMed, and Web of Science, with search terms such as angiogenesis and abnormal uterine bleeding. Included studies reported on angiogenesis in the endometrium of premenopausal women with AUB-E or AUB-I. Case reports, letters, reviews, editorial articles, and studies on AUB with causes classified by the International Federation of Gynecology and Obstetrics as myometrial, oncological, or infectious, were excluded. Study quality was assessed by risk of bias, using the Cochrane tool and the Newcastle-Ottawa Scale. OUTCOMES: Thirty-five out of 2158 articles were included. In patients with AUB-E, vascular endothelial growth factor A and its receptors (1 and 2), as well as the angiopoietin-1:angiopoietin-2 ratio and Tie-1, were significantly increased. Several studies reported on the differential expression of other pro- and antiangiogenic factors in patients with AUB-E, suggesting aberrant vascular maturation and impaired vessel integrity. Overall, endometrial microvessel density (MVD) was comparable in patients with AUB-E and controls. Interestingly, patients with AUB-I showed a higher MVD and higher expression of proangiogenic factors when compared to controls, in particular after short-term hormone exposure. This effect was gradually lost after longer-term exposure, while alterations in vessel maturation were observed after both short- and long-term exposures. WIDER IMPLICATIONS: AUB-E and AUB-I are most likely associated with aberrant endometrial angiogenesis and impaired vessel maturation. This review supports existing evidence that increased proangiogenic and decreased antiangiogenic factors cause impaired vessel maturation, resulting in more fragile and permeable vessels. This matches our hypothesis and these mechanisms appear to play an important role in the pathophysiology of AUB-E and AUB-I. Exploring the alterations in angiogenesis in these patients could provide treatment targets for AUB.

Effectiveness, complications, and reproductive outcomes after cesarean scar pregnancy management: a retrospective cohort study.

BACKGROUND: There is a dramatic rise in cesarean deliveries worldwide, leading to higher complication rates in subsequent pregnancies. One of these complications is a cesarean scar pregnancy. During the last decades, treatment options for cesarean scar pregnancies have changed, and less invasive interventions have been employed to preserve fertility and reduce morbidity. However, the optimal treatment approach and the influence of various treatments on reproductive outcomes have to be determined. OBJECTIVE: This study aimed to evaluate the short- and long-term outcomes after cesarean scar pregnancy management. STUDY DESIGN: We conducted a retrospective cohort study of women determined to have a cesarean scar pregnancy from 2010 to 2021 at a tertiary referral center, the Amsterdam University Medical Center, in the Netherlands. Outcomes of the following management strategies were compared: expectant management, methotrexate, curettage with temporary cervical cerclage, or a laparoscopic niche resection. We performed a curettage if the cesarean scar pregnancy did not cross the serosal line of the uterus, and a laparoscopic niche resection was performed if the cesarean scar pregnancy crossed the serosal line. The main outcomes were treatment efficacy and time to subsequent ongoing pregnancy or pregnancy leading to a live birth. RESULTS: Of the 60 included women, 5 (8.3%) were managed expectantly, 8 (13.3%) were treated with methotrexate, 31 (51.8%) were treated with a curettage, and 16 (26.7%) with a laparoscopic niche resection. The groups were not comparable. The gestational age and human chorionic gonadotropin levels were generally higher in women who received methotrexate or a laparoscopic niche resection. Additional treatment in the conservative group was needed for 4 (80%) women after expectant management and for 7 (87.5%) women after methotrexate treatment. In the surgical group, all 31 women treated with a curettage and all 16 treated with a laparoscopic niche resection did not require additional treatment. The subsequent ongoing pregnancy rate after cesarean scar pregnancy management was 81.1% (30/37) among women who wished to conceive, with a live birth rate of 78.4% (29/37); 1 woman was in her third trimester of pregnancy at the time of analyses. The time between cesarean scar pregnancy management and subsequent ongoing pregnancy was 4 months (interquartile range, 3-6; P=.02) after expectant management, 18 months (interquartile range, 13-22) after initial methotrexate treatment, 5 months (interquartile range, 3-14; P=.01) after a curettage, and 6 months (interquartile range, 4-15; P=.03) after a laparoscopic niche resection. CONCLUSION: Surgical treatment of a cesarean scar pregnancy led to a high success rate without additional interventions, high pregnancy rates with a short time interval between treatment, and subsequent pregnancy leading to an ongoing pregnancy or live birth. Conservative management, both with expectant management and methotrexate treatment, led to high (re)intervention rates. Different management approaches are indicated for different types of cesarean scar pregnancies.

Change of the residual myometrial thickness during pregnancy in women who underwent laparoscopic niche resection compared with controls without niche surgery: a prospective comparative cohort study.

BACKGROUND: Reduced residual myometrial thickness before and during pregnancy is associated with uterine rupture or dehiscence after vaginal birth after cesarean delivery. Laparoscopic niche resection performed in case of gynecologic symptoms has shown to increase residual myometrial thickness 6 months after surgery. OBJECTIVE: This study aimed to evaluate the change in residual myometrial thickness from baseline value before pregnancy to the third trimester of pregnancy in women with and without laparoscopic niche resection and evaluate niche presence, niche size during pregnancy vs before pregnancy, and obstetrical outcomes, including uterine rupture and dehiscence in both study groups. STUDY DESIGN: This was a prospective cohort study conducted in an academic medical center. Of note, 2 groups of pregnant women with a previously diagnosed niche were included: (1) women with a large symptomatic niche (residual myometrial thickness of <3 mm) followed by laparoscopic niche resection (LNR group) and (2) women with a niche without niche resection because of minimal symptoms or a residual myometrial thickness of ≥3 mm diagnosed before current pregnancy (expectant group). Participants underwent a transvaginal ultrasound at 12, 20, and 30 weeks of gestation. Changes in residual myometrial thickness and changes in niche measurements over time were analyzed with linear mixed models. RESULTS: A total of 100 women were included, 61 in the LNR group and 39 in the expectant group. The change in residual myometrial thickness from baseline value before niche resection to the third trimester of pregnancy was +2.0 mm in the LNR group vs -1.6 mm in the expectant group (P<.001). Residual myometrial thickness decreased from the first trimester of pregnancy onward in both groups. Although residual myometrial thickness was thinner at baseline in the LNR group, it was thicker in the LNR group than in the expectant group during all trimesters: 3.2 mm (P<.001) in the first trimester of pregnancy, 2.5 mm (P<.001) in the second trimester of pregnancy, and 1.8 mm (P=.001) in the third trimester of pregnancy. Uterine dehiscence was reported in 1 of 50 women (2%) in the LNR group and 7 of 36 women (19%) in the expectant group (P=.007) and was related to the depth of niche-to-residual myometrial thickness ratio before pregnancy (after niche resection) and residual myometrial thickness in the second trimester of pregnancy. No uterine rupture was reported. Most patients received a scheduled cesarean delivery in both groups. There was more blood loss during subsequent cesarean delivery in the LNR group than in the expectant group. CONCLUSION: Here, laparoscopic niche resection resulted in an increased residual myometrial thickness during a subsequent pregnancy. Moreover, a lower number of dehiscence was found in the LNR group than in the expectant group without niche surgery. Per-section blood loss was higher in the LNR group than in the expectant group. In general, laparoscopic niche resection is performed to improve gynecologic symptoms. Currently, there is no evidence to support a laparoscopic niche resection to improve obstetrical outcomes, but the trend toward more uterine dehiscence encourages further research.

The effect of transcervical resection of submucous fibroids on menstrual blood loss: A prospective cohort study.

OBJECTIVES: Transcervical resection of myoma (TCRM) is a widely implemented treatment for submucous fibroids. The aim of this study is to evaluate the effect of TCRM on menstrual bleeding, fibroid related symptoms and quality of life and hemoglobin (Hb) levels. STUDY DESIGN: A prospective cohort study was conducted in three teaching hospitals and two academic hospitals in the Netherlands. Patients with HMB (PBAC score > 150) and submucous fibroids (type 0, 1, 2, 3, 4 and hybrid type 2-5) scheduled for TCRM were eligible. At baseline and 3 months after TCRM a Trans Vaginal Ultrasound (TVU) was performed and a Hb sample was taken. Patients filled out the Pictorial Blood Assessment Chart (PBAC) and the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire at baseline and up to 6 months after surgery. Primary outcome was improvement in PBAC score 6 months after surgery. Secondary outcomes were improvement in PBAC score and Hb level 3 months after surgery and UFS-QOL scores 3 and 6 months after surgery. RESULTS: 126 patients were included and 104 were operated. PBAC were obtained from 98 patients. Six months after surgery, 56.6% of patients went from HMB to normal menstrual bleeding (PBAC < 150). A significant reduction in median PBAC scores of 427 (IQR 198 - 1392) (p <.0001) was found (86% improvement). UFS-QOL scores were obtained from 91 patients. Symptom severity improved from a median of 54 on a scale of 100 (IQR 44-66) at baseline to 22 (IQR 9-41) after 6 months (p <.0001) (59% improvement). Health related quality of life (HRQOL) improved from a median score of 44 on a scale of 100 (IQR 33-62) to 89 (IQR 67-97) 6 months after surgery (p <.0001) (102% improvement). CONCLUSION: TCRM significantly reduces the amount of menstrual bleeding, severity of fibroid related symptoms and improves HRQOL in patients with submucous fibroids.

Evaluation of marketing authorization and clinical implementation of ulipristal acetate for uterine fibroids.

Ulipristal acetate (UPA) is a medical treatment for uterine fibroids and was authorized for surgical pre-treatment in 2012 after the conduct of the PEARL I and II randomized controlled trials and for intermittent treatment after the observational PEARL III and IV trials. However, UPA came into disrepute due to its temporary suspension in 2017 and 2020 because of an apparent association with liver injury. This clinical opinion paper aims to review the process of marketing authorization and implementation of UPA, in order to provide all involved stakeholders with recommendations for the introduction of future drugs. Before marketing authorization, the European Medicines Agency (EMA) states that Phase III registration trials should evaluate relevant outcomes in a representative population, while comparing to gold-standard treatment. This review shows that the representativeness of the study populations in all PEARL trials was limited, surgical outcomes were not evaluated and intermittent treatment was assessed without comparative groups. Implementation into clinical practice was extensive, with 900 000 prescribed treatment cycles in 5 years in Europe and Canada combined. Extremely high costs are involved in developing and evaluating pre-marketing studies in new drugs, influencing trial design and relevance of chosen outcomes, thereby impeding clinical applicability. It is vitally important that the marketing implementation after authorization is regulated in such way that necessary evidence is generated before widespread prescription of a new drug. All stakeholders, from pharmaceutical companies to authorizing bodies, governmental funding bodies and medical professionals should be aware of their role and take responsibility for their part in this process.

Comparison of (Cost-)Effectiveness of Magnetic Resonance Image-Guided High-Intensity-Focused Ultrasound With Standard (Minimally) Invasive Fibroid Treatments: Protocol for a Multicenter Randomized Controlled Trial (MYCHOICE).

BACKGROUND: Magnetic resonance image-guided high-intensity-focused ultrasound (MR-HIFU) is a rather new, noninvasive option for the treatment of uterine fibroids. It is safe, effective, and has a very short recovery time. However, a lack of prospectively collected data on long-term (cost-)effectiveness of the MR-HIFU treatment compared with standard uterine fibroid care prevents the MR-HIFU treatment from being reimbursed for this indication. Therefore, at this point, when conservative treatment for uterine fibroid symptoms has failed or is not accepted by patients, standard care includes the more invasive treatments hysterectomy, myomectomy, and uterine artery embolization (UAE). Primary outcomes of currently available data on MR-HIFU treatment often consist of technical outcomes, instead of patient-centered outcomes such as quality of life (QoL), and do not include the use of the latest equipment or most up-to-date treatment strategies. Moreover, data on cost-effectiveness are rare and seldom include data on a societal level such as productivity loss or use of painkillers. Because of the lack of reimbursement, broad clinical implementation has not taken place, nor is the proper role of MR-HIFU in uterine fibroid care sufficiently clear. OBJECTIVE: The objective of our study is to determine the long-term (cost-)effectiveness of MR-HIFU compared with standard (minimally) invasive fibroid treatments. METHODS: The MYCHOICE study is a national, multicenter, open randomized controlled trial with randomization in a 2:1 ratio to MR-HIFU or standard care including hysterectomy, myomectomy, and UAE. The sample size is 240 patients in total. Women are included when they are 18 years or older, in premenopausal stage, diagnosed with symptomatic uterine fibroids, conservative treatment has failed or is not accepted, and eligible for MR-HIFU. Primary outcomes of the study are QoL 24 months after treatment and costs of treatment including direct health care costs, loss of productivity, and patient costs. RESULTS: Inclusion for the MYCHOICE study started in November 2020 and enrollment will continue until 2024. Data collection is expected to be completed in 2026. CONCLUSIONS: By collecting data on the long-term (cost-)effectiveness of the MR-HIFU treatment in comparison to current standard fibroid care, we provide currently unavailable evidence about the proper place of MR-HIFU in the fibroid treatment spectrum. This will also facilitate reimbursement and inclusion of MR-HIFU in (inter)national uterine fibroid care guidelines. TRIAL REGISTRATION: Netherlands Trial Register NL8863; https://www.trialregister.nl/trial/8863. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/29467.