The value of 4-dimensional hysterosalpingo-contrast sonography in predicting the possibility of spontaneous conception in infertile women

The seven factors (age, infertility type, years of infertility, parity, uterine cavity lesions, endometriosis, tubal patency) selected by univariate analysis were included in multivariate Cox regression analysis. The results showed that spontaneous pregnancy outcome after HyCoSy was associated with multiple factors. The clinical pregnancy rates decreased with older age, longer infertility duration, presence of uterine cavity lesions and endometriosis lesions, and poor tubal patency. No significant difference was observed in infertility type or multiparas (Table  2 ). Table 2 Cox regression analysis of the influencing factors with spontaneous conception after hycosy Factors Univariate regression Multiple stepwise regression HR (95%CI) P HR (95%CI) P Age group  <30 years 1 – 1 –  30–35 years 0.516(0.415–0.642) <0.001 0.581(0.461–0.733) <0.001  ≥ 35 years 0.269(0.177–0.408) <0.001 0.289(0.184–0.454) <0.001 Infertility type  Primary infertility 1 – 1 –  Secondary infertility 0.797(0.648–0.981) 0.032 1.109(0.857–1.434) 0.431 Years of infertility 0.821(0.723–0.894) <0.001 0.860(0.788–0.983) <0.001 Parity 0.679(0.537–0.859) 0.001 1.009(0.754–1.351) 0.950 Lesion of uterine cavity  No 1 – 1 –  Yes 0.601(0.447–0.801) 0.001 0.534(0.389–0.732) <0.001 Endometriosis  No 1 – 1 –  Yes 0.378(0.167–0.847) 0.018 0.426(0.189–0.920) 0.040 Tubal patency  Type I 1 – 1 –  Type Ⅱ 0.587(0.446–0.772) <0.001 0.629(0.475–0.832) 0.001  Type Ⅲ 0.235(0.138–0.403) <0.001 0.191(0.094–0.386) <0.001 HR Hazard ratio, CI Confidential interval Cox regression analysis of the influencing factors with spontaneous conception after hycosy HR Hazard ratio, CI Confidential interval

The study was designed as a retrospective cohort study. A total of 984 infertile patients, with at least 1 year of infertility, underwent 4D-HyCoSy in Women and Children’s Hospital, School of Medicine, Xiamen University between January 2021 and October 2022. Basic clinical data extracted from the records included age, duration of infertility, type of infertility, gravidity, parity, and menstrual cycle. This study was approved by the ethics committee of Women and Children’s Hospital, School of Medicine, Xiamen University (KY-2023-024-K01). The procedures used in this study adhere to the tenets of the Declaration of Helsinki. All participants signed informed consent before examinations. To protect patient privacy, all patient details were deidentified. The reporting of this study conforms to STROBE guidelines [ 11 ]. Women with hydrosalpinx by ultrasound examination, hysteroscopy and laparoscopy surgery or assisted reproductive technology (ART) treatment within a year after HyCoSy, severe male factor (total motile sperm count < 1 × 10 6 /ml) or loss to follow-up were excluded. A total of 776 patients were enrolled in our study (Fig.  1 ). Fig. 1 The flowchart of the study The flowchart of the study The examinations and evaluation reports were performed by two sonographers, both with more than 5 years of experience in using ultrasonography to perform gynecologic and obstetric examinations. A Mindray Nuewa R9S (Mindray Healthcare, China) with an RIC5–9-D volume probe (5.0–9.0 MHz) was used in the examinations. The SonoVue contrast agent was prepared by adding 5 ml of 0.9% saline solution to 59 mg of freeze-dried SonoVue powder (Bracco International BV, Amsterdam, the Netherlands). After sufficient shaking, 2 mL of the microbubble suspension was extracted and dissolved in 13 mL of 0.9% sodium chloride solution to prepare 15 ml of diluted contrast agent. 4D-HyCoSy was performed within 3 to 10 days after menstruation. A 12-Fr Foley catheter (Guangzhou Well Lead Medical Co., Ltd., Guangdong, China) was placed into the uterine cavity, and the external lumen was inflated with saline to prevent leakage from the cervix. Before the contrast agent was injected, two-dimensional transvaginal sonography was conducted to evaluate the uterus and ovaries (endometriosis, uterine cavity lesions such as endometrial polyps or adhesions and polycystic ovaries). Next, 4D-HyCoSy was activated and performed. The probe was kept at the same position with the region of interest as wide as possible. Then, 15 ml of contrast agent was injected into the catheter and adjusted in accordance with the development in the fallopian tubes. The contrast agent filled the uterine cavity, flowing though the uterine cornu to the fallopian tube and finally spraying in the fimbriae to the pelvis. The dynamic enhanced volume images were saved and analyzed after the injection of the contrast medium [ 12 , 13 ]. Fallopian tube patency (Fig.  2 A) was defined as the visualization of a steady flow of contrast medium in the fallopian tube or the visible contrast spill from the fimbriae end over the ovary. Poor patency (Fig.  2 B) was defined as the entire fallopian tube, and spillage at the fimbria of the tube was visible, but the passage of the tube was stiff, discontinuous, filamented, angled, circuitous, and directed upward. In an obstructed fallopian tube (Fig.  2 C), apparent resistance is encountered during the injection of the contrast medium. The fallopian tube fails to fill completely. No overflow of contrast medium from the fimbriae is observed, and the contrast medium does not diffuse into the pelvic cavity [ 9 ]. Both poor patency and obstruction were classified as tubal pathology. Fig. 2 Different tubal patency results of HyCoSy. ( A ) Type I, bilaterally patent Fallopian tubes. The tubes were patent, and the passage of the tube was soft and naturally. ( B ) Type II, one fallopian tube patent with pathology in the other. The right tube was patent while the left tube was poor patency, and the entire fallopian tube was stiff. ( C ) Type III, both tubes pathology. Both fallopian tubes were obstructed, we could not see the entire passage of the tube or spillage at the fimbriae end Different tubal patency results of HyCoSy. ( A ) Type I, bilaterally patent Fallopian tubes. The tubes were patent, and the passage of the tube was soft and naturally. ( B ) Type II, one fallopian tube patent with pathology in the other. The right tube was patent while the left tube was poor patency, and the entire fallopian tube was stiff. ( C ) Type III, both tubes pathology. Both fallopian tubes were obstructed, we could not see the entire passage of the tube or spillage at the fimbriae end The results were categorized as follows: type I, defined as both fallopian tubes patent; type II, defined as one fallopian tube patent with pathology in the other; and type III, defined as both tubal pathologies (Fig.  2 ). The primary end-point in this study was a spontaneous clinical pregnancy confirmed by ultrasonography. A spontaneous pregnancy was achieved by sexual intercourse during the expectant management, including ovulation induction and outpatient ovarian follicle monitoring. Time to pregnancy was calculated from the first day of the menstrual period when HyCoSy was performed to the first day of the menstrual period when conception occurred. Patients were followed up quarterly by telephone, clinical, and ultrasound examinations after HyCoSy. The follow-up lasted for 12 months or until the patient succeeded in the first clinical pregnancy. All statistical analyses were conducted with SPSS version 26.0 software (SPSS Inc., Chicago, IL, USA). The data are expressed as the mean ± standard deviation (SD), median (interquartile range) or percentage. Comparisons of pregnant and nonpregnant patients were made by using Student’s t tests for normally distributed variables and Mann‒Whitney U tests for nonnormally distributed variables. Categorical variables were compared by using chi-square tests. Kaplan–Meier curves were constructed and analyzed to calculate cumulative pregnancy rates and conception time in the three groups after 4D-HyCoSy. The log-rank test was performed to evaluate the clinical and ultrasound factors on spontaneous conception that included age, duration of infertility, infertility type, parity, lesion of uterine cavity (adhesions or/and polyps), endometriosis and tubal patency. Next, a stepwise multivariate Cox regression analysis was used to analyze the potential confounding factors associated with clinical pregnancy. A P value < 0.05 was considered significant.

A total of 776 patients who met the inclusion criteria were enrolled in our study. Each case was followed up for 1 year or until the first clinical pregnancy. The age of the participants ranged from 20 to 42 years, with an average age of 30.2 ± 3.8 years. The duration of infertility among patients ranged from 1 to 10 years, with a mean of 2.1 ± 1.5 years. Of these women, 363 (46.8%) became pregnant. Patients who achieved conception were younger, with a shorter duration of infertility and lower parity than non-conception patients ( P   0.05). However, the prevalence of uterine cavity lesions (endometrial polyps or adhesion of the uterine cavity) and endometriosis was significantly higher in non-conception women than in conception women ( P  < 0.05). The 4D-HyCoSy results suggested that there were 519 cases of type I, 171 cases of type II, and 86 cases of type III (Table  1 ). Table 1 Basic characteristics between conception group and non-conception group ALL N  = 776 Conception N  = 363 Non- conception N  = 413 t/Z/χ2 P Age, years 30.2 ± 3.8 29.0 ± 3.5 31.3 ± 3.8 8.663 <0.001 Age group, n (%) 61.591 <0.001  <30 years 331(42.7%) 205 (56.5%) 126 (30.5%)  30–35 years 338(43.6%) 133 (36.6%) 205 (49.6%)  ≥ 35 years 107(13.8%) 25 (6.9%) 82 (21.1%) Years of infertility 2.1 ± 1.5 1.8 ± 1.2 2.4 ± 1.7 5.415 <0.001 Infertility type, n (%) 3.409 0.065  Primary infertility 413(53.2%) 206 (56.7%) 207 (50.1%)  Secondary infertility 363(46.8%) 157 (43.3%) 206 (49.9%) Gravidity 0 (0,1) 0 (0,1) 0 (0,1) 3.409 0.065 Parity 0 (0,0) 0 (0,0) 0 (0,1) 13.968 <0.001 Polycystic ovary syndrome, n (%) 166 (21.4%) 84 (23.1%) 82 (19.1%) 1.240 0.265 Lesion of uterine cavity, n (%) 150 (19.3%) 51 (14.0%) 99 (24.0%) 12.195 <0.001 Endometriosis, n (%) 28 (3.6%) 6 (1.7%) 22 (5.3%) 7.498 0.006 Tubal patency, n (%) 54.869 <0.001  Type I 519 (66.9%) 287 (79.1%) 232 (56.2%)  Type Ⅱ 171 (22.0%) 62 (17.1%) 109 (26.4%)  Type Ⅲ 86 (11.1%) 14 (3.9%) 72 (17.4%) Tubal patency, Type I, defined as both fallopian tubes patent; Type II, defined as one fallopian tube patent with pathology in the other; and Type III, defined as double-sided tubal pathology Basic characteristics between conception group and non-conception group Tubal patency, Type I, defined as both fallopian tubes patent; Type II, defined as one fallopian tube patent with pathology in the other; and Type III, defined as double-sided tubal pathology Within a year after 4D-HyCoSy, the cumulative pregnancy rate was 46.8%, and the mean pregnancy time was 4.6 ± 2.8 months. There were also 4 (1.10%) ectopic pregnancies: 1 in type I, 2 in type II, and 1 in type III. The pregnancy rates at 1–3 months, 1–6 months, 1–9 months and 1–12 months were 21.8% (169/776), 35.3% (274/776), 43.3% (336/776), and 46.8% (363/776), respectively. The conception rates of 1–3 months, 4–6 months, 7–9 months and 10–12 months accounted for 46.6, 28.9, 17.1 and 3.5% of the total pregnancy rates, respectively (Fig.  3 A). Fig. 3 Cumulative pregnancy rate in all patients ( A ) and in patients with different types of fallopian tubes ( B ). The pregnancy rate was highest in Type I (55.3%), followed by Type II (36.3%) and Type Ⅲ (16.3%) (Log-rank test, P  < 0.001) Cumulative pregnancy rate in all patients ( A ) and in patients with different types of fallopian tubes ( B ). The pregnancy rate was highest in Type I (55.3%), followed by Type II (36.3%) and Type Ⅲ (16.3%) (Log-rank test, P  < 0.001) The cumulative clinical pregnancy rate was significantly highest in type I, reaching 55.3%, followed by type II (36.3%) and type III (16.3%). For patients with type I, the pregnancy rates at 1–3 months, 1–6 months, 1–9 months and 1–12 months were 25.6% (133/519), 39.5% (205/519), 48.9% (254/519), and 53.6% (278/519), respectively; for patients with type II, the pregnancy rates were 16.4% (28/171), 28.7% (49/171), 34.5% (59/171), and 36.3% (62/171), respectively; and for patients with type III, the pregnancy rates were 9.3% (8/86), 12.8% (11/86), 15.1% (13/86), and 16.3% (14/86), respectively (Fig.  3 B).

In China, the prevalence of infertility among reproductive-age couples has been estimated to reach as high as 25% [ 1 ]. Tubal infertility, defined as either blocked fallopian tubes or inability of the tubes to pick up an oocyte from the ovary, accounts for 30–67% of infertility cases [ 2 ]. Accurate examination of tubal patency is crucial not only for diagnosis but also for determining appropriate individualized treatment in a timely manner. Two traditional methods have been used to evaluate tubal patency: laparoscopy using dye and hysterosalpingography (HSG). However, laparoscopy is expensive and invasive. HSG produces radiation exposure and is associated with potentially allergenic agents [ 3 , 4 ]. During the last two decades, hysterosalpingo contrast sonography (HyCoSy), with a diagnostic accuracy of 87.5–92.9%, has been introduced as an alternative in clinical practice [ 5 – 7 ]. HyCoSy has gained increasing acceptance among clinicians and patients due to its ability to provide comprehensive, real-time evaluation of uterine and tubal morphology while maintaining advantages as a minimally invasive, cost-effective, and time-efficient procedure [ 8 , 9 ]. The results of HyCoSy provide valuable guidance for individualized fertility management. Previous studies showed that HyCoSy can help determine whether post-procedure assisted reproductive technology (ART) intervention is necessary [ 10 ]. We noticed that some infertile women could succeed in spontaneous conception after HyCoSy. Expectant management may be recommended to avoid overtreatment and optimize resource utilization. However, few studies have systematically evaluated the spontaneous pregnancy rate after HyCoSy. The advised period of expectant management after HyCoSy for different tubal patency was rarely recorded. This study aimed to evaluate spontaneous conception outcomes in infertile women relative to the time interval following HyCoSy. We also examined the association between spontaneous conception rates and tubal patency status. Our findings may provide clinical guidance for personalized infertility management following HyCoSy examination.

Bilateral tubal patency, along with age, duration of infertility, uterine cavity abnormalities, and endometriosis, were identified as independent factors associated with natural pregnancy. Infertile women with at least unilateral tube patency had a highest spontaneous pregnancy rate in the first 3 months after HyCoSy examination and could be advised a certain period of expectant management. However, infertile women with bilateral tube pathology should be counseled to pursue active fertility treatment.

Our study demonstrated that within a year after 4D-HyCoSy, 46.8% of infertile women could succeed in spontaneous conception, and the mean pregnancy time was 4.6 ± 2.8 months. The pregnancy rates of type I and type II patients were highest in 1–3 months after the examination and approached plateau after 9 months. This indicated that infertile women with at least one tube patent could have expectant treatment for a certain period to reduce overtreatment. Quite a few studies have reported spontaneous pregnancy rates after HyCoSy. Yu Liu et al. [ 13 ] reported a cumulative spontaneous conception rate of 40.9% in infertile women within a year after HyCoSy. Katjia et al. [ 14 ] showed that the pregnancy rate by intrauterine insemination was higher in the HyCoSy (41%) group than in the laparoscopic (30%) and HSG (38%) groups. Chunyan G et al. [ 15 ] suggested that 19.35% of women could conceive spontaneously within 6 months after HyCoSy, and the pregnancy rate was significantly higher in the first 30 days. The cumulative spontaneous conception rate was 46.8% in our study, higher than that in previous studies. The mean conception time was shorter than that reported by Yu Liu et al. (4.6 ± 2.8 months vs. 8.8 ± 0.3 months) [ 13 ]. This may be because we excluded women with hydrosalpinx and severe semen abnormalities of their husbands. In addition, the proportion of bilateral tube pathology (11.1% vs. 24.8%) was relatively lower in our study. Our study showed that the conception frequency of 1–3 months accounted for 46.6% of the total pregnancies, which might meet the hypothesis that ‘tube and endometrial flushing’ by HyCoSy examination could improve the pregnancy rate [ 16 , 17 ]. However, a randomized controlled study showed that the clinical pregnancy rate was not enhanced after HyCoSy flushing with water-soluble contrast media [ 18 ]. Research focused on the contrast medium showed that it was tubal flushing with oil-soluble contrast media that may increase the chance of pregnancy, whereas it was uncertain whether tubal flushing with water‐soluble contrast media improves those outcomes [ 19 ]. Interestingly, a recent study showed that endometrial blood distribution was improved after HyCoSy examination [ 20 ]. HyCoSy may have a therapeutic effect on improving spontaneous pregnancy among women with unexplained infertility by improving endometrial receptivity. The therapeutic effect of HyCoSy remains controversial. Further high-quality randomized controlled studies are needed for verification. Fallopian tube patency was significantly associated with the chance of spontaneous conception, which is consistent with previous studies [ 13 , 15 ]. The cumulative spontaneous pregnancy rate of women with one or both fallopian tubes patent was highest in the first 3 months after HyCoSy examination and then approached a plateau after 9 months. The results suggested that infertile women with at least unilateral tubal patency should be considered a certain time for expectant treatment. For patients with bilateral tube pathology, the cumulative spontaneous pregnancy rate was lowest (16.3%). Three out of 21 patients with both tubes obstructed became pregnant in the present study, which suggested that some cases of obstruction were misdiagnosed. Since it was difficult to achieve spontaneous conception among infertile patients with bilateral tube pathology, post-HyCoSy infertility intervention was necessary. A prospective study showed that 4D-HyCoSy could be a reliable examination in predicting the necessity of assisted reproductive technology for women with tubal factor infertility [ 10 ]. Similarly, our study proposed that 4D-HyCoSy could help predict the possibility of spontaneous conception in infertile women. In addition to assessing tubal patency via HyCoSy, we evaluated other clinical factors potentially affecting pregnancy outcomes. Univariate regression analysis revealed that age, duration of infertility, uterine cavity abnormalities, and endometriosis were significantly associated with spontaneous conception post-HyCoSy. A recent study aimed to develop a predictive model for natural pregnancy following 4D-HyCoSy. Their results identified age, infertility duration, endometrial thickness, and tubal patency as independent predictors of natural conception within three months after the procedure [ 21 ]. It should be emphasized that clinicians must combine the results of HyCoSy with information on patient age, ovarian reservation, history of pregnancy and delivery and other infertility factors [ 22 ]. There were two limitations in the present study. First, although the whole sample size was large, the sample size of patients with bilateral tube pathology was small. Quite a few patients with poor tube patency seeking assisted reproductive technology were excluded. Second, the retrospective design could not investigate the therapeutic effect of HyCoSy in spontaneous conception. Therefore, a large-scale, randomized controlled trial is needed to justify this assumption.

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