No pain relief by virtual reality during hysterosalpingography (HSG): results from a randomized controlled trial.

STUDY QUESTION: Is virtual reality (VR) an effective non-pharmacological tool to reduce procedural pain during hysterosalpingography (HSG)? SUMMARY ANSWER: An HSG with VR does not reduce procedural pain scores compared to an HSG without VR. WHAT IS KNOWN ALREADY: An HSG is often experienced as painful and uncomfortable. VR has been proven successful to reduce acute procedural pain during a variety of medical procedures and interventions. STUDY DESIGN, SIZE, DURATION: We performed a two-centre open-label randomized controlled trial between January 2021 and October 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women scheduled for HSG as part of their infertility work-up were screened for participation. After informed consent, women were randomized between HSG with or without VR. Due to the nature of the intervention, the study was not blinded. VR was administered by a head-mounted device displaying nature movies and/or relaxation exercises. The primary endpoint was procedural pain measured using VAS (scale 0.0-10.0 cm). Procedural pain was divided into overall pain score and peak pain score during the procedure. It was measured immediately after HSG. Secondary endpoints included patient satisfaction, VR preferences, and adverse effects of VR. MAIN RESULTS AND THE ROLE OF CHANCE: We included a total of 134 women, 69 to the intervention group (HSG with VR) and 65 to the control group (HSG without VR). The mean VAS for peak pain was 6.80 cm (SD 2.25) in the intervention group versus 6.60 cm (SD 2.40) in the control group (mean difference 0.28 (95% CI -0.57, 1.12), P = 0.52). The mean VAS for overall pain was 5.00 cm (SD 2.10) in the intervention group versus 4.90 cm (SD 2.13) in the control group (mean difference 0.06 (95% CI -0.71, 0.84), P = 0.88). The expectation that VR would be a good distraction from pain during HSG was correlated with both overall and peak pain scores. When correcting for this expectation, we found that women in the intervention group reported significantly higher scores, both in peak (adjusted MD 0.58 (95% CI -0.81, 1.97), P = 0.021) and overall (adjusted MD 0.43 (95% CI -0.84, 1.71), P = 0.013) pain, compared to the control group. There were no differences in the prevalence of symptoms that were considered as adverse effects of VR. LIMITATIONS, REASONS FOR CAUTION: The study was not blinded. Reasons for declining participation in the study were anxiety or wanting full control during HSG, which might have created selection bias. The distraction score possibly indicates that the level of VR immersiveness was not optimal due to the lack of sound and/or the type of VR applications. Future studies should investigate whether more immersive or interactive VR applications could decrease procedural pain scores during HSG. WIDER IMPLICATIONS OF THE FINDINGS: Since VR does not reduce procedural pain, this additional tool should not be used during HSG. STUDY FUNDING/COMPETING INTEREST(S): There was no external funding for this study. KR and AvH report receiving a travel grant from Merck outside the scope of this study. BM is supported by a National Health and Medical Research Council (NHMRC) investigator grant (GNT1176437) and BM reports consultancy for Merck, Organon, and Norgine and travel and research funding from Merck. BM holds stock for ObsEva. CL reports receiving research grants from Merck, and Ferring. KD and VM report receiving travel and speaker's fees from Guerbet and research grants from Guerbet. VM also reports research grants from Merck and Ferring. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER: The trial is registered prospectively in the Netherlands Trial Register (trialregister.nl registration number NL9203, currently accessible on trialsearch.who.int). TRIAL REGISTRATION DATE: 16-01-2021. DATE OF FIRST PATIENT'S ENROLMENT: The first participant was enrolled on 19 January 2021.

The effect of dietary interventions on pain and quality of life in women diagnosed with endometriosis: a prospective study with control group.

STUDY QUESTION: What is the influence of dietary interventions, namely the low fermentable oligo-, di-, mono-saccharides, and polyols (Low FODMAP) diet and endometriosis diet, on endometriosis-related pain and quality of life (QoL) compared to a control group? SUMMARY ANSWER: After adhering to a dietary intervention for 6 months, women with endometriosis reported less pain and an improved QoL compared to baseline whereas, compared to the control group, they reported less bloating and a better QoL in 3 of 11 domains. WHAT IS KNOWN ALREADY: Standard endometriosis treatment can be insufficient or may be accompanied by unacceptable side effects. This has resulted in an increasing interest in self-management strategies, including the appliance of the Low FODMAP diet and the endometriosis diet (an experience-based avoidance diet, developed by women with endometriosis). The Low FODMAP diet has previously been found effective in reducing endometriosis-related pain symptoms, whereas only limited studies are available on the efficacy of the endometriosis diet. A survey study recently found the endometriosis diet effective in improving QoL but currently no guidelines on use of the diet exist. STUDY DESIGN, SIZE, DURATION: A prospective one-center pilot study was performed between April 2021 and December 2022. Participants could choose between adherence to a diet-the Low FODMAP diet or endometriosis diet-or no diet (control group). Women adhering to a diet received extensive guidance from a dietician in training. The follow-up period was 6 months for all three groups. For all outcomes, women adhering to the diets were compared to their baseline situation and to the control group. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included women diagnosed with endometriosis (surgically and/or by radiologic imaging) who reported pain scores ≥3 cm on the visual analogue score (0-10 cm) for dysmenorrhea, deep dyspareunia, and/or chronic pelvic pain. The primary endpoint focused on pain reduction for all pain symptoms, including dysuria, bloating, and tiredness. Secondary endpoints, assessed via questionnaires, focused on QoL, gastro-intestinal health, and diet adherence. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 62 participants were included in the low FODMAP diet (n = 22), endometriosis diet (n = 21), and control group (n = 19). Compared to their baseline pain scores, participants adhering to a diet reported less pain in four of six symptoms (range P < 0.001 to P = 0.012) and better scores in 6 of 11 QoL domains (range P < 0.001 to P = 0.023) after 6 months. Compared to the control group, analyzed longitudinally over the 6-month follow-up period, participants applying a diet reported significant less bloating (P = 0.049), and better scores in 3 of 11 QoL domains (range P = 0.002 to P = 0.035). LIMITATIONS, REASONS FOR CAUTION: No sample size was calculated since efficacy data were lacking in the literature. In order to optimize dietary adherence, randomization was not applied, possibly resulting in selection bias. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that women could benefit from adherence to a dietary intervention, since we found lower pain scores and better QoL after 6 months. However, caution is implied since this is a pilot study, no sample size was calculated, and data on long-term effects (>6 months) are lacking. The results of this pilot study underline the importance of further research and the drawing up of guidelines. STUDY FUNDING/COMPETING INTEREST(S): A.v.H. reports receiving a travel grant from Merck outside the scope of this study. J.W., S.V., J.T., and B.D.B. have no conflicts of interest to report. A.d.V. reports having received KP-register points for internship guidance of J.W., performing paid consultations with endometriosis patients outside the study and receiving reimbursements for educational lectures at the local hospital (Albert Schweitzer Ziekenhuis, Dordrecht, the Netherlands). A.S. reports having received expenses for travel and hotel costs as an invited speaker from ESHRE. This was outside the scope of this study. M.v.W. reports that she is a Co-Ed of Cochrane Gynecology and Fertility. V.M. reports receiving travel and speaker's fees from Guerbet and research grants from Guerbet, Merck and Ferring. The department of reproductive medicine (V.M.) of the Amsterdam UMC, location VUmc, has received several research and educational grants from Guerbet, Merck and Ferring not related to the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Deep endometriosis muscular infiltration of the bowel wall: correlation between MRI and histopathology.

AIM: To assess the correlation between magnetic resonance imaging (MRI) and histopathology for predicting muscular infiltration of endometriosis in the bowel wall in patients undergoing colorectal resection. MATERIALS AND METHODS: All consecutive patients who underwent colorectal surgery for deep endometriosis (DE) with a preoperative MRI in a single tertiary care referral hospital between 2001 and 2019 were included in a prospective cohort. MRI images were revised by a single blinded radiologist. The MRI results regarding the infiltration depth (serosal, muscular, submucosal, or mucosal) and lesion expansion of DE were compared to histopathology. RESULTS: A total of 84 patients were eligible for evaluation. A sensitivity of 89% and positive predictive value of 97% was shown for predicting muscular involvement of the bowel wall. CONCLUSION: This study showed that MRI is valuable in predicting the involvement of the muscular layer of the colorectal wall. Therefore, in patients with symptomatic pelvic bowel endometriosis MRI is a useful tool in guiding the extent of colorectal surgery.

The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial.

BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. METHODS: This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. DISCUSSION: The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. TRIAL REGISTRATION NUMBER: The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

Oil-based versus water-based contrast media for hysterosalpingography in infertile women of advanced age, with ovulation disorders or a high risk for tubal pathology: study protocol of a randomized controlled trial (H2Oil2 study).

BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography (HSG) increases ongoing pregnancy and subsequent live birth rates when compared to tubal flushing with water-based contrast. It is currently unclear whether an HSG with oil-based contrast also results in more ongoing pregnancies and live births in women of advanced age, women with ovulation disorders, and women with potential tubal pathology when compared to an HSG with water-based contrast. METHODS: We plan an international, multicentre, open-label, randomized controlled trial (RCT) studying three groups of infertile women who have an indication for tubal patency testing according to their treating physician and additionally; (1) are 39 years of age or older, (2) have an ovulation disorder or (3) have a high risk for tubal pathology based on their medical history. Women with an allergy for iodinated contrast medium are excluded, as are women with diabetes, hyperprolactinemia or untreated hyper- or hypothyroidism, and women with a partner with severe male infertility. After informed consent, women will be randomly allocated to the intervention, tubal flushing with the use of oil-based contrast during HSG or the control group, tubal flushing with the use of water-based contrast during HSG in a 1:1 ratio by the web-based system Castor. The primary endpoint will be ongoing pregnancy leading to live birth with conception within six months after randomization. Secondary outcomes are other pregnancy outcomes, used fertility treatments, adverse events and cost-effectiveness. Based on the expected ongoing pregnancy rate of 17% in the control group and 27% in the intervention group, the sample size will be 930 women (465 per group). Study inclusion is expected to be complete in four years. DISCUSSION: This multicentre RCT will establish whether, for women of advanced age, women with ovulatory disease, and women who have a high risk for tubal pathology, there is a fertility enhancing effect of tubal flushing with oil-based contrast during HSG and whether the use of this contrast medium is cost-effective. Trial Registration The study was prospectively registered in the Netherlands Trial Register on August 1st 2019 as 'H2Oil2' (reference number NL7925, https://www.trialregister.nl/trial/7925 ).

Male microchimerism in females: a quantitative study of twin pedigrees to investigate mechanisms.

STUDY QUESTION: Does having a male co-twin, older brothers, or sons lead to an increased probability of persistent male microchimerism in female members of twin pedigrees? SUMMARY ANSWER: The presence of a male co-twin did not increase risk of male microchimerism and the prevalence of male microchimerism was not explained by having male offspring or by having an older brother. WHAT IS KNOWN ALREADY: Microchimerism describes the presence of cells within an organism that originate from another zygote and is commonly described as resulting from pregnancy in placental mammals. It is associated with diseases with a female predilection including autoimmune diseases and pregnancy-related complications. However, microchimerism also occurs in nulliparous women; signifying gaps in the understanding of risk factors contributing to persistent microchimerism and the origin of the minor cell population. STUDY DESIGN, SIZE, DURATION: This cross-sectional study composed of 446 adult female participants of the Netherlands Twin Register (NTR). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included in the study were female monozygotic (MZ) twins, female dizygotic same-sex twins and females of dizygotic opposite-sex twin pairs, along with the mothers and sisters of these twins. Peripheral blood samples collected from adult female participants underwent DNA extraction and were biobanked prior to the study. To detect the presence of male-origin microchimerism, DNA samples were tested for the relative quantity of male specific Y chromosome gene DYS14 compared to a common ß-globin gene using a highly sensitive quantitative PCR assay. MAIN RESULTS AND THE ROLE OF CHANCE: We observed a large number of women (26.9%) having detectable male microchimerism in their peripheral blood samples. The presence of a male co-twin did not increase risk of male microchimerism (odds ratio (OR) = 1.23: SE 0.40, P = 0.61) and the prevalence of male microchimerism was not explained by having male offspring (OR 0.90: SE 0.19, P = 0.63) or by having an older brother (OR = 1.46: SE 0.32, P = 0.09). The resemblance (correlation) for the presence of microchimerism was similar (P = 0.66) in MZ pairs (0.27; SE 0.37) and in first-degree relatives (0.091; SE 0.092). However, age had a positive relationship with the presence of male microchimerism (P = 0.02). LIMITATIONS, REASONS FOR CAUTION: After stratifying for variables of interest, some participant groups resulted in a low numbers of subjects. We investigated microchimerism in peripheral blood due to the proposed mechanism of cell acquisition via transplacental blood exchange; however, this does not represent global chimerism in the individual and microchimerism may localize to numerous other tissues. WIDER IMPLICATIONS OF THE FINDINGS: Immune regulation during pregnancy is known to mitigate allosensitization and support tolerance to non-inherited antigens found on donor cells. While unable to identify a specific source that promotes microchimerism prevalence within pedigrees, this study points to the underlying complexities of natural microchimerism in the general population. These findings support previous studies which have identified the presence of male microchimerism among women with no history of pregnancy, suggesting alternative sources of microchimerism. The association of detectable male microchimerism with age is suggestive of additional factors including time, molecular characteristics and environment playing a critical role in the prevalence of persistent microchimerism. The present study necessitates investigation into the molecular underpinnings of natural chimerism to provide insight into women's health, transplant medicine and immunology. STUDY FUNDING/COMPETING INTEREST(S): This work is funded by Royal Netherlands Academy of Science Professor Award (PAH/6635 to D.I.B.); The Netherlands Organisation for Health Research and Development (ZonMw)-Genotype/phenotype database for behavior genetic and genetic epidemiological studies (ZonMw 911-09-032); Biobanking and Biomolecular Research Infrastructure (BBMRI-NL, 184.021.007; 184.033.111); The Netherlands Organisation for Scientific Research (NWO)-Netherlands Twin Registry Repository (NWO-Groot 480-15-001/674); the National Institutes of Health-The Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06), Grand Opportunity grants Integration of genomics and transcriptomics in normal twins and major depression (NIMH 1RC2 MH089951-01), and Developmental trajectories of psychopathology (NIMH 1RC2 MH089995); and European Research Council-Genetics of Mental Illness (ERC 230374). C.B.L. declares a competing interest as editor-in-chief of Human Reproduction and his department receives unrestricted research grants from Ferring, Merck and Guerbet. All remaining authors have no conflict-of-interest to declare in regards to this work. TRIAL REGISTRATION NUMBER: N/A.

Thyroid function in neonates conceived after hysterosalpingography with iodinated contrast.

STUDY QUESTION: Does exposure to preconceptional hysterosalpingography (HSG) with iodinated oil-based contrast affect neonatal thyroid function as compared to iodinated water-based contrast? SUMMARY ANSWER: Preconceptional HSG with iodinated contrast did not influence the neonatal thyroid function. WHAT IS KNOWN ALREADY: HSG is a commonly applied tubal patency test during fertility work-up in which either oil- or water-based contrast is used. Oil-based contrast contains more iodine compared to water-based contrast. A previous study in an East Asian population found an increased risk of congenital hypothyroidism (CH) in neonates whose mothers were exposed to high amounts of oil-based contrast during HSG. STUDY DESIGN, SIZE, DURATION: This is a retrospective data analysis of the H2Oil study, a randomized controlled trial (RCT) comparing HSG with the use of oil- versus water-based contrast during fertility work-up. After an HSG with oil-based contrast, 214 women had an ongoing pregnancy within 6 months leading to a live birth compared to 155 women after HSG with water-based contrast. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 369 women who had a live born infant, 208 consented to be approached for future research and 138 provided informed consent to collect data on the thyroid function tests of their offspring (n = 140). Thyroid function tests of these children were retrieved from the Dutch neonatal screening program, which includes the assessment of total thyroxine (T4) in all newborns, followed by thyroid-stimulating hormone only in those with a T4 level of ≤ -0.8 SD score. Furthermore, amount of contrast medium used and time between HSG and conception were compared between the two study groups. MAIN RESULTS AND THE ROLE OF CHANCE: Data were collected from 140 neonates conceived after HSG with oil-based (n = 76) or water-based (n = 64) contrast. The median T4 concentration was 87.0 nmol/l [76.0-96.0] in the oil group and 90.0 nmol/l [78.0-106.0] in the water group (P = 0.13). None of the neonates had a positive screening result for CH.The median amount of contrast medium used was 9.0 ml [interquartile range (IQR), 6.0-11.8] in the oil-group and 10.0 ml [IQR, 7.5-14.0] in the water group (P = 0.43). No influence of the amount of contrast on the effect of contrast group on T4 concentrations was found (P-value for interaction, 0.37). LIMITATIONS, REASONS FOR CAUTION: A relatively small sample size and possible attrition at follow-up are limitations of this study. Although our results suggest that the use of iodinated contrast media for HSG is safe for the offspring, the impact of a decrease in maternal thyroid function on offspring neurodevelopment could not be excluded, as data on maternal thyroid function after HSG and during conception were lacking. WIDER IMPLICATIONS OF THE FINDINGS: As HSG with oil-based contrast does not affect thyroid function of the offspring, there is no reason to withhold this contrast to infertile women undergoing HSG. Future studies should investigate whether HSG with iodinated contrast influences the periconceptional maternal thyroid function and, consequently, offspring neurodevelopment. STUDY FUNDING/COMPETING INTEREST(S): This study received no funding. The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (Academic Medical Center and VU University Medical Center) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and intrepretation of the data. I.R. reports receiving travel fee from Guerbet. C.B.L. reports speakers fee from Ferring in the past and research grants from Ferring, Merck and Guerbet. K.D. reports receiving travel fee and speakers fee from Guerbet. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. V.M. reports receiving travel fee and speakers fee as well as research grants from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: Netherlands Trial Register NTR 7526 (Neonates born after the H2Oil study), NTR 3270 (original H2Oil study), www.trialregister.nl.

Low prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser syndrome.

STUDY QUESTION: Is there an increased prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives? SUMMARY ANSWER: Predominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism. WHAT IS KNOWN ALREADY: The etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences. STUDY DESIGN, SIZE, DURATION: An observational case-control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients' association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant. PARTICIPANTS/MATERIALS, SETTING, METHODS: After written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome-specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data. MAIN RESULTS AND THE ROLE OF CHANCE: The final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59-21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse. LIMITATIONS, REASON FOR CAUTION: We are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Dutch trial register, NTR5961.

Treatment effect of oil-based contrast is related to experienced pain at HSG: a post-hoc analysis of the randomised H2Oil study.

STUDY QUESTION: Does pain or volume of used contrast medium impact the effectiveness of oil-based contrast during hysterosalpingography (HSG)? SUMMARY ANSWER: In women who report moderate to severe pain during HSG, the use of oil-based contrast resulted in more ongoing pregnancies compared to the use of water-based contrast, whereas in women who reported mild or no pain, no difference in ongoing pregnancies was found. WHAT IS KNOWN ALREADY: We recently showed that in infertile women undergoing HSG, the use of oil-based contrast results in more ongoing pregnancies within 6 months as compared to the use of water-based contrast. However, the underlying mechanism of this fertility-enhancing effect remains unclear. STUDY DESIGN, SIZE, DURATION: We performed a post-hoc analysis of the H2Oil study, a multicentre randomised controlled trial (RCT) evaluating the therapeutic effect of oil- and water-based contrast at HSG. Here, we evaluated the impact of pain experienced at HSG and volume of used contrast media during HSG on ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a subset of 400 participating women, pain during HSG by means of the Visual Analogue Scale (VAS) (range: 0.0-10.0 cm) was reported, while in 512 women, we registered the volume of used contrast (in millilitres). We used logistic regression analyses to assess whether pain and volume of used contrast media modified the effect of oil-based contrast on ongoing pregnancy rates. Data were analysed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: In 400 women in whom pain scores were reported, the overall median pain score was 5.0 (Interquartile range (IQR) 3.0-6.8) (oil group (n = 199) 4.8 (IQR 3.0-6.4); water group (n = 201) 5.0 (IQR 3.0-6.7); P-value 0.28). There was a significant interaction between pain (VAS ≤5 versus VAS ≥6) and the primary outcome ongoing pregnancy (P-value 0.047). In women experiencing pain (VAS ≥6), HSG with oil-based contrast resulted in better 6-month ongoing pregnancy rates compared to HSG with water-based contrast (49.4% versus 29.6%; RR 1.7; 95% CI, 1.1-2.5), while in women with a pain score ≤5, 6-month ongoing pregnancy rates were not significantly different between the use of oil- (28.8%) versus water-based contrast (29.2%) (RR 0.99; 95% CI, 0.66-1.5). In the 512 women in whom we recorded contrast, median volume was 9.0 ml (IQR 5.7-15.0) in the oil group versus 8.0 ml (IQR 5.9-13.0) in the water group, respectively (P-value 0.72). Volume of used contrast was not found to modify the effect of oil-based contrast on ongoing pregnancy (P-value for interaction 0.23). LIMITATIONS, REASONS FOR CAUTION: This was a post-hoc analysis that should be considered as hypothesis generating. The RCT was restricted to infertile ovulatory women, younger than 39 years of age and with a low risk for tubal pathology. Therefore, our results should not be generalised to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS: The underlying mechanism of the fertility-enhancing effect induced by HSG with the use of oil-based contrast remains unclear. However, these findings suggest a possible mechanistic pathway, that is increasing intrauterine pressure occurring prior to dislodging pregnancy hindering debris or mucus plugs from the proximal part of otherwise normal fallopian tubes. This information might help in the search of the underlying fertility-enhancing mechanism found by using oil-based contrast during HSG. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports consultancy for Guerbet. H.V. reports consultancy fees from Ferring. C.B.L. reports speakers' fees from Ferring and research grants from Ferring, Merck and Guerbet. V.M. reports receiving travel and speakers fees as well as research grants from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. The other authors do not report conflict of interests. TRIAL REGISTRATION NUMBER: The H2Oil study was registered at the Netherlands Trial Registry (NTR 3270). TRIAL REGISTRATION DATE: 1 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 3 February 2012.

Iatrogenic endometriosis harbors somatic cancer-driver mutations.

STUDY QUESTION: Does incisional endometriosis (IE) harbor somatic cancer-driver mutations? SUMMARY ANSWER: We found that approximately one-quarter of IE cases harbor somatic-cancer mutations, which commonly affect components of the MAPK/RAS or PI3K-Akt-mTor signaling pathways. WHAT IS KNOWN ALREADY: Despite the classification of endometriosis as a benign gynecological disease, it shares key features with cancers such as resistance to apoptosis and stimulation of angiogenesis and is well-established as the precursor of clear cell and endometrioid ovarian carcinomas. Our group has recently shown that deep infiltrating endometriosis (DE), a form of endometriosis that rarely undergoes malignant transformation, harbors recurrent somatic mutations. STUDY DESIGN, SIZE, DURATION: In a retrospective study comparing iatrogenically induced and endogenously occurring forms of endometriosis unlikely to progress to cancer, we examined endometriosis specimens from 40 women with IE and 36 women with DE. Specimens were collected between 2004 and 2017 from five hospital sites in either Canada, Germany or the Netherlands. IE and DE cohorts were age-matched and all women presented with histologically typical endometriosis without known history of malignancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Archival tissue specimens containing endometriotic lesions were macrodissected and/or laser-capture microdissected to enrich endometriotic stroma and epithelium and a hypersensitive cancer hotspot sequencing panel was used to assess for presence of somatic mutations. Mutations were subsequently validated using droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) were performed as surrogates for somatic events resulting in functional loss of respective proteins. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, we detected somatic cancer-driver events in 11 of 40 (27.5%) IE cases and 13 of 36 (36.1%) DE cases, including hotspot mutations in KRAS, ERBB2, PIK3CA and CTNNB1. Heterogeneous PTEN loss occurred at similar rates in IE and DE (7/40 vs 5/36, respectively), whereas ARID1A loss only occurred in a single case of DE. While rates of detectable somatic cancer-driver events between IE and DE are not statistically significant (P > 0.05), KRAS activating mutations were more prevalent in DE. LIMITATIONS, REASONS FOR CAUTION: Detection of somatic cancer-driver events were limited to hotspots analyzed in our panel-based sequencing assay and loss of protein expression by IHC from archival tissue. Whole genome or exome sequencing, or epigenetic analysis may uncover additional somatic alterations. Moreover, because of the descriptive nature of this study, the functional roles of identified mutations within the context of endometriosis remain unclear and causality cannot be established. WIDER IMPLICATIONS OF THE FINDINGS: The alterations we report may be important in driving the growth and survival of endometriosis in ectopic regions of the body. Given the frequency of mutation in surgically displaced endometrium (IE), examination of similar somatic events in eutopic endometrium, as well as clinically annotated cases of other forms of endometriosis, in particular endometriomas that are most commonly linked to malignancy, is warranted. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by a Canadian Cancer Society Impact Grant [701603, PI Huntsman], Canadian Institutes of Health Research Transitional Open Operating Grant [MOP-142273, PI Yong], the Canadian Institutes of Health Research Foundation Grant [FDN-154290, PI Huntsman], the Canadian Institutes of Health Research Project Grant [PJT-156084, PIs Yong and Anglesio], and the Janet D. Cottrelle Foundation through the BC Cancer Foundation [PI Huntsman]. D.G. Huntsman is a co-founder and shareholder of Contextual Genomics Inc., a for profit company that provides clinical reporting to assist in cancer patient treatment. R. Aguirre-Hernandez, J. Khattra and L.M. Prentice have a patent MOLECULAR QUALITY ASSURANCE METHODS FOR USE IN SEQUENCING pending and are current (or former) employees of Contextual Genomics Inc. The remaining authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Effectiveness on fertility outcome of tubal flushing with different contrast media: systematic review and network meta-analysis.

OBJECTIVES: To compare, in women with infertility, the effectiveness and safety of tubal flushing using oil-based contrast medium, water-based contrast medium or their combination, and no tubal flushing, and to evaluate the effectiveness of tubal flushing on fertility outcome over time. METHODS: We performed a systematic review and network meta-analysis, searching the electronic databases MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, and trial registries, up to 25 September 2018. We included randomized controlled trials (RCTs) comparing the following interventions with each other or with no intervention in women with infertility: tubal flushing using water-based contrast medium, tubal flushing using oil-based contrast medium or additional tubal flushing with oil-based medium following diagnostic tubal flushing with water-based medium. The outcomes included clinical pregnancy, live birth, ongoing pregnancy, miscarriage, ectopic pregnancy and adverse events. RESULTS: Of the 283 studies identified through the search, 14 RCTs reporting on 3852 women with infertility were included. Network meta-analysis showed that tubal flushing using oil-based contrast medium was associated with higher odds of clinical pregnancy within 6 months after randomization and more subsequent live births compared with tubal flushing using water-based medium (odds ratio (OR), 1.67 (95% CI, 1.38-2.03), moderate certainty of evidence; and OR, 2.18 (95% CI, 1.30-3.65), low certainty of evidence, respectively) and compared with no intervention (OR, 2.28 (95% CI, 1.50-3.47), moderate certainty of evidence; and OR, 2.85 (95% CI, 1.41-5.74), low certainty of evidence, respectively). These results agreed with those of the pairwise meta-analysis. For clinical pregnancy within 6 months, there was insufficient evidence of a difference between tubal flushing with water-based contrast medium and no intervention (OR, 1.36 (95% CI, 0.91-2.04), low certainty of evidence). For fertility outcomes after 6 months, there was insufficient evidence of a difference in any comparison (low to very low certainty of evidence). Compared with tubal flushing using water-based contrast medium, the use of oil-based contrast medium was associated with higher odds of asymptomatic intravasation (OR, 5.06 (95% CI, 2.29-11.18), moderate certainty of evidence). CONCLUSIONS: In women with infertility undergoing fertility workup, tubal flushing using oil-based contrast medium probably increases clinical pregnancy rates within 6 months after randomization and may increase subsequent live-birth rates, compared with tubal flushing using water-based contrast medium and compared with no intervention. Evidence on fertility outcomes beyond 6 months is inadequate to draw firm conclusions. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Eficacia sobre el resultado de fertilidad del lavado de trompas con diferentes medios de contraste: revisión sistemática y metaanálisis en red OBJETIVOS: Comparar, en mujeres con infertilidad, la efectividad y seguridad del lavado de trompas con un medio de contraste a base de aceite, un medio de contraste a base de agua o una combinación, y el no lavado de trompas, y evaluar la efectividad del lavado de trompas en el resultado de la fertilidad con el tiempo. MÉTODOS: Se realizó una revisión sistemática y un metaanálisis en red, mediante búsquedas en las bases de datos electrónicas MEDLINE, EMBASE y el Registro Central Cochrane de Ensayos Controlados, y en otros registros de ensayos, hasta el 25 de septiembre de 2018. Se incluyeron ensayos controlados aleatorizados (ECA) que compararon las siguientes intervenciones entre sí o con la no intervención en mujeres con infertilidad: lavado de trompas con medio de contraste a base de agua, lavado de trompas con medio de contraste a base de aceite o lavado de trompas adicional con un medio a base de aceite después de un lavado de trompas con un medio a base de agua. Los resultados incluyeron el embarazo confirmado ecográficamente, el nacimiento vivo, el embarazo en curso, el aborto espontáneo, el embarazo ectópico y los eventos adversos. RESULTADOS: De los 283 estudios identificados mediante la búsqueda, se incluyeron 14 ECA que informaron sobre 3852 mujeres con infertilidad. El metaanálisis en red mostró que el lavado de trompas con medio de contraste a base de aceite se asoció con mayores probabilidades de embarazo confirmado ecográficamente dentro de los seis meses posteriores a la aleatorización y más nacimientos vivos posteriores en comparación con el lavado de trompas con medio a base de agua (razón de momios [RM], 1,67; IC 95%: 1,38-2,03), certeza moderada de evidencia; y RM, 2,18 (IC 95%: 1,30-3,65), certeza baja de evidencia, respectivamente) y en comparación con la no intervención (RM, 2,28 (IC 95%: 1,50-3,47), certeza moderada de evidencia; y RM, 2,85 (IC 95%: 1,41-5,74), certeza baja de evidencia, respectivamente). Estos resultados coincidieron con los del metaanálisis por pares. No hubo evidencia suficiente de una diferencia entre el lavado de trompas con medio de contraste a base de agua y la no intervención para el embarazo clínico dentro de los seis meses (RM, 1,36 (IC 95%: 0,91-2,04); certeza baja de evidencia). Para los resultados de fertilidad después de los seis meses, no hubo evidencia suficiente de diferencias en cualquier comparación (certeza de evidencia baja a muy baja). En comparación con el lavado de trompas con un medio de contraste a base de agua, el uso de un medio de contraste a base de aceite se asoció con mayores probabilidades de intravasación asintomática (RM, 5,06 (IC 95%: 2,29-11,18), certeza moderada de evidencia). CONCLUSIONES: En las mujeres con infertilidad que se someten a un examen de fertilidad, el lavado de trompas con medio de contraste a base de aceite aumenta la probabilidad de las tasas de embarazo clínico dentro de los 6 meses posteriores a la aleatorización y puede aumentar las tasas posteriores de nacimientos vivos, en comparación con el lavado de trompas con medio de contraste a base de agua y en comparación con la no intervención. La evidencia sobre los resultados de fertilidad después de los seis meses es inadecuada para establecer conclusiones firmes. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

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.

Immobilization or mobilization after IUI: an RCT.

STUDY QUESTION: Does 15 min of immobilization after IUI improve pregnancy rates? SUMMARY ANSWER: Immobilization for 15 min after IUI does not improve pregnancy rates. WHAT IS KNOWN ALREADY: Prior RCTs report a beneficial effect of supine immobilization for 15 min following IUI compared to immediate mobilization, however, these studies can be criticized. Given the importance for the logistics in daily practice and the lack of biological plausibility we planned a replication study prior to potential implementation of this procedure. STUDY DESIGN, SIZE, DURATION: A single centre RCT, based in an academic setting in the Netherlands, was performed. Participants were randomly assigned for 15 min of supine immobilization following IUI for a maximum of six cycles compared to the standard procedure of immediate mobilization following IUI. Participants and caregivers were not blinded to group assignment. An independent researcher used computer-generated tables to allocate treatments. Stratification occurred to the indication of IUI (unexplained or mild male subfertility). Revelation of allocation took place just before the insemination by the caregiver. The primary outcome was ongoing pregnancy rate per couple. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 498 couples diagnosed with unexplained or mild male subfertility and an indication for treatment with IUI were approached and randomized in the study, of which 244 participants were assigned to 15 min of supine immobilization and 254 participants to immediate mobilization. MAIN RESULTS AND THE ROLE OF CHANCE: Participant characteristics were comparable between the groups, and 236 participants were analysed in the immobilization group, versus 245 in the mobilization group. The ongoing pregnancy rate per couple was not found to be superior in the immobilization group (one-sided P-value = 0.97) with 76/236 ongoing pregnancies (32.2%) being accomplished in the immobilization and 98/245 ongoing pregnancies (40.0%) in the immediate mobilization group (relative risk 0.81; 95% CI [0.63, 1.02], risk difference: -7.8%, 95% CI [-16.4%, 0.8%]). No difference was found in miscarriage rate, multiple gestation rate, live birth rate and time to pregnancy between the groups. LIMITATIONS, REASONS FOR CAUTION: Owing to discontinuation of the planned treatment not all participants reached six IUI cycles or an ongoing pregnancy. However, this is as expected in IUI treatment and mirrors clinical practice. These participants were equally distributed across the two groups. Women with tubal pathology and endocrine disorders were excluded for this trial, and this might narrow generalizability. WIDER IMPLICATIONS OF THE FINDINGS: This study shows no positive effect of 15 min of immobilization following IUI on pregnancy rates. Based on available evidence today, including our study, a possible beneficial effect of supine immobilization after IUI is at least doubtful and straightforward implementation does not seem to be justified. STUDY FUNDING/COMPETING INTEREST(S): No funding was received. All authors have nothing to disclose. TRIAL REGISTRATION NUMBER: Dutch Trial Register NTR 2418. TRIAL REGISTRATION DATE: 20 July 2010. DATE OF FIRST PATIENT's ENROLMENT: 11 August 2010.

Spontaneous haemoperitoneum in pregnancy and endometriosis: a case series.

OBJECTIVE: To report pregnancy outcomes of SHiP (spontaneous haemoperitoneum in pregnancy) and the association with endometriosis. DESIGN: Retrospective case note review. SETTING: Dutch referral hospitals for endometriosis. SAMPLE: Eleven women presenting with 15 events of SHiP. METHODS: In collaboration with the Dutch Working Group on Endometriosis, unpublished cases of SHiP that occurred in the Netherlands between 2010 and 2015 were retrieved. MAIN OUTCOME MEASURES: Maternal and perinatal mortality and morbidity. RESULTS: SHiP occurred predominantly in the second and third trimester of pregnancy. The earliest and major presenting symptom was an acute onset of abdominal pain, often combined with low haemoglobin levels or signs of fetal distress. Imaging was a diagnostic tool when free peritoneal fluid could be observed. For surgical treatment of the bleeding site, a midline laparotomy was mostly needed, the median estimated amount of blood loss was 2000 mL. No fetomaternal or perinatal mortality was reported, despite a high rate of preterm births (54.5%). In all women, endometriosis was diagnosed at a certain moment in time and therefore was probably involved in the pathogenesis of SHiP. Four women showed recurrence of SHiP. In one of these cases the second event of SHiP occurred in a subsequent pregnancy. CONCLUSION: Pregnancy outcomes of SHiP are improving when compared with previous reports, with absent fetomaternal and perinatal mortality in this recent series. Growing knowledge and adequate multidisciplinary intervention may have contributed to these favourable results. Increasing awareness of this serious complication of pregnancy is advocated, especially in women diagnosed with endometriosis. TWEETABLE ABSTRACT: Growing awareness of SHiP is advocated, especially in women diagnosed with endometriosis.

Transanal minimally invasive rectal resection for deep endometriosis: a promising technique.

AIM: Surgical management of patients with deep endometriosis (DE) of the rectum is difficult. Inflammation and subsequent adhesions due to DE impede access to the lower pelvis and may lead to complications during laparoscopic low anterior resection (LAR). Transanal minimally invasive surgery (TAMIS) is an alternative to an abdominal approach with potential advantages. The aim of this study was to provide a description of the TAMIS technique and to present the perioperative results of TAMIS and of conventional LAR in patients with DE. METHOD: A prospective consecutive cohort of patients undergoing rectal resection for DE had either conventional laparoscopic LAR or TAMIS rectal excision. Pre-, intra- and postoperative parameters, such as patient symptomatology, operating time and postoperative complications were compared between the groups. Quality of life was assessed using the EORTC-QLQ-29/30 questionnaires. RESULTS: Between May 2014 and March 2016 a total of 11 rectal resections were performed, including five TAMIS procedures. No differences were found in the pre-, intra- or postoperative parameters. Two major complications occurred after conventional LAR and none after TAMIS. No differences in quality of life were found between the groups. CONCLUSION: Transanal minimally invasive surgery for DE of the rectum is feasible. Potential advantages include better surgical access to the pelvis, possibly fewer complications than LAR and no extraction incision with no difference in quality of life. Larger prospective studies are required to compare TAMIS with conventional rectal resection.

Hysteroscopic proximal tubal occlusion versus laparoscopic salpingectomy as a treatment for hydrosalpinges prior to IVF or ICSI: an RCT.

STUDY QUESTION: Does hysteroscopic proximal tubal occlusion by intratubal devices as a treatment for hydrosalpinges result in comparable ongoing pregnancy rates following IVF/ICSI when compared with laparoscopic salpingectomy? SUMMARY ANSWER: Hysteroscopic proximal tubal occlusion by intratubal devices is inferior to laparoscopic salpingectomy in the treatment of hydrosalpinges in women undergoing IVF/ICSI with respect to ongoing pregnancy rates. WHAT IS KNOWN ALREADY: It is known that women with hydrosalpinges undergoing IVF have poorer pregnancy outcomes compared with women with other forms of tubal infertility. In these women, both laparoscopic salpingectomy and laparoscopic proximal tubal ligation are known to improve IVF outcomes. At present, it is unclear whether a less-invasive hysteroscopic treatment with intratubal devices leads to similar ongoing pregnancy rates following IVF when compared with laparoscopic salpingectomy. STUDY DESIGN, SIZE, DURATION: A two-centre, randomized, controlled, non-inferiority trial. Between October 2009 and December 2014 a total of 85 women were included in this study; of whom, 42 were randomized to hysteroscopic proximal occlusion by intratubal device placement and 43 were randomized to laparoscopic salpingectomy. Randomization was based on a computer-generated randomization list. The study was unblinded. The primary outcome was ongoing pregnancy rate, defined as a fetal heartbeat on ultrasound beyond 10-week gestation following one IVF/ICSI treatment (fresh and frozen-thawed embryo transfers). PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied women aged 18-41 years, with uni- or bilateral ultrasound visible hydrosalpinges who were scheduled for an IVF/ICSI treatment. MAIN RESULTS AND THE ROLE OF CHANCE: The ongoing pregnancy rates per patient according to the intention-to-treat principle were 11/42 (26.2%) after hysteroscopic proximal occlusion by intratubal devices (intervention group) versus 24/43 (55.8%) after laparoscopic salpingectomy (control group) (P = 0.008) [absolute difference: 26.1%; 95% confidence interval (CI): 0.5-51.7, relative risk (RR): 0.56; 95% CI: 0.31-1.03, P = 0.01]. In the per protocol analysis, the ongoing pregnancy rate per patient following hysteroscopic proximal occlusion by intratubal devices was 9/27 (33.3%) compared with 19/32 (59.4%) following laparoscopic salpingectomy (P = 0.067) (absolute difference: 29.6%; 95% CI: 7.1 to 49.1, RR: 0.47; 95% CI: 0.27-0.83, P = 0.062). LIMITATIONS, REASONS FOR CAUTION: Masking participants and investigators would be difficult due to the nature of both interventions. Since we had objective outcome measurements, we withheld sham procedures, leaving the study unblinded. Furthermore, our low sample size resulted in wide CIs. A larger sample size would result in a more accurate treatment effect; however, this was non-feasible for recruitment and inclusion. WIDER IMPLICATIONS OF THE FINDINGS: In the treatment of hydrosalpinges prior to IVF/ICSI, hysteroscopic proximal occlusion by intratubal devices is inferior to laparoscopic salpingectomy. STUDY FUNDING/COMPETING INTERESTS: The intratubal devices were received from Conceptus, Inc., San Carlos, CA, USA, which was acquired by Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA in 2013. Conceptus, Inc./Bayer HealthCare Pharmaceuticals, Inc. had no role in the study design, data collection and analyses, decision to publish or preparation of the manuscript. The study as a whole was funded by the SWOG (foundation for scientific investigation in obstetrics and gynaecology of the VU University Medical Centre, Amsterdam, the Netherlands). P.G.A.H. has received non-financial support from Conceptus, Inc. during the conduct of this study. He has received grants from Ferring B.V., Merck Serono and Abbott outside the submitted work. M.H.E. has received personal fees from Smith and Nephew and IQ Medical Ventures outside the submitted work. TRIAL REGISTRATION NUMBER: The Dutch Trial Register: NTR 2073. TRIAL REGISTRATION DATE: October 21, 2009. DATE OF FIRST PATIENT'S ENROLMENT: October 26, 2009.

High miscarriage rate in women treated with Essure® for hydrosalpinx before embryo transfer: a systematic review and meta-analysis.

OBJECTIVES: Essure® has been tested as an alternative treatment for hydrosalpinx before embryo transfer (ET) in women undergoing assisted reproduction techniques. However, the persistence of a foreign body inside the uterine cavity might have a negative impact on the outcome of pregnancy. The present systematic review aimed at identifying, appraising and summarizing the available evidence regarding the effectiveness and safety of using Essure prior to ET for women with hydrosalpinx. METHODS: We searched for studies in PubMed, Scopus, CENTRAL, Web of Science and ClinicalTrials.gov and the reference lists of eligible studies. All studies including at least 10 women with hydrosalpinx who received Essure, any other intervention or no treatment prior to ET were considered eligible. Study selection, data extraction and evaluation of the risk of bias were performed independently by two authors. Study outcomes were miscarriage per clinical pregnancy, singleton preterm birth per singleton live birth and live birth/ongoing pregnancy and clinical pregnancy per ET. The pooled results for each outcome and intervention were summarized as proportions with their respective 95% CIs, using a random-effects model. RESULTS: Our electronic search of databases was performed on 7 November 2015, and 26 studies with 43 study arms were considered eligible: eight study arms evaluating Essure; seven assessing tubal aspiration; seven appraising effects of no treatment; 12 evaluating salpingectomy; two assessing tubal division; and seven evaluating tubal occlusion. When compared with women who had no intervention, women with Essure had a higher clinical pregnancy rate per ET (36% (95% CI, 0-43%) vs 13% (95% CI, 9-17%)). When compared with women who had other interventions, women with Essure had a higher miscarriage rate per clinical pregnancy (38% (95% CI, 27-49%) vs 15% (95% CI, 10-19%)). CONCLUSIONS: The available evidence suggests that, although Essure prior to ET in women with hydrosalpinx improves the chance of achieving a clinical pregnancy compared with no intervention, it is associated with a higher rate of miscarriage when compared with the other interventions. Although this evidence is based on observational studies, we believe that salpingectomy should be the first option for women who are eligible for videolaparoscopy. However, it is still premature to make recommendations for women who are not eligible for surgery, and randomized controlled trials are needed to clarify which is the best treatment alternative in such a scenario. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Laparoscopic Imaging Techniques in Endometriosis Therapy: A Systematic Review.

Endometriosis is a common disease associated with pelvic pain and subfertility. Laparoscopic surgical treatment has proven effective in endometriosis, but is hampered by a high rate of recurrence. The aim of this systematic review was to evaluate the intraoperative identification of endometriosis by enhanced laparoscopic imaging techniques, focusing on sensitivity and specificity. A systematic review was conducted according to PRISMA guidelines in PubMed, Embase, Cochrane Library, and Web of Science. Published prospective studies reporting on enhanced laparoscopic imaging techniques during endometriosis surgery were included. General study characteristics and reported outcomes, including sensitivity and specificity, were extracted. Nine studies were eligible for inclusion. Three techniques were described: 5-ALA fluorescence (5-ALA), autofluorescence (AFI), and narrow-band imaging (NBI). The reported sensitivity of 5-ALA and AFI for identifying endometriosis ranged from 91% to 100%, compared with 48% to 69% for conventional white light laparoscopy (WL). A randomized controlled trial comparing NBI + WL with WL alone reported better sensitivity of NBI (100% vs 79%; p < .001). All 9 studies reported an enhanced detection rate of endometriotic lesions with enhanced imaging techniques. Enhanced imaging techniques are a promising additive for laparoscopic detection and treatment of endometriosis. The 5-ALA, AFI, and NBI intraoperative imaging techniques had a better detection rate for peritoneal endometriosis compared with conventional WL laparoscopy. None of the studies reported clinical data regarding outcomes. Future studies should address long-term results, such as quality of life, recurrence, and need for reoperation.