Transgender persons' view on previous fertility decision-making and current infertility: a qualitative study.

STUDY QUESTION: How do adult transgender and gender diverse (TGD) people, who are infertile due to prior gender-affirming treatment, view their current infertility and their reproductive decisions made in the past? SUMMARY ANSWER: In a time where sterilization was mandatory, transgender adolescents prioritized gender-affirming treatment over their future fertility and would make the same choice today despite emotional challenges related to infertility experienced by some. WHAT IS KNOWN ALREADY: Under transgender law in the Netherlands, sterilization was required for legal gender recognition until 2014, resulting in permanent infertility. The long-term consequences of this iatrogenic infertility in transgender adolescents who have now reached adulthood remain underexplored. STUDY DESIGN, SIZE, DURATION: Qualitative study design based on 21 in-depth one-on-one semi-structured interviews. PARTICIPANTS/MATERIALS, SETTING, METHODS: TGD people in a stage of life where family planning may be a current topic were eligible for participation. They all received gender-affirming treatment in adolescence prior to the legislation change in 2014. A purposeful sampling technique was used from participants of another ongoing study. Eleven people assigned female at birth and ten people assigned male at birth were included. Interview transcripts were thematically analysed using a modified version of Braun and Clarke's six steps theory. MAIN RESULTS AND THE ROLE OF CHANCE: Six main themes were generated: (i) personal considerations regarding fertility and fertility preservation in the past; (ii) external considerations regarding fertility and fertility preservation in the past; (iii) current vision on past considerations and decisions; (iv) Current experiences and coping with infertility; (v) future family building; (vi) advice regarding fertility and fertility preservation decision-making. LIMITATIONS, REASONS FOR CAUTION: Selection, recall, and choice supportive bias may play a role in interpreting our results. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the importance of tailored counselling and comprehensive information on fertility preservation for transgender individuals, especially adolescents, undergoing gender-affirming treatment. STUDY FUNDING/COMPETING INTEREST(S): N/A. TRIAL REGISTRATION NUMBER: N/A.

How to perform standardized sonographic examination of Cesarean scar pregnancy in the first trimester.

Early diagnosis and appropriate management of Cesarean scar pregnancy (CSP) are crucial to prevent severe complications such as uterine rupture, severe hemorrhage and placenta accreta spectrum disorders. In this article, we provide a step-by-step tutorial for the standardized sonographic evaluation of CSP in the first trimester. Practical steps for performing a standardized transvaginal ultrasound examination to diagnose CSP are outlined, focusing on criteria and techniques essential for accurate identification and classification. Key sonographic markers, including gestational sac location, cardiac activity, placental implantation and myometrial thickness, are detailed. The evaluation process is presented according to assessment of the uterine scar, differential diagnosis, detailed CSP evaluation and CSP classification. This step-by-step tutorial emphasizes the importance of scanning in two planes (sagittal and transverse), utilizing color or power Doppler and differentiating CSP from other low-lying pregnancies. The CSP classification is described in detail and is based on the location of the largest part of the gestational sac relative to the uterine cavity and serosal lines. This descriptive classification is recommended for clinical use to stimulate uniform description and evaluation. Such a standardized sonographic evaluation of CSP in the first trimester is essential for early diagnosis and management, helping to prevent life-threatening complications and to preserve fertility. Training sonographers in detailed evaluation techniques and promoting awareness of CSP are critical. The structured approach to CSP diagnosis presented herein is supported by a free e-learning course available online. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Uterine junctional zone and adenomyosis: comparison of MRI, transvaginal ultrasound and histology.

The uterine junctional zone is the subendometrial area in the myometrium that contributes to peristalsis and aids in spermatozoa and blastocyst transport. Alterations in the appearance of the junctional zone on transvaginal sonography (TVS) or magnetic resonance imaging (MRI) are associated with adenomyosis. The lack of standardization of description of its appearance and ill-defined boundaries on both histology and imaging hamper understanding of the junctional zone and limit its role in the diagnosis of adenomyosis. The objectives of this review were to investigate the accordance in definition of the junctional zone across different diagnostic approaches and to examine how imaging findings can be linked to histological findings in the context of diagnosis of adenomyosis. A comprehensive literature review was conducted of articles describing the appearance on imaging and the histological structure of the uterine junctional zone. Our review suggests that the junctional zone is distinguished from the middle and outer myometrium by gradual changes in smooth-muscle cell density, extracellular space, connective tissue, water content and vascular properties. However, while the signal intensity from the junctional zone to the middle myometrium changes abruptly on MRI, the histopathological changes are gradual and its border may be difficult or impossible to distinguish on two-dimensional TVS. Moreover, the thickness of the junctional zone measured on MRI is larger than that measured on TVS. Thus, these two imaging modalities reflect this zone differently. Although a thickened junctional zone is often used to diagnose adenomyosis on MRI, the presence of adenomyosis can be described more accurately as interruptions of the junctional zone by endometrial tissue, which leads to direct signs on imaging such as subendometrial lines and buds on two- and three-dimensional TVS or bright foci on MRI. The histopathological criteria for diagnosis are based on enlargement of the uterus with severe adenomyosis, and might not reflect its early stages. Clinicians should be aware that findings on MRI cannot be extrapolated readily to ultrasound. An understanding of this is necessary when investigating the uterine junctional zone as a functional unit and the association between visualization of direct features of adenomyosis in the junctional zone and clinical symptoms. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Histological study on the influence of puberty suppression and hormonal treatment on developing germ cells in transgender women.

STUDY QUESTION: Can transgender women cryopreserve germ cells obtained from their orchiectomy specimen for fertility preservation, after having used puberty suppression and/or hormonal treatment? SUMMARY ANSWER: In the vast majority of transgender women, there were still immature germ cells present in the orchiectomy specimen, and in 4.7% of transgender women-who all initiated medical treatment in Tanner stage 4 or higher-mature spermatozoa were found, which would enable cryopreservation of spermatozoa or testicular tissue after having used puberty suppression and/or hormonal treatment. WHAT IS KNOWN ALREADY: Gender affirming treatment (i.e. puberty suppression, hormonal treatment, and subsequent orchiectomy) impairs reproductive function in transgender women. Although semen cryopreservation is generally offered during the transition process, this option is not feasible for all transgender women (e.g. due to incomplete spermatogenesis when initiating treatment in early puberty, in case of inability to masturbate, or when temporary cessation of hormonal treatment is too disruptive). Harvesting mature spermatozoa, or testicular tissue harboring immature germ cells, from orchiectomy specimens obtained during genital gender-affirming surgery (gGAS) might give this group a chance of having biological children later in life. Previous studies on spermatogenesis in orchiectomy specimens showed conflicting results, ranging from complete absence of germ cells to full spermatogenesis, and did not involve transgender women who initiated medical treatment in early- or late puberty. STUDY DESIGN, SIZE, DURATION: Histological and immunohistochemical analyses were performed on orchiectomy specimens from 214 transgender women who underwent gGAS between 2006 and 2018. Six subgroups were identified, depending on pubertal stage at initiation of medical treatment (Tanner stage 2-3, Tanner stage 4-5, adult), and whether hormonal treatment was continued or temporarily stopped prior to gGAS in each of these groups. PARTICIPANTS/MATERIALS, SETTING, METHODS: All transgender women used a combination of estrogens and testosterone suppressing therapy. Orchiectomy specimen sections were stained with Mayer's hematoxylin and eosin and histologically analyzed to assess the Johnsen score and the ratio of most advanced germ cell types in at least 50 seminiferous tubular cross-sections. Subsequently, immunohistochemistry was used to validate these findings using spermatogonia, spermatocytes or spermatids markers (MAGE-A3/A4, γH2AX, Acrosin, respectively). Possibilities for fertility preservation were defined as: preservation of spermatozoa, preservation of spermatogonial stem cells or no possibilities (in case no germ cells were found). Outcomes were compared between subgroups and logistic regression analyses were used to assess the association between the duration of hormonal treatment and the possibilities for fertility preservation. MAIN RESULTS AND THE ROLE OF CHANCE: Mature spermatozoa were encountered in 4.7% of orchiectomy specimens, all from transgender women who had initiated medical treatment in Tanner stage 4 or higher. In 88.3% of the study sample orchiectomy specimens only contained immature germ cells (round spermatids, spermatocytes or spermatogonia, as most advanced germ cell type). In 7.0%, a complete absence of germ cells was observed, all these samples were from transgender women who had initiated medical treatment in adulthood. Cessation of hormonal treatment prior to gGAS did not affect the presence of germ cells or their maturation stage, nor was there an effect of the duration of hormonal treatment prior to gGAS. LIMITATIONS, REASONS FOR CAUTION: Since data on serum hormone levels on the day of gGAS were not available, we were unable to verify if the transgender women who were asked to temporarily stop hormonal treatment 4 weeks prior to surgery actually did so, and if people with full spermatogenesis were compliant to treatment. WIDER IMPLICATIONS OF THE FINDINGS: There may still be options for fertility preservation in orchiectomy specimens obtained during gGAS since a small percentage of transgender women had full spermatogenesis, which could enable cryopreservation of mature spermatozoa via a testicular sperm extraction procedure. Furthermore, the vast majority still had immature germ cells, which could enable cryopreservation of testicular tissue harboring spermatogonial stem cells. If maturation techniques like in vitro spermatogenesis become available in the future, harvesting germ cells from orchiectomy specimens might be a promising option for those who are otherwise unable to have biological children. STUDY FUNDING/COMPETING INTEREST: None. TRIAL REGISTRATION NUMBER: N/A.

Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?

INTRODUCTION: The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals. METHOD: Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard. RESULTS: We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74-0.86), followed by RMI (0.71, 95%CI 0.64-0.78) and CA125 (0.69, 95%CI 0.62-0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same. CONCLUSION: HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital.

How to use power Doppler ultrasound in transvaginal assessment of uterine fibroids.

Measuring vascularization in uterine fibroids is important for their diagnosis, treatment and prognosis. Vascularization can be measured by power Doppler ultrasound. The power Doppler signal depends on fibroid characteristics and on a variety of ultrasound-machine settings. Literature describing which machine settings influence the power Doppler signal is limited. Each manufacturer names settings and presets at their own discretion, with little information available publicly. Consistency of machine settings is important for correct interpretation of images in daily practice and is essential in yielding reproducible data for research. The aims of this paper, drawing from both a literature search and semistructured interviews with ultrasound-machine engineers and clinical experts in gynecological ultrasound, were: (1) to provide comprehensive background information on ultrasound physics and fibroid characteristics; (2) to present an overview of machine settings relevant to both two- and three-dimensional power Doppler, including power Doppler frequency, pulse repetition frequency, gain, wall-motion filter, acoustic power, persistence and signal rise; and (3) to provide a step-by-step tutorial on the optimal settings for vascular evaluation of uterine fibroids using power Doppler. The step-by-step tutorial comprises six steps to optimize the power Doppler signal, create a preset and acquire a reliable three-dimensional volume. This step-by-step tutorial should help research groups and clinicians to use power Doppler correctly and reproducibly in the evaluation of uterine fibroids. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Consensus on revised definitions of Morphological Uterus Sonographic Assessment (MUSA) features of adenomyosis: results of modified Delphi procedure.

OBJECTIVES: To evaluate whether the Morphological Uterus Sonographic Assessment (MUSA) features of adenomyosis need to be better defined and, if deemed necessary, to reach consensus on the updated definitions. METHODS: A modified Delphi procedure was performed among European gynecologists with expertise in ultrasound diagnosis of adenomyosis. To identify MUSA features that might need revision, 15 two-dimensional (2D) video recordings (four recordings also included three-dimensional (3D) still images) of transvaginal ultrasound (TVS) examinations of the uterus were presented in the first Delphi round (online questionnaire). Experts were asked to confirm or refute the presence of each of the nine MUSA features of adenomyosis (described in the original MUSA consensus statement) in each of the 15 videoclips and to provide comments. In the second Delphi round (online questionnaire), the results of the first round and suggestions for revision of MUSA features were shared with the experts before they were asked to assess a new set of 2D and 3D still images of TVS examinations and to provide feedback on the proposed revisions. A third Delphi round (virtual group meeting) was conducted to discuss and reach final consensus on revised definitions of MUSA features. Consensus was predefined as at least 66.7% agreement between experts. RESULTS: Of 18 invited experts, 16 agreed to participate in the Delphi procedure. Eleven experts completed and four experts partly finished the first round. The experts identified a need for more detailed definitions of some MUSA features. They recommended use of 3D ultrasound to optimize visualization of the junctional zone. Fifteen experts participated in the second round and reached consensus on the presence or absence of ultrasound features of adenomyosis in most of the still images. Consensus was reached for all revised definitions except those for subendometrial lines and buds and interrupted junctional zone. Thirteen experts joined the online meeting, in which they discussed and agreed on final revisions of the MUSA definitions. There was consensus on the need to distinguish between direct features of adenomyosis, i.e. features indicating presence of ectopic endometrial tissue in the myometrium, and indirect features, i.e. features reflecting changes in the myometrium secondary to presence of endometrial tissue in the myometrium. Myometrial cysts, hyperechogenic islands and echogenic subendometrial lines and buds were classified unanimously as direct features of adenomyosis. Globular uterus, asymmetrical myometrial thickening, fan-shaped shadowing, translesional vascularity, irregular junctional zone and interrupted junctional zone were classified as indirect features of adenomyosis. CONCLUSION: Consensus between gynecologists with expertise in ultrasound diagnosis of adenomyosis was achieved regarding revised definitions of the MUSA features of adenomyosis and on the classification of MUSA features as direct or indirect signs of adenomyosis. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Definition and sonographic reporting system for Cesarean scar pregnancy in early gestation: modified Delphi method.

OBJECTIVE: To develop a standardized sonographic evaluation and reporting system for Cesarean scar pregnancy (CSP) in the first trimester, for use by both general gynecology and expert clinics. METHODS: A modified Delphi procedure was carried out, in which 28 international experts in obstetric and gynecological ultrasonography were invited to participate. Extensive experience in the use of ultrasound to evaluate Cesarean section (CS) scars in early pregnancy and/or publications concerning CSP or niche evaluation was required to participate. Relevant items for the detection and evaluation of CSP were determined based on the results of a literature search. Consensus was predefined as a level of agreement of at least 70% for each item, and a minimum of three Delphi rounds were planned (two online questionnaires and one group meeting). RESULTS: Sixteen experts participated in the Delphi study and four Delphi rounds were performed. In total, 58 items were determined to be relevant. We differentiated between basic measurements to be performed in general practice and advanced measurements for expert centers or for research purposes. The panel also formulated advice on indications for referral to an expert clinic. Consensus was reached for all 58 items on the definition, terminology, relevant items for evaluation and reporting of CSP. It was recommended that the first CS scar evaluation to determine the location of the pregnancy should be performed at 6-7 weeks' gestation using transvaginal ultrasound. The use of magnetic resonance imaging was not considered to add value in the diagnosis of CSP. A CSP was defined as a pregnancy with implantation in, or in close contact with, the niche. The experts agreed that a CSP can occur only when a niche is present and not in relation to a healed CS scar. Relevant sonographic items to record included gestational sac (GS) size, vascularity, location in relation to the uterine vessels, thickness of the residual myometrium and location of the pregnancy in relation to the uterine cavity and serosa. According to its location, a CSP can be classified as: (1) CSP in which the largest part of the GS protrudes towards the uterine cavity; (2) CSP in which the largest part of the GS is embedded in the myometrium but does not cross the serosal contour; and (3) CSP in which the GS is partially located beyond the outer contour of the cervix or uterus. The type of CSP may change with advancing gestation. Future studies are needed to validate this reporting system and the value of the different CSP types. CONCLUSION: Consensus was achieved among experts regarding the sonographic evaluation and reporting of CSP in the first trimester. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Reduced pregnancy and live birth rates after in vitro fertilization in women with previous Caesarean section: a retrospective cohort study.

STUDY QUESTION: Does a previous Caesarean section affect reproductive outcomes, including live birth, in women after IVF or ICSI? SUMMARY ANSWER: A previous Caesarean section impairs live birth rates after IVF or ICSI compared to a previous vaginal delivery. WHAT IS KNOWN ALREADY: Rates of Caesarean sections are rising worldwide. Late sequelae of a Caesarean section related to a niche (Caesarean scar defect) include gynaecological symptoms and obstetric complications. A systematic review reported a lower pregnancy rate after a previous Caesarean section (RR 0.91 CI 0.87-0.95) compared to a previous vaginal delivery. So far, studies have been unable to causally differentiate between problems with fertilisation, and the transportation or implantation of an embryo. Studying an IVF population allows us to identify the effect of a previous Caesarean section on the implantation of embryos in relation to a previous vaginal delivery. STUDY DESIGN, SIZE, DURATION: We retrospectively studied the live birth rate in women who had an IVF or ICSI treatment at the IVF Centre, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands, between 2006 and 2016 with one previous delivery. In total, 1317 women were included, of whom 334 had a previous caesarean section and 983 had previously delivered vaginally. PARTICIPANTS/MATERIALS, SETTING, METHODS: All secondary infertile women, with only one previous delivery either by caesarean section or vaginal delivery, were included. If applicable, only the first fresh embryo transfer was included in the analyses. Patients who did not intend to undergo embryo transfer were excluded. The primary outcome was live birth. Multivariate logistic regression analyses were used with adjustment for possible confounders ((i) age; (ii) pre-pregnancy BMI; (iii) pre-pregnancy smoking; (iv) previous fertility treatment; (v) indication for current fertility treatment: (a) tubal, (b) male factor and (c) endometriosis; (vi) embryo quality; and (vii) endometrial thickness), if applicable. Analysis was by intention to treat (ITT). MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics of both groups were comparable. Live birth rates were significantly lower in women with a previous caesarean section than in women with a previous vaginal delivery, 15.9% (51/320) versus 23.3% (219/941) (OR 0.63 95% CI 0.45-0.87) in the ITT analyses. The rates were also lower for ongoing pregnancy (20.1 versus 28.1% (OR 0.64 95% CI 0.48-0.87)), clinical pregnancy (25.7 versus 33.8% (OR 0.68 95% CI 0.52-0.90)) and biochemical test (36.2 versus 45.5% (OR 0.68 95% CI 0.53-0.88)). The per protocol analyses showed the same differences (live birth rate OR 0.66 95% CI 0.47-0.93 and clinical pregnancy rate OR 0.72 95% CI 0.54-0.96). LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design. Furthermore, 56 (16.3%) cases lacked data regarding delivery outcomes, but these were equally distributed between the two groups. WIDER IMPLICATIONS OF THE FINDINGS: The lower clinical pregnancy rates per embryo transfer indicate that implantation is hampered after a caesarean section. Its relation with a possible niche (caesarean scar defect) in the uterine caesarean scar needs further study. Our results should be discussed with clinicians and patients who consider an elective caesarean section. STUDY FUNDING/COMPETING INTEREST(S): Not applicable. TRIAL REGISTRATION NUMBER: This study has been registered in the Dutch Trial Register (Ref. No. NL7631 http://www.trialregister.nl).

Impaired semen quality in trans women: prevalence and determinants.

STUDY QUESTION: What is the semen quality in trans women at time of fertility preservation, prior to the start of gender-affirming hormone treatment? SUMMARY ANSWER: Before the start of gender-affirming hormone treatment, semen quality in trans women was already strongly decreased compared to the general population. WHAT IS KNOWN ALREADY: Hormone treatment for -trans women (birth-assigned males, female gender identity) consists of anti-androgens combined with estrogens in order to achieve feminization and it is accompanied by a loss of reproductive capability. Trans women can opt for semen cryopreservation prior to their medical transition to retain the possibility to parent genetically related offspring. Post-thaw semen parameters determine which ART can be used. Knowledge of semen quality and the factors negatively influencing semen parameters in trans women are important to improve semen quality before fertility preservation. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study was performed between 1972 and 2017. In total, 260 trans women were included for this study. Due to the study design, there was no loss to follow-up or attrition. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied the quality of the preserved semen in trans women, prior to their medical transition, who visited our gender clinic. Semen parameters were collected, as well as data on age, alcohol consumption, smoking, cannabis use, BMI, previous use of estrogens or anti-androgens and endocrine laboratory results. Semen parameters were categorized using reference values for human semen of the World Health Organization (WHO) and compared with data from the general population. Logistic regression analyses were performed to analyze the extent to which factors known to have a negative impact on semen quality in the general population explained the impaired semen quality in the cohort. MAIN RESULTS AND THE ROLE OF CHANCE: The cohort consisted of 260 trans women between the age of 16 and 52 years. Semen quality in trans women was significantly decreased compared to WHO data from the general population. In total, 21 trans women had an azoospermia and median semen parameters for the remaining trans women and the general population, respectively, were as follows: volume 2.7 and 3.2 ml (P < 0.05), sperm concentration 40 and 64 million/ml (P < 0.05), total sperm number 103 and 196 million (P < 0.05) and progressive motility 41% and 57% (P < 0.05). Smoking (odds ratio (OR) 2.35 (95% CI 1.06-5.21)) and a higher age at time of fertility preservation (OR 1.04 (95% CI 1.00-1.08)) were found to correlate with an impaired progressive motility. Twelve trans women reported to have used anti-androgens and estrogens, and all had discontinued for at least 3 months prior to the first attempt for semen cryopreservation. No correlation was found between previous gender-affirming hormone use and decreased semen parameters. The median post-thaw total motile sperm count was 1.0 million per vial (interquartile range 0.1-3.1) and in only 26.4% of thawed semen samples was the quality adequate for a minimally invasive IUI. LIMITATIONS, REASONS FOR CAUTION: Limitations include the retrospective design and insufficient data on transgender-specific factors, such as bringing the testes into the inguinal position (tucking), wearing tight underwear and low masturbation frequency. WIDER IMPLICATIONS OF THE FINDINGS: Semen quality in trans women was decreased compared to the general population, which could not be explained by known risk factors, such as BMI, alcohol consumption, cannabis use, gender-affirming hormone use or abnormal endocrine laboratory results. Although a negative impact of smoking was observed, it was insufficient to explain the overall decreased semen quality in this cohort. Since low pre-freeze semen quality results in an even lower post-thaw semen quality, the majority of trans women and their female partner or surrogate may need an invasive and burdensome treatment to establish a pregnancy. STUDY FUNDING/COMPETING INTEREST(S): For this study, no external funding was obtained and there were no competing interests. TRIAL REGISTRATION NUMBER: NA.

Septum resection in women with a septate uterus: a cohort study.

STUDY QUESTION: Does septum resection improve reproductive outcomes in women with a septate uterus? SUMMARY ANSWER: In women with a septate uterus, septum resection does not increase live birth rate nor does it decrease the rates of pregnancy loss or preterm birth, compared with expectant management. WHAT IS KNOWN ALREADY: The septate uterus is the most common uterine anomaly with an estimated prevalence of 0.2-2.3% in women of reproductive age, depending on the classification system. The definition of the septate uterus has been a long-lasting and ongoing subject of debate, and currently two classification systems are used worldwide. Women with a septate uterus may be at increased risk of subfertility, pregnancy loss, preterm birth and foetal malpresentation. Based on low quality evidence, current guidelines recommend removal of the intrauterine septum or, more cautiously, state that the procedure should be evaluated in future studies. STUDY DESIGN, SIZE, DURATION: We performed an international multicentre cohort study in which we identified women mainly retrospectively by searching in electronic patient files, medical records and databases within the time frame of January 2000 until August 2018. Searching of the databases, files and records took place between January 2016 and July 2018. By doing so, we collected data on 257 women with a septate uterus in 21 centres in the Netherlands, USA and UK. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included women with a septate uterus, defined by the treating physician, according to the classification system at that time. The women were ascertained among those with a history of subfertility, pregnancy loss, preterm birth or foetal malpresentation or during a routine diagnostic procedure. Allocation to septum resection or expectant management was dependent on the reproductive history and severity of the disease. We excluded women who did not have a wish to conceive at time of diagnosis. The primary outcome was live birth. Secondary outcomes included pregnancy loss, preterm birth and foetal malpresentation. All conceptions during follow-up were registered but for the comparative analyses, only the first live birth or ongoing pregnancy was included. To evaluate differences in live birth and ongoing pregnancy, we used Cox proportional regression to calculate hazard rates (HRs) and 95% CI. To evaluate differences in pregnancy loss, preterm birth and foetal malpresentation, we used logistic regression to calculate odds ratios (OR) with corresponding 95% CI. We adjusted all reproductive outcomes for possible confounders. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 257 women were included in the cohort. Of these, 151 women underwent a septum resection and 106 women had expectant management. The median follow-up time was 46 months. During this time, live birth occurred in 80 women following a septum resection (53.0%) compared to 76 women following expectant management (71.7%) (HR 0.71 95% CI 0.49-1.02) and ongoing pregnancy occurred in 89 women who underwent septum resection (58.9%), compared to 80 women who had expectant management (75.5%) (HR 0.74 (95% CI 0.52-1.06)). Pregnancy loss occurred in 51 women who underwent septum resection (46.8%) versus 31 women who had expectant management (34.4%) (OR 1.58 (0.81-3.09)), while preterm birth occurred in 26 women who underwent septum resection (29.2%) versus 13 women who had expectant management (16.7%) (OR 1.26 (95% CI 0.52-3.04)) and foetal malpresentation occurred in 17 women who underwent septum resection (19.1%) versus 27 women who had expectant management (34.6%) (OR 0.56 (95% CI 0.24-1.33)). LIMITATIONS, REASONS FOR CAUTION: Our retrospective study has a less robust design compared with a randomized controlled trial. Over the years, the ideas about the definition of the septate uterus has changed, but since the 257 women with a septate uterus included in this study had been diagnosed by their treating physician according to the leading classification system at that time, the data of this study reflect the daily practice of recent decades. Despite correcting for the most relevant patient characteristics, our estimates might not be free of residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that septum resection, a procedure that is widely offered and associated with financial costs for society, healthcare systems or individuals, does not lead to improved reproductive outcomes compared to expectant management for women with a septate uterus. The results of this study need to be confirmed in randomized clinical trials. STUDY FUNDING/COMPETING INTEREST(S): A travel for JFWR to Chicago was supported by the Jo Kolk Studyfund. Otherwise, no specific funding was received for this study. The Department of Obstetrics and Gynaecology, University Medical Centre, Groningen, received an unrestricted educational grant from Ferring Pharmaceutical Company unrelated to the present study. BWM reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck, personal fees from Guerbet, other payment from Guerbet and grants from Merck, outside the submitted work. The other authors declare no conficts of interest. TRIAL REGISTRATION NUMBER: N/A.

Predicting return to work among patients with colorectal cancer.

BACKGROUND: The increase in prevalence of colorectal cancer among young patients coupled with an older retirement age in developed countries means that more patients are being diagnosed with colorectal cancer while still at work. The aim of this study was to develop prediction models for return to work by 1 and 2 years after the start of sick leave. METHODS: This was a retrospective registry-based cohort study of data from a nationwide occupational health service in the Netherlands. Only employed patients with colonic or rectal cancer treated with curative intent were included. Two predictor variable models were developed using multivariable logistic regression with backward selection. Calibration, discrimination and explained variance were used to assess model performance, and internal validation by bootstrapping was performed. RESULTS: Median time to return to work for 317 included patients was 423 (95 per cent c.i. 379 to 467) days. Two-thirds of patients had returned to work by 2 years after the start of the sick leave. Presence of metastases, adjuvant treatment, stoma, emotional distress and postoperative complications were predictors of not returning to work in the 1-year model. In the 2-year model, presence of metastases, emotional distress, postoperative complications, company size and the trajectory of the return-to-work process were predictors. CONCLUSION: Almost 70 per cent of patients with colorectal cancer in this population returned to work within 2 years after the start of sick leave. The models can be used to guide patients early in colorectal cancer treatment about the likelihood of returning to work, and to identify and modify barriers that could facilitate this.

ANTECEDENTES: El aumento de la prevalencia del cáncer colorrectal (colorectal cancer, CCR) en pacientes jóvenes, junto con una edad de jubilación más avanzada en los países desarrollados, significa un mayor número de pacientes en edad laboral diagnosticados de CCR. El objetivo de este estudio fue desarrollar modelos de predicción del regreso al trabajo uno y dos años después del inicio de la baja por enfermedad para el tratamiento de CCR. MÉTODOS: Se trata de un estudio de cohortes retrospectivo basado en el registro de datos nacionales de salud laboral en los Países Bajos. Solo se incluyeron pacientes con cáncer de colon o recto tratados con intención curativa. Se desarrollaron dos modelos de variables de predicción utilizando regresión logística multivariante con selección de variables hacia atrás. Para evaluar el rendimiento del modelo se utilizaron la calibración, la discriminación y la varianza explicada y se realizó la validación interna mediante bootstrap. RESULTADOS: La mediana de tiempo de regreso al trabajo de 317 pacientes incluidos fue de 423 días (i.c. del 95%: 378,6-467,4). Dos tercios de los pacientes habían regresado al trabajo dos años después del inicio del período de baja por enfermedad. La presencia de metástasis, el tratamiento adyuvante, el estoma, la angustia emocional y las complicaciones postoperatorias fueron factores predictivos de no volver a trabajar en el modelo de un año. En el modelo de dos años, la presencia de metástasis, la angustia emocional, las complicaciones postoperatorias, el tamaño de la empresa y la trayectoria del proceso de retorno al trabajo fueron factores predictores del regreso laboral. CONCLUSIÓN: Casi el 70% de los pacientes con CCR en esta población volvieron a trabajar dentro de los dos años posteriores al inicio del periodo de baja por enfermedad. Los modelos se pueden usar para guiar a los pacientes con CCR al inicio de su tratamiento sobre su probabilidad de regresar al trabajo, así como para identificar y modificar las barreras que podrían facilitarlo.

Sonographic examination of uterine niche in non-pregnant women: a modified Delphi procedure.

OBJECTIVE: To generate guidance for detailed uterine niche evaluation by ultrasonography in the non-pregnant woman, using a modified Delphi procedure amongst European experts. METHODS: Twenty gynecological experts were approached through their membership of the European Niche Taskforce. All experts were physicians with extensive experience in niche evaluation in clinical practice and/or authors of niche publications. By means of a modified Delphi procedure, relevant items for niche measurement were determined based on the results of a literature search and recommendations of a focus group of six Dutch experts. It was predetermined that at least three Delphi rounds would be performed (two online questionnaires completed by the expert panel and one group meeting). For it to be declared that consensus had been reached, a consensus rate for each item of at least 70% was predefined. RESULTS: Fifteen experts participated in the Delphi procedure. Consensus was reached for all 42 items on niche evaluation, including definitions, relevance, method of measurement and tips for visualization of the niche. A niche was defined as an indentation at the site of a Cesarean section with a depth of at least 2 mm. Basic measurements, including niche length and depth, residual and adjacent myometrial thickness in the sagittal plane, and niche width in the transverse plane, were considered to be essential. If present, branches should be reported and additional measurements should be made. The use of gel or saline contrast sonography was preferred over standard transvaginal sonography but was not considered mandatory if intrauterine fluid was present. Variation in pressure generated by the transvaginal probe can facilitate imaging, and Doppler imaging can be used to differentiate between a niche and other uterine abnormalities, but neither was considered mandatory. CONCLUSION: Consensus between niche experts was achieved regarding ultrasonographic niche evaluation. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Single- versus double-layer closure of the caesarean (uterine) scar in the prevention of gynaecological symptoms in relation to niche development - the 2Close study: a multicentre randomised controlled trial.

BACKGROUND: Double-layer compared to single-layer closure of the uterus after a caesarean section (CS) leads to a thicker myometrial layer at the site of the CS scar, also called residual myometrium thickness (RMT). It possibly decreases the development of a niche, which is an interruption of the myometrium at the site of the uterine scar. Thin RMT and a niche are associated with gynaecological symptoms, obstetric complications in a subsequent pregnancy and delivery and possibly with subfertility. METHODS: Women undergoing a first CS regardless of the gestational age will be asked to participate in this multicentre, double blinded randomised controlled trial (RCT). They will be randomised to single-layer closure or double-layer closure of the uterine incision. Single-layer closure (control group) is performed with a continuous running, unlocked suture, with or without endometrial saving technique. Double-layer closure (intervention group) is performed with the first layer in a continuous unlocked suture including the endometrial layer and the second layer is also continuous unlocked and imbricates the first. The primary outcome is the reported number of days with postmenstrual spotting during one menstrual cycle nine months after CS. Secondary outcomes include surgical data, ultrasound evaluation at three months, menstrual pattern, dysmenorrhea, quality of life, and sexual function at nine months. Structured transvaginal ultrasound (TVUS) evaluation is performed to assess the uterine scar and if necessary saline infusion sonohysterography (SIS) or gel instillation sonohysterography (GIS) will be added to the examination. Women and ultrasound examiners will be blinded for allocation. Reproductive outcomes at three years follow-up including fertility, mode of delivery and complications in subsequent deliveries will be studied as well. Analyses will be performed by intention to treat. 2290 women have to be randomised to show a reduction of 15% in the mean number of spotting days. Additionally, a cost-effectiveness analysis will be performed from a societal perspective. DISCUSSION: This RCT will provide insight in the outcomes of single- compared to double-layer closure technique after CS, including postmenstrual spotting and subfertility in relation to niche development measured by ultrasound. TRIAL REGISTRATION: Dutch Trial Register ( NTR5480 ). Registered 29 October 2015.

Cancer survivors' needs during various treatment phases after multimodal treatment for colon cancer - is there a role for eHealth?

BACKGROUND: More colon cancer patients are expected to fully recover after treatment due to earlier detection of cancer and improvements in general health- and cancer care. The objective of this study was to gather participants' experiences with full recovery in the different treatment phases of multimodal treatment and to identify their needs during these phases. The second aim was to propose and evaluate possible solutions for unmet needs by the introduction of eHealth. METHODS: A qualitative study based on two focus group discussions with 22 participants was performed. The validated Supportive Care Needs Survey and the Cancer Treatment Survey were used to form the topic list. The verbatim transcripts were analyzed with Atlas.ti. 7th version comprising open, axial and selective coding. The guidelines of the consolidated criteria for reporting qualitative research (COREQ) were used. RESULTS: Experiences with the treatment for colon cancer were in general positive. Most important unmet needs were 'receiving information about the total duration of side effects', 'receiving information about the minimum amount of chemo needed to overall survival' and 'receiving a longer aftercare period (with additional attention for psychological guidance)'. More provision of information online, a chat function with the oncological nurse specialist via a website, and access to scientific articles regarding the optimal dose of chemotherapy were often mentioned as worthwhile additions to the current health care for colon cancer. CONCLUSIONS: Many of the unmet needs of colon cancer survivors occur during the adjuvant treatment phase and thereafter. To further optimize recovery and cancer care, it is necessary to have more focus on these unmet needs. More attention for identifying patients' problems and side-effects during chemotherapy; and identifying patients' supportive care needs after finishing chemotherapy are necessary. For some of these needs, eHealth in the form of blended care will be a possible solution.

Misoprostol for cervical priming prior to hysteroscopy in postmenopausal and premenopausal nulliparous women; a multicentre randomised placebo controlled trial.

OBJECTIVE: To evaluate the reduction of pain by misoprostol compared with placebo prior to hysteroscopy in postmenopausal and premenopausal nulliparous women. DESIGN: Randomised multicentre double-blind placebo controlled trial. SETTING: Two Dutch teaching hospitals and one Dutch university medical centre. POPULATION: Postmenopausal and premenopausal nulliparous women undergoing office hysteroscopy. METHODS: Patients were randomised to receive either 400 microgram misoprostol or placebo 12 and 24 hours before hysteroscopy. Pain was quantified by the use of real time pain measurement using the continuous pain score meter (CPSM) and VAS scores. MAIN OUTCOME MEASURES: Primary outcome was pain measured by the CPSM during passage of the hysteroscope through the cervical canal, quantified by the area under the curve (AUC). Secondary outcomes included VAS scores, other CPSM parameters, failures and side effects. RESULTS: In all, 149 patients were randomly assigned to either misoprostol (n = 74) or placebo (n = 75). The AUC during introduction did not significantly differ between the intervention and the placebo group. The VAS score during introduction, however, demonstrated a significant difference in premenopausal nulliparous women favouring misoprostol: 2.9 (95% CI 1.3-4.4) versus placebo 5.5 (95% CI 3.9-7.1), P = 0.02, as well as the AUC during the entire procedure: 618 (95% CI 410-827) versus 1126 (95% CI 671-1580), P = 0.04. Failures were equally distributed between the misoprostol (16%) and placebo group (13%). Intestinal side effects occurred significantly more frequently in the misoprostol group (67%) than in the placebo group (32%) [OR 4.2 (95% CI 2.1-8.3), P < 0.01]. CONCLUSION: Misoprostol prior to hysteroscopy reduces pain in premenopausal nulliparous women but not in postmenopausal women. It does cause side effects. TWEETABLE ABSTRACT: RCT: misoprostol versus placebo prior to hysteroscopy in 149 women significantly reduces some pain parameters.

High-quality human preimplantation embryos actively influence endometrial stromal cell migration.

PURPOSE: The purpose of this paper is to study whether human preimplantation embryos regulate endometrial stromal cell (hESC) migration. METHODS: Primary hESCs were isolated from fertile patients undergoing hysterectomy for benign conditions (uterine scar niche n = 3, dysmenorrhea n = 2; no hormonal treatment). Migration and proliferation assays were performed by culturing decidualized or non-decidualized hESCs in the presence of embryo conditioned medium (ECM) from high-quality embryos (fragmentation ≤ 20%) or from low-quality embryos (fragmentation > 20%) or in non-conditioned medium from the same dishes (control). ECM samples from 425 individually cultured human embryos were used in this study. RESULTS: ECM from high-quality embryos, i.e., with a low percentage of fragmentation, actively stimulated decidualized hESC migration (p < 0.001). This effect was consistent throughout embryonic development from cleavage stage embryos with 2-7 cells (high quality vs. control; p = 0.036), 8-18 cells (high quality vs. control; p < 0.001) to morulae (high quality vs. control; p = 0.003). Additionally, linear regression analysis showed that hESC migration was influenced by embryo quality (fragmentation, ß - 0.299; p = 0.025) and not developmental stage (cell number, ß 0.177; p = 0.176) or maternal age (ß - 0.036; p = 0.78). Opposite to decidualized hESCs, the migration response of non-decidualized hESCs was inhibited by ECM from high-quality embryos (p = 0.019). ECM from low-quality embryos, i.e., with a high percentage of fragmentation, did not cause an altered migration response in decidualized hESCs (p = 0.860) or non-decidualized hESCs (p = 0.986). Furthermore, ECM of both high- and low-quality human embryos did not influence the number of proliferating cells (p = 0.375) and the cell cycle time (p = 0.297) of non-decidualized or decidualized hESCs. CONCLUSION: This study reveals a mechanism by which high-quality human preimplantation embryos actively interact with the endometrium to increase their chances of successful implantation.

3D power Doppler in uterine fibroids; influence of gain, cardiac cycle and off-line measurement techniques.

This study answers the question of whether ultrasound machine settings and the cardiac cycle can influence 3D power Doppler (3D PD) indices in the evaluation of uterine fibroid vascularisation. These parameters were reported to affect the vascular indices and cause undesired variation. 3D PD ultrasound was performed using three different gain settings: a fixed predetermined gain (50 dB), a higher gain (65 dB) and an individualised subjectively most optimal gain. Two consecutive 3D PD sweeps were taken to evaluate the effect of the cardiac cycle. A predetermined most optimal fixed gain setting was not different from the individually most optimal chosen gain in vascular assessment of fibroids. A higher gain corresponded with a significantly higher vascular index (VI). Potential variation during the cardiac cycle does not disturb the VI in fibroids.

Diagnostic workup for postmenopausal bleeding: a randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of hysteroscopy for the detection and treatment of endometrial polyps versus expectant management in women with postmenopausal bleeding (PMB), a thickened endometrium and benign endometrial sampling. DESIGN: Multicentre, randomised controlled trial. SETTING: Three academic hospitals and nine non-academic teaching hospitals in the Netherlands. POPULATION: Women with PMB, an endometrial thickness >4 mm and benign result from endometrial sampling. METHODS: Women were randomised to either further diagnostic workup by hysteroscopy (preceded by saline infusion sonography) or expectant management. MAIN OUTCOMES: The primary outcome measure was recurrence of PMB within a year after randomisation. Secondary outcome measures were time to recurrent bleeding and recurrent bleeding after more than 1 year. In the hysteroscopy group, the presence of polyps and the results of their histology were registered. RESULTS: Between January 2010 and October 2013, 200 women were randomised; 98 to hysteroscopy and 102 to expectant management. Within 1 year a total of 15 women (15.3%) in the hysteroscopy group experienced recurrent bleeding, versus 18 (18.0%) in the expectant management group (relative risk 0.85 (95% CI 0.46-1.59). In the hysteroscopy group, 50/98 (51%) polyps were diagnosed of which 6/98 (6%) showed evidence of endometrial (pre)malignancy; final pathology results after hysterectomy showed three women with hyperplasia with atypia and three women with endometrial cancer. CONCLUSION: In women with PMB, a thickened endometrium and benign endometrial sampling, operative hysteroscopy does not reduce recurrent bleeding. Hysteroscopy detected focal endometrial (pre)malignancy in 6% of women who had benign endometrial sampling. This finding indicates that in these women, further diagnostic workup is warranted to detect focal (pre)malignancies, missed by blind endometrial sampling. TWEETABLE ABSTRACT: In women with PMB, hysteroscopy does not reduce recurrent bleeding but is warranted to detect focal malignancy.