Comparative analysis of hysterosalpingography and hysterosalpingo-contrast sonography for assessing tubal patency in women with endometriosis-related infertility: a propensity score-matched study

Purpose This study aimed to compare the clinical pregnancy rates of hysterosalpingography (HSG) with water-based contrast and hysterosalpingo-contrast sonography (HyCoSy) to investigate their impact on fertility outcomes in women with endometriosis-related infertility.

This retrospective study included 296 women with endometriosis-related infertility, aged 18–39, undergoing HSG or HyCoSy at the First Affiliated Hospital of Guangxi Medical University (January 2020–June 2022). Propensity score matching was applied to balance demographic and clinical variables. Clinical pregnancy outcomes were compared between the groups.

The HSG group showed a higher clinical pregnancy rates compared to the HyCoSy group. Logistic regression demonstrated an odds ratio (OR) of 0.41 (95% CI 0.20–0.82, p < 0.001) for clinical pregnancy in the HyCoSy group compared to HSG. After propensity score matching, the OR was 0.37 (95% CI 0.18–0.75). Similar results were observed across multivariable and IPTW analyses, suggesting that HSG may be associated with better clinical pregnancy outcomes than HyCoSy.

Hysterosalpingography (HSG) with water-based contrast appears to be associated with higher clinical pregnancy rates compared to HyCoSy in women with endometriosis-related infertility. This suggests that HSG may be a more favorable diagnostic method for optimizing fertility outcomes, though further research is needed to confirm these findings.

Hysterosalpingography (HSG) · Hysterosalpingo-contrast sonography (HyCoSy) · Fertility outcomes · Endometriosis-related infertility · Propensity score matching (PSM) * Aiping Qin [email protected] 1 Center of Reproductive Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China 2 Gynecology Department, The Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning, China 3 Center for Reproductive Medicine, Maternal and Child Health Hospital in Guangxi, Guangxi 530021, China 4 Department of Obstetrics and Gynecology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China What does this study add to the clinical work This study suggests that hysterosalpingography (HSG) with water-based contrast appears to improve clinical pregnancy rates compared to hysterosalpingo-contrast sonography (HyCoSy) in women with endometriosis-related infertility. It highlights the importance of selecting diagnostic

that not only evaluate tubal patency but also help improve fertility outcomes. 506 Archives of Gynecology and Obstetrics (2025) 312:505–513

Tubal pathology represents a significant contributor to female infertility, with a prevalence ranging from 11 to 30%, often attributed to factors such as infections, prior surgical interventions, or conditions like endometriosis [1, 2]. Consequently, evaluating the fallopian tubes is a fundamental aspect of the fertility assessment process. Hysterosalpingography (HSG) remains the primary choice for assessing tubal patency during fertility investigations [3 ]. This technique is notable for its potential to improve female fertility. Initially employed for infertility screening and diagnosis [3 ], the expanded utilization of HSG among infertility patients underscores its efficacy in enhancing fertility outcomes [ 4–6]. A retrospective cohort study found no significant difference in IUI outcomes between women who underwent HSG and those who had laparoscopy, suggesting both tests have similar effects on treatment success [7 ]. However, the impact of HSG on fertility may vary based on the type of contrast agent utilized [8 ]. Research indicates that oil- based contrast agents may have an advantage over their water-based counterparts in enhancing conception in infertile individuals [9 ]. Hysterosalpingo-contrast sonography (HyCoSy) has emerged as a comparably effective alternative technique. It uses transvaginal ultrasonography combined with the injection of an echogenic contrast agent into the fallopian tubes and uterus to simultaneously visualize the ovaries. Studies have demonstrated that its accuracy in assessing tubal patency parallels that of HSG [10, 11]. Endometriosis is a challenging and complex disorder affecting about 10% of women of reproductive age worldwide [12]. Its prevalence highlights its significance as a contributing factor in intractable infertility cases, accounting for an estimated 30–50% of such instances [13]. Mental health issues, such as depression and anxiety, are also more common among infertile women, especially in Asia [14]. Our team’s earlier research [15] revealed that HSG using oil-based contrast agents may be more effective than water-based agents in increasing fertility in individuals struggling with endometriosis-related infertility. Currently, both HSG and HyCoSy are widely utilized hysterotubal ultrasonography techniques in clinical settings. However, the comparative efficacy of HSG with water-based contrast agents and HyCoSy in improving fertility outcomes in patients with endometriosis-related infertility remains unexplored. To address this question, we conducted a retrospective study comparing the impact of HyCoSy and HSG using iodinated water contrast agents on the success of pregnancies in patients with endometriosis-related infertility.

Study design This study included patients who, between January 2020 and June 2022, received either HSG or HyCoSy at the First Affiliated Hospital of Guangxi Medical University due to infertility concurrent with endometriosis. The research protocol was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and followed the principles outlined in the STROBE Statement. The inclusion criteria were: (1) female patients aged 18–39 with endometriosis; (2) regular menstrual cycles; and (3) having undergone HSG. Exclusion criteria included: (1) a total motile sperm count after sperm wash of less than 3 million sperm per milliliter in the male partner (or less than 1 million sperm per milliliter in the absence of post-wash analysis); (2) uncontrolled endocrine disorders known to reduce natural pregnancy chances, such as the acute phase of systemic lupus erythematosus; (3) incomplete data. Baseline characteristics of the patients included age, comorbidities, BMI, length of infertility, smoking status, surgical history, total number of prior live births, miscarriages, and treatment after hysterosalpingography procedures. Definition of endometriosis Endometriosis was defined using one or more of the following criteria: (1) surgical confirmation via laparoscopic or transabdominal operations; (2) ultrasonography identification of an endometrioma using transvaginal ultrasonography, which typically appears as a single or multilocular cyst with ground glass echogenicity [16]; (3) clinical signs of possible endometriosis, defined by the presence of three out of five characteristics: infertility, dysmenorrhea, dyspareunia, discomfort in the sacral ligament, or CA125 values higher than 15 mIU/mL [17]. HSG procedures Within the HSG group, the contrast medium utilized was either Iohexol 300 (General Electric Pharmaceutical (Shanghai) Co., Ltd., Shanghai, China), Iopromide 300 (Bayer Healthcare Co., Ltd., Beijing, China), or Ioversol 320 (Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, Jiangsu Province, China). The HSG procedure was performed as follows: all patients had empty bladders. A lidocaine injection (0.1 g) was administered to the cervix before endotracheal intubation. Via the vagina, a balloon catheter (model 12B; Zhanjiang Star Enterprise Co., Ltd., Zhanjiang, China) was placed into the cervix and secured. Once the uterine cavity was completely filled or the contrast 507Archives of Gynecology and Obstetrics (2025) 312:505–513 had entered the pelvic cavity, the prewarmed contrast was gradually injected. Dynamically displayed on the TV screen, the process of the contrast entering the uterus and fallopian tubes was documented, with the relevant photos taken. Pressure during the injection was controlled based on the clinician’s experience. In case of intravasation or interstitial reflux, patients were instructed to discontinue the contrast agent injection right away, get out of bed, walk, and inhale oxygen. HyCoSy performance The preparation before HyCoSy was the same as that for the HSG group. SonoVue® (sulfur hexafluoride; Shanghai Bracco Sine Pharmaceutical Corp., Ltd., Shanghai, China) was used to evaluate tubal patency, with a maximum of 15 ml. The sight of a continuous flow of contrast medium throughout the fallopian tube or observable contrast spill from the fimbrial end over the ovary was described as fallopian tube patency. Each tube was then categorized as patent, occluded, or uncertain. Main outcomes The main outcome was the commencement of the last menstrual cycle within a year after HSG, designated as the key endpoint for clinical pregnancy. The existence of a gestational sac found by ultrasonography was indicative of a clinical pregnancy. Statistical analysis For continuous variables, descriptive statistics were used;

were shown as mean/standard deviation (SD), median/interquartile range (IQR), and proportions (%) for categorical variables. Logistic regression models were utilized to investigate the association between the HSG and HyCoSy groups across four models. Model 1 was a crude model, providing an unadjusted assessment of the relationship between the HSG and HyCoSy groups. Model 2 adjusted for sociodemographic factors, including age, BMI, and smoking status. Model 3 incorporated adjustments from Model 2 and additional variables such as complications, miscarriage occurrences, and treatment received after hysterosalpingography techniques. Model 4 further adjusted for the duration of infertility, surgical history, and the total number of previous pregnancies resulting in live births. These sequential adjustments aimed to comprehensively address potential confounding factors and enhance the understanding of the association between the HSG and HyCoSy groups. To reduce potential biases associated with confounding variables, a matched propensity score (PSM) analysis was carried out given the non-randomized research design. The propensity scores were estimated using multivariable logistic regression, incorporating factors such as age, complications, BMI, duration of infertility, smoking status, surgical history, total number of previous pregnancies resulting in live births, miscarriage occurrences, and treatment received after HSG. Additional pertinent study parameters were added as independent variables for PSM. Using a greedy-matching method, the logit-transformed propensity scores were used to match participants in a 1:1 ratio without replacement. A caliper width of 0.2 standard deviation was applied to ensure closer matches between the participants. The balance of covariates between the HSG and HyCoSy groups was assessed using standardized differences, with a value of less than 10% indicating satisfactory balance [18]. Sample size determination was based on available data, with no a priori statistical power assessments conducted. Statistical analyses were performed using R 3.3.2, a statistical software program developed by The R Foundation, Shanghai, China (accessed on 10 January 2023), in conjunction with Free Statistics Software 1.5 [19]. A descriptive analysis was conducted on all individuals to comprehensively characterize the dataset. For hypothesis testing, a two-tailed analysis was employed, and a significance level of 0.05 was utilized to determine statistical significance. This widely accepted threshold denotes a standard level of confidence in interpreting the

and drawing meaningful conclusions from the analyses conducted.

Study population Between January 2020 and June 2022, 296 women with endometriosis-related infertility underwent hysterosalpingography procedures at the First Affiliated Hospital of Guangxi Medical University. Among them, 173 patients received hysterosalpingo-contrast sonography (HyCoSy), and 123 patients received hysterosalpingography (HSG) with water-based contrast. Following propensity score matching (PSM), 89 matched pairs were included in the final analysis (Fig.  1). Clinical characteristics The demographic and baseline clinical characteristics of patients before and after PSM are summarized in Table  1. The mean age of the patients was 31.2 years (SD 4.1) in the HyCoSy group and 31.5 years (SD 3.9) in the HSG group. Other baseline characteristics such as BMI, duration 508 Archives of Gynecology and Obstetrics (2025) 312:505–513 of infertility, and smoking status were well balanced after PSM, with standardized differences below 10%. Relationship between various hysterosalpingography techniques and clinical pregnancy outcomes Table  2 illustrates the relationships between different hysterosalpingography techniques and clinical pregnancy outcomes. Univariate analysis revealed potential associations, suggesting correlations between clinical pregnancy outcomes and variables such as miscarriage occurrences, treatment received after hysterosalpingography techniques, and the specific technique used for hysterosalpingography. Further research with multivariate analyses may be useful to explore the potential contributions of each factor to clinical pregnancy outcomes. In comparison to individuals in the HSG group, and after adjustments for age, BMI, smoking status, complications, miscarriage occurrences, treatment received after hysterosalpingography techniques, duration of infertility, surgical history, and total number of previous pregnancies resulting in live births, the adjusted odds ratio (OR) values for various hysterosalpingography techniques with clinical pregnancy outcomes were 0.41 (95% CI 0.20–0.82, p = 0.012) (Table 3). Associations between various hysterosalpingography techniques and clinical pregnancy outcomes: crude, multivariable, and propensity score analyses (HyCoSy group vs. HSG group) The HyCoSy group showed an unadjusted model Odds Ratio (OR) of 0.49 (95% CI 0.29–0.85, p = 0.011) compared to the HSG group. Multivariable analysis revealed an OR of 0.41 (95% CI 0.20–0.82, p = 0.012). The OR using inverse probability of treatment weighting (IPTW) regression analysis was 0.48 (95% CI 0.27–0.85, p = 0.013). In addition, the OR was 0.37 (95% CI 0.18–0.75, p = 0.006) when propensity score matching was used. These statistical

indicate that the HSG group had a higher clinical pregnancy rate compared to the HyCoSy group, although further research is needed to confirm these findings (refer to Table  4 for details). Fig. 1 Flowchart of study recruitment and inclusion/exclusion criteria 509Archives of Gynecology and Obstetrics (2025) 312:505–513

In this retrospective study, we observed a significant difference in clinical pregnancy rates 1  year after surgery for women with endometriosis-related infertility undergoing HSG with water contrast versus those who underwent HyCoSy. Specifically, the clinical pregnancy rate was higher in the HSG group compared to the HyCoSy group. These findings suggest a potential benefit of HSG in improving fertility outcomes in patients with endometriosis-related infertility, but further studies are needed to confirm these results. HyCoSy has gained popularity as a method for examining tubal patency due to its avoidance of radiation exposure and lower invasiveness, while maintaining sensitivity and specificity comparable to hysterosalpingography [2 ]. In addition to its diagnostic role, new clinical evidence and earlier research suggest HyCoSy’s potential therapeutic use for infertility; some infertile women undergoing the procedure were able to conceive spontaneously [20]. Specifically, HyCoSy has been associated with improved spontaneous pregnancy rates within 6 months following the procedure. Emilio et al. [21] proposed that HyCoSy could trigger ovulation, while Gao et al. [22] suggested that the liquid flow during HyCoSy could disintegrate small Table 1 Patient characteristics before and after propensity score matching HSG hysterosalpingography, HyCoSy hysterosalpingo-contrast sonography, BMI Body Mass Index Parameter All patients (n = 296) PS-matched pairs (n = 178) HSG group HyCoSy group SMD HSG group HyCoSy group SMD n = 123 n = 173 n = 89 n = 89 Age (year), mean (SD) 31.24 (3.77) 32.30 (3.72) 0.284 31.54 (3.77) 31.65 (3.78) 0.030 Complication (%) 0.255 0.695  No 76 (61.8) 107 (61.8) 54 (60.7) 78 (87.6)  Intrauterine adhesion 5 (4.1) 4 (2.3) 2 (2.2) 2 (2.2)  Thyroid disease 5 (4.1) 14 (8.1) 5 (5.6) 1 (1.1)  Chronic endometritis 5 (4.1) 3 (1.7) 5 (5.6) 2 (2.2)  Adenomyosis 3 (2.4) 7 (4.0) 3 (3.4) 2 (2.2)  Others 29 (23.6) 38 (22.0) 20 (22.5) 4 (4.5) BMI (kg/m2), mean (SD) 20.85 (2.66) 20.82 (2.33) 0.012 20.92 (2.33) 20.63 (2.37) 0.124 Duration of infertility (year), mean (SD) 2.86 (2.29) 2.98 (2.39) 0.051 3.03 (2.43) 2.93 (2.16) 0.041 Surgical history (%) 0.477 0.307  No 115 (93.5) 151 (87.3) 85 (95.5) 89 (100.0)  Myoma or polyp resection or cystectomy 1 (0.8) 13 (7.5) 1 (1.1) 0 (0.0)  Tubal surgery 3 (2.4) 6 (3.5) 3 (3.4) 0 (0.0)  Cesarean section 4 (3.3) 0 (0.0) 0 (0.0) 0 (0.0)  Others 0 (0.0) 3 (1.7) 0 (0.0) 0 (0.0)  Smoking status, n (%) 3 (2.4) 4 (2.3) 0.008 1 (1.1) 1 (1.1) < 0.001 Total number of previous pregnancies resulting in live births (%) 0.169 0.228  0 99 (80.5) 150 (86.7) 75 (84.3) 79 (88.8)  1 22 (17.9) 21 (12.1) 12 (13.5) 10 (11.2)  2 2 (1.6) 2 (1.2) 2 (2.2) 0 (0.0) Miscarriage times (%) 0.151 0.662  0 96 (78.0) 141 (81.5) 73 (82.0) 89 (100.0)  1 19 (15.4) 23 (13.3) 10 (11.2) 0 (0.0)  2 8 (6.5) 8 (4.6) 6 (6.7) 0 (0.0)  3 0 (0.0) 1 (0.6) 0 (0.0) 0 (0.0) Treatment after hysterosalpingography techniques (%) 0.891 0.251  Expectant management 69 (56.1) 99 (57.2) 65 (73.0) 56 (62.9)  IUI 9 (7.3) 27 (15.6) 9 (10.1) 16 (18.0)  IVF/ICSI 15 (12.2) 47 (27.2) 15 (16.9) 17 (19.1)  Laparoscopy and/or hysteroscopy 30 (24.4) 0 (0.0) 0 (0.0) 0 (0.0) 510 Archives of Gynecology and Obstetrics (2025) 312:505–513 adhesions in the fallopian tubes, increasing the likelihood of spontaneous pregnancy. However, the precise mechanism leading to the increased conception rates after HyCoSy remains unclear. Another study [23] suggested that HyCoSy examination might improve endometrial perfusion and have a therapeutic impact on natural conception in infertile women. Nonetheless, conflicting evidence exists, as some studies have failed to confirm an enhanced pregnancy rate after HyCoSy [24]. HSG has traditionally been the preferred method for tubal patency testing, primarily due to its capability to visualize and assess tubal patency using an iodinated contrast medium [25]. The efficacy of HSG in enhancing fertility outcomes is believed to involve the mechanical flushing action of the contrast medium, which aids in removing tubal debris, mucus plugs, and other obstructive substances [26]. Beyond this mechanical action, the anti-inflammatory and antimicrobial properties of iodine, the component used Table 2 Association of covariates and clinical pregnancy HSG hysterosalpingography, HyCoSy hysterosalpingo-contrast sonography, BMI Body Mass Index, OR odds ratio, CI confidence interval, Ref

Variable OR_95CI p_value Variable OR_95CI p_value Age (year), n (%) Total number of previous pregnancies resulting in live births   35 1.84 (0.95–3.59) 0.073  1 0.97 (0.47–2) 0.935 BMI (kg/m2), n (%)  2 1.13 (0.12–11.02) 0.918   25 5.57 (0.72–43.08) 0.1  0 1 (reference) Duration of infertility (year)  1  0.5 (0.25–0.99) 0.045  ≤ 3 1 (reference)  2 1.47 (0.4–5.33) 0.559  > 3 1.17 (0.7–1.97) 0.545 Treatment after hysterosalpingography techniques (%) Complication (%)  Expectant management 1 (reference)  No 1 (reference)  IUI 0.38 (0.18–0.83) 0.015  Intrauterine adhesion 1.47 (0.29–7.28) 0.641  IVF/ICSI 0.36 (0.19–0.68) 0.002  Thyroid disease 3.56 (0.79–15.93) 0.097  Laparoscopy and/or Hysteroscopy 0.57 (0.24–1.36) 0.205  Chronic endometritis 1.26 (0.25–6.42) 0.784 Different techniques of hysterosalpingography  Adenomyosis 1.67 (0.34–8.14) 0.523  HSG group 1 (reference)  Others 1.06 (0.57–1.96) 0.859  HyCoSy group 0.49 (0.29–0.85) 0.011 Surgical history (%) Smoking status, n (%)  No  No 1 (reference)  Myoma or polyp resection or cystectomy 1.36 (0.37–5.02) 0.644  Yes 0.49 (0.11–2.25) 0.361  Tubal surgery 0.74 (0.18–3.05) 0.679  Cesarean section 1.11 (0.11–10.88) 0.926  Others 0.19 (0.02–2.08) 0.172 Table 3 Correlation of various hysterosalpingography techniques with clinical pregnancy outcomes Model 1 was a crude model Model 2 was adjusted for sociodemographic (age, BMI and smoking status).Model 3 was adjusted for model 2 plus complication, miscarriage times and treatment after hysterosalpingography techniques.Model 4 was adjusted for model 3 plus duration of infertility, surgical history and total number of previous pregnancies resulting in live births HSG hysterosalpingography, HyCoSy hysterosalpingo-contrast sonography, OR odds ratio, CI confidence interval, Ref reference, BMI Body Mass Index Variable Total OR (95% CI) Model 1 p_value Model 2 p_value Model 3 p_value Model 4 p_value HSG group 123 1 (Ref) 1 (Ref) 1 (Ref) 1 (Ref) HyCoSy group 173 0.49 (0.29–0.85) 0.011 0.47 (0.27–0.81) 0.007 0.43 (0.22–0.84) 0.014 0.41 (0.2–0.82) 0.012 511Archives of Gynecology and Obstetrics (2025) 312:505–513 in the contrast medium, also contribute to its potential therapeutic effects. Research suggests [27] that women with endometriosis often exhibit elevated levels of localized and systemic inflammation. Earlier studies have shown that endometriosis is known to have a strong immunosuppressive microenvironment [28]. Therefore, the anti-inflammatory effects of iodine may play a significant role in improving fertility outcomes in patients with endometriosis-related infertility. Several mechanisms support this notion. First, iodine is crucial for normal thyroid hormone synthesis and release, indirectly promoting ovulation. Normal thyroid-stimulating hormone (TSH) levels support follicular growth in oocytes, as TSH acts on the follicle-stimulating hormone (FSH) receptors, enhancing pre-antral follicular growth induced by FSH [29]. In addition, iodine has a direct effect on the ovaries [30]. Secondly, Johnson et al. [9] demonstrated that Lipiodol, an iodine-based contrast agent, induced alterations in the endometrial dendritic cell phenotype in rats. This implies that iodine might be responsible for immunological changes in the endometrium, thereby enhancing embryo implantation. Ahmed FO et al. reported improved fertility in cows with unexplained infertility following uterine instillation of Lugol’s iodine, suggesting that infertility might be secondary to subclinical endometritis, and the bactericidal action of iodine could help restore the damaged endometrium. Moreover, some studies [31–33] suggest that iodide can modulate the proportion of T helper 17 (Th17) cells, regulatory T cells (Treg), and natural killer (NK) cells, exerting immune activity. This suggests that iodine may change the immune environment and thus affect embryo implantation. These findings suggest that the mechanical flushing action and inflammatory response elicited by the iodinated contrast medium during HSG may contribute to its ability to enhance tubal patency and promote successful conception in this patient population. In contrast, HyCoSy, which utilizes an echogenic contrast medium, lacks the anti-inflammatory properties inherent to iodine. While HyCoSy may offer advantages in terms of visualization and patient comfort, its inability to address the underlying inflammatory component of endometriosis may limit its effectiveness in improving fertility outcomes in this patient population. Therefore, the unique anti-inflammatory properties of iodine-based contrast agents used in HSG may play a crucial role in enhancing fertility outcomes, particularly in patients with endometriosis-related infertility. In this study, no severe allergic reactions were observed with either oil-based or water-based contrast agents during hysterosalpingography (HSG). While iodine-based contrast agents used in water-based HSG can potentially cause allergic reactions, our results showed no such events. This aligns with findings from two well-conducted randomized controlled trials (RCTs). The 2017 RCT [4] reported no allergic reactions in either the oil-based or water-based contrast groups during HSG. Similarly, the 2022 RCT [34] conducted in China also found no allergic events in either group. These well-designed RCTs, together with our findings, suggest that both oil-based and water-based contrast agents are safe for use in HSG. Furthermore, the retrospective cohort study [35] also supports these results, although the RCTs provide more robust evidence for their safety. The strengths of our study include its rigorous methodology, including propensity score matching to account for potential confounders, and the inclusion of a substantial number of patients. However, several limitations warrant consideration. First, the retrospective design introduces the potential for selection bias and limits the generalizability of the results. Second, reliance on medical records for data collection may have introduced information bias, as the accuracy of the data depends on the quality of the records. In addition, while the sample size is relatively large, it may not have been sufficient to detect small differences in pregnancy outcomes between the two groups. Finally, the study did not include long-term follow-up on pregnancy outcomes, which is important for evaluating the effectiveness of the diagnostic methods. Further large-scale, prospective studies with longer follow-up are needed to confirm these findings.

In summary, this research offers valuable insights into the relative efficacy of HyCoSy and HSG in enhancing reproductive outcomes for individuals with Table 4 HyCoSy versus HSG: clinical pregnancy comparison HSG hysterosalpingography, HyCoSy hysterosalpingo-contrast sonography a Shown is the odds ratio from the multivariable logistic model, with adjusted for all covariates in table (age, complication, BMI, duration of infertility, smoking status, surgical history, total number of previous, pregnancies resulting in live births, miscarriage times and treatment after different hysterosalpingography techniques) b Shown is the primary analysis with multivariable logistic model with the same covariates with inverse probability weighting according propensity score c Shown is the odds ratio from the multivariable logistic model with the same strata and covariates with matching according to the propensity score. The analysis included 89 patients (89 in the HSG group and 89 in the HyCoSy group) Analysis OR_95CI p_value Crude analysis 0.49 (0.29–0.85) 0.011 Multivariable analysisa 0.41 (0.2–0.82) 0.012 Weighted IPTWb 0.48 (0.27–0.85) 0.013 Propensity score matchedc 0.37 (0.18–0.75) 0.006 512 Archives of Gynecology and Obstetrics (2025) 312:505–513 endometriosis-related infertility. Despite the limitations, our findings suggest a possible benefit of HSG with water contrast in achieving clinical pregnancy in this patient population. Larger sample sizes and more prospective studies are needed to validate these results and explore the underlying factors causing the observed variations in fertility outcomes between the two approaches. These efforts will further inform clinical practice and enhance the management of infertility in patients with endometriosis.

Thank you to the 'Clinical Scientist' team for their support to us. Author contributions W.T.: project development, data collection, statistical analyses, manuscript drafting. A.Q.: project development, manuscript drafting, critical revision. Y.H., F.L., J.Y., B.X.: data collection, data interpretation. Q.H.: statistical analyses, data interpretation. All the authors: data interpretation, critical revision, approval of the final version of the manuscript. Funding This study received no funding. Data availability The data underlying this article will be shared on reasonable request to the corresponding author. Declarations Conflict of interest The authors declare that they have no conflicts of interest. Ethics approval This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University. As this is a retrospective cohort study, written informed consent was not required. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by- nc- nd/4. 0/.

1. Snick HK, Snick TS, Evers JL, Collins JA (1997) The spontaneous pregnancy prognosis in untreated subfertile couples: the Walcheren primary care study. Hum Reprod 12(7):1582–1588 2. Farquhar CM, Bhattacharya S, Repping S, Mastenbroek S, Kamath MS, Marjoribanks J, Boivin J (2019) Female subfertility. Nat Rev Dis Primers 5(1):7 3. Infertility Workup for the Women’s Health Specialist (2019) ACOG Committee opinion summary, number 781. Obstet Gynecol 133(6):1294–1295 4. Dreyer K, van Rijswijk J, Mijatovic V, Goddijn M, Verhoeve HR, van Rooij IAJ, Hoek A, Bourdrez P, Nap AW, Rijnsaardt- Lukassen HGM et al (2017) Oil-based or water-based contrast for hysterosalpingography in infertile women. N Engl J Med 376(21):2043–2052 5. Fang F, Bai Y, Zhang Y, Faramand A (2018) Oil-based versus water-based contrast for hysterosalpingography in infertile women: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril 110(1):153-160.e153 6. van Rijswijk J, van Welie N, Dreyer K, Pham CT, Verhoeve HR, Hoek A, de Bruin JP, Nap AW, van Hooff MHA, Goddijn M et al (2020) Tubal flushing with oil-based or water-based contrast at hysterosalpingography for infertility: long-term reproductive outcomes of a randomized trial. Fertil Steril 114:155–162 7. Joseph T, Karuppusami R, Kunjummen AT, Kamath MS (2023) Impact of tubal patency test selection on the live birth rate following intrauterine insemination in couples with unexplained infertility: a retrospective cohort study. Arch Gynecol Obstet 308(2):621–629 8. Wang R, van Welie N, van Rijswijk J, Johnson NP, Norman RJ, Dreyer K, Mijatovic V, Mol BW (2019) Effectiveness on fertility outcome of tubal flushing with different contrast media: systematic review and network meta-analysis. Ultrasound Obstet Gynecol 54(2):172–181 9. Johnson NP, Bhattu S, Wagner A, Blake DA, Chamley LW (2005) Lipiodol alters murine uterine dendritic cell populations: a potential mechanism for the fertility-enhancing effect of lipiodol. Fertil Steril 83(6):1814–1821 10. Saunders RD, Shwayder JM, Nakajima ST (2011) Current

of tubal patency assessment. Fertil Steril 95(7):2171–2179 11. Lim SL, Jung JJ, Yu SL, Rajesh H (2015) A comparison of hysterosalpingo-foam sonography (HyFoSy) and hysterosalpingo- contrast sonography with saline medium (HyCoSy) in the assessment of tubal patency. Eur J Obstet Gynecol Reprod Biol 195:168–172 12. Giudice LC (2010) Clinical practice. Endometriosis. N Engl J Med 362(25):2389–2398 13. Hodgson RM, Lee HL, Wang R, Mol BW, Johnson N (2020) Interventions for endometriosis-related infertility: a systematic review and network meta-analysis. Fertil Steril 113(2):374-382. e372 14. Salari N, Babajani F, Hosseinian-Far A, Hasheminezhad R, Abdoli N, Haydarisharaf P, Mohammadi M (2024) Global prevalence of major depressive disorder, generalized anxiety, stress, and depression among infertile women: a systematic review and meta- analysis. Arch Gynecol Obstet 309(5):1833–1846 15. Xie B, Huang Y, Hang F, Yu J, Hu Q, Li J, Qin A (2024) Impact of oil-based contrast agents in hysterosalpingography on fertility outcomes in endometriosis: a retrospective cohort study. Reprod Biol Endocrinol 22(1):19 16. Exacoustos C, Zupi E, Piccione E (2017) Ultrasound imaging for ovarian and deep infiltrating endometriosis. Semin Reprod Med 35(1):5–24 17. Nisenblat V, Bossuyt PM, Shaikh R, Farquhar C, Jordan V, Scheffers CS, Mol BW, Johnson N, Hull ML (2016) Blood biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev 2016(5):CD012179 18. Austin PC (2011) A tutorial and case study in propensity score analysis: an application to estimating the effect of in-hospital smoking cessation counseling on mortality. Multivariate Behav Res 46(1):119–151 19. Yang Q, Zheng J, Chen W, Chen X, Wen D, Chen W, Xiong X, Zhang Z (2021) Association between preadmission metformin use and outcomes in intensive care unit patients with sepsis and type 2 diabetes: a cohort study. Front Med (Lausanne) 8:640785 513Archives of Gynecology and Obstetrics (2025) 312:505–513 20. Liu Y, Zhang N, He Y, Shi J, Zhou M, Xu J, Liu H (2020) Spontaneous conception outcome in infertile women after four-dimensional hysterosalpingo-contrast-sonography. BMC Pregnancy Childbirth 20(1):638 21. Giugliano E, Cagnazzo E, Bazzan E, Patella A, Marci R (2012) Hysterosalpingo-contrast sonography: is possible to quantify the therapeutic effect of a diagnostic test? Clin Exp Reprod Med 39(4):161–165 22. Chunyan G, Bin P, Ping Y, Yue Z, Yang X, Hongju T, Li S, Xi X (2018) Assessment of the influence on spontaneous pregnancy of hysterosalpingo-contrast sonography. Biomed Res Int 2018:4901281 23. Li R, Qiu X, Chen XF, He M, Wang W, Qiao J, He J, Shi Q (2022) Effects of hysterosalpingo-contrast sonography examination on endometrial receptivity among women with unexplained infertility. Arch Gynecol Obstet 306(3):893–900 24. Lindborg L, Thorburn J, Bergh C, Strandell A (2009) Influence of HyCoSy on spontaneous pregnancy: a randomized controlled trial. Hum Reprod 24(5):1075–1079 25. Swart P, Mol BW, van der Veen F, van Beurden M, Redekop WK, Bossuyt PM (1995) The accuracy of hysterosalpingography in the diagnosis of tubal pathology: a meta-analysis. Fertil Steril 64(3):486–491 26. Broeze KA, Opmeer BC, Van Geloven N, Coppus SF, Collins JA, Den Hartog JE, Van der Linden PJ, Marianowski P, Ng EH, Van der Steeg JW et al (2011) Are patient characteristics associated with the accuracy of hysterosalpingography in diagnosing tubal pathology? An individual patient data meta-analysis. Hum Reprod Update 17(3):293–300 27. Symons LK, Miller JE, Kay VR, Marks RM, Liblik K, Koti M, Tayade C (2018) The immunopathophysiology of endometriosis. Trends Mol Med 24(9):748–762 28. Chen Y, Wang K, Xu Y, Guo P, Hong B, Cao Y, Wei Z, Xue R, Wang C, Jiang H (2019) Alteration of Myeloid-derived suppressor cells, chronic inflammatory cytokines, and exosomal miRNA contribute to the peritoneal immune disorder of patients with endometriosis. Reprod Sci 26(8):1130–1138 29. Kobayashi N, Orisaka M, Cao M, Kotsuji F, Leader A, Sakuragi N, Tsang BK (2009) Growth differentiation factor-9 mediates follicle-stimulating hormone-thyroid hormone interaction in the regulation of rat preantral follicular development. Endocrinology 150(12):5566–5574 30. Slebodzinski AB (2005) Ovarian iodide uptake and triiodothyronine generation in follicular fluid. The enigma of the thyroid ovary interaction. Domest Anim Endocrinol 29(1):97–103 31. Zhao X, Jiang Y, Wang L, Li Z, Li Q, Feng X (2018) Advances in understanding the immune imbalance between T-lymphocyte subsets and NK cells in recurrent spontaneous abortion. Geburtshilfe Frauenheilkd 78(7):677–683 32. Wang WJ, Zhang H, Chen ZQ, Zhang W, Liu XM, Fang JY, Liu FJ, Kwak-Kim J (2019) Endometrial TGF-beta, IL-10, IL-17 and autophagy are dysregulated in women with recurrent implantation failure with chronic endometritis. Reprod Biol Endocrinol 17(1):2 33. Yang X, Gao T, Shi R, Zhou X, Qu J, Xu J, Shan Z, Teng W (2014) Effect of iodine excess on Th1, Th2, Th17, and Treg cell subpopulations in the thyroid of NOD.H-2h4 mice. Biol Trace Elem Res 159(1–3):288–296 34. Zhang J, Lan W, Wang Y, Chen K, Zhang G, Yang W, Chen H, Xu W, Ma J, Qin W et al (2022) Ethiodized poppyseed oil- based contrast medium is superior to water-based contrast medium during hysterosalpingography regarding image quality improvement and fertility enhancement: A multicentric, randomized and controlled trial. EClinicalMedicine 46:101363 35. Lu J, Qi D, Xu W (2022) Fertility-enhancing effect of oil-based contrast agents during hysterosalpingography and the variation of this effect within a 3-year follow-up period in infertile patients. Front Med (Lausanne) 9:948945 Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.