Comparison of pregnancy outcomes in infertile patients with different types of adenomyosis treated with high-intensity focused ultrasound

Abstract Objective This study assessed the improvement of symptoms and pregnancy outcomes in infertile patients with various types of adenomyosis who were treated with high-intensity focused ultrasound (HIFU). Materials and methods Between October 2017 and January 2022, 129 infertile patients with adenomyosis who wished to conceive were treated with HIFU. Based on the relationship between the adenomyotic lesion, the endometrium, and the subserosa of the uterus on magnetic resonance imaging, the adenomyotic lesions were divided into internal, external, intramural, and full-thickness types. Menstruation pain score, menstruation blood volume score, anti-Müllerian hormone (AMH) levels, reproductive results, pregnancy and delivery complications, and other clinical variables were compared among these four groups. Results Patients with external adenomyosis had the greatest menstrual distress, whereas patients with internal adenomyosis had the greatest menstrual blood volume. Dysmenorrhea and heavy menstruation were significantly improved after HIFU treatment in all groups. AMH levels were not significantly different before and six months after HIFU. Of the 129 patients, 50 (38.7%) became pregnant after HIFU, and patients with internal adenomyosis had the highest pregnancy rate. Patients with adenomyotic lesions located in the posterior wall of the uterus had a higher pregnancy rate than those with lesions located in the fundus of the uterus. Conclusions The classification of adenomyosis is closely related to distinctions in clinical symptoms and pregnancy outcomes. Infertile patients with different types of adenomyosis could be effectively treated with HIFU. HIFU can be considered as an option for infertile patients with adenomyosis who want to maintain their fertility.


Introduction
The term adenomyosis refers to the invasion of the endometrium into the uterine myometrium, which causes enlargement of the uterus and the development of an adenomyotic lesion [1].The prevalence of adenomyosis ranges between 20% and 25% in reproductive-age women, and the disease affects eight out of ten women between the ages of 40 and 50 years, compared to two out of ten women under 40 years of age [2,3].More than half of the patients report irregular bleeding, pelvic discomfort, and infertility [4][5][6].
Adenomyosis in premenopausal women was previously only identified by pathological examination following hysterectomy [7,8].Currently, the diagnosis of adenomyosis is more dependent on imaging methods such as magnetic resonance imaging (MRI) and transvaginal ultrasound scans [9].However, the precision of sonography appears to depend strongly on the operator [10][11][12].MRI is the gold standard for the noninvasive identification of adenomyosis in patients with infertility [13] and can clearly demonstrate the presence of adenomyosis with symmetric or asymmetric lesions of the internal or exterior layers of the myometrium [14].The normal junctional zone (JZ) is located immediately beneath the endometrium and represents the innermost compact layer of the myometrium [15].Patients with adenomyosis may exhibit focal or diffuse JZ hypertrophy.A JZ threshold thickness of 12 mm or greater is the most frequently cited diagnostic criterion for adenomyosis, and a measurement of less than 8 mm has a high negative predictive value for the presence of the disorder [16,17].According to the relationship between adenomyotic lesions and uterine structure revealed by MRI, adenomyosis is classified as follows: type I intrinsic (i.e.adenomyosis affecting only the interior uterine layer and not the outer layer); type II extrinsic (i.e.adenomyosis affecting the outer layer of the uterus but not the interior layer); type III intramural (i.e.adenomyosis residing alone, not involving the JZ or serosa); and type IV indeterminate (i.e.not matching subtypes I-III) [18].By enhancing these MRI classification criteria, Gong et al. recently confirmed the safety and success rate of high-intensity focused ultrasound (HIFU) treatments for patients with various subtypes of adenomyosis, and that MRI classification of adenomyosis is clinically important for predicting medium-term efficacy [19].
The treatment of adenomyosis remains an intense challenge in the field of gynecology.Hysterectomy is the only definitive cure for adenomyosis, but it is not suitable for patients who want to conceive in the future.As the boundary of the adenomyotic lesion is unclear, it is difficult to remove the lesion completely, and the recurrence rate after adenomectomy is very high, reaching 50% in some studies [20].As a noninvasive treatment, HIFU ablation has been utilized in the treatment of adenomyosis.Several studies have shown the pregnancy outcomes of HIFU treatment in patients with adenomyosis.A previous study showed that the clinical effectiveness rate was approximately 80% when the non-perfused volume (NPV, indicative of successful ablation) reached 70% or higher.However, it is not clear if the symptom improvement is related to the NPV ratio of the adenomyotic lesion, the adenomyosis subtype, or both [21,22].Therefore, this study aimed to evaluate the improvement and pregnancy outcomes of HIFU treatment in patients with various subtypes of adenomyosis and infertility based on the classification of MRI results.

Ethical considerations
The study was approved by the ethics committee of our institution (No.KS-LW-2023-001).The requirement for informed consent was waived due to the retrospective nature of this study.

Patients
A total of 129 infertile patients with adenomyosis who underwent HIFU at Liuzhou Maternal and Child Health Care Hospital in Guangxi, China, between October 2017 and January 2022 were reviewed retrospectively.
Inclusion criteria were as follows: (1) aged more than 18 years but younger than 45 years; (2) adenomyosis was diagnosed using medical history, transvaginal ultrasound, and MRI; (3) defined infertility (inability to conceive after a year of regular sex without the use of contraceptive measures); (4) desire to conceive; and (5) availability of comprehensive clinical data.Exclusion criteria included: (1) ongoing contraception or an asexual lifestyle after HIFU; (2) a partner who was infertile, or there were obvious causes of infertility other than adenomyosis; and (3) suspected or confirmed uterine malignant tumors.

MRI evaluation
All patients underwent pre-and one-day post-HIFU MRI evaluations with a 1.5 T MRI.A series of standard T1-weighted images (T1WI), T2-weighted images (T2WI), and contrastenhanced MRIs were performed on all patients.
According to the relationship between the adenomyotic lesion, the endometrium, and the uterine serosa, four types of adenomyotic lesions have been identified: internal adenomyosis in which the lesion occurs in the enlarged JZ but healthy muscle components are retained outside the adenomyosis region; external adenomyosis in which the lesion is positioned in the outer myometrium of the uterine wall, healthy muscular structures are retained between the adenomyotic lesion and junctional zone, and the junctional zone is intact and devoid of any abnormalities; intramural adenomyosis in which the lesion is confined to the myometrium, avoiding the JZ and serosa; and full-thickness adenomyosis in which the lesion develops in both the inner and outer layers of the uterus [19].

HIFU ablation
Before HIFU treatment, patients were required to ingest semi-liquid meals for two days, followed by ingestion of liquid food for one day, and then fast for 12 h, after which they received an enema before HIFU on the treatment day.Skin preparation included shaving the hair of the abdominal wall between the umbilicus and the superior border of the symphysis pubis, and thereafter degreasing and degassing with 75% ethanol and degassed water.A urinary catheter was inserted into the bladder, and the bladder volume was adjusted by infusing warm normal saline (40 C) to obtain a safe acoustic pathway.
HIFU treatment was performed under sedation (fentanyl at 0.8-1 lg/kg administered at 30-40-min intervals; midazolam hydrochloride, at 0.02-0.03mg/kg, administered at 30-40-min intervals) using the Focused Ultrasound Tumor Therapeutic System (Model-JC200, Chongqing Haifu Medical Technology Co., Ltd., China) equipped with an ultrasound imaging device (MyLab 70, Esaote, Genova, Italy) for real-time guidance during the procedure.The patients were required to report any discomfort during the procedure, and vital signs such as heart rate, blood pressure, respiration, and oxygen saturation were monitored.
The patients were placed carefully in a prone position, with the abdominal wall in contact with degassed water.A cold, degassed water balloon was placed on the abdominal wall to compress and push the bowel away from the acoustic pathway.The treatment began from the posterior to the anterior, from the inferior to the superior part of the adenomyotic lesion.The focus was kept at least 1.5 cm away from both the endometrium and the boundary of the adenomyosis.During the procedure, the sonication power was adjusted based on the feedback from the patients and the changes in grayscale on the ultrasound imaging.The treatment was terminated when the hyperechoic area covered the entire adenomyotic lesion or the contrast-enhancement ultrasound showed no blood supply in the lesion.The patients were asked to report any adverse effects during the procedure and after HIFU treatment.

Follow-up observation
Follow-up visits were arranged at 1, 3, 6, and 12 months following the treatments.Menstrual pain was measured using a visual analog scale: mild pain (1-3 points), moderate pain (4-6 points), and severe pain (7-10 points).The menstrual flow was evaluated using the Pictorial Blood Loss Assessment Chart (PBAC) method [23].Uterine volume and adenomyotic lesion volume were determined as ellipsoids using the following formula: volume ¼ 0.523abc.The variables a, b, and c denote, respectively, the uterine long, transverse, and anteroposterior dimensions as determined by MRI.Anti-M€ ullerian hormone (AMH) levels were examined prior to and six months after HIFU ablation to evaluate whether or not HIFU influenced ovarian reserve.To evaluate the reproductive outcomes of HIFU-treated patients, the number of women who became pregnant, the pregnancy interval, the delivery method, and complications during pregnancy were also recorded.

Statistical analysis
Statistical analysis was performed using SPSS (version 26.0; SPSS Inc., Chicago, IL, USA).Normally distributed data were presented as mean ± standard deviation (SD), whereas skewed distribution information was presented as median and interquartile ranges.For comparing variables between groups, a one-way analysis of variance or Kruskal-Wallis test was conducted; when a significant difference was observed, a post-hoc test was performed to identify the differences between subgroups.The Friedman test or paired t-test was utilized to compare the differences between different time periods within each group.The counting data were expressed as percentages (%), and the Chi-square test or Fisher exact test was used for comparison.When a significant difference was discovered, a posthoc Bonferroni test was used to confirm the subgroup differences.Using univariate and multivariate logistic regression analysis, the factors influencing pregnancy in patients after HIFU treatment were determined.Statistical significance was set at a p-value of <0.05.

Peri-HIFU treatment parameters and outcomes
There was no significant difference between patients with various subtypes of adenomyosis in terms of HIFU treatment settings and procedures.Each group of adenomyosis patients was treated using comparable sonication power, sonication time, and treatment time, resulting in equivalent energy efficiency factor (EEF).The NPV ratio in patients with internal adenomyosis was significantly higher than in patients with external adenomyosis and full-thickness adenomyosis.Patients with intramural adenomyosis had a significantly higher NPV ratio than patients with external adenomyosis (Table 2).

Adverse effects and complications
During the procedure, transient mild leg pain, gluteal pain, skin burning sensation, and lower groin pain were reported by patients.No serious complications occurred in this study.There were no statistically significant differences in adverse effects between patients with different types of adenomyosis (Table 3).

Improvement of dysmenorrhea
Before HIFU treatment, 127 of the 129 patients had menstruation pain.One patient with internal adenomyosis and one patient with intramural adenomyosis who did not experience menstrual pain before HIFU treatment were excluded from this statistical analysis.Patients with external adenomyosis had the highest menstrual discomfort level prior to HIFU.The menstrual discomfort level was lower in patients with internal adenomyosis than in those with full-thickness adenomyosis.
After HIFU treatment, the pain scores in each group decreased significantly.At one month following HIFU treatment, patients with internal adenomyosis had the lowest menstrual discomfort level.At 3 and 12 months following HIFU treatment, there were no statistically significant variations in pain scores between patients with different types of adenomyosis.At six months following HIFU treatment, the menstrual discomfort level was lower in patients with internal adenomyosis than in those with external adenomyosis (Table 4).

Improvement of menstruation blood volume
Before HIFU treatment, 28 patients in this study had varying degrees of heavy menstrual blood volume.This statistical analysis included 11 patients with internal adenomyosis, 5 patients with external adenomyosis, 5 patients with intramural adenomyosis, and 7 patients with full-thickness adenomyosis.Among them, patients with internal adenomyosis had the highest menstrual blood volume score.
After HIFU treatment, the menstrual blood volume score decreased significantly.At 3 and 12 months following HIFU treatment, there were no statistically significant differences in menstrual blood volume scores between patients with various forms of adenomyosis.At six months after HIFU treatment, the menstrual blood volume score was lower in patients with internal adenomyosis than in those with external and full-thickness adenomyosis.At three months following HIFU treatment, the menstrual blood volume scores for all 28 patients who had experienced heavy menstrual bleeding had decreased to normal (Table 5).

AMH levels
For the patients with internal adenomyosis, the mean AMH level was 2.9 ± 1.0 ng/mL before and 2.9 ± 1.0 ng/mL six months after HIFU treatment.For the patients with external adenomyosis, the mean AMH level was 3.0 ± 1.2 ng/mL before and 2.9 ± 1.1 ng/mL six months after HIFU treatment.For the patients with intramural adenomyosis, the mean AMH level was 3.2 ± 1.0 ng/mL before and 3.3 ± 1.0 ng/mL six months after HIFU treatment.In the patients with full-thickness adenomyosis, the mean AMH level was 3.1 ± 1.0 ng/mL before and 3.0 ± 1.0 ng/mL six months after HIFU treatment.There were no statistically significant differences in AMH levels between patients with different types of adenomyosis either before or six months after HIFU treatment, and there   were no significant differences in AMH levels between the two time points (Table 6).7).

Logistic regression analysis of variables influencing reproductive outcomes following HIFU therapy
To examine the determinants influencing reproductive outcomes, a univariate logistic regression analysis was conducted.We discovered no significant association between BMI, NPV ratio, adverse effects, uterine position, adenomyosis volume, and reproductive outcomes.Nevertheless, substantial variations in patient age, AMH levels, location of lesions (posterior vs. fundus), and types of adenomyosis (internal vs. full-thickness) were detected between the pregnant and non-pregnant groups.
We evaluated the link between age, AMH, adenomyosis type, lesion location, and reproductive outcomes to corroborate the results of the univariate logistic regression analysis.The pregnancy rate was substantially greater in patients with posterior adenomyosis compared to patients with fundus adenomyosis and significantly higher in patients with internal adenomyosis compared to patients with full-thickness adenomyosis.The results demonstrated that the pregnancy rate was substantially higher among patients under 35 years of age (Table 8).
Using the receiver operating characteristic curve, we then studied the relationship between AMH levels and pregnancy rates.According to the data, AMH had the highest Youden Index at 3.35.Our results demonstrated that patients with AMH levels over 3.35 ng/mL had substantially higher pregnancy rates (Figure 1).

Discussion
Adenomyosis has a significant impact on pregnancy rates.A previous study has shown that a thickened uterine wall, morphological distortion, and a larger uterus can affect the shape of the uterine cavity [1].Focused outer myometrial adenomyosis was independently associated and significantly correlated with primary infertility (adjusted odds ratio: 1.9; 95% confidence interval: 1.1-3.3)[24].In this assessment of the reproductive outcomes in patients with various types of adenomyosis after HIFU treatment, internal adenomyosis, external adenomyosis, intramural adenomyosis, and fullthickness adenomyosis were recorded in 40.3% (52/129), 27.1% (35/129), 13.2% (17/129), and 19.3% (25/129) of patients, respectively.No statistically significant variations in infertility between the various types of adenomyosis were discovered in our investigation; this finding may have been influenced by the limited sample size (Table 1).During a median of 26 (interquartile range: 20-35.5)months of followup, the pregnancy rate following HIFU treatment for patients with internal adenomyosis, external adenomyosis, intramural adenomyosis, and full-thickness adenomyosis was 59.6%, 22.9%, 17.6%, and 32.0%, respectively.After HIFU treatment, patients with internal adenomyosis had the highest pregnancy rate, and patients with internal adenomyosis had a higher natural pregnancy rate than those with external adenomyosis.There were no statistically significant differences in the pregnancy interval, miscarriage rate, rate of vaginal or cesarean delivery, or rate of delivery complications between patients with different types of adenomyosis after HIFU treatment (Table 7).According to a previous study, exogenous focal adenomyosis has a favorable reproductive prognosis after surgical treatment, whereas diffuse endogenous adenomyosis, particularly the asymmetric type, has a significant impact on pregnancy [25].Therefore, when examining the effect of adenomyosis subtypes on pregnancy outcomes, it is evident that we must refine the typing and consider different treatment strategies.Menstruation pain is generally the first complaint of patients with adenomyosis.In this study, 127 patients had menstruation pain before HIFU treatment, with patients with external adenomyosis experiencing the most severe pain and patients with internal adenomyosis experiencing less severe pain than those with full-thickness adenomyosis.A previous study revealed that outer myometrium lesions are more frequently associated with endometriosis, especially deep endometriosis, which may help explain this phenomenon [26].The average pain score decreased considerably after HIFU treatment in every group of patients, indicating that HIFU was effective at reducing menstrual pain in patients with different types of adenomyosis.Patients with internal adenomyosis experienced the least menstrual discomfort one month after HIFU treatment and less menstrual discomfort than those with external adenomyosis six months after HIFU treatment.At 3 and 12 months following HIFU treatment, there were no statistically significant variations in pain scores between patients with different types of adenomyosis (Table 4).
Our results also showed that patients with internal adenomyosis had the highest menstrual blood volume scores.A previous study suggested that the different stages of adenomyosis may be a key factor influencing menstrual volume scores [19].In this study, the menstrual blood volume score decreased significantly after HIFU.Our results showed that 6 months following HIFU, patients with internal adenomyosis had the lowest menstrual blood volume score, and the menstrual blood volume score was lower in patients with internal adenomyosis than in those with external and full-thickness adenomyosis.In contrast to the extrauterine myometrium, the medial myometrium differs not only structurally but also functionally from the extrauterine myometrium.The endometrium is hormone-dependent for cyclic contractions, which can be impaired in patients with adenomyosis, leading to autotrauma of the uterus and an increase in the endometrial area.This is particularly common in patients with internal adenomyosis, which may lead to increased menstrual flow [27,28].The most commonly held view is that the development of internal adenomyosis originates from endometrial invasion.After HIFU, the ectopic endometrium in the muscle layer was eliminated, reducing estrogen levels at the lesion site and cyclooxygenase-2 (COX-2), prostaglandin, and uterine motor function-related oxytocin receptor (OTR) levels [29].However, this does not sufficiently explain the significant reduction in menstrual flow in patients with internal adenomyosis six months after HIFU treatment compared to those with other types of the condition.Nevertheless, our findings provide a direction for future research.Irreversible coagulative necrosis of tissue in the focal area occurs during the treatment of internal adenomyosis; however, the physiological, molecular, and histological effects on the endothelial tissue of the extra-focal tissue and whether such effects are indeed reversible are unclear (Table 5).
Due to the fact that HIFU is considered a fertility-preserving treatment suitable for infertile patients, we have placed an emphasis on its safety.Two previous studies have demonstrated no statistical difference in AMH levels in patients with adenomyosis before and six months after therapy [30,31].This study provides substantial support for the safety of HIFU in terms of ovarian reserve.We consider it safe to recommend this treatment to women seeking future pregnancies in light of these findings (Table 6).Our results revealed that patients with internal adenomyosis had the highest pregnancy rates after HIFU.The natural pregnancy rate in the internal adenomyosis group was significantly higher than that in the external adenomyosis group.Additionally, the results of the multivariate logistic regression analysis showed that age, AMH levels, adenomyosis type, and location of lesions all had an impact on the pregnancy rate.A previous study showed that patients with posterior uterine wall adenomyosis had better HIFU postoperative reproductive results than those with anterior or lateral uterine wall adenomyosis, whereas patients with diffuse adenomyosis experienced less improvement in reproductive outcomes than those with focal adenomyosis [22].Our study also suggested that patients with posterior adenomyosis were much more likely to become pregnant than those with fundus adenomyosis, whereas patients with internal adenomyosis were significantly more likely to become pregnant than those with full-thickness adenomyosis.In a retrospective study, Won et al. analyzed 43 women who had undergone adenomyomectomy and wanted to conceive.Fifteen patients became pregnant after the surgery.Significant indicators of pregnancy success were younger ages and higher AMH levels [32].These findings are similar to the results of the present study.Our study revealed that the pregnancy rate was significantly higher among patients younger than 35 years of age and patients with AMH levels greater than 3.35 ng/mL (Table 8) (Figure 1).In a cross-sectional study, Pedachenko et al. observed that women with endometriosis and infertility had lower AMH levels than infertile women without endometriosis [33].Kim et al. investigated 58 post-hysterectomy uterine tissues for myoma and/or adenomyosis.They used immunohistochemical labeling and reverse transcriptasepolymerase chain reaction to find the AMH receptor II (AMHRII) in each tissue.Their study found AMHRII and AMHRII mRNA to be expressed at a high level in the adenomyosis tissue, implying that AMH may be examined as a biological modulator or perhaps as a potential treatment drug for adenomyosis expressing AMHRII [34].In our study, we found a considerably greater pregnancy rate in patients with AMH >3.35 ng/mL based on receiver operating characteristic curves and speculated that AMH has a potential prognostic role in pregnancy in adenomyosis; however, more research is required to substantiate this assertion.
As a noninvasive treatment, HIFU is performed under the guidance of ultrasound.The adenomyotic lesion was selectively ablated without damaging the surrounding structures.Thus, patients who undergo HIFU treatment can attempt to conceive more quickly than those who undergo surgical treatment and have a reduced likelihood of uterine rupture during pregnancy or delivery [35].Therefore, HIFU treatment is an attractive alternative to traditional surgical methods for patients who wish to conceive.Due to its mild clinical symptoms and signs, adenomyosis is often overlooked, but it is prevalent in patients with infertility, abortive failure, and recurrent miscarriages.The classification of adenomyosis is closely associated with its likely mechanism of occurrence, treatment strategies, and therapeutic efficacy.Therefore, prior to treatment, adenomyosis imaging should be adequately evaluated.
We conducted this retrospective study to evaluate the pregnancy outcomes, after HIFU treatment, of infertile patients with different types of adenomyosis based on MRI classification.This study had several limitations related to its design, being a retrospective analysis of patients from a single site.The study was further restricted by the limited number of samples of certain types.Additionally, several patients did not undergo MRI or ultrasound imaging to assess volumetric changes in adenomyotic lesions after treatment; therefore, the efficacy of HIFU could not be adequately demonstrated.In the future, our research center intends to use MRI-based adenomyosis classification to predict and analyze the pregnancy outcomes of patients, enhance our capacity for early diagnosis and intervention, and investigate the optimal treatment strategy based on pregnancy outcomes under various treatment plans.

Conclusions
This study confirms that the classification of adenomyosis is closely related to differences in clinical symptoms and pregnancy outcomes.When patients with infertility are suspected of having adenomyosis, it is advised that an MRI be performed as soon as feasible to clarify the diagnosis and classification.Infertile patients with different types of adenomyosis could be effectively treated with HIFU.HIFU can be considered an option for infertile patients with adenomyosis who want to maintain their fertility.
patient with internal adenomyosis and one patient with intramural adenomyosis who did not experience menstrual pain before HIFU treatment were excluded from this statistical analysis.a. Indicates a significant difference between patients with internal adenomyosis and patients with external adenomyosis (p < 0.01).b.Indicates a significant difference between patients with internal adenomyosis and patients with full-thickness adenomyosis (p < 0.01).c.Indicates a significant difference between patients with external adenomyosis and patients with intramural adenomyosis (p < 0.01).d.Indicates a significant difference between patients with external adenomyosis and patients with full-thickness adenomyosis (p < 0.01).e. Indicates a significant difference between patients with internal adenomyosis and patients with intramural adenomyosis (p < 0.01).

Table 1 .
Comparison of Baseline characteristics of patients between different types of adenomyosis.

Table 3 .
Comparison of adverse effects between different types of adenomyosis.

Table 4 .
Comparison of dysmenorrhea Severity pain scores between different types of adenomyosis.

Table 2 .
Comparison of HIFU treatment outcomes between different types of adenomyosis.

Table 5 .
Comparison of menorrhagia severity scores between different types of adenomyosis.patients with internal adenomyosis, 5 patients with external adenomyosis, 5 patients with intramural adenomyosis, and 7 patients with full-thickness adenomyosis who had heavy menstrual blood volume before HIFU treatment were included in this statistical analysis.a. Indicates a significant difference between patients with internal adenomyosis and patients with external adenomyosis (p < 0.01).b.Indicates a significant difference between patients with internal adenomyosis and patients with intramural adenomyosis (p < 0.01).c.Indicates a significant difference between patients with internal adenomyosis and patients with full-thickness adenomyosis (p < 0.01).

Table 6 .
Comparison of AMH level between different types of adenomyosis.

Table 7 .
Comparison of pregnancy outcomes between different types of adenomyosis.
Notes: a. Indicates a significant difference between patients with internal adenomyosis and patients with external adenomyosis (p < 0.01).b.Indicates a significant difference between patients with internal adenomyosis and patients with intramural adenomyosis (p < 0.01).c.Indicates a difference between patients with internal adenomyosis and patients with full-thickness adenomyosis (p < 0.05).

Table 8 .
Univariate and multivariate logistic regression analysis of factors influencing pregnancy outcomes after HIFU treatment.