The effect of prior hysterosalpingo-foam sonography or hysterosalpingography on tubal patency: a secondary analysis of a randomized controlled trial.

STUDY QUESTION: Does hysterosalpingo-foam sonography (HyFoSy) prior to hysterosalpingography (HSG) or HSG prior to HyFoSy affect visible tubal patency when compared HSG or HyFoSy alone? SUMMARY ANSWER: Undergoing either HyFoSy or HSG prior to tubal patency testing by the alternative method does not demonstrate a significant difference in visible tubal patency when compared to HyFoSy or HSG alone. WHAT IS KNOWN ALREADY: HyFoSy and HSG are two commonly used visual tubal patency tests with a high and comparable diagnostic accuracy for evaluating tubal patency. These tests may also improve fertility, although the underlying mechanism is still not fully understood. One of the hypotheses points to a dislodgment of mucus plugs that may have disrupted the patency of the Fallopian tubes. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of the randomized controlled FOAM study, in which women underwent tubal patency testing by HyFoSy and HSG, randomized for order of the procedure. Participants either had HyFoSy first and then HSG, or vice versa. Here, we evaluate the relative effectiveness of tubal patency testing by HyFoSy or HSG prior to the alternative tubal patency testing method on visible tubal patency, compared to each method alone. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women aged between 18 and 41 years scheduled for tubal patency testing were eligible for participating in the FOAM study. Women with anovulatory cycles, endometriosis, or with a partner with male infertility were excluded. To evaluate the effect HyFoSy on tubal patency, we relied on HSG results by comparing the proportion of women with bilateral tubal patency visible on HSG in those who underwent and who did not undergo HyFoSy prior to their HSG (HyFoSy prior to HSG versus HSG alone). To evaluate the effect of HSG on tubal patency, we relied on HyFoSy results by comparing the proportion of women with bilateral tubal patency visible on HyFoSy in those who underwent and who did not undergo HSG prior to their HyFoSy (HSG prior to HyFoSy versus HyFoSy alone). MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, we randomized 1160 women (576 underwent HyFoSy first followed by HSG, and 584 underwent HSG first followed by HyFoSy). Among the women randomized to HyFoSy prior to HSG, bilateral tubal patency was visible on HSG in 467/537 (87%) women, compared with 472/544 (87%) women who underwent HSG alone (risk difference 0.2%; 95% CI: -3.8% to 4.2%). Among the women randomized to HSG prior to HyFoSy, bilateral tubal patency was visible on HyFoSy in 394/471 (84%) women, compared with 428/486 (88%) women who underwent HyFoSy alone (risk difference -4.4%; 95% CI: -8.8% to 0.0%). LIMITATIONS, REASONS FOR CAUTION: The results of this secondary analysis should be interpreted as exploratory and cannot be regarded as definitive evidence. Furthermore, it has to be noted that pregnancy outcomes were not considered in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: Tubal patency testing by either HyFoSy or HSG, prior to the alternative tubal patency testing method does not significantly affect visible tubal patency, when compared to alternative method alone. This suggests that both methods may have comparable abilities to dislodge mucus plugs in the Fallopian tubes. STUDY FUNDING/COMPETING INTEREST(S): The FOAM study was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, or interpretation of the data. H.R.V. reports consultancy fees from Ferring. M.v.W. received a travel grant from Oxford University Press in the role of Deputy Editor for Human Reproduction and participates in a Data Safety and Monitoring Board as an independent methodologist in obstetrics studies in which she has no other role. M.v.W. is coordinating editor of Cochrane Fertility and Gynaecology. B.W.J.M. received an investigator grant from NHMRC (GNT1176437) and research funding from Merck KGaA. B.W.J.M. reports consultancy for Organon and Merck KGaA, and travel support from Merck KGaA. B.W.J.M. reports holding stocks of ObsEva. V.M. received research grants from Guerbet, Merck and Ferring and travel and speaker fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746.

Neurodevelopmental outcomes of school-age children conceived after hysterosalpingography with oil-based or water-based iodinated contrast: long-term follow-up of a nationwide randomized controlled trial.

STUDY QUESTION: Does preconceptional exposure to oil-based iodinated contrast media during hysterosalpingography (HSG) impact children's neurodevelopment compared with exposure to water-based alternatives? SUMMARY ANSWER: Our study found no large-sized effects for neurodevelopment in children with preconceptional exposure to oil-based iodinated contrast media during HSG compared with water-based alternatives. WHAT IS KNOWN ALREADY: HSG is widely used as a diagnostic tool in the female fertility work-up. Tubal flushing with oil-based iodinated contrast has been shown to enhance fertility outcomes in couples with unexplained infertility, increasing the chances of pregnancy and live birth compared with water-based alternatives. However, oil-based contrast contains higher doses of iodine and has a longer half-life, and concerns exist that iodinated contrast media can affect women's iodine status and cause temporary (sub)clinical hypothyroidism in mothers and/or foetuses. Considering that thyroid hormones are vital to embryonal and foetal brain development, oil-based contrast media use could increase the risk of impaired neurodevelopment in children conceived shortly after HSG. Here we examine neurodevelopmental outcomes in school-aged children conceived after HSG. STUDY DESIGN, SIZE, DURATION: This is a long-term follow-up of the H2Oil trial in which oil-based or water-based contrast was used during HSG (Netherlands; 2012-2014; NTR3270). Of 369 children born <6 months after HSG in the study, we contacted the mothers of 140 children who gave consent to be contacted for follow-up. The follow-up study took place from January to July 2022 (NCT05168228). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: The study included 69 children aged 6-9 years who were conceived after HSG with oil-based (n = 42) or water-based contrast (n = 27). The assessments targeted intelligence (Wechsler Intelligence Scale for Children), neurocognitive outcomes (computerized neurocognitive tests), behavioural functioning (parent and teacher questionnaires), and academic performance. Linear regression models, adjusted for age, sex, and parental educational attainment were employed to compare groups. MAIN RESULTS AND THE ROLE OF CHANCE: School-aged children born to mothers after oil-based contrast HSG did not significantly differ from children born to mothers after water-based contrast HSG, in regards to intelligence, neurocognitive functioning, behavioural functioning, or academic performance, with the exception of better performance for visuomotor integration functions in children exposed to oil-based contrast preconception. After exploratory correction for multiple comparisons, none of the group differences was statistically significant. LIMITATIONS, REASONS FOR CAUTION: The small sample size of this follow-up study limited statistical power. This study provides evidence for the absence of large-sized differences between preconceptional exposure to the two contrast media types but does not rule out more subtle effects on neurodevelopment compared to naturally conceived children without preconceptional exposure to HSG. WIDER IMPLICATIONS OF THE FINDINGS: This study contributes to our knowledge about the long-term effects of different types of iodinated contrast media used in fertility work-up, indicating that choosing oil-based over water-based iodinated contrast media is unlikely to have major effect on the long-term neurodevelopmental outcomes of children conceived shortly after HSG. However, further research should focus on the overall safety of iodine exposure during HSG, comparing children conceived after HSG to those conceived naturally as both types of contrast contain high amounts of iodine. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil randomized controlled trial was an investigator-initiated study that was funded by the two academic hospitals now merged into the Amsterdam University Medical Centre. The current follow-up study (Neuro-H2Oil) is funded through a research grant awarded to the authors by the Amsterdam Reproduction & Development (AR&D) research institute. S.K. is funded by a AMC MD/PhD Scholarship from the Amsterdam UMC. S.K. reports holding voluntary roles in the civil society organizations Universities Allied for Essential Medicines and People's Health Movement. V.M. reports receiving travel and speaker fees as well as research grants from Guerbet, Merck and Ferring. K.D. reports receiving travel and speaker fees as well as research grants from Guerbet. BWM is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy, travel support and research funding from Merck, consultancy for Organon and Norgine, and holding stock from ObsEva. The other authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NCT05168228.

Severe Pain and Postoperative Effects during Hysterosalpingography: A Meta-Analysis.

Background: We aimed to evaluate the impact of pain on patients during Hysterosalpingography (HSG). Methods: PubMed, PMC and other journals were searched for randomized controlled trials (RCTS) on HSG. Appropriate articles were selected for inclusion and reasonable exclusion according to keywords. Following a thorough review of the relevant literature, the process of literature screening was conducted in accordance with the aforementioned criteria. The methodological quality of the studies was assessed using the risk of bias assessment tool developed by the Cochrane Collaboration. Meta-analysis was conducted using RevMan 5.4.1 software. Results: Twelve studies were included, including 1530 cases in the experimental group and 1545 cases in the control group. The literature summarizes the basic information of patients during HSG and makes statistics on the differences in visual analog scale (VAS) and pain perception. The findings from the HSG examination revealed a lack of significant association between patients' pain sensation and their age and BMI. However, the duration of pregnancy in patients decreased following HSG treatment (95%CI (-18.84 to -3.58), P=0.004).Compared with conventional testing, HSG could effectively reduce the pregnancy time of patients (95%CI (-18.84, -3.58), P=0.004), reduce the VAS of patients (95%CI (-4.73, -1.51), P=0.0001), and increase the number of patients without pain (95%CI (1.80, 10.43), P=0.001). Conclusion: During the HSG examination, acceptable pain avoidance is generated and can be relieved over time. At present, there is no effective alternative method, so the patient should cooperate with the doctor to complete the examination, to relieve the pain.

Hysterosalpingo-foam sonography versus hysterosalpingography during fertility work-up: an economic evaluation alongside a randomized controlled trial.

STUDY QUESTION: What are the costs and effects of tubal patency testing by hysterosalpingo-foam sonography (HyFoSy) compared to hysterosalpingography (HSG) in infertile women during the fertility work-up? SUMMARY ANSWER: During the fertility work-up, clinical management based on the test results of HyFoSy leads to slightly lower, though not statistically significant, live birth rates, at lower costs, compared to management based on HSG results. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during the fertility work-up is performed by HSG. The FOAM trial, formally a non-inferiority study, showed that management decisions based on the results of HyFoSy resulted in a comparable live birth rate at 12 months compared to HSG (46% versus 47%; difference -1.2%, 95% CI: -3.4% to 1.5%; P = 0.27). Compared to HSG, HyFoSy is associated with significantly less pain, it lacks ionizing radiation and exposure to iodinated contrast medium. Moreover, HyFoSy can be performed by a gynaecologist during a one-stop fertility work-up. To our knowledge, the costs of both strategies have never been compared. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation alongside the FOAM trial, a randomized multicenter study conducted in the Netherlands. Participating infertile women underwent, both HyFoSy and HSG, in a randomized order. The results of both tests were compared and women with discordant test results were randomly allocated to management based on the results of one of the tests. The follow-up period was twelve months. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 1160 infertile women (18-41 years) scheduled for tubal patency testing. The primary outcome was ongoing pregnancy leading to live birth. The economic evaluation compared costs and effects of management based on either test within 12 months. We calculated incremental cost-effectiveness ratios (ICERs): the difference in total costs and chance of live birth. Data were analyzed using the intention to treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 of the 1160 women underwent both tubal tests and had data available: 747 women with concordant results (48% live births), 136 with inconclusive results (40% live births), and 143 with discordant results (41% had a live birth after management based on HyFoSy results versus 49% with live birth after management based on HSG results). When comparing the two strategies-management based on HyfoSy results versus HSG results-the estimated chance of live birth was 46% after HyFoSy versus 47% after HSG (difference -1.2%; 95% CI: -3.4% to 1.5%). For the procedures itself, HyFoSy cost €136 and HSG €280. When costs of additional fertility treatments were incorporated, the mean total costs per couple were €3307 for the HyFoSy strategy and €3427 for the HSG strategy (mean difference €-119; 95% CI: €-125 to €-114). So, while HyFoSy led to lower costs per couple, live birth rates were also slightly lower. The ICER was €10 042, meaning that by using HyFoSy instead of HSG we would save €10 042 per each additional live birth lost. LIMITATIONS, REASONS FOR CAUTION: When interpreting the results of this study, it needs to be considered that there was a considerable uncertainty around the ICER, and that the direct fertility enhancing effect of both tubal patency tests was not incorporated as women underwent both tubal patency tests in this study. WIDER IMPLICATION OF THE FINDINGS: Compared to clinical management based on HSG results, management guided by HyFoSy leads to slightly lower live birth rates (though not statistically significant) at lower costs, less pain, without ionizing radiation and iodinated contrast exposure. Further research on the comparison of the direct fertility-enhancing effect of both tubal patency tests is needed. STUDY FUNDING/COMPETING INTEREST(S): FOAM trial was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, and interpretation of the data. K.D. reports travel-and speakers fees from Guerbet and her department received research grants from Guerbet outside the submitted work. H.R.V. received consulting-and travel fee from Ferring. A.M.v.P. reports received consulting fee from DEKRA and fee for an expert meeting from Ferring, both outside the submitted work. C.H.d.K. received travel fee from Merck. F.J.M.B. received a grant from Merck and speakers fee from Besins Healthcare. F.J.M.B. is a member of the advisory board of Merck and Ferring. J.v.D. reported speakers fee from Ferring. J.S. reports a research agreement with Takeda and consultancy for Sanofi on MR of motility outside the submitted work. M.v.W. received a travel grant from Oxford Press in the role of deputy editor for Human Reproduction and participates in a DSMB as independent methodologist in obstetrics studies in which she has no other role. B.W.M. received an investigator grant from NHMRC GNT1176437. B.W.M. reports consultancy for ObsEva, Merck, Guerbet, iGenomix, and Merck KGaA and travel support from Merck KGaA. V.M. received research grants from Guerbet, Merck, and Ferring and travel and speakers fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746.

Ultrasound-guided Lipiodol® hysterosalpingography: A prospective study on pregnancy and complication rates.

BACKGROUND: Fluoroscopic hysterosalpingography (HSG) with Lipiodol® is safe and has a therapeutic effect on fertility: transient in endometriosis-related infertility and sustained in unexplained infertility. Ultrasound is replacing fluoroscopy as the preferred imaging modality for HSG due to comfort and radiation safety (no ionising radiation). The safety of ultrasound-guided Lipiodol® HSG is uncertain. AIMS: Prospectively observe pregnancy and complication rates after ultrasound-guided Lipiodol® HSG. MATERIALS AND METHODS: A single-centre prospective study of women with unexplained infertility undergoing ultrasound-guided Lipiodol® uterine bathing and tubal flushing after tubal patency confirmed with ExEm® Foam HyFoSy (hysterosalpingo-foam-sonography). Pregnancy outcomes at six months and serum and urinary thyroid function at one, three and eight weeks were recorded. Pain scores were recorded during and immediately after HSG. Descriptive statistics are reported. RESULTS: Fifty-two participants were enrolled between July 2019 and April 2021, median age 33 years (range 21-45). Only 45 (87%, 45/52) completed the Lipiodol® HSG; 5/7 experienced intravasation during initial HyFoSy. Of 30 women at follow-up, 57% had biochemical (17/30, 95% CI 37%-75%), 53% clinical (16/30 95% CI 34%-72%) and 35% ongoing pregnancies (11/30, 95% CI 20%-56%). The rate of subclinical hypothyroidism (SCH) at two months was 41% (7/17). One intravasation event occurred during Lipiodol® HSG (2%, 1/45). Median pain score was 5/10 (range 0-9, interquartile range 2.5-7). No anaphylaxis, infection or oil embolism was observed. CONCLUSION: Outpatient ultrasound-guided Lipiodol® HSG was safe, with pregnancy rates comparable to previous studies of fluoroscopic guidance. Rates of intravasation and SCH were also similar, confirming the need to monitor thyroid function.

Impact of oil-based contrast agents in hysterosalpingography on fertility outcomes in endometriosis: a retrospective cohort study.

BACKGROUND: Previous studies have suggested that oil-based contrast agents used during hysterosalpingography (HSG) in infertile patients can enhance fertility. However, limited research has investigated the effect of oil-based contrast medium specifically in individuals with endometriosis-related infertility. OBJECTIVE: This study aims to explore the impact of oil-based contrast medium on fertility outcomes in women with endometriosis-related infertility. METHODS: Conducted at the First Affiliated Hospital of Guangxi Medical University (January 2020 to June 2022), the study included 512 patients undergoing HSG. Patients were categorized into oil-based and non-oil-based groups, and after propensity score matching, demographic characteristics were compared. Main outcomes included clinical pregnancy rates, live birth rates, early miscarriage rates, and ectopic pregnancy rates. RESULTS: In our analysis, the Oil-based group showed significantly better outcomes compared to the Non-oil-based group. Specifically, the Oil-based group had higher clinical pregnancy rates (51.39% vs. 27.36%) and increased live birth rates (31.48% vs. 19.93%). This trend held true for expectant treatment, IUI, and IVF/ICSI, except for surgical treatment where no significant difference was observed. After adjusting for various factors using propensity score matching, the Non-oil-based group consistently exhibited lower clinical pregnancy rates compared to the Oil-based group. The Odds Ratio (OR) was 0.38 (95%CI: 0.27-0.55) without adjustment, 0.34 (0.22-0.51) in multivariable analysis, 0.39 (0.27-0.57) using inverse probability of treatment weighting (IPTW), and 0.22 (0.14-0.35) in propensity score matching. CONCLUSION: Oil-based contrast medium used in HSG for women with endometriosis-related infertility is associated with higher clinical pregnancy rates and live birth rates compared to Non-oil-based contrast medium.

Sequential-contingent strategy for fallopian tube evaluation using hysterosalpingo foam sonography: a cost analysis.

Background: Tubal pathology is the etiological factor in 20% of couples with female infertility. Historically, diagnostic evaluation of the fallopian tubes has been performed by means of hysterosalpingography (HSG). Hysterosonosalpingography with EXEM® foam is a recent technique with supposedly comparable effectiveness to HSG, but with better tolerability for patients. Methods: Tubal patency was assessed in patients who were candidates for intrauterine insemination (IUI) between January 2020 and July 2021. (I) Hysterosonosalpingography with EXEM® foam. (II) If the patient had both tubes patent, IUI was proposed. In case of inconclusive or pathological results, HSG was performed. (III) If the HSG concludes tubal patency, IUI is proposed. On the other hand, if it results in tubal obstruction, in vitro fertilization (IVF) is proposed. Results: Assessment of tubal patency by HSG showed concordance with previous Hysterosonosalpingography with EXEM® foam results in 45.5% (n=15) of cases of unilateral obstruction and 66.7% (n=6) of cases of bilateral obstruction. When we compare the total cost of HSG (€54,899.46) with the sum of patients who only required Hysterosonosalpingography with EXEM® foam together with those who underwent both tests (€45,575.96), it shows that the latter represents a cost benefit strategy (cost difference €9,323.50). Conclusions: Our results suggest a benefit of €9,323.50 when performing the contingent sequential strategy, in case of pathological or inconclusive results, compared to performing a systematic HSG in all patients. Patients with an obstructive hysterosalpingogram with EXEM® and a patent hysterosalpingogram will be the subgroup that will benefit the most, as IUI can be proposed instead of IVF. In addition, there is a benefit in terms of optimizing the medical procedure, hospital visits and speeding up the time to start assisted reproductive technology (ART).

What are the risks associated with lipiodol hysterosalpingography? A literature review.

INTRODUCTION: Hysterosalpingography is widely used as a first-line investigation for infertility, and may also be therapeutic, increasing pregnancy rates. Aqueous and oil-based contrast agents can be used. Some studies suggest Lipiodol hysterosalpingography has a greater therapeutic effect on fertility than aqueous contrast, though this is contentious. There are additionally safety concerns surrounding Lipiodol hysterosalpingography. This review summarises the adverse effects associated with Lipiodol hysterosalpingography, particularly on thyroid function. KEY FINDINGS: 331 articles were identified. Of these, 46 met inclusion criteria. 3 further articles were identified from reference lists. Complications typically cited in the literature include pain, intravasation, life-threatening oil embolism, and lipogranuloma formation. Emerging evidence suggests that Lipiodol hysterosalpingography may also impact maternal and neonatal thyroid function. Women may develop hypo- or hyperthyroidism. Thyroid dysfunction is clinically significant as even subclinical hypothyroidism reduces fertility, increases the risk of pregnancy complications including miscarriage, pre-eclampsia and perinatal mortality, and adversely impacts foetal neurodevelopment. One study suggested a possible link with neonatal congenital hypothyroidism. CONCLUSION: There is emerging evidence to suggest that Lipiodol hysterosalpingography can cause hypo- or hyperthyroidism, in addition to known adverse effects of pain, intravasation, oil embolism, and lipogranuloma formation. IMPLICATIONS FOR PRACTICE: Given the significance of these risks, and contention surrounding whether Lipiodol truly increases pregnancy rates compared to aqueous mediums, careful consideration is required in the selection of contrast agent. In particular, Lipiodol hysterosalpingography may not be suitable for women with pre-existing thyroid dysfunction.

Adjuvant therapy with Huatan Sanjie Granules improves the prognosis of patients with primary liver cancer: a cohort study and the investigation of its mechanism of action based on network pharmacology.

Objective: Nowadays, primary liver carcinoma (PLC) is one of the major contributors to the global cancer burden, and China has the highest morbidity and mortality rates in the world. As a well-known Chinese herbal medicine (CHM) prescription, Huatan Sanjie Granules (HSG) has been used clinically for many years to treat PLC with remarkable efficacy, but the underlying mechanism of action remains unclear. Methods: A clinical cohort study was conducted to observe the overall survival of PLC patients with vs. without oral administration of HSG. Meanwhile, the BATMAN-TCM database was used to retrieve the potential active ingredients in the six herbs of HSG and their corresponding drug targets. PLC-related targets were then screened through the Gene Expression Omnibus (GEO) database. The protein-protein interaction (PPI) network of targets of HSG against PLC was constructed using Cytoscape software. The cell function assays were further carried out for verification. Results: The results of the cohort study showed that the median survival time of PLC patients exposed to HSG was 269 days, which was 23 days longer than that of the control group (HR, 0.62; 95% CI, 0.38-0.99; p = 0.047). In particular, the median survival time of Barcelona Clinic Liver Cancer stage C patients was 411 days in the exposure group, which was 137 days longer than that in the control group (HR, 0.59; 95% CI, 0.35-0.96; p = 0.036). Meanwhile, the enrichment analysis result for the obtained PPI network consisting of 362 potential core therapeutic targets suggest that HSG may inhibit the growth of liver cancer (LC) cells by blocking the PI3K-Akt/MAPK signaling pathways. Furthermore, the above prediction results were verified by a series of in vitro assays. Specifically, we found that the expressions TP53 and YWHA2, the targets of the hepatitis B virus signaling pathway, were significantly affected by HSG. Conclusion: HSG shows promising therapeutic efficacy in the adjuvant treatment of PLC.

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).

Intravasation complicating hysterosalpingo-foam sonography (HyFoSy) using ExEm® Foam.

BACKGROUND: Transvaginal hysterosalpingo-foam sonography (HyFoSy) assesses tubal patency in an outpatient setting and without ionising radiation, unlike traditional hysterosalpingography (HSG) under fluoroscopy. Like HSG, HyFoSy may be complicated by uterine intramural contrast leak, leading to venous intravasation. Intravasation of particulate contrast agents risks pulmonary or cerebral emboli. AIMS: We aimed to assess the intravasation rate of HyFoSy using ExEm® Foam and association with endometrial thickness, ExEm® Foam volume, uterine length, adenomyosis severity, uterine morphology or pain score. METHODS: An ethics-approved retrospective study on all HyFoSy examinations between 23 January 2018 and 27 October 2021 on sub-fertile patients, trying to conceive. Initial transvaginal sonography confirmed anatomy, uterine morphology, adenomyosis severity and endometrial thickness. Subspecialist radiologists performed HyFoSy with sonographer assistance. Intravasation was identified in real time but also checked for afterwards. Patients were asked to rate instillation pain/discomfort from one to ten immediately afterward. RESULTS: Four hundred and thirty-six (n = 436) patients met inclusion criteria. Thirty (6.9%) experienced intravasation. Endometrial thickness and pain score were associated with intravasation. For every millimetre increase in endometrial thickness, the odds of intravasation decreased by 26% (P = 0.010). For every point increase on the pain scale, the odds of intravasation increased by 22% (P = 0.032). There was no evidence of an association between instilled ExEm® Foam volume or the other previously published parameters with intravasation. CONCLUSION: A 6.9% rate of intravasation was observed. Both endometrial thickness and pain score were significantly associated with intravasation. There was no evidence of an association between ExEm® Foam volume and intravasation.

Bicornuate uterus: A rare case of a viable full term pregnancy in the right uterine horn.

Bicornuate uterus is a rare congenital uterine malformation and structural abnormality that affects less than 05 % of women in the United States. Resulting pregnancies are rarely carried to term and commonly result in fetal abnormalities and complications such as decreased fertility and risks of complicated pregnancies such as spontaneous abortion and miscarriages, IUGR, preterm delivery, cervical incompetence, and fetal malpresentations. This report highlights a case in which a 32-year-old patient with a bicornis bicollis uterus who had a viable pregnancy in one of the uterine horns later delivered a live male neonate at term without complications via spontaneous vaginal delivery (SVD). The study underscores the importance of using the imaging modalities of ultrasonography, magnetic resonance imaging, and hysterosalpingograms to aid in the diagnosis and monitoring throughout the duration of the pregnancy.

Formation of spread-out Bragg peak for helium-ion beam using microdosimetric kinetic model.

PURPOSE: To evaluate the applicability of microdosimetric kinetic model (MKM) to helium-ion therapy by forming a spread-out Bragg peak (SOBP) of a helium-ion beam using the MKM developed for carbon-ion radiotherapy and confirming the predictions in biological experiments. METHODS: Using a ridge filter, a 90-mm wide SOBP for a 210 MeV/u helium-ion beam was created in a broad beam delivery system. The ridge filter was designed such that a uniform biological response was achieved with a cell survival rate of 7% over the SOBP region. Biological experiments were then performed using the SOBP beam in a human salivary gland (HSG) cell line to measure the cell survival rates. RESULTS: The biological responses were uniform in the SOBP region, as expected by the MKM; however, the mean of the measured cell survival rates was (11.2 ± 0.6) % in the SOBP region, which was 60% higher than the designed rate. When investigating the biological parameters of the HSG cell line used in the experiments, we found that they were altered slightly from the MKM parameters used for carbon-ion radiotherapy. The new ß parameter reproduced the measured survival rates within 6.5% in the SOBP region. CONCLUSION: We produced biologically uniform SOBP using MKM for carbon-ion radiotherapy. The measured survival rates in the SOBP region were higher than expected, and the survival rates were reproduced by modifying the MKM parameter. This study was limited to one SOBP, and further investigations are required to prove that MKM is generally applicable to helium-ion radiotherapy.

Synthetic Glabridin Derivatives Inhibit LPS-Induced Inflammation via MAPKs and NF-κB Pathways in RAW264.7 Macrophages.

Glabridin is a polyphenolic compound with reported anti-inflammatory and anti-oxidative effects. In the previous study, we synthesized glabridin derivatives-HSG4112, (S)-HSG4112, and HGR4113-based on the structure-activity relationship study of glabridin to improve its biological efficacy and chemical stability. In the present study, we investigated the anti-inflammatory effects of the glabridin derivatives in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We found that the synthetic glabridin derivatives significantly and dose-dependently suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2), and decreased the level of inducible nitric oxygen synthase (iNOS) and cyclooxygenase-2 (COX-2) and the expression of pro-inflammatory cytokines interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor alpha (TNF-α). The synthetic glabridin derivatives inhibited the nuclear translocation of the NF-κB by inhibiting phosphorylation of the inhibitor of κB alpha (IκB-α), and distinctively inhibited the phosphorylation of ERK, JNK, and p38 MAPKs. In addition, the compounds increased the expression of antioxidant protein heme oxygenase (HO-1) by inducing nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) through ERK and p38 MAPKs. Taken together, these results indicate that the synthetic glabridin derivatives exert strong anti-inflammatory effects in LPS-stimulated macrophages through MAPKs and NF-κB pathways, and support their development as potential therapeutics against inflammatory diseases.

Comparative Study Between Hysterosalpingo-Contrast Sonography and Hysterosalpingography in Evaluating Tubal Patency at Aminu Kano Teaching Hospital, Kano.

Background: Tubal diseases contribute significantly to secondary infertility, affecting 25-35% of couples seeking infertility treatment. Traditional methods for assessing tubal patency, such as laparoscopy and dye tests, are invasive, costly, and require specialized expertise. Hysterosalpingography (HSG) is an alternative, but it involves pain and radiation exposure. This study aimed to compare the effectiveness of Hysterosalpingo-contrast Sonography (HyCoSy) using a saline and air mixture to HSG in assessing tubal patency in infertility patients at Aminu Kano Teaching Hospital. Methodology: A cross-sectional study involved 50 consenting patients seeking fertility evaluation. The researchers used a semi-structured questionnaire to gather demographic information. HyCoSy with the saline and air mixture was performed between the 5th and 10th day of the menstrual cycle, followed by HSG within the next five days. The patency of each fallopian tube was assessed, and pain levels experienced during both procedures were recorded using a numerical rating scale. Results: The results indicated that 68.8% of patients had bilateral patent tubes according to HyCoSy, while 60.4% were found to have patent tubes with HSG. A comparison of findings for individual tubes showed an 89.6% concordance rate between the two tests, with a Kappa index of 0.73, indicating substantial agreement. Importantly, patients reported significantly less pain during the HyCoSy procedure (mean NRS score of 4.1) compared to HSG (mean NRS score of 7.1). Conclusion: This study demonstrated that HyCoSy using a saline and air mixture is highly comparable to HSG in assessing tubal patency. Notably, HyCoSy was preferred by patients due to its reduced pain and better tolerance, with minimal adverse effects. This suggests that HyCoSy may be a more patient-friendly and cost-effective alternative for tubal assessment in cases of infertility.

Modern assessment of the uterine cavity and fallopian tubes in the era of high-efficacy assisted reproductive technology.

The high efficacy of modern assisted reproductive technology (ART) and increase in the number of noninfertile patients who are using ART for family building in the United States call into question the relevance of the standard, one-size-fits-all infertility evaluation. Here, we explore whether all patients presenting for ART need uterine cavity and tubal assessment and what tests are most appropriate, efficient, and cost-effective in current times.

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 ).

Is hysterosalpingo-foam sonography (HyFoSy) more tolerable in terms of pain and anxiety than hysterosalpingography (HSG)? A prospective real-world setting multicentre study.

BACKGROUND: In 60% of sterile couples a female factor is present, with these being tubal factors in 30-50% of cases. A tubal patency test is also required in women without a male partner undergoing fertility treatment. Thus, an accurate, safe and tolerable technique should be available. The aim of this study is to determine and to compare hysterosalpingo-foam sonography (HyFoSy) and hysterosalpingography (HSG) tolerability in terms of pain and anxiety. METHODS: This is a prospective real-world setting multicentre study conducted in two tertiary hospitals in Madrid. 210 infertile women/women without a male partner looking to get pregnant were recruited; 111 for the HyFoSy group and 99 for the HSG group. Tolerability was measured in terms of anxiety by the State Trait Anxiety Inventory (STAI) and pain by the Visual Analogue Scale (VAS). RESULTS: Median VAS score in HyFoSy group was 2 (P25; P75: 1; 3) versus 5 (4; 8) in HSG group, p < 0.001. The median State-STAI score in the HSG group was 18 points (10; 26) versus 10 (7; 16) in the HyFoSy group (p < 0.001); the median Trait-STAI score in the HSG group was 15 (11; 21) versus 13 (9; 17) in the HyFoSy group (p = 0.044). CONCLUSIONS: HyFoSy shows higher tolerability to both: pain and anxiety. It is related to less pain and less post-test anxiety than HSG.

The effect of hyoscine-N-butylbromide on pain perception during and after hysterosalpingography in infertile women: a systematic review and meta-analysis of randomised controlled trials.

This paper reports a systematic review and meta-analysis of the effectiveness of hyoscine-N-butylbromide (HBB) administration in hysterosalpingography (HSG). Four electronic databases were searched for randomised controlled trials (RCTs) that compared HBB versus placebo or no intervention in infertile women undergoing HSG. Pain during and after HSG and different adverse events including nausea, vomiting, and dizziness were evaluated. Three RCTs with 335 patients were included. The analysis showed HBB was significantly effective in reducing pain during and after HSG (MD = -0.76 mm, 95% CI [-1.35, -0.17], p = 0.01) and (MD = -0.81 mm, 95% CI [-1.07, -0.56], p < 0.001), respectively. There were no significant differences in adverse events between HBB and control groups. The methodological evidence quality was high as evaluated by GRADEpro. In conclusion, this review provides good evidence that prior administration of HBB is effective in reducing induced pain during and after HSG with tolerable side effects.