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).

Infertility: Evaluation and Management.

Infertility is the inability to achieve a pregnancy after 12 months of regular, unprotected sexual intercourse. Evaluation and treatment are recommended earlier than 12 months when risk factors for infertility exist, if the female partner is 35 years or older, and in the setting of nonheterosexual partnerships. A comprehensive medical history and physical examination emphasizing the thyroid, breast, and pelvic areas should be performed to help direct diagnosis and treatment. Causes of infertility in females include uterine and tubal factors, ovarian reserve, ovulatory dysfunction, obesity, and hormone-related disorders. Common male factor infertility issues include abnormal semen, hormonal disorders, and genetic abnormalities. Semen analysis is recommended for the initial assessment of the male partner. Evaluation of the female should include assessment of the uterus and fallopian tubes with ultrasonography or hysterosalpingography when indicated. Laparoscopy, hysteroscopy, or magnetic resonance imaging may be needed to evaluate for endometriosis, leiomyomas, or evidence of a previous pelvic infection. Treatment with ovulation induction agents, intrauterine insemination, in vitro fertilization, donor sperm or eggs, or surgery may be necessary. Unexplained male and female infertility can be treated with intrauterine insemination or in vitro fertilization. Limiting alcohol intake, avoiding tobacco and illicit drug use, consuming a profertility diet, and losing weight (if obese) may improve pregnancy success rates.

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.

Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial.

STUDY QUESTION: Does hysterosalpingo-foam sonography (HyFoSy) lead to similar pregnancy outcomes, compared with hysterosalpingography (HSG), as first-choice tubal patency test in infertile couples? SUMMARY ANSWER: HyFoSy and HSG produce similar findings in a majority of patients and clinical management based on the results of either HyFoSy or HSG, leads to comparable pregnancy outcomes. HyFoSy is experienced as significantly less painful. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during fertility work-up is performed by HSG. HyFoSy is an alternative imaging technique lacking ionizing radiation and iodinated contrast medium exposure which is less expensive than HSG. Globally, there is a shift towards the use of office-based diagnostic methods, such as HyFoSy. STUDY DESIGN, SIZE, DURATION: This multicentre, prospective, comparative study with a randomized design was conducted in 26 hospitals in The Netherlands. Participating women underwent both HyFoSy and HSG in randomized order. In case of discordant results, women were randomly allocated to either a management strategy based on HyFoSy or one based on HSG. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included infertile women between 18 and 41 years old who were scheduled for tubal patency testing during their fertility work-up. Women with anovulatory cycles not responding to ovulation induction, endometriosis, severe male infertility or a known iodine contrast allergy were excluded. The primary outcome for the comparison of the HyFoSy- and HSG-based strategies was ongoing pregnancy leading to live birth within 12 months after inclusion in an intention-to-treat analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 women underwent HyFoSy and HSG. HyFoSy was inconclusive in 97 of them (9.5%), HSG was inconclusive in 30 (2.9%) and both were inconclusive in 9 (0.9%). In 747 women (73%) conclusive tests results were concordant. Of the 143/1026 (14%) with discordant results, 105 were randomized to clinical management based on the results of either HyFoSy or HSG. In this group, 22 of the 54 women (41%) allocated to management based on HyFoSy and 25 of 51 women (49%) allocated to management based on HSG had an ongoing pregnancy leading to live birth (Difference -8%; 95% CI: -27% to 10%). In total, clinical management based on the results of HyFoSy was estimated to lead to a live birth in 474 of 1026 women (46%) versus 486 of 1026 (47%) for management based on HSG (Difference -1.2%; 95% CI: -3.4% to 1.5%). Given the pre-defined margin of -2%, statistically significant non-inferiority of HyFoSy relative to HSG could not be demonstrated (P = 0.27). The mean pain score for HyFoSy on the 1-10 Visual Analogue Scale (VAS) was 3.1 (SD 2.2) and the mean VAS pain score for HSG was 5.4 (SD 2.5; P for difference < 0.001). LIMITATIONS, REASONS FOR CAUTION: Since all women underwent both tubal patency tests, no conclusions on a direct therapeutic effect of tubal flushing could be drawn. WIDER IMPLICATIONS OF THE FINDINGS: HyFoSy or HSG produce similar tubal pathology findings in a majority of infertile couples and, where they differ, a difference in findings does not lead to substantial difference in pregnancy outcome, while HyFoSy is associated with significantly less pain. STUDY FUNDING/COMPETING INTEREST(S): The FOAM study was an investigator-initiated study funded by ZonMw, The Netherlands organization for Health Research and Development (project number 837001504). ZonMw funded the whole project. 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 speaker fees from Guerbet. F.J.M.B. reports personal fees as a member of the external advisory board for Merck Serono, The Netherlands, and a research support grant from Merck Serono, outside the submitted work. C.B.L. reports speakers' fee from Ferring in the past, and his department receives research grants from Ferring, Merck and Guerbet. J.S. reports a research agreement with Takeda on MR of motility outside the submitted work. M.V.W. reports leading The Netherlands Satellite of the Cochrane Gynaecology and Fertility Group. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet and research funding from Merck and Guerbet. V.M. reports non-financial support from IQ medicals ventures, during the conduct of the study; grants and personal fees from Guerbet, outside the submitted work. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: NTR4746/NL4587 (https://www.trialregister.nl). TRIAL REGISTRATION DATE: 19 August 2014. DATE OF FIRST PATIENT'S ENROLMENT: 7 May 2015.

Evaluation of the safety and effectiveness of tubal inflammatory drugs in patients with incomplete tubal obstruction after four-dimensional hysterosalpingo-contrast-sonography examination.

BACKGROUND: To investigate the safety and effectiveness of tubal inflammatory drugs in patients with incomplete tubal obstruction of at least one side after four-dimensional hysterosalpingo-contrast-sonography (4D-HyCoSy) examination. METHODS: Two hundred fifteen cases of tubal incomplete obstruction were diagnosed by ultrasonography from February 2019 to November 2020.According to retrospective analysis,the patients in this study were divided into experimental and control groups; the experimental group combined with salpingitis drugs, and the control group received blank control. Basic information, degree of pain, postoperative complications, and pregnancy rate were then compared between the two groups. RESULTS: Compared with the control group, there was no significant difference in the basic information; in preoperative, intraoperative, or postoperative pain; or in postoperative complications (P > 0.05). The cumulative pregnancy rate of the experimental group (26.8%) was statistically different from that of the control group (14.4%) (P < 0.05). CONCLUSIONS: We observed that for infertile patients with incomplete obstruction of at least one fallopian tube as diagnosed by contrast-enhanced ultrasonography, salpingitis-treatment drugs effectively improved the pregnancy rate postoperatively, with high effectiveness and safety. This regimen is thus worthy of further investigation and promotion in the future.

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 ).

Lipiodol flushing under ultrasound guidance at time of hystero-salpingo contrast sonography (HyCoSy): A retrospective observational study.

BACKGROUND: Up to 30% of female infertility can be attributed to tubal abnormalities. Assessment of fallopian tube patency forms a component of the basic assessment of infertility. Tubal patency can be checked through hysterosalpingogram (HSG) under radiologic guidance with oil- or water-based contrast medium (OBCM or WBCM), or hystero-salpingo contrast sonography (HyCoSy) under ultrasound guidance with WBCM. Tubal flushing with OBCM has been shown to improve fertility rates. OBJECTIVES: To study the feasibility and tolerability of performing Lipiodol (ethiodised oil) flush concurrently with HyCoSy. To examine the in vivo sonographic visibility of Lipiodol vs normal saline. MATERIALS AND METHODS: Retrospective observational study of patients with subfertility referred for Lipiodol flushing under ultrasound guidance between August 2017-September 2020 at six private ultrasound practices in Sydney, Australia. RESULTS: There were 412 patients who were referred for Lipiodol flushing. Of these, 86 patients did not have concurrent Lipiodol flush at HyCoSy performed due to strict exclusion criteria. Of the 326 patients who proceeded with Lipiodol flushing at HyCoSy, all cases were successful, with no cases of extravasation. There were no major complications. In vivo sonographic visualisation of Lipiodol was similar to that of the commonly used agitated 0.9% saline (n = 20; mean visibility score 4.3 ± 0.9 vs 4.0 ± 1.2). CONCLUSION: Our study has shown that Lipiodol flushing at time of HyCoSy as a single procedure is feasible and tolerable to patients. Flushing with Lipioidol during HyCoSy is likely as sonographically visible as 0.9% saline.

Comparison between X-ray-hysterosalpingography and 3 Tesla magnetic resonance-hysterosalpingography in the assessment of the tubal patency in the cause of female infertility.

OBJECTIVES: XR-hysterosalpingography currently represents the gold standard for tubal pathology evaluation. Magnetic resonance-HSG is an innovative technique. With our study, we aim to comprehend if and how MR-HSG, compared to traditional XR-HSG, could give us this additional information in the diagnostic/therapeutic process. MATERIALS AND METHODS: This study included 19 patients between 30 and 42 years old (average age 37.7) affected by infertility. Patients underwent contextually both XR-HSG and MR-HSG, using a single catheterization. The dynamic MR-HSG exam consisted a MR sequence during contrast administration through the cervical catheter. RESULTS: Both XR-HSG and MR-HSG documented that 15 of the 19 patients had bilateral tubal patency, while four patients had monolateral tubal patency. However, MR-HSG allowed us to diagnose additional findings: Two active endometriosis foci in adnexal localization and a condition of adenomyosis A unicornuate uterus malformation A submucous uterine myoma near the tubal ostium A decrease of the ovarian reserve in a patient So MR-HSG could potentially detect in 10/19 (52%) women the cause of their infertility, compared to 4/19 (21%) detected with XR-HSG and about 30% of women would have resulted as false negatives if we only used XR-HSG. Finally, with a questionnaire, we demonstrated that MR-HSG is less painful than XR-HSG. CONCLUSIONS: These data thus confirm that XR-HSG and MR-HSG present the same diagnostic of assessing tubal patency. We also demonstrated that MR-HSG is able to detect further collateral findings that could likewise be a possible therapeutic target and it could possibly become the new gold standard in female infertility diagnostics.

What is the fertility-enhancing effect of tubal flushing? A hypothesis article.

Hysterosalpingographies (HSGs) have formed an essential part of the fertility workup for more than a century. More recently, tubal flushing, especially with oil-based contrast, has been shown to significantly improve the natural conception rates. Critically, the mechanism of this fertility-enhancing effect during tubal flushing is still unclear. This article postulates hypotheses, based on published and own research, on the potential mechanisms and root cause of tubal flushing fertility enhancement. Possible explanations for the increased fertility rates, especially with oil-based contrast, are divided into the biochemical and interfacial effects derived from the contrast properties. The biochemical effects may include the immunological response of the endometrium or peritoneum, the impact on the endometrial opioid receptors or the iodine content. The interfacial effects may include improvement of interfacial factors due to the lubricant effect or dislodgement of mucus debris within the Fallopian tubes. Impact StatementWhat is already known on this subject? Tubal flushing during hysterosalpingographies (HSGs) increases natural conception rates, and using oil-based over water-based contrast increases that effect even further. However, the underlying mechanism of the observed fertility-enhancing effect is still poorly understood.What do the results of this study add? This article postulates different hypotheses on the potential mechanisms and root cause of the fertility enhancement from tubal flushing.What are the implications of these findings for clinical practice and/or further research? We suggest additional research on the different hypotheses, intending to determine which subfertile women will benefit most from tubal flushing using oil-based contrast and at which stage of their subfertility. Furthermore, we suggest research on administering tubal flushing with oil-based contrast, besides in HSG.

Serum thyroid-stimulating hormone receptor antibody levels and thyroid dysfunction after hysterosalpingography: a case-control study.

OBJECTIVE: Hysterosalpingography (HSG) performed with an iodine contrast media can cause thyroid dysfunction, including thyrotoxicosis and hypothyroidism. We investigated the association between the serum levels of thyroid-stimulating hormone receptor antibody (TRAb), an indicator of Graves' disease, and abnormal thyroid function after performing HSG. METHODS: The screening of TRAb was conducted in 362 patients who first visited the Tawara IVF Clinic between April and September 2018. The association between TRAb levels and the effects of HSG examinations on thyroid function were evaluated. RESULTS: Of the 362 patients, 2 (0.55%) had high levels (>2.0 IU/L) of TRAb, whereas 18 (5.0%) had intermediate TRAb levels, ranging from 0.3 to 1.9 IU/L. Of the 98 women (including 7 of the 18 women with TRAb level 0.3-1.9 IU/L, and 91 of the 342 women with TRAb level <0.3 IU/L) who had undergone HSG, two women developed overt thyrotoxicosis after HSG, and the frequency was significantly higher (p = .0044) in the group with intermediate levels of TRAb (28.6%, 2 of 7) than that in the group with low TRAb levels (<0.3 IU/L; 0.0%, 0 of 91). CONCLUSIONS: These findings indicate that increased serum levels of TRAb are significantly associated with the development of thyrotoxicosis after HSG.

Effect of X-ray exposure during hysterosalpingography on capabilities of female germ cells.

PURPOSE: To elucidate the effect of X-ray exposure during hysterosalpingography (HSG) on subsequent laboratory outcomes in in vitro fertilization (IVF). METHODS: A total of 1458 oocytes, consisting of 990 oocytes retrieved from 70 women (89 cycles) who underwent HSG prior to IVF and 468 oocytes from 45 women (57 cycles) who underwent IVF without HSG, were evaluated for their retrieval number, maturity, fertilization, and development post fertilization. X-ray exposure during HSG was recorded as reference air kerma (RAK) (mGy). Subjects were stratified according to the amount of RAK (Nil: IVF without HSG, L-RAK: RAK < 16.23, mH-RAK: RAK ≥ 16.23). The number of oocytes retrieved, oocyte maturation, fertilization, and embryo development was compared among 3 groups. Further, multivariate analyses were performed to investigate the effect of X-ray exposure on laboratory outcomes in IVF. RESULTS: There was a statistically significant difference in the fertilization rate among 3 groups (Nil: 71.6%, L-RAK: 80.5%, mH-RAK: 78.3%). The good-quality blastocyst rate in mH-RAK (46.2%) was significantly higher than L-RAK (35.3%) and Nil (32.4%). Multivariate analyses revealed that X-ray exposure was associated with higher fertilization, higher blastocyst development, and higher good-quality blastocyst development rates with adjustment for patient age, BMI, ovarian stimulation types, and fertilization methods. Association between X-ray exposure and the number of oocytes retrieved, and oocyte maturation was not confirmed. CONCLUSIONS: The present study suggests that X-ray exposure of the female reproductive organs during HSG could enhance the potential of oocytes rather than adversely.

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.

Magnetic resonance hysterosalpingography in diagnostic work-up of female infertility - comparison with conventional hysterosalpingography: a randomised study.

OBJECTIVE: To compare diagnostic accuracy of MR-hysterosalpingography (MR-HSG) and conventional hysterosalpingography (X-HSG) in the evaluation of female infertility. METHODS: Forty women received prospectively both X-HSG, the gold standard technique, and MR-HSG on the same day but the order in which they were conducted was randomised. A 1.5 Tesla MRI was performed with classical sequences for pelvic analysis and an additional 3D T1-weighted sequence with intra-uterine injection of gadolinium. Two radiologists independently interpreted X-HSG and MR-HSG according to randomisation, blinded to the other results. They both then performed a second interpretation of MR-HSG blinded to the first reading with a minimum time delay of 1 week. Diagnostic performance of MR-HSG for analysis of tubal and intracavity abnormalities was evaluated by calculating sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Twenty-six patients were included. Diagnostic performance of MR-HSG was: Se: 91.7% (95% CI 61.5-99.8); Sp: 92.9% (95% CI 66.1-99.8) ; PPV: 91.7% (95% CI 61.5-99.8); NPV: 92.9% (95% CI 66.1-99.8). Pain analysis showed a significant statistical difference between the two procedures: average VAS for X-HSG was 4.43 (95% CI 3.50-5.36) versus 3.46 (95% CI 2.62-4.31) for MR-HSG, p=0,01. Intra- and inter-rater agreements for detection of tubal or intracavity abnormalities were 0.92 (95% CI 0.78-1.00) and 0.76 (95% CI 0.52-1.00). CONCLUSION: MR-HSG is a well-tolerated technique demonstrating high accuracy in investigating tubal patency and intra-uterine abnormalities for diagnostic work-up of female infertility. KEY POINTS: • MR-hysterosalpingography is an innovative technique. • Hysterosalpingography can be used to investigate tubal patency and intracavity abnormalities. • Hysterosalpingography is a potential 'one-stop-shop' imaging technique for a single comprehensive examination of female infertility.

Cutaneous small-vessel vasculitis following hysterosalpingo-foam sonography (HyFoSy).

We present a case of diffuse skin immune reaction, diagnosed as cutaneous small-vessel vasculitis, following assessment of tubal patency by contrast ultrasound, which appears to be the first reported case of hypersensitivity reaction to sonographic tubal patency testing, based on a literature search. A 32-year-old woman presented with non-thrombocytopenic palpable purpura the day after assessment of tubal patency by two-/three-dimensional hysterosalpingo-foam sonography (HyFoSy) using ExEm® Foam. During real-time ultrasound, the observer identified flow in only the right tube when using saline with air as contrast medium; however, the same observer identified flow in both tubes after injecting ExEm Foam and the woman left the clinic without any complications. The next day, the patient was admitted with a complaint of a red-purple skin rash noticed the same morning, associated with moderate leg pain. Slow-motion analysis of the recorded videos and three-dimensional ultrasound datasets showed previously unnoticed venous intravasation of ExEm Foam into the myometrial vessels. Palpable purpura is typically found in vasculitis as a result of extravasation of red cells outside the inflamed blood vessel. This previously unreported side effect of tubal patency testing by HyFoSy, its potential rare organ consequences, as well as unknown consequences of venous intravasation by foam, should be included in the informed consent prior to the examination. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Hysterosalpingosonography Is Not as Effective as Hysterosalpingography to Increase Chances of Pregnancy.

OBJECTIVE: This study sought to examine whether hysterosalpingosonography (sono-HSG) is as effective as hysterosalpingography (HSG) in facilitating conception by comparing pregnancy rates in the 6 months following the procedures. METHODS: This retrospective noninferiority study (Canadian Task Force classification II-2) was conducted at a tertiary university centre. The investigators studied 440 consecutive eligible infertile women. Bilateral tubal occlusion, severe male infertility, and having undergone both procedures were exclusion criteria. Tubal testing, as part of the infertility workup, was performed by either sono-HSG or HSG. The primary outcome was pregnancy, defined as a positive fetal heartbeat on ultrasonographic examination, in the 6 months following the procedure. RESULTS: A total of 57 pregnancies (26%) were observed in the HSG group and 33 (15%) in the sono-HSG group. Adjusted and non-adjusted relative risks of pregnancy in the 6 months following sono-HSG compared with HSG were 0.61 (95% CI 0.42-0.89) and 0.58 (95% CI 0.39-0.85). Adverse events were infrequent with both procedures (sono-HSG, 1%; HSG, 4%; P = 0.16). CONCLUSION: This study suggests that uterine flushing as performed during sono-HSG is not as effective as when performed during HSG to increase the chances of pregnancy, but further studies will be required because of bias related to the retrospective study design.

Use of atropine in four-dimensional hysterosalpingo-contrast sonography: Does it suppress pain during infertility examination?

This study aimed to ascertain if atropine is useful for suppressing the pain suffered during four-dimensional hysterosalpingo-contrast sonography (4D-HyCoSy) when assessing infertility in women. A total of 252 patients were divided into 2 groups to receive or not receive atropine (0.5 mg) injection 30 minutes before 4D-HyCoSy. Pain was evaluated using a numerical rating scale (NRS): during 4D-HyCoSy; upon 2-dimensional transvaginal sonography; before catheter insertion; upon insertion and fixation of the catheter into the uterine cavity; 30 minutes after 4D-HyCoSy. According to the degree of patency of Fallopian tubes, the 6 patterns observed were integrated further into 3 patient groups: all-negative (both Fallopian tubes were negative), positive-and-negative (one Fallopian tube showed patency and the other showed stenosis or non-patency), and all-positive (both Fallopian tubes showed stenosis or non-patency). We compared the NRS scores and prevalence of side-effects other than pain between the atropine-injection and non-atropine-injection groups within the three groups mentioned above. The NRS score showed no significant differences among the groups at any time point (all P > .05). The different prevalence of side-effects other than pain was significant between the atropine-injection and atropine-non-injection groups (P = .012). These data suggest that atropine does not reduce pain in patients during 4D-HyCoSy. However, atropine may reduce the prevalence of other side-effects during 4D-HyCoSy, which needs a further, large, prospective, multi-cohort study to verify.

The FOAM study: is Hysterosalpingo foam sonography (HyFoSy) a cost-effective alternative for hysterosalpingography (HSG) in assessing tubal patency in subfertile women? Study protocol for a randomized controlled trial.

BACKGROUND: Tubal pathology is a causative factor in 20% of subfertile couples. Traditionally, tubal testing during fertility work-up is performed by hysterosalpingography (HSG). Hysterosalpingo-foam sonography (HyFoSy) is a new technique that is thought to have comparable accuracy as HSG, while it is less expensive and more patient friendly. HyFoSy would be an acceptable alternative for HSG, provided it has similar effectiveness in terms of patient outcomes. METHODS/DESIGN: We aim to compare the effectiveness and costs of management guided by HyFoSy or by HSG. Consenting women will undergo tubal testing by both HyFoSy and HSG in a randomized order during fertility work-up. The study group will consist of 1163 subfertile women between 18 and 41 years old who are scheduled for tubal patency testing during their fertility work-up. Women with anovulatory cycles not responding to ovulation induction, endometriosis, severe male subfertility or a known contrast (iodine) allergy will be excluded. We anticipate that 7 % (N = 82) of the participants will have discordant test results for HyFoSy and HSG. These participants will be randomly allocated to either a management strategy based on HyFoSy or a management strategy based on HSG, resulting in either a diagnostic laparoscopy with chromopertubation or a strategy that assumes tubal patency (intrauterine insemination or expectant management). The primary outcome is ongoing pregnancy leading to live birth within 12 months after randomization. Secondary outcomes are patient pain scores, time to pregnancy, clinical pregnancy, miscarriage rate, multiple pregnancy rate, preterm birth rate and number of additional treatments. Costs will be estimated by counting resource use and calculating unit prices. DISCUSSION: This trial will compare the effectiveness and costs of HyFoSy versus HSG in assessing tubal patency in subfertile women. TRIAL REGISTRATION: Dutch Trial Register (NTR 4746, http://www.trialregister.nl ). Date of registration: 19 August 2014.

The effect of oil and water-soluble contrast medium in hysterosalpingography on thyroid function.

Hysterosalpingography (HSG) using iodinated contrast medium is X-ray diagnostic test that examines the inside of the uterus and fallopian tubes in infertile women. In this study, we compared thyroid function (thyroid stimulating hormone: TSH and free-T4: FT4 levels) after HSG with an oil-soluble contrast medium (OSCM) and a water-soluble contrast medium (WSCM). One hundred and sixty-four and 94 patients with normal thyroid function received HSG with OSCM and WSCM, respectively. Approximately 25% of the women in the OSCM group developed subclinical hypothyroidism (SCH), whereas only less than 10% of the patients in the WSCM group developed SCH. Our data clearly indicate that WSCM is safe for thyroid function in women who plan to get pregnant.

Pain Intensity During Ultrasound Assessment of Uterine Cavity and Tubal Patency With and Without Painkillers: Prospective Observational Study.

STUDY OBJECTIVE: To determine the pain intensity and incidence of mild to severe pain during the ultrasound assessment of the uterine cavity and tubal patency using saline, air and saline, and foam as contrasts with and without painkiller. DESIGN: Prospective observational study (Canadian Task Force classification II-1). SETTING: Private clinic. PATIENTS: Three hundred infertile women who were consecutively submitted to uterine cavity and tubal patency assessment by ultrasound using saline, air, and foam in single exam between October 2012 and November 2013. INTERVENTIONS: No painkillers were used until March 2013 when we started offering an effervescent codeine tablet containing paracetamol 500 mg and codeine phosphate 30 mg approximately 1 hour before the procedure. MEASUREMENTS AND MAIN RESULTS: Pain intensity measured with an 11-point (0-10) numerical rating scale and incidence of moderate/severe levels of pain (numerical rating scale > 3) during the main components of the procedure (speculum insertion, catheter insertion, saline infusion, air and saline infusion, foam infusion, and after the procedure [0 minutes, 15 minutes, 30 minutes, and 24 hours]) were assessed. The incidence of moderatesevere pain was significantly lower in women using painkillers considering any moment of the procedure: 49 of 175 (28%) versus 65 of 125 (52%); relative risk, .54; 95% confidence interval, .40-.72; p < .001; number needed to treat, 4. Less women presented with moderate/severe pain during air and saline compared with foam infusion: 31 of 300 (10%) versus 75 of 300 (25%); p < .001; relative risk, .41, 95% confidence interval, .28-.61. CONCLUSION: The incidence of moderate/severe pain during the ultrasound assessment of the uterine cavity and tubal patency is common. Our results suggest that using paracetamol + codeine before the procedure reduces the pain level, but randomized controlled trials are required.