Foam ultrasound, also called hystero-salpingo-foam sonography (HyFoSy), and Hystero-salpingo-contrast sonography (HyCoSy), is an alternative diagnostic tool for checking tubal patency. Foam ultrasound is increasingly used as diagnostic test and seems to be less painful than hysterosalpingography (HSG). In this PICO we investigate reliability (diagnostic value) of HyFoSy (foam ultrasound) compared to HSG. Moreover, side effects and chance of spontaneous pregnancy are investigated.

Population: Women from sub fertile couples at low risk for tubal pathology

Intervention: foam ultrasound

Comparator: HSG

_{1. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias; Imprecision: very serious. Only data from one study with few patients and few to zero events;}

_{2. Risk of Bias: serious. No information provided on how and if assessors and participants were blinded; Imprecision: very serious. Data from only one study with few patients and few events;}

_{3. Risk of Bias: very serious. Inadequate sequence generation/ generation of comparable groups, resulting in potential for selection bias, Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, Incomplete data and/or large loss to follow up, Inadequate sequence generation/ generation of comparable groups, resulting in potential for selection bias; Inconsistency: serious.  The magnitude of statistical heterogeneity was high, with I^2:89 %.; Imprecision: very serious. due to recalculating the mean (SD) and a lack of subgroup analysis in a cross-over design;}

_{4. Risk of Bias: very serious. due to many areas of the Risk of bias and applicability concerns based on QUADAS-2 being labeled as unclear.;}

_{5. Risk of Bias: very serious. due to many areas of the Risk of bias and applicability concerns based on QUADAS-2 being labeled as unclear.;} 

_{6. Risk of Bias: serious. Inadequate sequence generation/ generation of comparable groups, resulting in potential for selection bias, Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias; Inconsistency: serious. due to not being able to pool the studies; Imprecision: very serious. Low number of patients and low number of events.}

Description of studies

A total of five studies were included in the analysis of the literature. Important study characteristics and results are summarized in table 1. The assessment of the risk of bias is summarized in the risk of bias tables (under the tab ‘Evidence tabellen’).

Maheux-Lacroix (2014) performed a systematic review with meta-analysis on the accuracy of hysterosalpingosonography (sono-HSG), representing foam ultrasound, for diagnosing tubal occlusion in subfertile women and how it performs compared with hysterosalpingography (HSG). The systematic review did not provide information about whether a CAT was performed among patients in the included studies. In nine studies representing 582 women and 1055 tubes, all participants underwent HSG in addition to sono-HSG and laparoscopy, allowing direct comparison of the accuracy of sono-HSG and HSG. Studies were searched in Medline, Embase, Cochrane Library and the Web of Science from inception to 14 November 2012. Biosis was used to identify relevant abstracts and conference proceedings. Only studies using exclusively laparoscopy as reference standard were included.

Van Welie (2022) conducted a multicenter, prospective, comparative noninferiority trial of hysterosalpingo-foam sonography (HyFoSy) versus hysterosalpingography (HSG), with randomization of couples with discordant test results. Women included in this study were infertile, between 18 and 41 years and scheduled for tubal patency testing during their fertility work-up. All women underwent both tubal patency tests in a randomized order. Of the 1160 consenting women that were assigned to undergo the two tubal patency tests, 1026 received both tests and were included in the analysis. The sample included patients with high- and low risk for tubal pathology. Data regarding risk for tubal pathology was available for 888 women, of whom 135 (15%) had a high risk.

Dreyer (2014) conducted a two-center, prospective, open-label, randomized, controlled trial comparing tubal testing by HyFoSy versus HSG. Inclusion criteria were women aged 18 – 41 years who had a valid indication for tubal patency testing as part of their fertility workup according to the Dutch NVOG guidelines. Women with a high risk for tubal pathology were excluded. In total, 40 women were enrolled in the study and randomized to receive either the HyFoSy procedure or the HSG. No form of premedication was given before tubal patency testing.

Serrano González (2022) conducted a prospective multicenter study with the consecutive data of 210 women. The inclusion criteria were women aged 18–40 years undergoing assisted reproduction that required a tubal patency test, including women with a male partner and a history of sterility/ infertility (have not achieved ongoing pregnancy leading to live birth after at least a year of attempt), women with a female partner and single women who wished to become pregnant. Patients were premedicated with oral azithromycin (1 g) the night before the test, and with a step 1 WHO Pain Ladder drug (Aneker, 2021) 1 h before the test. Among the study population were patients with medical history related to the internal genital tract (0% versus 8.4% in the HSG and HyFoSy group respectively). Previous abdominopelvic surgery was reported in both groups (26.8% versus 36.5% in the HSG and HyFoSy group respectively).

Maxim (2021) conducted a prospective, intervention case-control study. Inclusion criteria were: female patients aged between 18-40 years with a history of infertility, previously uninvestigated for uterine or tubal anomalies, presenting to the fertility center for an initial diagnostic work-up. Whether patients were tested for chlamydia antibodies was not reported. A total of 56 patients were randomized. Women in both groups did not receive any pain medication before undergoing the procedure and no antibiotic therapy was

prescribed.

Table 1. Characteristics of included studies

_{*For further details, see risk of bias table in the appendix}

_{† For the studies included in the systematic review of Maheux-Lacroix (2014) the RoB is based on the risk of bias and applicability concerns of the studies based on QUADAS-2 presented in the supplementary data of the systematic review. When ≥ 3 of the areas were labeled as unclear, the overall RoB was unclear.} 

_{VAS: Visual Analogue Scale}

Results

(Diagnostic accuracy of) unilateral or bilateral tubal pathology – Critical outcome

All studies reported on the outcome (Diagnostic accuracy of) unilateral or bilateral tubal pathology. This outcome is split into diagnostic accuracy and the detection of tubal pathology.

Diagnostic accuracy (sensitivity and specificity)

The systematic review of Maheux-Lacroix (2014) compared the diagnostic accuracy between sono-HSG and HSG and found no statistically significant differences between the two techniques (p=0.4). The laparoscopy was used as a reference test. For sono-HSG, pooled estimates of sensitivity and specificity were 0.95 (95% CI: 0.78–0.99) and 0.93 (95% CI: 0.89–0.96), respectively. For HSG, pooled estimates of sensitivity and specificity were 0.94 (95% CI: 0.74–0.99) and 0.92 (95% CI: 0.87–0.95), respectively. The differences between the estimated sensitivity and specificity between HSG and sono-HSG were not clinically relevant. There is no mention of inconclusive test results for either sono-HSG or HSG.

Detection of tubal pathology

Four studies reported the outcome detection of tubal pathology, without using a reference test (van Welie (2022); Dreyer (2014); Serrano González (2022); Maxim (2021)). We only report the amount of tubal pathologies detected per studies. There is no certainty whether a higher detection rate of tubal pathology also means a better diagnostic accuracy since, due to the lack of a reference test, no information was provided on the amount of false positive and false negative test results. Overall, there seems to be no large difference in the detection of tubal pathology when comparing the foam ultrasound to HSG.

Van Welie (2022) compared the results between HyFoSy and HSG. Of the 1026 women that underwent HyFoSy, 129 (13%) had a test result of tubal pathology, either one-sided tubal pathology (n=90, 9%) or double-sided tubal pathology (n=39, 4%). Of the 1026 women that underwent HSG, 134 (13%) had a test result of tubal pathology, either one-sided tubal pathology (n=104, 10%) or double-sided tubal pathology (n=28, 3%). The proportion of women with one-or dual-sided pathology was comparable (13% vs. 13%).

Dreyer (2014) reported the outcome conclusion after tubal testing which had four levels: both tubes patent, unilateral proximal occlusion, bilateral proximal occlusion or other. Two of the 19 (11%) women that underwent HyFoSy appeared to have a unilateral proximal occlusion compared to 1 of the 20 (5%) women that underwent HSG. None of the 19 women that underwent HyFoSy appeared to have a bilateral proximal occlusion compared to 1 of the 20 (5%) women that underwent HSG.

Serrano González (2022) reported the results for tubal patency. Bilateral obstruction was found in 8 of the 107 (7.5%) women in the HyFoSy group and in 3 of the 82 (3.7%) women in the HSG group (p = 0.267).

Maxim (2021) reported the unilateral and bilateral obstruction in the study groups. Three of the 29 (10.3%) women in the HyCoSy and 3 of the 27 (11.1%) women in the HSG had an unilateral obstruction (p=1), whereas 2 of the 29 (6.9%) women in the HyCoSy and 5 of the 27 (18.5%) women in the HSG had a bilateral obstruction (p=0.2).

Chance of spontaneous pregnancy – important outcome

Dreyer (2014) reported the prognostic chance in percentage on natural conception during 12 months following the tubal pathology test. This chance on natural conception was 34.3% (IQR 18.8) in women who underwent HyFoSy (based on 16 patients) and 32.3% (IQR 19.2) in women who underwent HSG (based on 12 patients) (p=0.60).

Side effects – important outcome

Maxim (2021) reported the side-effects in both treatments. In the HSG group, 4 of the 27 (14.8%) women reported a vagal effect compared to none of the women in the HyCoSy group of 29 women (p < 0.001). This difference is not considered clinically relevant.    

Pain – Important outcome

Four of the five studies reported on the outcome pain. All studies used a pain score measured using the 1 – 10 Visual Analogue Scale (VAS), as scoring system with a range from 1 (‘no pain’) to 10 (‘pain as bad as it could possibly be’). 

In the study by Van Welie (2022) VAS pain scores for HyFoSy were reported by 1003 of the 1026 women (98%) and VAS scores for HSG were reported by 953 of the 1026 women (93%). The mean VAS pain score for HyFoSy was 3.1 (SD 2.2) and the mean VAS score for HSG was 5.4 (SD 2.5). Although the mean VAS pain score of HyFoSy was not affected by the order of the tests (P = 0.57), the mean VAS pain score of HSG was higher when it was administered first, before HyFoSy (P = 0.01). Dreyer (2014) reported a lower VAS pain score for the HyFoSy procedure (median 1.7 cm IQR 2.1) compared with HSG (median 3.7 cm IQR 4.2) (P<0.01).  Serrano González (2022) reported a significantly lower median VAS in the HyFoSy group (2 (P25; P75: 1; 3)) compared to the HSG group (5 (4; 8)) (p < 0.001).  Maxim (2021) also reported a lower VAS score for the HyCoSy group (median: 1; P25: 1, P75: 2) compared with HSG (median: 5; P25: 4; P75: 6) (P<0.001).

All outcomes were recalculated to their mean (SD) and the pooled together, see figure 1. The mean difference in the pain score between foam ultrasound and HSG is -2.99 (95% -3.93 to -2.04). The difference in pain score between the foam ultrasound and the HSG is considered clinically relevant.

Figure 1. Forest plot of the mean difference in reported pain score in women undergoing diagnosis for tubal pathology using foam ultrasound or HSG

_{^a For Dreyer (2014), Maxim (2021), and Serrano González (2022), the mean (SD) was calculated using the reported median (IQR) or median (P25;P75)}

_{^b For van Welie (2022), patients that reported their VAS pain scores are taken into this analysis twice since they received both interventions in a randomized order}

A systematic review of the literature was performed to answer the following question(s):

What is the value of foam ultrasound in comparison to HSG in terms of diagnosing tubal pathology, complications of treatment and chance of spontaneous pregnancy?

Relevant outcome measures

The guideline panel considered diagnostic accuracy of tubal pathology as a critical outcome measure for decision making; and chance of spontaneous pregnancy, risk of miscarriage, ectopic pregnancy, side effects, pain, and costs as an important outcome measure for decision making.

A priori, the guideline panel did not define the outcome measures but used the definitions used in the studies.

The guideline panel defined a 25% difference (RR < 0.8 or > 1.25) for dichotomous outcomes and 0.5 SD for continuous outcomes as a minimal clinically (patient) important difference. A 2-point difference on the 10-point Visual Analogue Scale (VAS) pain scale was considered as a minimal clinically (patient) important difference

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from 2011 until March 13, 2024. The detailed search strategy is listed under the tab ‘Literature search strategy’. The systematic literature search resulted in 299 hits. Studies were selected based on the following criteria: studies reporting original data, systematic reviews and RCTs on foam ultrasound. Thirty-three studies were initially selected based on title and abstract screening. After reading the full text, twenty-eight studies were excluded (see the exclusion table under the tab ‘Appendices’), and five studies were included.