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.

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.

Transvaginal hydrolaparoscopy versus hysterosalpingography in the work-up for subfertility: a randomized controlled trial.

RESEARCH QUESTION: Is transvaginal hydrolaparoscopy (THL) non-inferior to hysterosalpingography (HSG) as a first-line tubal patency test in subfertile women in predicting the chance of conception leading to live birth? DESIGN: A multicentre, randomized controlled trial in four teaching hospitals in the Netherlands, which randomized subfertile women scheduled for tubal patency testing to either THL or HSG as a first-line tubal patency test. The primary outcome was conception leading to live birth within 24 months after randomization. RESULTS: A total of 149 women were randomized to THL and 151 to HSG. From the intention-to-treat population, 83 women from the THL group (58.5%) conceived and delivered a live born child within 24 months after randomization compared with 82 women (55.4%) in the HSG group (difference 3.0%, 95% CI -8.3 to 14.4). Time to conception leading to live birth was not statistically different between groups. Miscarriage occurred in 16 (11.3%) women in the THL group, versus 20 (13.5%) women in the HSG group (RR = 0.66, 95% CI 0.34 to 1.32, P = 0.237), and multiple pregnancies occurred in 12 (8.4%) women in the THL group compared with 19 (12.8%) women in the HSG group (RR = 0.84, 95% CI 0.46 to 1.55, P = 0.58). Ectopic pregnancy was diagnosed in two women in the HSG group (1.4%) and none in the THL group (P = 0.499). CONCLUSION: In a preselected group of subfertile women with a low risk of tubal pathology, use of THL was not inferior to HSG as a first-line test for predicting conception leading to live birth.

Transvaginal hydrolaparoscopy and laparoscopy.

RESEARCH QUESTION: To evaluate the findings of outpatient transvaginal hydrolaparoscopy (THL) in comparison with diagnostic laparoscopy combined with chromopertubation in subfertile women. DESIGN: In a retrospective study in four large teaching hospitals, all subfertile women who underwent a THL and a conventional laparoscopy as part of their fertility work-up in the period between 2000 and 2011 were studied. Findings at THL were compared with findings at diagnostic and therapeutic laparoscopies. Tubal occlusion, endometriosis and adhesions were defined as abnormalities. RESULTS: Out of 1119 women, 1103 women underwent THL. A complete evaluation or incomplete but diagnostic procedure could be performed in 989 (89.7%) and 28 (2.5%), respectively. An incomplete non-diagnostic procedure was performed in 11 (1.0%) women. Failure of THL occurred in 75 women (6.8%) and 40 of these women (3.6%) subsequently underwent laparoscopy. Laparoscopy was performed in a total of 126 patients with a median time interval of 7 weeks (interquartile range [IQR] 3-13 weeks). Of 64 patients who successfully underwent both THL and laparoscopy, concordant findings were found in 53 women and discordant results in 11 women, 6 of which were caused by tubal spasm. Sensitivity of THL in detecting abnormalities was 100% and specificity was 22.2%, with a likelihood ratio of 1.29. CONCLUSION: THL in an outpatient setting can detect anatomical abnormalities comparable to the more invasive reference standard diagnostic laparoscopy. If THL succeeds, there is no need to add a diagnostic laparoscopy in the work-up.

The prognostic capacity of transvaginal hydrolaparoscopy to predict non-IVF conception.

Transvaginal hydrolaparoscopy (THL) is performed to investigate tubal pathology in subfertile women. This retrospective multicentre cohort study investigated the results of THL and subsequent pregnancy rates. Between 2000 and 2011, 1033 subfertile women participated in the study. The primary outcome measure was intrauterine pregnancy, either after natural conception or after treatment with intrauterine insemination or ovulation induction. Cumulative intrauterine pregnancy rates were calculated using Kaplan-Meier analysis and fecundity rate ratios (FRR) were established. THL showed bilateral patent tubes in 83%, one-sided tubal occlusion in 12.4% and bilateral tubal occlusion in 4.6% of women. Cumulative intrauterine pregnancy rates after 36 months were 52% for women with bilateral patent tubes, 44% for one-sided tubal occlusion (FRR 1.04; 95% confidence interval [CI], 0.78 to 1.39) and 7% for bilateral tubal occlusion (FRR 0.13; 95% CI, 0.04 to 0.43). Endometriosis was diagnosed in 6.4%, and adhesions in 9.1%, while 3.9% of women had both. Corresponding FRR were 0.73 (95% CI, 0.49 to 1.09), 0.68 (95% CI, 0.46 to 1.02) and 0.42 (95% CI, 0.20 to 0.84). In conclusion, women with bilateral tubal occlusion or a combination of endometriosis and adhesions found on THL significantly reduced chances of natural conception.