Pregnancy outcomes following ultrasound-guided high-intensity focused ultrasound in submucous leiomyomas: a retrospective study

Abstract Objective To investigate the impact of ultrasound-guided high-intensity focused ultrasound (USgHIFU) on pregnancy in submucous leiomyomas. Materials and methods Between October 2015 and October 2021, a retrospective observational study was conducted at the Affiliated Hospital of North Sichuan Medical College, China, for 32 women with submucous leiomyomas who became pregnant after USgHIFU. Pregnancy outcomes, submucous leiomyomas characteristics, and USgHIFU parameters were analyzed. Results A total of 17 (53.1%) deliveries were successfully achieved, with full-term delivery in 16 (94.1%) patients and preterm delivery in 1 (5.9%). After USgHIFU, the effective volume in the uterus cavity and the volume of submucous leiomyomas shrank in all 32 patients. The median time to achieve pregnancy after USgHIFU was 11.0 months. Before pregnancy, myoma type was downgraded in 13 (40.6%) patients, stable in 10 (31.3%) and upgraded in 9 (28.1%). The vaginal expulsion rate of submucous leiomyomas was 28.1%, with complete expulsion in 3 (9.4%) patients and partial expulsion in 6 (18.8%). After USgHIFU, the size of submucous leiomyomas did not increase in each trimester (all p > 0.05). The high complications rate during pregnancy (7/17, 41.2%) was associated with advanced maternal age, with only one (5.9%) premature rupture of membranes possibly associated with submucous leiomyomas. There were 6 (35.5%) vaginal delivery and 11 (64.7%) cesarean sections. All 17 newborns developed well, with a mean birth weight of 3482 g. Conclusions In patients with submucous leiomyomas, pregnancies and full-term deliveries can be successfully achieved following USgHIFU, with few related complications.


Introduction
Submucous leiomyomas are partially or entirely located in the uterine cavity at the time of diagnosis, depending on their relationship to the uterine wall [1].Most patients present with clinical symptoms due to endometrial cavity distortion when submucous leiomyomas grow in a specific location adjacent to the endometrium.Submucous leiomyomas are associated with abnormal uterine bleeding [2,3], infertility [4,5], and miscarriages [6][7][8].Women with submucous leiomyomas had a significantly lower clinical pregnancy rate, implantation rate, and live birth rate and a considerably higher spontaneous abortion rate compared to infertile women without submucous leiomyomas [8].
The ideal treatment of submucous leiomyomas should be noninvasive or minimally invasive to preserve the uterus and fertility.Hysteroscopic myomectomy (HM) is the gold standard conservative surgical therapy for managing submucous leiomyomas no larger than 5 cm [1,9,10].Regardless of a cold knife or hot knife, monopolar or bipolar electro section, HM is effective for submucous leiomyomas, but the indications differ.However, the larger the size and the higher the grade of the submucous leiomyomas, the lower the onestep success rate and the more serious the complications are [10][11][12].In HM, the highest incidence of uterine perforation is 4.1% [13], the incidence of intrauterine adhesions varies from 1.5-20.5% [14], and the re-intervention rate after surgery ranges from 7-29% [9], limiting the application of hysteroscopic surgery in submucous leiomyomas, especially in large type 2 submucous leiomyomas.Although the benefit of HM for improving clinical pregnancy in subfertile women cannot be ruled out, there is no clear consensus regarding the effect of HM on fertility in women with submucous leiomyomas [15][16][17].Meanwhile, it is unknown whether HM reduces the risk of miscarriage in women with submucous leiomyomas.As a result, it is critical to investigate alternative procedures that may increase fertility.
Although uterine artery embolization (UAE) is a minimallyinvasive treatment for submucous leiomyomas, there is no clear consensus on how UAE affects fertility [18].UAE has been linked to miscarriage, prematurity, and low birth weight, because it can impair ovarian reserve and cause severe intrauterine adhesion [18][19][20].As a noninvasive treatment, the therapeutic mechanism of high-intensity focused ultrasound (HIFU) involves thermal and cavitation effects [21].Patients with HIFU treatment for uterine leiomyomas can have full-term deliveries with no additional obstetric risks or serious perinatal complications [20,22].Many studies have shown that HIFU is effective and safe for submucous leiomyomas [23][24][25].Still, there has been no report on the pregnancy outcomes of patients with submucous leiomyomas who have received HIFU treatment.
In this retrospective study, we investigated pregnancy outcomes after ultrasound-guided high-intensity focused ultrasound (USgHIFU) treatment in reproductive-age women with submucous leiomyomas.

Materials and methods
This retrospective study was approved by the ethics committee of Affiliated Hospital of North Sichuan Medical College (No. 2022ER071-1).Patient data were anonymized and protected according to national standards.

Patients
In this 6-year study, 366 premenopausal patients received USgHIFU treatment for submucous leiomyomas at the Affiliated Hospital of North Sichuan Medical College (China).The pregnancy rate after USgHIFU was 27.9% (17/61) in those who attempted to conceive, and 4.9% (15/305) in those who were unwilling to conceive.Finally, 32 patients with submucous leiomyomas who became pregnant after USgHIFU treatment between October 2015 and October 2021 were included (Table 1).
Patients were included if they had type 1 or type 2 submucous leiomyomas diagnosed by pelvic color Doppler ultrasound and pelvic magnetic resonance imaging (MRI), if they were premenopausal women with solitary submucous leiomyoma with a maximum diameter of more than 2.5 cm, and if they did not have severe systemic diseases.Exclusion criteria included: patients with malignant or suspected malignant tumors, type 0 submucous leiomyomas, type 2-5 uterine leiomyomas or absolute contraindications to USgHIFU.
The length (D1), thickness(D2) and width (D3) of each target submucous leiomyoma were measured, and the submucous leiomyoma volume was calculated using the following formula: [26].The effective volume in the uterus cavity of submucous leiomyomas was defined as the volume of the part of the submucous leiomyomas that protrude into the uterine cavity.The inner protrusion ratio was defined as the ratio of the effective volume in the uterine cavity to the volume of submucous leiomyomas [26].

USgHIFU therapy
HIFU treatment was performed using a Focused Ultrasound Tumor Therapeutic System (Model-JC200, Chongqing Haifu Medical Technology Co. Ltd., Chongqing, China).The patient was positioned prone on the USgHIFU table, with the anterior abdominal wall in contact with degassed water.To compress and push the bowel away from the acoustic pathway, a degassed water balloon was placed between the abdominal wall and the transducer [26].Point sonication was used, with the power set to 300-400 watts.The focal point was set at 0.5 cm away from the endometrium to avoid endometrial damage.During treatment, patients were asked to lie still to report any discomfort.The therapy was terminated when a significant grey-scale change was observed in the entire treatment area on the ultrasound image or when the therapeutic dosage was reached.To evaluate the effectiveness of ablation, color Doppler ultrasonography and contrastenhanced ultrasound (CEUS) were performed (Figure 1(A)).Sonication time (i.e., time of HIFU ablation in seconds or s), treatment intensity (s/h; sonication time Â 60/treatment time), and non-perfused volume ratio (%; the volume of nonperfused region/volume of target fibroid tumor Â 100%) were all recorded.

Adverse effects
Based on the society of interventional radiology (SIR) classification system for complications by the outcome, in conjunction with the application of HIFU in gynecology, the severity of adverse effects was classified as follows [27,28]: (1) Class A: no therapy, no consequence; (2) Class B: nominal therapy, no consequence; (3) Class C: require therapy, minor hospitalization (<48 h); (4) Class D: required major therapy, unplanned increase in the level of care, prolonged hospitalization (>48 h); ( 5) Class E: permanent adverse sequelae; (6) Class F: death.In this system, Class A and B were considered to be minor complications.

Follow up
After HIFU treatment, patients were included in long-term management.Outpatient follow-up and imaging reviews were done regularly.Additionally, pregnancy outcomes were regularly queried and monitored.

Statistical analysis
We used SPSS version 22.0 (SPSS, Inc, Chicago, IL, USA) for statistical analysis, and a P value <0.05 was considered statistically significant.The mean ± standard deviation was reported for quantitative data with a normal distribution, which was compared using the t-test.On the other hand, the Mann-Whitney U test was used to analyze variables expressed as medians (interquartile range).

Baseline characteristics
As shown in Table 1, the mean age of these participants was 35.5 years (range, 24-45 years).Most patients with submucous leiomyomas were symptomatic, with hypermenorrhea in 20 (62.5%) cases, a history of miscarriage and (or) sterility in 10 (31.3%), and both of these in 6 (18.8%).

USgHIFU treatment parameters in patients who became pregnant
The HIFU treatment parameters for submucous leiomyomas in 32 patients who became pregnant were shown in Table 3.The average HIFU sonication time was 615.5 s, ranging from 190 s to 1587s.The mean delivered energy was 271825 ± 142556 J, ranging from 57000 J to 634800 J.The mean non-perfused volume ratio was 82.6 ± 9.8 percent, ranging from 65.7-96.9%.All HIFU treatments were completed successfully, and gray-scale changes were observed in all 32 patients during surgery, with overall gray-scale change in 24 cases (75.0%) and lumpy gray-scale change in 8 cases (25.0%).Adverse events occurred in 16 patients (50.0%), all of which were SIR A or B level, with lower abdominal pain in 12 cases (37.5%), 'Hot' skin sensation in 4 patients (12.5%), and no serious adverse events.

Pregnancy outcome of 32 women after USgHIFU treatment
As shown in Table 4, following HIFU treatment, both the effective volume in the uterus cavity and the volume of submucous leiomyomas shrank in all 32 patients.Submucous leiomyomas were primarily type 2 in 32 patients who became pregnant after USgHIFU, with 27 (84.4%)cases of type 2 and 5 (15.6%) cases of type 1 (Table 2).Myoma type was downgraded in 13 cases (40.6%), stable in 10 cases (31.3%), and upgraded in 9 cases (28.1%).After subgroup analysis according to myoma type, type 2 was downgraded in 10 cases (37.0%), stable in 8 cases (29.6%), and upgraded in 9 cases (33.3%).And type 1 was downgraded in 3 cases (60.0%) and stable in 2 cases (40.0%).After HIFU treatment, the ratio of vaginal expulsion of submucous leiomyomas was 28.1%, with complete expulsion in 3 cases (9.4%) and partial expulsion in 6 cases (18.8%).The mean maternal age at conception was 36.8 years (range, 25-45 y), with a median time to pregnancy after HIFU treatment of 11.0 months (range, 1 month to 41 months).Termination of pregnancy occurred in 15 cases (46.9%) due to an unplanned pregnancy, and delivery occurred in 17 cases (53.1%), with full-term delivery in 16 cases (94.1%) and preterm delivery in 1 case (5.9%).

Obstetric characteristics of 17 deliveries after USgHIFU treatment
As shown in Table 5, the natural conception rate in these 17 deliveries was 88.2% (15/17) and the remaining 11.8% (2/17) were in vitro fertilization (IVF) pregnancies.The median time from conception to pregnancy was 11.0 months (range, 1-39 m).After HIFU treatment, both the effective volume in the uterus cavity and the volume of submucous leiomyomas shrank in all 17 patients (Figure 1(B,C)).The maximum diameter of submucous leiomyomas was 3.0 ± 1.5 cm (range, 1.0-6.6 cm) before pregnancy.Although the size of submucous leiomyomas gradually increased with the pregnancy and gestational weeks after HIFU treatment, there was no significant growth of submucous leiomyomas at each trimester, i.e., 3.3 ± 1.7 cm (range, 1.0-7.2cm) in early pregnancy (Figure 1(D)), 3.4 ± 1.8 cm (range, 1.0-7.6 cm) in middle pregnancy, and 3.5 ± 1.9 cm (range, 1.0-7.8cm) in late pregnancy (All p > 0.05).

Complications associated with pregnancy after USgHIFU treatment
The complications discovered during pregnancy (7/17, 41.2%) included 3 (17.6%)cases of gestational diabetes mellitus, 2 (11.8%) cases of subclinical hypothyroidism, 1 (5.9%) case of premature rupture of membranes (PROM) and 1(5.9%) case of fetal foramen oval opening limitation.There were 4 (29.4%)cases with placenta implantation at prior submucous leiomyomas locations.Still, it did not increase blood loss during delivery, with mean quantities of blood loss of 300 ml (range, 200-1100 ml).Among them, postpartum hemorrhage occurred in 2 (11.8%) cases.One is a vaginal delivery case with a bleeding volume of 600 ml due to manual and incomplete placental removal.Another case was a cesarean section for dystocia, with a bleeding volume of 1100 ml due to hypotonic uterine inertia.There were 6 (35.5%) cases of vaginal delivery and 11 (64.7%)cases of cesarean section.Only 1 (9.1%) case of indications for cesarean section was related to HIFU treatment, despite concerns about the risk of uterine rupture after HIFU treatment.The mean birth weight of the 17 newborns was 3482 ± 246 g (range, 3090-4090 g).

Discussion
In the report of successful pregnancies and full-term deliveries after USgHIFU treatment for uterine leiomyomas, the number of submucous leiomyomas cases is very small [29][30][31][32][33][34].Furthermore, there is no separate evidence of submucous leiomyomas data, such as the characteristics of submucous leiomyomas, USgHIFU treatment parameters, and improvement of submucous leiomyomas after USgHIFU treatment.
According to our findings, pregnancies and full-term deliveries can be successfully achieved with few related complications in women with submucous leiomyomas after fertility-sparing noninvasive treatment of USgHIFU.To the best of our knowledge, our study is the first to report the pregnancy outcomes after USgHIFU treatment for submucous leiomyomas.During the 6-year study period, 32 patients with submucous leiomyomas became pregnant, and 17 (53.1%)deliveries were successful, with full-term delivery in 16 (94.1%)cases and preterm delivery in 1 (5.9%).Although the termination rate of pregnancy was relatively high (46.9%) in this study, USgHIFU treatment for submucous leiomyomas did not promote the termination rate of pregnancy in women who attempted to conceive.Because all termination of pregnancy occurred in women without the desire to conceive.After USgHIFU treatment for submucous leiomyomas, the pregnancy outcomes improved in women with a history of miscarriage and (or) sterility.Ten out of 32 (31.3%) patients became pregnant, and eight out of seventeen (47.1%) successful deliveries had a history of miscarriage and/or sterility.
On the contrary, due to a lack of evidence, the effect of HM on fertility in women with submucous leiomyomas remains controversial as a first-line uterine preservation therapy [16,17].Additionally, we found that after USgHIFU treatment for submucous leiomyomas, women could become pregnant and achieve successful delivery, regardless of the type, location and T2 signal intensity on MRI of submucous leiomyomas.Among the women who delivered successfully, the mean maximum diameter of submucous leiomyomas was 4.8 cm before HIFU treatment, with the largest size of 8.2 cm and the smallest size of 2.8 cm.The median volume of submucous leiomyomas was 30.1 cm 3 , ranging from 11.0 cm 3 to 238.4 cm 3 .Both the size and volume of submucous leiomyomas were the largest known to date [29][30][31][32][33][34][35].
The effective volume in the uterine cavity of submucous leiomyomas in determining fertility has never been reported before.In the reports that HM can effectively improve the pregnancy rate, complete or partial resection of submucous leiomyomas was decisive, which eliminated or reduced the impact on the uterine cavity morphology [8,36,37].The effective volume in the uterine cavity of submucous leiomyomas disappeared or decreased correspondingly with the complete or partial removal of submucous leiomyomas.In this study, the USgHIFU treatment was effective for submucous leiomyomas.The volume of submucous leiomyomas shrank in all patients after USgHIFU treatment.The D1, D2 and (or) D3 of the part of submucous leiomyomas in the uterine cavity reduced, along with the shrinkage of submucous leiomyomas.With the uterine contraction, the ratio of the size of submucous leiomyomas in the uterine cavity to the size of submucous leiomyomas may change, which could lead to conversion of the submucous leiomyomas type.First, because the type was upgraded from type 2 to type of intramural leiomyomas, the effective volume in the uterus cavity of submucous leiomyomas disappeared along with the reduction in the volume of submucous leiomyomas, which could improve fertility.Second, because of the downgraded or stable type, the effective volume in the uterine cavity shrank, along with the reduced volume of submucous leiomyomas.This is comparable to the partial resection of submucous leiomyomas which may improve fertility by reducing the impact on the uterine cavity morphology.Finally, due to the downgraded type and reduced effective volume in the uterus cavity, vaginal expulsion of submucous leiomyomas, especially the complete expulsion, could improve fertility.Therefore, submucous leiomyomas were primarily type 2 in women who became pregnant after USgHIFU.Compared with type 1 with the same size, the effective volume in the uterine cavity of submucous leiomyomas of type 2 was relatively smaller and may be more likely to disappear or decrease after USgHIFU treatment.Furthermore, Patients with type 1 submucous leiomyoma tended to accept HM as another reason.The size of this part determines the symptoms of the submucous leiomyomas.
Compared to women with uterine leiomyomas (13.6 ± 9.5 months), those with submucous leiomyomas had a shorter time to achieve pregnancy after USgHIFU treatment [38].Both the effective volume in the uterine cavity and the volume of submucous leiomyomas shrank prior to pregnancy in all 17 patients who delivered successfully.There was no increase in the size of submucous leiomyomas after HIFU treatment during pregnancy.The high incidence of complications associated with pregnancy after USgHIFU treatment may be related to the age at delivery (34.9 ± 4.9 years, ranging from 26-44 y) (Table 5).Women with advanced maternal age (AMA, !35 years) were more likely to suffer from gestational diabetes mellitus, subclinical hypothyroidism, and PROM [39,40].Among the complications, only one case of PROM may be related to submucous leiomyomas.However, it does not indicate that it was associated with HIFU.Although the effective volume in the uterus cavity and the volume of submucous leiomyomas shrank before pregnancy, the occurrence of placental abnormality and bleeding during pregnancy and delivery should be emphasized due to residual submucous leiomyomas.Previous research found that the ratio of placenta implantation at a prior myomectomy site was 58.3% (14/24) after HM [41] and 29.4% after HIFU treatment.HIFU treatment did not increase the blood loss during delivery, with the mean amount of blood loss of 300 ml (range, 200-1100ml), which was lower than that after a single-step HM (541 ml) [41].There is currently no evidence of uterine rupture during pregnancy following HIFU treatment for submucous leiomyomas, which may be an advantage of HIFU treatment over HM [42].It is unnecessary to consider the uterus after HIFU treatment as scarred uterus while there were no related complications, but more evidence is required to support this conclusion.
This study has some limitations that should be considered.For example, because this was a retrospective study, we could not take into account enough factors affecting pregnancy.Furthermore, HIFU pretreatment was not compared with other procedures or a control group.More prospective and controlled studies are needed to verify fertility improvement after HIFU treatment of submucous leiomyomas.

Conclusions
The volume of submucous leiomyomas and the adequate volume in the uterus cavity can be effectively reduced with USgHIFU treatment.Pregnancies and full-term deliveries can be accomplished with few complications, with vaginal delivery being feasible.More attention should be paid to uterine contractions and postpartum hemorrhage during delivery.interpretation of the data and analyses.All of the authors have read and approved the manuscript.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The work was supported by the Bureau of Science and Technology Nanchong City under Grant [19SXHZ0338] and Affiliated Hospital of North Sichuan Medical College [2021LC005].

Figure 1 .
Figure 1.A 33-year-old woman, with a history of miscarriage, achieved a successful full-term delivery via cesarean section after USgHIFU treatment for type 2 submucous leiomyoma.The maximum diameter was 4.2 cm, with an effective volume in the uterus cavity of 6.1 cm 3 and a volume of submucous leiomyoma of 27.2 cm 3 .The contrast-enhanced ultrasound revealed no perfusion of uterine lesion immediately after the surgery (arrow pointing in Figure A).One year after USgHIFU treatment, both the effective volume in the uterine cavity and the volume of submucous leiomyoma shrank obviously (arrow pointing in Figure B in the sagittal plane and Figure C in the coronal plane).The maximum diameter was 2.4 cm, with an effective volume in the uterus cavity of 3.0 cm 3 and a volume of submucous leiomyoma of 6.0 cm 3 .After 16 months, pregnancy was achieved.Gestational sac (blue arrow pointing in Figure D) was seen along with the reduced residual submucous leiomyoma, with a maximum diameter of 2.2 cm (white arrow pointing in Figure D).USgHIFU, ultrasound-guided high-intensity focused ultrasound.

Table 1 .
Baseline characteristics of the 32 patients with submucous leiomyomas who became pregnant after USgHIFU treatment.

Table 2 .
Characteristics of submucous leiomyomas in 32 patients who became pregnant after USgHIFU treatment.

Table 3 .
HIFU treatment parameters for submucous leiomyomas in 32 patients who became pregnant.

Table 4 .
Pregnant characteristics of 32 pregnant women after USgHIFU treatment.