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

Tubal patency testing is an important part of the fertility work-up. Hysterosalpingo-foam sonography (HyFoSy) and hysterosalpingography (HSG) are both commonly used visual tubal patency tests ( NICE, 2013 ; The Unexplained Infertility guideline group, 2023 ). During the HyFoSy or HSG procedure, a contrast medium is flushed through the uterine cavity and Fallopian tubes, while in the meantime, respectively, a transvaginal ultrasound is performed or radiographs are taken. These images reveal the flow of the contrast medium, enabling clinicians to evaluate patency of the Fallopian tubes. HyFoSy and HSG have a high and comparable diagnostic accuracy for evaluating tubal patency, compared to laparoscopy with dye chromopertubation as the reference standard ( Broeze et al. , 2011 ; Maheux-Lacroix et al. , 2014 ; Alcázar et al. , 2020 ). The FOAM study showed that clinical management, following a fertility work-up based on the results of either HyFoSy or HSG, resulted in comparable pregnancy rates, while HyFoSy was experienced as significantly less painful. Furthermore, compared to HSG, HyFoSy lacks exposure to ionizing radiation and iodinated contrast medium ( van Welie et al. , 2022 ). Besides its diagnostic purpose, tubal patency testing can also be applied for its fertility enhancing effect, by tubal flushing. Previous studies have shown that tubal flushing by HSG increases pregnancy rates in women with unexplained infertility, and that this effect is even greater when oil-based contrast is used in comparison with water-based contrast ( Fang et al. , 2018 ; Wang et al. , 2019 ; Wang et al. , 2020 ). To date only small observational studies lacking a control group have reported on pregnancy rates after tubal flushing by HyFoSy ( Emanuel et al. , 2012 ; Exacoustos et al. , 2015 ; Tanaka et al. , 2018 ). The mechanism underlying the fertility enhancing effect of tubal flushing during HSG, especially with oil-based contrast is not yet fully understood. Multiple hypotheses have been proposed to clarify this effect ( Roest et al. , 2022 ): improvement of fertilization and implantation due to immunological effects on the peritoneum and endometrium ( Mikulska et al. , 1994 ; Yun and Lee, 2004 ; Johnson, 2014 ; Izumi et al. , 2017 ); increases in the receptivity of opioid receptors in the endometrium ( Totorikaguena et al. , 2017 ); improvement of the transport of gametes within the Fallopian tube by the lubricating effect of the contrast on the cilia ( Soules and Spadoni, 1982 ); and mechanical dissolution of debris and/or mucus plugs in the proximal part of the Fallopian tubes ( Gillespie, 1965 ; Kerin et al. , 1992 ). The aim of this analysis was to evaluate and compare the effect of tubal patency testing by HyFoSy and HSG prior to the alternative tubal patency testing method on visible tubal patency. The results of this analysis might shed light on the ability of both methods to dislodge obstructing proximal plugs in otherwise normal anatomical tubes.

Between May 2015 and January 2019, 1160 eligible and consenting women were included within the FOAM study. They underwent the two tubal patency tests in a randomized order as previously described: 576 women were allocated to undergo HyFoSy first followed by HSG, and 584 women to HSG first followed by HyFoSy. Figure 1 represents the flowchart of the women included in this secondary analysis. Flowchart of the women included in this secondary analysis. HyFoSy: hysterosalpingo-foam sonography; HSG: hysterosalpingography. Of the 576 women allocated to HyFoSy first followed by HSG, 537 women had HSG test results available for analysis. Of the 584 women allocated to HSG first followed by HyFoSy, 544 women had HSG test results available. The baseline characteristics for both groups are presented in Table 1 . No notable differences were observed. Among the women allocated to HyFoSy prior to HSG, bilateral tubal patency was visible on HSG in 467 (87%) women compared with 472 (87%) women who underwent HSG alone (risk difference 0.2%; 95% CI: −3.8% to 4.2%). Baseline characteristics of women who underwent HyFoSy prior to HSG, and women who underwent HSG alone. HyFoSy: hysterosalpingo-foam sonography; HSG: hysterosalpingography. The BMI is the weight in kilograms divided by the square of the height in metres. Data on BMI were missing for 14 women in the HyFoSy group and for 15 women in the no HyFoSy group. Data on smoking were missing for 9 women in the HyFoSy group and for 11 women in the no HyFoSy group. Data on risk for tubal pathology were missing for 68 women in the HyFoSy group and for 73 women in the no HyFoSy group. High risk for tubal pathology included Chlamydia Antibody titre, previous symptomatic Chlamydia infection (pelvic inflammatory disease), previous ectopic pregnancy or unilateral tubectomy, previous ruptured appendicitis or peritonitis, or previous pelvic surgery. Of the 584 women allocated to HSG first followed by HyFoSy, 471 women had HyFoSy test results available for analysis. Of the 576 women allocated to HyFoSy first followed by HSG, 486 women had HyFoSy results available. The baseline characteristics for both groups are presented in Table 2 . Again, no notable differences were observed. Among the women allocated to HSG prior to HyFoSy, bilateral tubal patency was visible on HyFoSy in 394 (84%) women compared with 428 (88%) women who underwent HyFoSy alone (risk difference −4.4%; 95% CI: −8.8% to 0.0%). Baseline characteristics of women who underwent HSG prior to HyFoSy, and women who underwent HyFoSy alone. HyFoSy: hysterosalpingo-foam sonography; HSG: hysterosalpingography. The BMI is the weight in kilograms divided by the square of the height in metres. Data on BMI were missing for 12 women in the HSG group and for 13 women in the no HSG group. Data on smoking were missing for 10 women in the HSG group and for 8 women in the no HSG group. Data on risk for tubal pathology were missing for 68 women in the HSG group and for 67 women in the no HSG group. High risk for tubal pathology included Chlamydia Antibody titre, previous symptomatic Chlamydia infection (pelvic inflammatory disease), previous ectopic pregnancy or unilateral tubectomy, previous ruptured appendicitis or peritonitis, or previous pelvic surgery. When considering the use of oil-based contrast during HSG, 380 women who underwent HyFoSy first followed by HSG with oil-based contrast had HSG results available, while 391 women who underwent HSG with oil-based contrast first followed by HyFoSy had HSG results available. HyFoSy prior to HSG with oil-based contrast resulted in a comparable proportion of women with bilateral tubal patency on HSG with oil-based contrast, compared to women who underwent HSG with oil-based contrast alone (329/380 (87%) vs 353/391 (90%); risk difference −3.7%; 95% CI: −8.2% to 8.1%). When considering the use of water-based contrast during HSG, 157 women who underwent HyFoSy first followed by HSG with water-based contrast had HSG results available, while 156 women who underwent HSG with water-based contrast first followed by HyFoSy had HSG results available. HyFoSy prior to HSG with water-based contrast resulted in an increased proportion of women who had bilateral tubal patency on HSG with water-based contrast, compared to women who underwent HSG with water-based contrast alone (138/157 (88%) vs 119/156 (78%); risk difference 10.1%; 95 CI: 3.2% to 20.0%). When considering the use of oil-based contrast during HSG, 330 women who underwent HSG with oil-based contrast first followed by HyFoSy had results available, while 480 women who underwent HyFoSy first followed by HSG (with either oil- or water-based contrast) had test results available. HSG with oil-based contrast prior to HyFoSy resulted in a comparable proportion of women with bilateral tubal patency on HyFoSy compared to women who underwent HyFoSy alone (283/330 (86%) vs 424/480 (88%); risk difference −2.5%; 95% CI: −7.2% to 2.2%). When considering the use of water-based contrast during HSG, 137 women who underwent HSG with water-based contrast first followed by HyFoSy had results available, while 480 women who underwent HyFoSy first followed by HSG (with either oil- or water-based contrast) had test results available. HSG with water-based contrast prior to HyFoSy resulted in a decreased proportion of women with bilateral tubal patency on HyFoSy compared to women who underwent HyFoSy alone (108/137 (79%) vs 424/480 (88%); risk difference −9.5%; 95% CI: −16.9% to −0.2%).

This is a secondary analysis of the FOAM study, a multicentre comparative study with a randomized design, conducted in The Netherlands from May 2015 to January 2019 ( van Welie et al. , 2022 ). The main objective of this study was to compare the effectiveness of clinical management strategies based on the results of tubal patency testing by either HyFoSy or HSG during the fertility work-up. The study was approved by the Institutional Review Board (IRB) of the Amsterdam UMC, location VU Medical Centre (No. 2014.454), the National Central Committee on Research involving Human Subjects (CCMO, The Netherlands; No. NL50484.029.14), and the local board of directors of the participating hospitals. The study is registered in the International Clinical Trials Registry Platform (No. NTR4746), and the study protocol has been published previously ( van Rijswijk et al. , 2018 ). Infertile women were eligible if they were aged between 18 and 41 years and scheduled for tubal patency testing. Excluded were women with: known endometriosis diagnosed on imaging (ultrasound and/or magnetic resonance imaging) or during surgery, anovulatory menstrual cycles unresponsive to ovulation induction, an allergy to iodinated contrast medium, and/or a partner (or a sperm donor) with impaired semen quality (total post washed motile sperm count <3 × 10 6 per milliliter). Upon meeting the eligibility criteria and providing consent, participating women underwent both tubal patency tests in a randomly assigned order (HyFoSy-HSG or HSG-HyFoSy). Both tubal patency tests were performed during the follicular phase of the menstrual cycle. For HyFoSy, a volume of 5 to 10 ml of echogenic foam was infused into the uterine cavity using a special catheter with cervical cannula. This foam was created by mixing 5 ml ExEm ® -gel with 5 ml sterile purified water (IQ Medical Ventures BV, Rotterdam, The Netherlands). During infusion of the foam, a transvaginal ultrasound was performed to determine the passage of the foam in the uterine cavity and through the Fallopian tubes into the abdominal cavity, indicating whether the Fallopian tubes were patent or not. During HSG, a contrast medium (oil-based or water-based, depending on local protocols of the participating hospitals) was infused into the uterine cavity using a special HSG-balloon catheter, cervical vacuum cup, or hysterophore. Approximately four to six radiographs were taken to assess patency of the Fallopian tubes, while the contrast medium was being infused into the uterine cavity. HyFoSy and HSG were performed by a gynaecologist or fertility specialist who was blinded to the results of the alternative test. The test results of HyFoSy were evaluated by the clinician who performed the procedure, while the evaluation of HSG could be done by another gynaecologist and/or radiologist. Both tubal patency tests were assessed as normal, abnormal, or not interpretable. Normal test results were defined as bilateral tubal patency visible on HSG or HyFoSy, whereas abnormal test results were defined as at least one-sided tubal obstruction (including proximal and distal occlusions). In cases where a definitive assessment of tubal patency could not be established, the results were classified as not interpretable. For this analysis, the primary outcome was the proportion of women with bilateral tubal patency visible on either HyFoSy or HSG. To evaluate the effect of 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 HyFoSy prior to their HSG and those 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 HSG prior to their HyFoSy and those who did not undergo HSG prior to their HyFoSy (HSG prior to HyFoSy versus HyFoSy alone). Effects are expressed as risk differences with 95% confidence intervals. In a subgroup analysis, the same analysis was performed considering the type of contrast medium used during HSG (oil- and water-based contrast). We used SPSS version 28.0.1.1 (IBM SPSS Statistics for Windows, 2021) for analysis.

In this secondary analysis of the multicentre randomized controlled FOAM study, we evaluated the effect of HyFoSy prior to HSG and vice versa on visible tubal patency compared to the alternative tubal patency testing method alone. We found that either HyFoSy or HSG prior to the other tubal patency testing method did not demonstrate a significant difference in visible tubal patency when compared to the alternative method alone. When considering the different types of contrast media used during HSG, we found that the use of water-based contrast during HSG was associated with less bilateral tubal patency. However, the number of women in this subgroup was relatively small and therefore we cannot exclude confounding. We used results of a large study group who were randomly allocated to first undergo HyFoSy followed by HSG, or first HSG followed by HyFoSy. Both tests were performed by different clinicians, and the clinician who performed the second test was blinded for the results of the first test and vice versa. This analysis was not included in the initial study protocol and therefore no power analysis was performed in advance. The results, though adding further data, should be interpreted as exploratory; they cannot be regarded as definitive evidence. The design of the FOAM study gave us the ability to evaluate whether undergoing either HyFoSy or HSG prior to the alternative tubal patency testing method led to a difference in the proportion of women with visible bilateral tubal patency, when compared to those undergoing the alternative method alone. It should be noted that neither HyFoSy nor HSG is the actual reference standard for the diagnosis of tubal patency. This could potentially lead to an incorrect assessment of the factual tubal status. However, the diagnostic accuracy of hysterosalpingo sonography (hysterosalpingo contrast sonography (HyCoSy) and HyFoSy) and HSG for tubal patency is reportedly high when compared to diagnostic laparoscopy with dye chromopertubation, with a sensitivity of respectively 0.95 and 0.94 and a specificity of 0.93 and 0.92 ( Maheux-Lacroix et al. , 2014 ). Furthermore, due to the design of the FOAM study, women underwent both tubal patency tests, therefore the potential direct fertility enhancing effect by tubal flushing of both methods could not be compared. We acknowledge that this study design only allowed detection of visible changes of tubal patency using ultrasound and fluoroscopy. These imaging modalities might not be able to detect more subtle yet consequential changes in tubal patency and function, for example effects on tubal mucosa and cilia. The proportion of women with uninterpretable test results was higher for HyFoSy than for HSG. This could be explained by HyFoSy being a relatively new tubal patency test. Therefore, clinicians were less experienced in performing and interpreting HyFoSy. In the FOAM study, women were not randomized for the use of oil- and water-based contrast during HSG. The type of contrast media used during HSG depended on the local protocol of the participating hospitals. Since publication of the H2Oil study in 2017 ( Dreyer et al. , 2017 ), oil-based contrast has become the most commonly used HSG contrast medium in the Netherlands ( Roest et al. , 2020 ). This resulted in a smaller number of women in the subgroup with water-based contrast during HSG, and also we cannot exclude confounding. Literature on the effect of tubal patency testing on tubal patency is limited. In a prospective observational study, 132 infertile women underwent in the following order 2D air/saline HyCoSy, 2D/3D HyFoSy, and 2D/3D high-definition flow (HDF) HyFoSy in the same menstrual cycle followed by laparoscopy with dye chromopertubation. This study found that the proportion of women with patent Fallopian tubes increased with each consecutive sonographic tubal patency test. This could imply a mechanical improvement by using each tubal patency testing method on tubal patency, although the authors attributed this higher proportion of tubal patency to the higher diagnostic accuracy of HyFoSy with the addition of HDF ( Ludwin et al. , 2017 ). This is supported by the results of a feasibility study showing that the addition of power-Doppler has increased the ability to visualize the distal part of the Fallopian tube and spill of the contrast medium into the abdominal cavity when compared to conventional HyCoSy ( Sladkevicius et al. , 2000 ). One of the hypothesis for the fertility enhancing effect of tubal flushing is dislodgment of mucus debris within the proximal part of the Fallopian tubes ( Gillespie, 1965 ). Proximal tubal occlusion by these plugs have been observed in a study of Sulak et al. (1987) . In their study, the proximal part of the tubes in women with proximal tubal occlusion on HSG were excised and studied histologically. In some of these tubes, amorphous material of unknown aetiology ‘debris plugs’ was found in the tubal lumen ( Sulak et al. , 1987 ). These debris plugs have been observed by falloposcopy as well and histological examination showed that it is composed of a mixture of endothelial cells and amorphous debris. This debris can possibly cause proximal tubal occlusion in Fallopian tubes without other anatomical abnormalities of the tubes ( Kerin et al. , 1992 ). The hypothesis of dislodgment of mucus plugs is supported by a study reporting on experienced pain during HSG in relation to pregnancy chances. Women who experienced moderate to severe pain (Score of ≥6 cm measured on the Visible Analogue Score scale) during tubal flushing with oil-based contrast by HSG had significantly higher ongoing pregnancy rates compared to women who reported a pain score <6 cm. This relation between pain score and chance of pregnancy was not found in women who underwent tubal flushing with water-based contrast. It is hypothesized that a higher intrauterine pressure, which is associated with more pain, may dislodge the debris plugs in the proximal part of the tubes and therefore enhance pregnancy chances ( van Welie et al. , 2019 ). Dessole et al. (2000) showed in a prospective study that in women with tubal occlusion after HSG with infusion of contrast medium with low pressure, the number of women with tubal patency increased if HSG was repeated after one month with high pressure infusion of the contrast medium. Our analysis showed that performing either HyFoSy or HSG prior to the other tubal patency testing method did not significantly affect visible tubal patency, when compared to performing the alternative method alone. One can imagine that, in case of obstructing plugs in the proximal part of the Fallopian tubes, these plugs may be dislodged during the first performed test, resulting in a comparable number of women with bilateral tubal patency within both groups. This suggests that both methods may have comparable abilities to dislodge tubal debris from the proximal part of the tubes. In the subgroup analysis, we found that if the type of contrast medium used during HSG was considered, the results for HSG with oil-based contrast were comparable to the results of the primary analysis. Contrarily, the use of water-based contrast during HSG seemed to negatively affect the proportion of women with bilateral tubal patency, although the number of women in this subgroup was relatively small and we cannot exclude confounding. Further studies on the mechanical and chemical differences between oil- and water-based contrast during tubal patency testing are needed. In conclusion, the performance of either HyFoSy or HSG prior to the alternative tubal patency testing method did not significantly affect visible tubal patency, when compared to the performance of the other test alone. This suggests that both methods may have comparable abilities to dislodge tubal debris or mucus plugs in the proximal part of the Fallopian tubes. It has to be noted that pregnancy outcomes were not considered in this analysis.