HIFU as an alternative modality for patients with uterine fibroids who require fertility-sparing treatment

Abstract Objectives To compare pregnancy outcomes after high-intensity focused ultrasound ablation (HIFU), myomectomy and uterine artery embolization (UAE) for fertility-sparing patients with uterine fibroids and to investigate the possible mechanism of improving pregnancy by HIFU. Materials and methods A meta-analysis of 54 studies containing 12,367 patients was conducted to compare the pregnancy outcomes of three fertility-sparing therapies. And a retrospective self-control study of 26 patients with uterine fibroids from May 2019 to December 2020 was performed to assess the blood flow impedance of bilateral uterine arteries before and after HIFU. Results In the analysis by treatment option, the pregnancy rate after myomectomy was 0.43 (95% CI 0.36–0.49), which was higher than 0.18 (95% CI 0.10–0.26) after HIFU, the latter was significantly higher than that after UAE (ratio 0.08, 95% CI 0.06–0.10). The miscarriage rate after HIFU was 0.08 (95% CI 0.04–0.12), which was similar to 0.15 (95% CI 0.09–0.21) after myomectomy and also similar to 0.16 after UAE (95% CI 0.01–0.30). In the subgroup analysis, women who received ultrasound guided HIFU (USgHIFU) were more likely to have ideal pregnancy outcomes than that after magnetic resonance imaging-guided HIFU. The pulsatility index and resistance index on the right side were significantly higher 3 months after HIFU than before (1.637 ± 0.435 vs. 1.845 ± 0.469; p = 0.033; 0.729 ± 0.141 vs. 0.784 ± 0.081, p = 0.039). Conclusions HIFU, especially USgHIFU, may be an alternative fertility-sparing modality for patients with uterine fibroids over 40 years old. HIFU may contribute to improving pregnancy rates by elevating uterine blood flow impedance.


Introduction
Uterine fibroids are prevalent noncancerous tumors in women of reproductive age [1].Fibroids impair fertility, and the treatments can also lead to subsequent fertility impairment.Current uterus-sparing treatments for fibroids include drug therapy, myomectomy, uterine artery embolization (UAE), high-intensity focused ultrasound ablation (HIFU) and so on.These techniques may have different degrees of influence on pregnancy [2], but HIFU is noninvasive, repeatable, of less anesthesia involvement and more suitable for patients [3].Clinical follow-up results have found that HIFU could effectively improve the postoperative pregnancy rate of patients with uterine fibroids [4].However, some studies indicate that the reproductive outcome of HIFU is uncertain [5][6][7].
There are also literatures that have revealed a correlation between sufficient uterine blood flow and fertility [8,9].Hemodynamic parameters of uterine artery may be one of the effective indexes to evaluate endometrial receptivity [10].At present, the mechanism why HIFU can affect fertility is still unknown.Considering the relationship between uterine blood flow and fertility, the effect of HIFU ablation on uterine blood flow may be one of the reasons for improving pregnancy.
To study the role of HIFU for fertility improvement, we have carried out two parts of work.Firstly, a meta-analysis to compare the pregnancy outcomes of HIFU, myomectomy and UAE have been conducted; secondly, we have designed a retrospective study to demonstrate the improvement of the blood flow impedance before and after HIFU.

Search strategy
PubMed, Cochrane Library and Embase electronic databases were thoroughly searched, and the following medical subject heading terms, keywords, and their combinations were used: high-intensity focused ultrasound ablation, HIFU, laparoscopy, laparoscopes, laparoscopic, laparotomy, laparotomy, laparotomies, abdominal, uterine artery embolization, UAE, leiomyoma, uterine fibroid, myoma, pregnancy, and fertility.The reviewed articles included primary research, such as randomized controlled trials (RCTs), cohort studies, case control studies and case series.The literature search was updated on August 2021.

Literature selection
Two reviewers (Li Yin and Li Fang) independently completed the initial title and abstract screening for all three databases.Full texts were retrieved when studies possibly met our inclusion criteria.Studies with the number of patients more than 30 and reported in the English language were considered eligible.Because not all patients could decide before surgery whether they want to get pregnant or not and that willingness could be changed in some time, a desire for future pregnancy was not considered as an inclusion criterium for each study.In case of disagreement, a third investigator was consulted (Fan Xu).Specific literature screening strategies are shown in Figure 1.

Data extraction and quality assessment
Two reviewers (Li Yin and Fang Li) independently extracted data from all eligible studies.Pregnancy outcomes were assessed by rates of pregnancy and miscarriage.The level of evidence of all articles were assessed independently by the same two authors according to the guidelines of the Newcastle-Ottawa Scale (NOS) for case-control studies.The higher the score of the study was, the higher its quality [3].In cases of discrepancy, the opinion of a third investigator was sought (Fan Xu).

Patients
Between May 2019 and December 2020, twenty-six patients with a diagnosis of uterine fibroids who were hospitalized at Liuzhou Maternal and Child Health Care Hospital in Guangxi, China, were enrolled in this study.All of them had signed the informed consent.The HIFU ablation procedure has been described in the literature [11].Ethics approval for the study was granted by the research ethics committee of our hospital (NO.KS-KY-2019-005).
All patients who met the following criteria were included in the study: (1) confirmed diagnosis by enhanced magnetic resonance imaging (MRI); (2) diameters of fibroids !1 cm; (3) safe acoustic pathway.The exclusion criteria could also be referred to the literature [11].
Bilateral Doppler flow velocity measurements were performed using a vaginal approach (Philips EPIQ 5, C10-3V, Netherlands).For the uterine artery spectral waveform analysis, manual tracing of the waveforms was performed to generate the Doppler parameters.The values of three consecutive waveforms were averaged, and the means were recorded.Moreover, the following parameters were recorded: the pulsatility index (PI), the resistance index (RI) and the ratio of the systolic peak value and the end-diastolic velocity of blood flow (S/D).Doppler measurements were performed 2-8 days before (median 3 days) and 3 months after HIFU by one of the two examiners.The effects on all subjects of this study were examined by T2-weighted MRI (T2WI) and T1weighted MRI (T1WI) with gadolinium injection before, 1 day after and 3 months after HIFU.

Statistical analysis
The meta-analysis was performed with Stata (version 12), and were expressed as summary treatment effects (ratios) with corresponding 95% confidence intervals (CIs) for every intervention.A random-effects model was used for pooling the data.The I 2 statistic was used to determine the heterogeneity.When I 2 > 50% and p < 0.05, the between-study heterogeneity was considered to be significant.Publication bias was assessed using Egger's test.
SPSS 26 (SPSS, Inc., Chicago, IL) was used for statistical analysis.Pregnancy rate equals (number of patients who became pregnant after treatment)/(number of patients who were treated); Miscarriage rate equals (number of patients who had a miscarriage)/(number of patients who became pregnant after treatment).Continuous variables were expressed as the means ± SEs and tested by using independent-sample t tests.Categorical data are expressed as percentages.p < 0.05 was considered statistically significant.

Quality assessment and heterogeneity
In this review, we evaluated the quality of the studies based on the Newcastle-Ottawa scale for observational and nonrandomized studies.All studies had a score ranging from 3 to 8. Of them 6 studies were scored 3, 8 scored 4, 13 scored 5, 7 scored 6, 18 scored 7 and 2 scored 8 (Table 1).Studies were regarded as high quality researches only if they scored more than 4 [64].
As there was heterogeneity among the pregnancy rate and miscarriage rate, the lower number of cases was considered as one of the reasons causing heterogeneity.Moreover, guiding methods of HIFU were explored that might partially explain high levels of heterogeneity.Subgroup analysis based on HIFU showed that the different guiding methods might be the sources of heterogeneity.

Publication bias
The publication bias of the studies was assessed with Egger's test, and no significant publication bias was found (p > 0.05).

Characteristics of patients and uterine hemodynamics data
All 26 patients underwent HIFU successfully without any severe complications.The general information of the patients is summarized in Table 3.The mean patient age was 35.38 ± 5.53 years (mean ± SD; range, 25-40 years), and mean BMI was 22.00 ± 3.28 kg/m 2 (range, 20-25 kg/m 2 ).Before the treatment, 46.2% of patients had menometrorrhagia, 57.7% of the patients had dysmenorrhea, 30.8% of the patients had polyuria and/or constipation, and 38.5% of the patients were diagnosed with anemia by routine blood tests.
The symptom severity scores (SSS) and Uterine Fibroid Symptom Quality of Life (UFS-QOL) questionnaire subscales, and the volume of fibroids before and 3 months after HIFU ablation showed significant differences.The hemodynamics data before and 3 months after HIFU ablation are summarized in Table 4.Although the PI and RI in the left side and the S/D were similar for both groups, the PI and RI in the right side were significantly higher 3 months after HIFU than before (1.637 ± 0.435 vs. 1.845 ± 0.469; p ¼ 0.033; 0.729 ± 0.141 vs. 0.784 ± 0.081, p ¼ 0.039).The self-control of PI, RI and S/D before and after HIFU are listed in Table 5.

Discussion
This was the first study to investigate the possible mechanism by a self-contrast approach and the first meta-analysis to compare the pregnancy outcomes of HIFU with those of other therapies.Unlike the pregnancy outcomes, in patients who received HIFU, the miscarriage rate was found similar to that after myomectomy or UAE.However, the pregnancy rate after USgHIFU was discovered similar to that after myomectomy.By comparing the changes of PI and RI in uterine arteries before and after HIFU treatment, we found that PI and RI in the right side of uterine artery were significantly increased after HIFU treatment.
Our study showed that the pregnancy rate after USgHIFU was similar to that after myomectomy, but significantly higher than that after UAE.Khaw supported the outcome that no statistically significant differences were found in pregnancy rate between HIFU ablation and myomectomy [1].
The coagulative necrotic fibroid tissue was absorbed by surrounding tissues after HIFU ablation.With the reduction of fibroids, the structure and the environment of uterus gradually healed [65].It may be the reason that the pregnancy rate after USgHIFU was similar to that after myomectomy.Meanwhile, no report of uterine rupture during pregnancy or delivery after HIFU was found.However, the scar caused by myomectomy might lead to risk elevation of placental abnormality and uterine rupture [66].Furthermore, the reasons for low pregnancy rate after UAE was mainly the effect on the ovary blood supply and function of the endometrium.
Interestingly, when we scanned the characteristics of patients in all the literatures, we found that the ages of patients treated with HIFU for uterine fibroids ranged from 31.4 to 44.5 and those of patients underwent myomectomy ranged from 28 to 36.1.And the average ages of patients in seven studies were over 40 years old, but we could not do a pooled analysis as the ages of patients in some of the literature was recorded by median, and in others by mean.Since it would take time for patients who desired fertility to wait for the reconstruction of the myometrium after myomectomy, meanwhile, the ovarian function decreased rapidly over time, HIFU might be an alternative fertility-sparing modality for the patients with uterine fibroids over 40 years old.
In our study, the miscarriage rates after HIFU, myomectomy and UAE were similar.And only one relevant study reported that the miscarriage rate after HIFU was lower than that after myomectomy or UAE [1].Due to limited data, the mechanism of miscarriage after myomectomy remains unclear.However, high intensity focused ultrasound waves can be focused to coagulate the tumor cells on the targeted fibroids during ablation [67], and the precise ablation can preserve the integrity of myometrium and endometrium [68].On the contrary, myomectomy impairs the integrity of the myometrium and endometrium.The influence of UAE on ovarian function, uterine perfusion, uterine cavity and endometrium may result in early pregnancy losses [14].In this sense, HIFU ablation may help to obtain ideal outcomes of pregnancy.
For the subgroup analysis, the pregnancy rate after USgHIFU was significantly higher than that after MRgHIFU, while the miscarriage rate was similar to that after MRgHIFU.Firstly, an MRgHIFU procedure could not be monitored in real time during treatment, so the operators might be relatively cautious about the ablation range.Secondly, in order to avoid the side effects of MRI contrast agents to patients, supplementary sonication was not allowed after the contrastenhanced MRI [69].However, a higher none perfusion volume (NPV) ratio may be induced after USgHIFU since the ultrasound contrast imaging can be used to assess the need for supplementary sonication.Thus the NPV ratio of fibroids was smaller after MRgHIFU than that after USgHIFU [49,59].
A larger NPV ratio might indicate a better therapeutic effect after HIFU [17].
The mechanism for improving pregnancy after HIFU treatment still lacks evidence.The blood supply to the uterus originates mainly from the uterine artery [70].The meta-analysis showed that a uterine artery PI of <3 measured on the day of fresh embryo transfer was associated with higher clinical pregnancy rates [71].Zhen Li reported that repeated implantation failure was positively correlated with uterine artery blood flow RI [72].But there was no literature report on whether S/D had an effect on pregnancy rate or not, but S/D remained an important indicator evaluate fetal oxygen supply during pregnancy.The effect of HIFU on uterine artery blood flow is not clear.The authors found that PI and RI on the right side of the uterine artery were significantly increased after HIFU treatment.Ernest Hung Yu Ng and Pak Chung Ho also reported that PI and RI of the right uterine artery were much lower in patients with fibroids who failed to get pregnant, the same as the mean values of PI and RI in bilateral uterine arteries [73].Therefore, we hypothesized that the improvements in blood supply after HIFU affected the pregnancy rate.
We performed a broad search and discovered some explanations for the different pregnancy outcomes associated with different treatments.This study may provide much-needed information about treatments for uterine fibroids and pregnancy outcomes, which can help to advise the infertile women with fibroids.We are aware that the present study has some limitations.Firstly, we still need more RCTs to elucidate the results of this analysis in the future, although this meta-analysis can provide much needed information about treatments for uterine fibroids and may benefit in advising patients in terms of subsequent pregnancy.Secondly, the study on blood flow impedance remains only a hypothesis, which is hard to illustrate the effect of HIFU in pregnancy.Whether there are other possible mechanisms or not is still unclear.In view of the limitations of retrospective studies, we need to expand the sample size and design more prospective trials to further verify our hypothesis in the future.Thirdly, our meta-analysis might have some bias.However, we performed a subgroup analysis which hinted the pregnancy rate after USgHIFU was similar to that after myomectomy, but greater than that after MRgHIFU.Since MRgHIFU has been generally used in western countries, while USgHIFU has been widely used in China, different populations and guiding methods may have an impact on the heterogeneity.Therefore, more clinical trials on these two guidance methods are urgently needed to expand the sample size and to confirm our findings.
In conclusion, compared with myomectomy and UAE, HIFU, especially USgHIFU, maybe a fertility-sparing option for patients with uterine fibroids over 40 years old.HIFU may contribute to improving pregnancy rates through elevating the uterine blood flow impedance.

Disclosure statement
No potential conflicts of interest are reported by the author(s).

Funding
There was no funding associated with the work featured in this article.

Figure 1 .
Figure 1.Flow diagram of literature selection was shown, with the final number of studies as 54.

Table 1 .
Characteristics and quality assessment of the included studies.

Table 2 .
Pregnancy rate and miscarriage rate following HIFU and other surgical methods in the treatment of uterine fibroids.

Table 3 .
Pregnancy rate and miscarriage rate following USgHIFU and MRgHIFU in the treatment of uterine fibroids.

Table 4 .
Characteristics of the patients with uterine fibroids treated with HIFU (n ¼ 26).

Table 5 .
Self-control of PI, RI and S/D before and after HIFU.