Hysterosalpingo-Foam Sonography to Replace HSG in Evaluating Tubal Patency in Indonesian Subfertile Patients

Aim: To evaluate whether hysterosalpingo-foam sonography (HyFoSy) can replace HSG as first-line evaluation for tubal patency in subfertile Indonesian patients by evaluating agreement level and comparing patients’ subjective complaints. Methods: Twenty subfertile female patients at Cipto Mangunkusumo Central General Referral Hospital (RSCM) from January 2018 to January 2019 were recruited conveniently to undergo both HSG and subsequent two-dimensional transvaginal HyFoSy after a minimum interval of 48 hours. Data on tubal patency and side effects inflicted by each examination within 24 hours were collected. Results: There were 20 subjects enrolled in this study. In 2 subjects, stenosis of internal uterine ostium was identified on HyFoSy procedure. Out of 36 remaining tubes undergoing adequate tubal patency evaluation by HSG and HyFoSy, agreement was seen in 81% cases (kappa value 0.42). The discordant tubal evaluation results in 7 of 36 tubes were associated with partial tubal obstruction, presence of co-existing gynae-cological pathology, and tubal spasm. Less pain (p < 0.001) was experienced in HyFoSy as compared to HSG, with mean VAS of 1.8 ± 1.4 cm and 5.4 ± 2.4 cm, respectively. Seven of 20 patients experienced side effects due to HSG, such as abdominal cramp, spotting, backache, and bloating, in contrast to only one subject experiencing spotting due to HyFoSy. There was no hypersensitivity reaction observed in all subjects during HSG and HyFoSy procedure. Conclusions: HyFoSy has shown an excellent acceptance in Indonesian patients and could be a good alternative to replace HSG as a first line tubal patency examination. https://doi.org/10.4236/ojog.2020.10100129


Introduction
Approximately 15% of couples suffered from subfertility, 40% of which were attributed to tubal factor in developing countries [1] [2] necessitating a feasible and well-tolerated tubal patency examination across the geographically scattered islands in Indonesia for easier and earlier access to subfertility treatment. An emerging non-invasive and bedside tubal patency examination with superior diagnostic value and patient's satisfaction as compared to HSG, known as hysterosalpingo-foam sonography (HyFoSy), has been initiated in Indonesia at Ciptomangunkusumo Central General Referral Hospital (RSCM) since 2018. Ludwin et al. described that HyFoSy has a sensitivity of 87% and specificity of 94% [3], which was higher than HSG that had a sensitivity of 63% and specificity of 89% [4]. Zizolfi et al. in Italy performed a concordance study between HyFoSy and HSG that was performed on 50 women who had undergone hysteroscopic Essure microinsert placement and found a concordance rate of 100% [5].
Another study by Dreyer et al. in the Netherlands showed a 97.4% concordance between HyFoSy and HSG in evaluating tubal occlusion in 26 women undergoing Essure placement due to hydrosalpinx before in vitro fertilization [6].
Standard HSG examination for tubal patency has several drawbacks in patient's perspective, among others is pain during and after procedure, allergy to contrast agent, side effects, and the lengthy procedure of arranging appointment to the radiology department and returning the HSG result to the gynecologist on the multiple visits. Meanwhile, HyFoSy offers an instant tubal patency result in an approximately 5-minute bedside procedure requiring only a two-dimensional (2D) transvaginal ultrasonography and the ExEm-foam kit consisting of hydroxyethylcellulose-glycerol gel and its cervical cannula. Tolerance study that was performed by Dreyer et al. in 2015 in the Netherlands to compare the pain experienced during HyFoSy in comparison to HSG found a significantly lower pain score for HyFoSy with median VAS score of 2.0 cm compared to HSG with median VAS score of 5.1 cm [6].
To the best of our knowledge, this study was the first implementation of Hy-FoSy in Indonesian population. Although HyFoSy had shown an excellent acceptance in Caucasian patients [6] [7] [8], there was yet a tolerance study on Indonesian population. Considering the possible effect of ethnicity on patients' tolerance, as already exemplified on the frequency of carbamazepine-induced Steven-Johnson syndrome/toxic epidermal necrolysis that was only 5% -6% in Europe in contrast to 25% -33% in Taiwan [9] [10], therefore this study on Indonesian population was necessary to prove the safety and acceptability of HyFoSy procedure in Indonesian patients. The aim of this study was to evaluate whether HyFoSy can replace HSG as a first-line evaluation for tubal patency in subfertile Indonesian patients by evaluating their agreement rate and patients' tolerance level.

Methods
This concordance study was conducted prospectively in RSCM from January Open Journal of Obstetrics and Gynecology 2018 to January 2019 . Inclusion criteria were all subfertile patients with stable   hemodynamic at the outpatient clinic, while exclusion criteria were patients with   cervical neoplasm, Mullerian agenesis, and impaired kidney function. A total of   20 subfertile Indonesian women were recruited conveniently and underwent both HSG and subsequent HyFoSy after a minimum interval of 48 hours. Data on side effects inflicted by each examination within 24 hours was collected by interview. The secondary outcome measures included pain experienced during HyFoSy and HSG, measured by Visual Analogue Scale (VAS) scores (1 -10 cm), as well as nominal data on subjective complaints experienced by the subjects within 24 hours since the initiation of the procedure.
While the HSG procedures were performed in one appointed radiology installation with a standard procedure of passing radio-opaque dye from the cer-

Results
Between January 2018 and January 2019, twenty subfertile Indonesian females were examined with HSG and subsequent HyFoSy to demonstrate tubal patency.
The mean age of patients was 33.5 ± 6.0 years with a mean subfertility duration of 4.0 ± 3.6 years. Of the 20 included subjects, one patient was categorised as secondary subfertility and five patients admitted dysmenorrhea (Table 1).
All women underwent HSG followed by HyFoSy after a minimum interval of 48 hours. Of the 20 women having undergone adequate tubal evaluation by HSG, 2 women showed internal uterine ostium stenosis during HyFoSy that voided tubal patency evaluation from these 2 HyFoSy procedures ( Figure 2).
Hence, only 36 of 40 tubes were included in the agreement analysis.  Table 2).
Discrepancy of tubal patency results between HSG and HyFoSy was seen in 7 of 36 tubes. Five of which were patent according to HSG, but the tubal patency result during HyFoSy described otherwise. Meanwhile, 2 tubes were showing occlusion during HSG, but were found to be patent during HyFoSy examination.
Patients were asked to rate the worst pain experienced within 24 hours following HSG and HyFoSy procedure using the VAS score, with 0 corresponding to no pain and 10 corresponding to maximum pain. The VAS score was significantly lower in HyFoSy compared to HSG, with mean VAS score of 1.8 ± 1.4 and 5.4 ± 2.4 (p < 0.001), respectively (Table 3).

Discussion
To the best of our knowledge, this is the first study in Indonesian population HyFoSy was obstruction by extra tubal mass. In Figure 4, the presence of adenomyosis obstructed the flow of foam through the interstitial part of the Fallopian tube during HyFoSy, yet the higher contrast infusion pressure in HSG could overcame the resistance caused by the extra tubal adenomyosis and created peritoneal spill that was interpreted as patent tube while overlooking the presence of the radiolucent adenomyosis. Considering that the physiologic transport of gametes within the fallopian tube was not augmented by external pressure [14], therefore the patency described by the HSG in this case could be regarded as a false negative result. Standing on another point of view, HSG could be a testing modality to predict whether removal of an adjacent obstructing mass would return the patency of an obstructed tube.
In this study, the 2 cases of occluded tubes according to HSG that were shown patent by HyFoSy comprised of 1 proximal occlusion and 1 distal occlusion.
Proximal tubal occlusion had been previously described to have a false positive rate of 39% due to tubal spasm [15]. Therefore, the case of proximal tubal occlusion, seen as the absence of contrast filling beyond the interstitial part during HSG ( Figure 5) that was seen patent in HyFoSy, was likely due to tubal spasm.
Meanwhile, the case of distal occlusion observed in the discordant case was caused by the displacement of the Fallopian tube to the lateral side due to an undetected radiolucent large leiomyoma, hence no contrast spill was seen spreading to the pelvic floor during HSG examination. Interestingly, the leiomyoma could be clearly seen during HyFoSy procedure and the hyperechoic foam could be tracked flowing from the uterine cavity, passing through the interstitial part of the Fallopian tube, and filling the whole Fallopian tube along the perimeter of the leiomyoma until it spilled to the peritoneal cavity ( Figure 6).    [16]. During HyFoSy procedure, the foam could not pass the narrowed internal uterine ostium because the type of cervical cannula provided in the ExEm foam kit was flexible cannula and was not assisted by tenaculum. In comparison, HSG procedure employed a metallic cervical cannula that was fixated by tenaculum. Therefore, the cervical cannula in HyFoSy would bend instead of forcing through upon meeting resistance. In contrast, the metallic cervical cannula used in HSG may exert blunt force that, though more traumatic, may provide benefit by mechanically dilating a pre-existing stenosis of internal uterine ostium.
Considering that HyFoSy had similar procedure to HSG in terms of creating distension of the uterine cavity, therefore the anticipated side effects due to both procedures would both encompass possibility of vasovagal reaction and pain.
This study found a significantly less pain (p < 0.001) due to HyFoSy with VAS score of 1 psychological factor of expecting pain in the subsequent procedure [17]. In regard to possible therapeutic effect of conventional HSG that may have altered the findings on HyFoSy, the studies on the effect of tubal flushing with HSG to increase live birth rate had a low quality of evidence [18]. Therefore, conventional HSG was not likely to have altered the findings on HyFoSy in our study.
Chou Phay Lim et al. argued that HSG was out of date and had no place in modern infertility work up in the emergence of newer tubal patency examinations [19]. As seen in this study, HyFoSy had better patient's tolerance with moderate agreement to HSG while avoiding radiation exposure, omitting the need of fluoroscopy instrument and shortening the diagnostic time by deducting liaison with radiology department. Yet, this study had also shown that HSG may be a better option to evaluate tubal patency in the presence of stenosis of internal uterine ostium. HSG also allowed comparison of contrast spill with the contralateral side in conjunction with the difference in contrast infusion pressure needed that would be useful to distinguish patent but diseased tubes with high risk for ectopic pregnancy. Furthermore, HyFoSy could offer a wider utility beyond dichotomizing between a patent tube and an occluded tube. As seen from this study, when HyFoSy was complemented with the higher contrast infusion pressure of HSG, it could distinguish a candidate that might benefit from removal of obstructing extra tubal mass.
A challenge in the dissemination of the practice of 2D-HyFoSy in Indonesia would be the necessity to climb the learning curve. Ranaweera et al. had suggested a shallow learning curve for a person with experience in transvaginal ultrasound to achieve confidence in performing saline sonographic hydrotubation after 5 -10 cases [20]. Considering that the foam in HyFoSy can visualise Fallopian tube far longer than saline, therefore a similar learning curve threshold of 5 to 10 cases would be adequate to achieve confidence in performing HyFoSy.

Conclusion
HyFoSy had a moderate agreement of 81% (kappa value of 0.42) to HSG and had a better patient's tolerance as compared to HSG in Indonesian population.
Hence, HyFoSy is a potentially more preferable alternative as a first line tubal patency evaluation in subfertile Indonesian patients.