Three-dimensional Hysterosalpingo Contrast Sonography with Lignosal as Contrast for Evaluation of Tubal Patency in the Infertile Women – An Observational Cohort Study

INTRODUCTION

Fallopian tube factors are significantly increased and responsible for up to 25%–33% of infertile women and evaluation of tubal patency plays a key role in infertility workup.^[1] At present, several tests are available to assess the tubal patency. Although X-ray hysterosalpingography (HSG) and laparoscopic chromopertubation are regarded as gold standard techniques for diagnosing tubal patency, they have several disadvantages. X-ray HSG using oil or water-based contrast has limitations due to severe pain and carries a risk associated with iodine allergy and ionizing radiation. Laparoscopic chromopertubation evaluation with methylene blue involves a patient admission and has some risk associated with anesthesia, surgical morbidity and is also an expensive technique. Another ultrasound guided modality, hysterosalpingo contrast sonography (HyCoSy) using normal saline and air mixed as contrast (saline infusion sonography) allows the visualization of fluid and air bubbles around the ovaries while doing transvaginal ultrasonography and also a cost-effective technique; nevertheless, it is associated with severe pain, vomiting, and syncopal attacks, and problem of nonvisualization of tubes.^[2]

Three-dimensional (3D)-HyCoSy using the Echovist (Schering AG, Berlin, Germany) or Sono Vue (Bracco international BV, Amsterdam, Netherlands) as contrast agents for tubal patency is another ultrasound-guided technique, which contains a suspension of micro air bubbles in an aqueous galactose solution.^[3,4] Although 3D-HyCoSy is more accurate without many side effects for evaluation of the uterus, ovaries, and tubal occlusion, the method requires expertise in 3D technique and also Echovist and Sono Vue have limited availability due to high cost. Later, a mixture containing hydroxyl methylcellulose and glycerol as contrast (hysterosalpingo-foam sonography [HyFoSy]) was introduced for tubal patency evaluation (ExEm-gel Gynaecologiq BV, Delft, The Netherlands).^[5] Although HyFoSy was also reported as an accurate and safe procedure, non-availability and cost make it less attractive in deploying this method in routine sonography for tubal patency testing, especially in low-income countries.

In view of the limitations cited above in the evaluation of tubal patency, there is a high necessity for the development of a new contrast, which is not only as accurate as currently available contrasts but also should be cost-effective, available, and safe. This led us to develop the novel application of lignocaine (a mixture of 2% lignocaine jelly in normal saline, hereafter referred to as lignosal) as a new ultrasound contrast in HyCoSy procedure. The study was planned with the following objectives: (1) To evaluate the feasibility and reliability of two-dimensional (2D)/3D-HyCoSy using lignosal as contrast agent for assessing fallopian tubal patency in comparison with the X-ray HSG and (2) to further study the HyCoSy using lignosal as a routine technique for the evaluation of tubal patency in a large group of infertile female patients in a prospective observational setting.

MATERIALS AND METHODS

Study design

This prospective nonrandomized observational single-center study was performed at Shilpa Scan Center, a referral scan center at Palakollu, Andhra Pradesh state, in rural India. The present study was designed to execute in two phases. The first phase of the study (n: 20) involves the comparison of the diagnostic efficacy of 2D-HyCoSy using lignosal with X-ray HSG for the standardization and feasibility of the technique for tubal patency evaluation. In the second phase of the study (n: 548), primary and secondary infertile women who were a part of infertility evaluation to undergo timed intercourse or intrauterine insemination were studied to evaluate the beneficial effects of the lignosal as contrast media (Figure 1). Pain episodes, adverse reactions, and clinical pregnancy rate were also recorded. The study protocol was approved by the Institutional Review Board. All the patients were informed about the study objectives, and written consent was obtained from every patient before the start of the study. This study was conducted according to the Declaration of Helsinki for medical research, and approved by the local area ethics committee.

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Figure 1

Flow diagram depicting the plan of the study. (HyCoSy: Hysterosalpingo contrast sonography, HSG: Hysterosalpingography).

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RESULTS

Demographic characteristics of patients

The mean average age of the patient was 25.96 ± 4.42 years and the average duration of subfertility was 5.20 ± 3.75 years with the mean body mass index of 21.83 ± 2.10. Out of the total 520 patients, 320 were with primary infertility and 200 patients with secondary infertility which includes 11 patients with unilateral post salpingectomy done for previous ectopic, and 12 patients underwent recanalization, and two patients had ectopic, managed with methotrexate. Out of 520 female patients 65 have small single to multiple fibroids, 34 patients were amenorrheic, 23 patients with adenomyosis, unilateral or bilateral small chocolate cysts were found in 30 patients, unilateral hydrosalpinx in 26 patients, one patient with chronic pelvic kochs, 26 patients with uterine malformations, and 27 patients with ovarian cysts including 14 dermoid cysts were identified. Of the total sample, 280 subjects were from low socioeconomic status (Table 2).

Table 2 Demographic characteristics of the study population of 520 women undergoing 3D-HyCoSy with lignosal

Parameters	Total (n = 520)
Age (years)	25.96±4.42
BMI	21.83±2.10
ML (years)	5.20±3.75
Primary infertility (%)	320 (61.53)
Secondary infertility (%)	200 (38.46)
Female factor
Uterine fibroids (%)	65 (12.50)
Irregular menstruation (%)	34 (6.53)
Adenomyosis (%)	23 (4.42)
Hydrosalpinx (%)	26 (5)
Stenosis (%)	53 (10.19)
PCOS (%)	55 (10.57)
Chocolate cysts (%)	30 (5.76)
Ovarian cysts (%)	27 (5.19)
Uterine malformations (%)	26 (5)
Uterine polyps (%)	15 (2.88)
Tubal patency
Patency (%)	463 (89.03)
Unilateral occlusion (%)	49 (9.42)
Bilateral occlusion (%)	8 (1.53)

BMI: Body mass index, 3D: Three-dimensional, HyCoSy: Hysterosalpingo contrast sonography, PCOS: Polycystic ovary syndrome

A combined 2D- and the 3D-Hycosy approach with lignosal contrast medium was followed in 520 patients as a 2D only HyCoSy imaging in 25 out 520 patients failed to see the tubes and spill. Nevertheless, with 3D imaging, tubes, as well as a spill, were seen in 20 out of 25 patients, whereas in 5 patients 3D-HyCoSy failed to detect the pathology and further HSG examination showed bilateral patency in these five patients. Out of total 520 patients, with combined 2D- and 3D-HyCoSy, 463 patients were found with patent tubes, eight patients with the bilateral tubal block and 49 patients with unilateral blocks were diagnosed (Table 2, Figure 2 and Figure 3). Further, 76 patients reported a clinical pregnancy within 2–6 months after the HyCoSy procedure was performed with lignosal.

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Figure 2

(a) A 25-year-old women with 6 years of infertility. Two-dimensional hysterosalpingo contrast sonography (HyCoSy) with lignosal contrast showed both tubes as echogenic and spill from fimbrial ends as a shower suggests, bilateral tubal patency. (b) The three-dimensional HyCoSy image of the same patient (25-year-old women with 6 years of infertility) shows both tubes and fimbrial ends.

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Figure 3

(a) A 32-year-old lady with 13 years of infertility. H/o right salpingectomy for previous ectopic pregnancy. Two-dimensional hysterosalpingo contrast sonography (HyCoSy) with lignosal shows nonvisualization of both tubes and spill suggests a bilateral proximal block. (b) Three-dimensional HyCoSy of the same patient shows nonvisualization of both tubes (bilateral proximal block).

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DISCUSSION

Tubal patency testing constitutes the major part of the tubal infertility management as the tubal disease has a wide spectrum of pathologies, such as obstruction, stenosis, dilatation, and altered peristaltic function, which occurs as a result of changes in the anatomy of fallopian tubes by conditions such as salpingitis, adenomyosis, or any surgical procedures.^[7-9] Several of the techniques such as lap-and-dye, though gold standard investigation, do not allow internal assessment of the tube and also carries a risk of morbidity and mortality. HSG considered being a traditional method; however, its application is limited due to iodine allergy and ionizing radiation. With the introduction of HyCoSy, it is now possible to have a real-time assessment of pelvic organs, ovaries, and myometrium. In the present prospective observational setting, we used the 3D-HyCoSy and this is the first of its kind largest study to evaluate the efficacy of lignosal (lignocaine 0.2% jelly with normal saline) as a contrast medium in HyCoSy for testing tubal patency.

Plan to employ 3D-HyCoSy technology in the present study for the evaluation of tubal patency was supported by a previous systematic review which reported a high diagnostic accuracy with 3D-HyCoSy with 98% sensitivity and 90% specificity.^[10] 3D volume imaging makes the possibility of complete visualization of entire length fallopian tubes, and this alleviates the false patency results which otherwise may found with the 2D-HyCoSy acquisition in convoluted tubes. In the present study, HyCoSy with lignosal contrast detected tubal patency in 95% of the tubes and radiographic HSG has shown 97.5% tubal patency with 5% inconclusive results by HyCoSy. These results were in agreement with earlier studies where the saline HyCoSy and HSG had similar sensitivity, specificity, and diagnostic predictive values in the diagnosis of tubal patency.^[11,12] In the present study, data from 520 patients showed bilateral tubal patency in 463 patients (89.03%), unilateral tubal occlusion in 49 patients (9.42%), and bilateral tubal occlusion in eight patients (1.53%). In one of the earlier studies with HSG, performed as part of routine infertility evaluation in a group of 494 women, the bilateral proximal tubal obstruction was observed in 3% of cases, and unilateral obstruction was seen in 2% of the cases.^[13] Data from a total of 272 HSG studies by Bukar et al. revealed a unilateral tubal block in 8.5% of women and the bilateral block in 6.3% women.^[14] The variations observed between the present study and previous reports might be due to criteria followed in the intake of subjects during the study settings (age, inclusion, and exclusion of patients with pelvic infections, endometriosis, and fibroids, etc.) and changes in general patient health conditions over time. The concordance rate of 95% observed in the present pilot study between the results of 2D-HyCoSy and HSG. A meta-analysis of three comparative studies of Echovist-200, (solution of galactose and 1% palmitic acid [Echovist-Schering-AG, Germany]) including 1007 women showed that the results of HyCoSy and HSG were identical in 138 of 202 patients (68.3%) or 320 of 384 individual. In our study, a discordant rate of 2.5% (1/40 tubes) was observed between HyCoSy and HSG. The failure of detection of an occluded tube by HyCoSy might not entirely due to the technique as false results can occur with HSG as well as with lap-and-dye, which is not a perfect gold standard and is also susceptible to false occlusion results.^[7,15,16]

During the HyCoSy procedure, foleys 8f catheter with steel stylet to facilitate easy insertion of the soft catheter into the uterine cavity was used. Using real-time ultrasound imaging, the passage of echogenic foam through the patent tubes was seen as echogenic from the interstitial portion up to fimbrial ends and spill was visualized as a shower into the peritoneal cavity. In case of the myometrial spasm at the cornual end, the passage of contrast from the interstitial portion was delayed for 2–3 mts. Therefore, in some cases, a waiting period was necessary to visualize the flow. It must be noted that a positive HyCoSy result is conclusive. With the addition of 3D rendering an increased diagnostic accuracy was observed, when compared to only 2D-HyCoSy. If tubal patency cannot be demonstrated, it could be due to the real tubal block or temporary tubal block and due to the myometrial spasm or presence of mucus plugs at the proximal end.

In the first-ever report on gel instillation sonohysterography by Exalto et al., a sterile gel preparation containing hydroxyethyl cellulose, glycerol, lidocaine (2%), and chlorhexidine was used.^[17] However, the study did not report the role of the presence of lidocaine (2%) in the gel with regard to echogenicity and study involved direct installation of the gel with intrauterine canula without further dilution. In the present study, we observed a stable microbubble formation (5 min) with a much lower concentration of lignocaine (0.2%) for sonographic examination of tubal patency. Lignocaine, 2% jelly, is already being used as an intrauterine local anesthetic in hysteroscopic procedures, and large quantities of the intraperitoneal lignocaine infusion mixed with saline are being used without any side effects for the relief of pain in post-operative laparoscopic procedures. Lignocaine, 2% jelly, approved by the FDA is a sterile aqueous product which contains methylparaben, propylparaben, hypromellose as preservatives, and available as sterile preparation. Gel also contains sodium hydrochloride to maintain the pH value to 6–7. The effects of lignocaine on fertility were examined in rat mates. The sperm parameters were found to be harmless on either fertility in females or sperm parameters in the male. Gel preparations containing lidocaine and chlorhexidine as an intrauterine, local, and topical anesthetic were used for pain relief during various diagnostic and therapeutic procedures by several authors; however, no demonstrable benefit for the reduction of pain was reported.^[18] Since the usage of gel in the present study is limited to small amounts in diluted state (0.2%) in our HyCoSy procedure, no cases of peritoneal irritation were observed and a previous study by Rousseau et al. reported a minimal systemic absorption of lidocaine after the intrauterine administration of lidocaine gel as esthetic even by direct application after endometrial ablation.^[19] Moreover, lignocaine gel up to 10% w/w was reported to be safe for vaginal, intrauterine, and intraperitoneal applications.^[20] Apart from its central nervous system action properties, lidocaine is also administered as an intravenous infusion for its antiarrhythmic properties. This warrants the heightened attention for systemic safety during the local administration. In a study by Martell et al., the pharmacokinetic data revealed that the peak lidocaine concentration that was observed after a 10% local lidocaine administration for vaginal application was 10–20-fold lower than the concentrations required for the antiarrhythmic regimen.^[21] Therefore, with the dose employed in the present study (0.2%) the safety margin is still wider, and there would be of an extremely low chance for systemic toxicity.

Mild pain was reported by some patients and was relieved by administering simple analgesics. No major complications were recorded. No infection was noted in any case. No syncopal attacks were observed. This study illustrates both the feasibility and accuracy of 3D HyCoSy with lignosal contrast (0.2% Lignocaine) in the diagnosis of tubal patency when compared to X-ray HSG. This technique employing lignocaine as contrast was proved to be the most efficient and safe outpatient procedure in present prospective observational study conditions.

CONCLUSION

This study illustrates the novel application of lignocaine (0.2%) as a sonography contrast medium. We infer from the present data that the 3D-HyCoSy with lignosal procedure shall be a good alternative when compared to other modalities which are currently available for sonographic evaluation of tubal patency as lignosal contrast found to be a safe, reliable, accurate, and simple outpatient procedure due to ease of accessibility, cost-effectiveness, and moreover may also reduces the pain associated with the procedure.