Successful pregnancies in women with diffuse uterine leiomyomatosis after high-intensity focused ultrasound ablation: report of three cases

Abstract Objective To describe the reproductive outcomes of patients with diffuse uterine leiomyomatosis (DUL) treated with high-intensity focused ultrasound (HIFU) ablation. Materials and methods Three patients of reproductive age with DUL who underwent HIFU treatment were enrolled, all of whom had a strong desire to become pregnant. All patients underwent routine laboratory tests, electrocardiography (ECG), chest X-ray radiography, ultrasound, and magnetic resonance imaging (MRI) examinations after routine medical history collection and physical examination. The treatment time, treatment power, sonication time, and adverse events were recorded. One day after HIFU, MRI was performed to evaluate treatment efficacy. The patients were scheduled for follow-up at 3-, 6-, 12-, and 24-month after HIFU treatment. Results All the three patients completed HIFU treatment successfully without any major complication. Uterine size and menstrual volume significantly decreased with the combination of medical and HIFU treatments. The shrinkage rate of uterine volume was 31–44% and the menstrual volume reduced by 1/2 or returned to normal at 3 months post-HIFU. Three patients had successful conceptions between 3 and 11 months after HIFU with healthy deliveries. No uterine rupture occurred during pregnancy and delivery. Conclusion HIFU ablation may help achieve a successful pregnancy in patients with DUL.


Introduction
Diffuse uterine leiomyomatosis (DUL) is a rare condition that usually affects young women of reproductive age [1].Under these conditions, the uterus is symmetrically enlarged with the myometrium replaced by innumerable ill-defined, small smooth muscle nodules that range from a few millimeters to several centimeters in diameter and may cause menorrhagia, infertility, and postpartum hemorrhage [2,3].To date, hysterectomy has been the only definitive treatment for this condition [2,4], as the diffuse nature of the lesion makes it difficult to perform a complete myomectomy with excision of all myomatous nodules.However, for patients who have reproductive desires, it is necessary to explore an alternative treatment strategy that can preserve uterine function and fertility.In this case report, we report the reproductive results of three DUL patients who were successfully treated with high-intensity focused ultrasound (HIFU).

Cases presentation
The patients in this case report were recruited from the Chongqing Haifu Hospital (cases 1 and 2) and the Affiliated Hospital of Zunyi Medical University (case 3).The protocol for this case report was approved by the ethics committee of our institute (NO.CQMU-2021011) and the requirement for informed consent was waived.
All patients underwent routine laboratory tests, electrocardiography (ECG), chest X-ray, ultrasound, and magnetic resonance imaging (MRI) examinations after routine medical history collection and physical examination.
The patients were requested to complete specific bowel preparation before HIFU treatment.They were asked to ingest semi-liquid or liquid food 2 days prior HIFU treatment first, followed by an enema on the morning of the HIFU treatment day after a 12 h fasting.Routine skin preparation was mandatory and every patient was requested to shave her abdominal wall from the lower edge of the umbilicus to the upper margin of the pubic symphysis, and then degreasing and degassing the skin with 70% of ethanol and degassed water.Before HIFU treatment, a urinary catheter was inserted to adjust the bladder volume by infusing normal saline during the procedure of HIFU treatment to obtain a safe acoustic pathway.
The procedure of HIFU treatment was described previously [5,6].Briefly, HIFU treatment was performed using a Focused Ultrasound Tumor Therapeutic System (Model JC or JC200; Chongqing Haifu Medical Technology Co. Ltd., China) with an ultrasound imaging device for treatment guidance.Therapeutic focused ultrasound energy was produced by a transducer with a diameter of 20 cm, a focal length of 15 cm, and a frequency of 0.8 MHz.Each patient was carefully positioned prone on the HIFU table.The anterior abdominal wall was in contact with degassed water in the reservoir under HIFU table and a degassed water balloon was placed between the abdominal wall and the transducer.The procedure of HIFU ablation was performed under conscious sedation.The sagittal ultrasound scanning mode was selected for both planning and sonication.The targeted nodules were divided into sections at a distance of 5 mm between the two sections.A point scan energy delivery was used, and the treatment power of 300-400 W was used based on feedback of patients from patients.The treatment was terminated when the increased grayscale covered the treated nodules, and a contrast-enhanced ultrasound was performed immediately after HIFU.Additional treatment was then performed if the contrast-enhanced ultrasound showed an unsatisfactory nonperfused volume (NPV) ratio.One day post-HIFU, MRI was performed to evaluate treatment efficacy.The patients were scheduled for follow-up at 3-, 6-, 12-, and 24-months after HIFU treatment.

Case 1
A 26-year-old woman presented with menorrhagia and dysmenorrhea for 6 years and infertility for more than 1 year, with a uterine size of 110 Ã 104 Ã 103 mm.MRI revealed more than 30 leiomyomas measuring 0.3-5 cm in diameter, distributed in all aspects of the endometrial cavity and throughout the myometrium (Figure 1(A and B)).Considering the safety of HIFU treatment, two sessions of HIFU ablation were planned because of the large size of the uterus.
The patient underwent the first HIFU treatment session on August 17, 2016.Leiomyomas adjacent to the endometrium were treated first.The sonication power used was 400 W, the total treatment time was 215 min, and the sonication time was 3100s.One day post-HIFU, MRI revealed satisfactory ablation results for the targeted leiomyomas (Figure 1(C)).The patient reported that her menstrual volume reduced by 1/2, and dysmenorrhea was completely relieved, and the uterine volume reduced by 37% at 3 months post-HIFU.The patient underwent a second session of HIFU treatment on November 30, 2016.The sonication power used was 400 W, the treatment time was 220 min, and the sonication time was 2700s.One day post-HIFU, MRI showed a satisfactory ablation volume in the remaining leiomyomas (Figure 1(D)).No serious complications occurred during the HIFU treatment.The patient was discharged from the hospital after the post-HIFU MRI examination.Thereafter, she received three cycles of gonadotropin-hormone-releasing analogues (GnRHa) treatment and conceived spontaneously 11 months after the last HIFU treatment session.The patient underwent routine antenatal care and had an uneventful pregnancy.The patient underwent cesarean section at term due to her own concerns about the risk of vaginal delivery and delivered a healthy baby.The placenta was removed without difficulty, with good uterine contraction and no signs of postpartum hemorrhage.

Case 2
A 32-year-old gravida 1, para 0 woman who underwent HIFU treatment for DUL 2 years earlier at an outside hospital presented to our hospital with an enlarged uterus measuring the uterine size 114 Ã 69 Ã 94 mm.The pre-HIFU MRI revealed four main submucosal leiomyomas with size of 0.5-2.0cm in diameter adjacent to the uterine cavity, and more leiomyomas ranging from 1 cm to 6 cm in diameter in the myometrium (Figure 2 (A and B)).Due to the large number of uterine leiomyomas, we scheduled to ablate the leiomyomas in two sessions after a full discussion with the patient.The first session of HIFU treatment targeted the main leiomyomas, which may have been the cause of her symptoms.The sonication power used was 400 W, the total treatment time was 210 min, and the sonication time was 3348s.Post-HIFU MRI revealed that a satisfactory ablation volume was achieved (Figure 2(C)).Thereafter, the patient received three cycles of GnRHa treatment, and a follow-up MRI revealed that the volume of the uterus decreased by 44% at 3 months post-HIFU.We then performed a second session of HIFU treatment to ablate the rest of the leiomyomas, and a satisfactory ablation volume was achieved (Figure 2(D)).The patient conceived spontaneously three months later and underwent routine antenatal care.She had an uneventful pregnancy and underwent a cesarean section at term because she was worried about the risk of vaginal delivery and delivered a healthy baby with an uneventful postpartum recovery.

Case 3
A 27-year-old woman presented with infertility and severe menorrhagia (hemoglobin, 78 g/L) at the Affiliated Hospital of Zunyi Medical University.The uterus measured 107 Â 82 Â 98 mm in size, with eight submucosal fibroids ranging between 0.8 cm and 3.6 cm in diameter, and more than 20 smaller fibroids disseminated throughout the myometrium (Figure 3(A andB)).The first session of HIFU treatment was performed on 18 November 2020, to target relatively large fibroids adjacent to the endometrium to alleviate the symptoms of menorrhagia and repair the morphology of the uterine cavity.The sonication power used was 400 W, the total treatment time was 105 min, and the sonication time was 1080s.Contrast-enhanced ultrasonography immediately after HIFU ablation revealed a satisfactory ablation volume (Figure 3(C and D)).MRI at 6 months post-HIFU showed a relatively normal uterine cavity and a significantly decreased uterine volume without administering any medication (Figure 3(E and F)).To further improve the symptoms, the patient received a second session of HIFU treatment on 22 June 2021, with three months of subsequent hormonal treatment.After the second HIFU treatment, menstrual volume, periods, and cycles became normal, and no dysmenorrhea was observed.Spontaneous conception occurred in April 2022, 10 months after HIFU ablation.The patient underwent routine antenatal care and had an uneventful pregnancy.She underwent cesarean section at term due to her own choice and delivered a healthy baby with an uneventful postpartum recovery.

Discussion
As a novel non-invasive treatment, HIFU ablation has proven to be safe and effective in the management of multiple uterine leiomyomas [7,8].However, only a few cases of DUL Figure 3. MRI obtained from a 27-year-old patient with DUL.(A&B) the pre-HIFU treatment T2-weighted imaging showed that the uterus,107mm Â 85mm Â 100 mm in size, was pervaded with tumors of varied sizes in the myometrium, which mainly was Isointense on T2WI.(C&D) the contrast-enhanced ultrasound showed non-perfusion in most of the leiomyomas immediately after HIFU treatment.(E&F)T2-weighted image revealed the uterus was 104 mm Â 81mm Â 89 mm in size, with a 17.6% shrinkage at 6 months compared to its initial volume prior to the treatment.treated with HIFU have been reported, and to our knowledge, no study has investigated the effect of HIFU on fertility in patients with DUL [9,10].This report presents encouraging results regarding the treatment of young women with DUL.The strengths of this treatment include preservation of the uterus, avoidance of extensive myometrial wounding with recovery from menorrhagia, and a satisfactory outcome of improved clinical symptoms and fertility.
DUL is a rare, benign disease, but treatment of patients with DUL who wish to remain fertile is a challenge.Owing to the diffuse nature of leiomyomas, it is impossible to identify the masses and remove the tumors completely [11,12].Grignon et al. were the first to report pregnancy after conservative surgery.Their patient achieved pregnancy and delivered a live birth after enucleation, but total hysterectomy was performed postpartum due to placenta accreta [13].
Conservative treatments for DUL other than myomectomy include hormonal therapy, uterine artery embolization (UAE), and HIFU treatment [14][15][16][17][18][19].Purohit et al. reported a patient with natural pregnancy after GnRHa administration [14].If leiomyomas protruding into the uterine cavity disappear with GnRHa therapy, successful pregnancy with GnRHa therapy may be anticipated.However, in many cases, hormonal therapy alone has not been successful, and is usually used in conjunction with surgery [2].Koh et al. reported on a patient who became pregnant after treatment with UAE [18].However, pregnancy after UAE is controversial when it is desired after treatment [15].Yen et al. performed hysteroscopic myomectomy in five patients with DUL, and three patients who wished to conceive achieved pregnancy and live births [3].However, it is mainly suitable for patients with early stage DUL if the submucosal leiomyomas are small and few.
In this case series, HIFU treatment was performed under ultrasound guidance, and the leiomyomas could be precisely ablated without injuring normal adjacent tissues [9].In our study, we did not attempt to clean out all leiomyomas at once but ablated the nudules in batches because of the large number of leiomyomas and a comparatively larger uterus with sizes of 14 to 16 weeks of gestation.HIFU treatment first targeted submucosal and intramural leiomyomas to reduce the negative effects of DUL on infertility and symptoms.Some nodules may have a tendency to spontaneously expel after HIFU ablation.Thus, HIFU treatment contributed to a progressive reduction in uterine size and reconstruction of the endometrium and uterine cavity, and may result in fertility.In this case report, one patient conceived spontaneously 3 months after HIFU treatment, while the other two patients conceived in one year without any signs of abortion, bleeding, or uterine rupture.
GnRH-a treatment followed HIFU treatment in all three patients in this case report, which may be one reason for our encouraging results.Although there is no evidence that treatment with GnRH-a increases the pregnancy rate, one patient with DUL achieved pregnancy with GnRH-a therapy alone [3].In addition, GnRH-a is widely considered useful for preoperative treatment before hysteroscopic myomectomy [2].A recent study described successful pregnancy following a 6-month course of hormonal therapy with subsequent hysteroscopic myomectomy [19].Therefore, GnRH-a therapy is recommended for patients after HIFU treatment and has achieved encouraging results.
Complications related to pregnancy in women with DUL are reported to include miscarriage, preterm delivery, and intrapartum hemorrhage [2,13].These are similar to the generally recognized complications of pregnancy in women with uterine leiomyomas [20].However, in the present study, pregnancy-related complications did not increase during the prepartum, intrapartum, or postpartum periods despite the short interval between ablation and pregnancy.Vaginal delivery appeared to be safe in our patients, but the patients in this case report opted for cesarean section because they were worried about the risk of vaginal delivery.

Conclusion
In conclusion, HIFU treatment is safe, effective, and reliable in patients with DUL.Based on our results, although limited to three cases, DUL may be managed by combining medical treatment and HIFU treatment with encouraging outcomes with conception.However, future studies involving more patients are required to establish the effectiveness of HIFU in DUL.

Figure 1 .
Figure 1.Magnetic resonance image (MRI) obtained from a 26-year-old patient with diffuse uterine leiomyomatosis (DUL).(A) The pre-HIFU T2-weighted images showed that the uterus was pervaded with tumors of varied sizes in the myometrium.The size of the enlarged uterus, measuring 104 mm Â 110mm Â 103 mm, corresponded to that of 16 weeks of gestation.(B) Pre-HIFU contrast enhanced MRI revealed significant enhancement of leiomyomas.(C) Post-HIFU contrast enhanced MRI revealed non-perfused leiomyomas that distributed along the anterior wall.(D) Contrast enhanced MRI after second HIFU revealed non-perfused leiomyomas that distributed along both the anterior and posterior walls.

Figure 2 .
Figure 2. MRI obtained from a 32-year-old patient with DUL.(A and B) the T2WI and contrast-enhanced imaging revealed an enlarged uterus Filled with innumerable perfused fibroid nodules in each layer of the uterus before HIFU treatment.(C) MRI obtained one day after the first HIFU treatment show no enhancement of the leiomyomas at anterior uterine wall.(D) MRI obtained one day after the second HIFU treatment show no enhancement of leiomyomas at both the anterior and posterior walls of the uterus.