Uterine fibroids: a narrative review of epidemiology and management, with a focus on uterine artery embolization

Introduction

Leiomyomas of the uterus, commonly referred to as uterine fibroids (UF), are the most common benign gynecologic neoplasm amongst women (1,2). Abnormal uterine bleeding (AUB) is the most common presenting symptom for UF, however this symptom is responsible for 70% of gynecologic consults (3). Costs associated with UF mount up to $34 billion dollars in the United States (1,4). Recent advances in the technical quality, availability, and decreased cost in imaging modalities for the diagnosis and characterization of these tumors have led to an increase in patients seeking treatment. In a recent prospective analysis, 29–33% of the study cohort reported an incidental diagnosis of UF (5). Several risk factors have been identified in studies (1) and racial disparities remain one of the main barriers in treatment.

UF continues to be the primary indication for hysterectomy (2), and is the underlying diagnosis in nearly 40% of hysterectomies performed (6). Despite recent developments in alternative drug therapies and minimally invasive options, 27% of hysterectomies are performed for UF disease (5). The aim of this paper is to provide an overview of UF with a more detailed review of uterine artery embolization (UAE) as one of the growing minimally-invasive therapeutic approaches. We present this article in accordance with the Narrative Review reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-57/rc).

Methods

A comprehensive literature search was conducted to gather a wide range of studies on UF. Table 1 provides details of the search strategy. PubMed was used as the primary database, and both Medical Subject Headings (MeSH) and free text searches were queried using the primary keyword “uterine fibroid”. No timeframe restrictions were applied, although more recent publications were given higher weight in the narrative review. No specific inclusion or exclusion criteria were applied, ensuring a broad capture of relevant literature without limitations on study type, language, or other restrictions.

Overview of fibroids

Symptomatic UF disease may be present in 25–50% of individuals (1), and up to half of affected women may remain asymptomatic (3). The most common symptoms include AUB, bulk symptoms from tumor mass effect, and infertility. Direct and indirect cost associated with UF vary among countries: $34 billion in the US, $348 million in Germany, $120 million in France, and $86 million in England (7). Hysterectomy is the gold standard for definitive treatment. Effective drug therapy remains an elusive goal. In select patient populations, less invasive options such as myomectomy, UAE, or magnetic resonance-guided high intensity ultrasound (MRgHIUS) offer effective alternatives.

Pathophysiology

There is a complex interplay of genetic mutation, clonal expansion, and local and systemic signaling which leads to the formation of UF’s. Underlying genetic components have been identified in smaller studies of specific familial mutations. However, only a limited number of studies are adequately powered to assess a generalized population and reproducibility has not been well established (5). A widely studied mutation of the MED12 gene confers a universal risk and is only seen in fibroid cells (2,4). A critical step involves transforming growth factor beta (TGF-β), which induces formation of an extracellular matrix (ECM), which protects the fibroid from normal signaling and immune response (5). Subsequent upregulation of miRNA targeting genes involved with cell growth and ECM remodeling changes locoregional flora and endometrial regulation via altering angiogenesis and inflammation. Vascular endothelial growth factor-A (VEGF-A) expression in UF has been observed to be independent of its size (4), higher in UF compared to normal endometrial tissue, and is strongly influenced by estrogen and progesterone (5). This positive feedback loop and local environmental impact leads to local proliferation. In addition to local disruption of normal endometrial function, mass effect contributes to symptomatology and interferes with many aspects of pregnancy.

Epidemiology

UF accounts for a significant degree of health burden across the globe, affecting an estimated 70% of women worldwide, a significant proportion of which is underreported (2,8). The true extent of disease burden varies considerably between studies, as a majority of studies investigating incidence are based on hospital discharge coding, nationally representative studies, and large prospective cohorts (5). There is disease regression following menopause, although risk factors of obesity and hormone replacement therapy (HRT) have been cited as risk factors for disease in post-menopausal women.

Risk factors

The most consistently identified risk factors include ethnicity, genetic predisposition, age, hypertension, early menarche, late menopause, polycystic ovarian syndrome (PCOS), and nulliparity (2,5,8). UF were found in 60% of black women by 35–49 years of age, and 80% over the age of 50 years. By contrast, UF were found in 40% of white women under the age of 35, and 70% over the age of 50 years (2,7). Based on an early pregnancy screening ultrasound study, onset of disease was 10 years earlier for black women (5). More broadly, 30% of the new diagnoses are made between 45–49 years old, and the second highest incidence occurs between 50–54 years old (3). Risk increases linearly with increasing weight (2) likely related to aromatase metabolism of adrenal androgens to estrogen (5). Vitamin D deficiency likely impacts pathogenesis through altered inflammatory response increasing the likelihood of UF growth (2). Protective factors include multiparity, normal body weight, and depot medroxyprogesterone acetate (DMPA) contraception (2,8). Fibroid progression is predominantly thought to be influenced by estrogen and progesterone. This is especially evident in an early pregnancy and post-partum ultrasound screening study involving 171 women with a single UF, where 36% had complete regression, and the remainder shrank on average (5). This hormonal drive is observed in clinically progressive fibroid growth in the premenopausal population as well as growth during states of pronounced hormonal surges and changes such as pregnancy. Despite the absence of further growth post menopause, without intervention, large fibroids can take a long time to shrink and cause persistent bulk symptoms (9,10).

Symptoms/clinical presentation

Patient symptoms and severity are directly related to fibroid size and location. Bulk symptoms, AUB, and infertility are the most common clinical presentations of symptomatic leiomyomas (11). AUB can present with or without symptomatic anemia. Bulk symptoms are variable and depend on the size of the fibroid(s) and the enlarged uterus. These symptoms include pelvic pressure, abdominal pain and distention, urinary dysfunction, constipation, and obstructive uropathy.

Generally, fibroids that cause mass effect of the endometrium and endometrial cavity cause AUB and those that are more intramural and/or exophytic cause uterine enlargement and bulk symptoms. Fibroids also impact fertility, pregnancy, and postpartum recovery. Fibroids were present in 27% of patients seeking reproductive assistance and may account for 1–3% of infertility (4). The volume and/or number of fibroids correlates with increased patient symptoms and worsening of patient reported quality of life.

Fibroid location/International Federation of Gynecology and Obstetrics (FIGO) classification

The FIGO classification of leiomyomas proposed by Munro et al. (12) has been used to categorize lesions as well as guide management (Figure 1). The FIGO classification uses a previously established system by Wamsteker et al. (13) to categorize UFs based on their mural location. Among submucosal UFs, pedunculated intracavitary lesions are considered type 0, and lesions with <50% and ≥50% intramural components are types 1 and 2. Among intramural lesions, type 3 and 4 are those with or without contact with the endometrium, types 5 and 6 are subserosal lesions with ≥50% and <50% intramural components, and type 7 are subserosal pedunculated lesions. Type 8 lesions are those that don’t involve the myometrium at all, such as cervical lesions or lesions of the broad ligament. The classification also accounts for transmural lesions that simultaneously affect the serosa and endometrium. These hybrid leiomyomas are described using two numbers separated by a hyphen. The first number describes the lesion’s relationship to the endometrium, while the second number describes the relationship to the serosa.

Figure 1 Types of uterine fibroids according to the FIGO classification system. The class numbers are presented in parentheses. FIGO, International Federation of Gynecology and Obstetrics.

Treatment of UF

Therapeutic intervention aims to remove or reduce the volume and/or size of fibroids in symptomatic UFs. Asymptomatic patients should not be treated, regardless of radiological findings. Medical, surgical, and non-surgical therapeutic modalities for treating UF have been extensively described in the literature. In the subsequent sections, we will review the treatment modalities with emphasis on UAE (14).

A summary of the treatment modalities, indications, and their advantages, disadvantages and risks has been presented in Table 2.

Medical management

Estrogen and progesterone therapy

The use of medical contraceptives therapy for AUB has long been a common, yet paradoxical, first line therapeutic (15). In vitro studies investigating the effects of single progestin therapy and estrogen-progestin therapy on leiomyomas have shown increased mitotic activity and cell growth stimulation, respectively (16,17). Despite this, in the case of combined oral contraceptives, the use of low dose hormones was not found to induce fibroid growth (18,19). On the contrary, one study suggested that oral contraceptives might be a protective factor for UFs (20). In a prospective study by Friedman et al., the oral contraceptive group experienced a statistically significant improvement in menorrhagia and dysmenorrhea with a decrease in menstrual duration of more than 2 days and a 2.5-point increase in hematocrit compared to the control group without significant difference in the mean uterine size (21).

Data regarding the use of systemic progestin-only therapy are inconsistent, and studies that may have shown improvement have not been reproducible (22). A statistically significant decrease in bleeding has been observed with levonorgestrel releasing intrauterine devices (23). However, a systematic review of the studies showed a non-statistically significant tendency for expulsion of intrauterine devices in fibromatous uteri (24).

Common side effects include weight gain, decreased libido, acne, breast tenderness, among others. Serious side effects include the risk of developing hepatic adenomas and increased risk of venous thromboembolic events including stroke, particularly in older women who smoke or have comorbid hypertension (25).

In the absence of significant bulk symptoms, the use of medical contraceptive therapy can have a role controlling AUB symptoms in patients nearing menopause (14).

GNRH agonists

Compared to combined or progesterone only contraceptive therapy, the use of gonadotropin releasing hormone agonists is a more effective and reproducible medical therapy in treating symptomatic fibroids. The therapeutic effect is achieved by inducing a hypoestrogenic state. The GNRH agonists manipulate the hormonal feedback loop by decreasing the available GNRH receptors on the anterior pituitary, leading to a downstream decrease in LH and FSH levels. The induced functional menopause-like state results in amenorrhea as well as shrinking of fibroid(s) size. In addition to the central hormonal modulation, GNRH agonists cause a local decrease of estrogen in the fibroid(s) by suppressing aromatase P450 (26,27). Several studies have shown this central and local hormone suppression to be effective in treating fibroid-related AUB and bulk symptoms. Significant improvement in menorrhagia as well as hematocrit levels were seen in patients with symptomatic anemia (28). Up to 35% reduction in overall uterine size and 30% reduction in fibroid size were noted within 8 weeks of therapy in several studies (28-30).

Despite the efficacy of GNRH agonist therapy, its use is limited by a significant adverse effect profile. The side effects are a direct result of the induced menopause-like state and most commonly include amenorrhea, vasomotor flushing, decreased libido and vaginal dryness; less common side effects include emotional lability, insomnia, and arthralgias (31-33). The most problematic long-term issue is the effect on calcium metabolism, and resultant increase in bone resorption (29). The bone density loss with long-term therapy can have significant sequelae, particularly in younger patients who are not as close to natural menopause. A variety of “Add-back” protocols utilizing progesterone analogs and selective estrogen modulators have been investigated to mitigate bone resorption, with mixed results (34). Some Add-back protocols with medroxyprogesterone have shown slowed resorption rates, but a net loss of bone density, with no change in bone formation (29).

It should also be noted that the effects of GNRH agonist therapy are not permanent. Although some patients may be asymptomatic for up to a year after the cessation of treatment, most patients will resume their menstrual cycles within 8 weeks with return of the fibroid size to pretreatment measures by 24 weeks (35).

Selective progesterone receptor modulators (SPRM)

Recent phase II clinical trials of novel SPRM’s such as mifepristone and ulipristal acetate (UA) have shown some promise, with a dose dependent relationship of reduction in AUB and fibroid volume. The side effects include hepatotoxicity, headaches, hot-flashes, and endometrium changes. The most concerning issue relates to effects on the endometrium called progesterone receptor modulator-associated endometrial changes (PAEC) (36). A clinical trial by Donnez et al. demonstrated that endometrial changes resolved after 3 months following a long-term, intermittent administration regimen (37). A Cochrane review concluded that SPRMs use is associated with improved fibroid symptoms severity and quality of life, reduced uterine bleeding and higher rates of amenorrhea (38).

Surgical management

Hysterectomy remains the gold standard of treatment for UFs and is the only therapy that is 100% effective in alleviating fibroid related AUB and bulk symptoms. In a randomized study comparing hysterectomy to medical therapy in the treatment of fibroids, patients in the hysterectomy arm reported a significantly higher improvement in symptoms and health-related quality of life (HRQL) compared to the medical therapy group (39). In that study, 53% of the patients in the medical therapy arm opted for a hysterectomy at the conclusion of the trial (39). In the Maine women’s health study, 3% of women reported a negative psychological impact due to the surgery, and 72% reported improvement in their symptoms (9,10). Although the vast majority of patients will see no change or even improvement in their psychological health after a hysterectomy, a subgroup may experience psychosomatic side effects. One review demonstrated that up to 20% of women may experience depressive symptoms, impaired body image, and reduced libido after a hysterectomy despite improvement in pain (40).

Myomectomy is a uterus-preserving surgical treatment for symptomatic fibroids that has the benefit of sparing fertility and excising the lesion. Nonetheless, it is an invasive option that carries similar risk profile as traditional hysterectomy. Studies have shown no significant decrease in perioperative morbidity between hysterectomies and myomectomies (41). Some of these surgical risks include recovery time, blood loss, uterine distortion, postoperative adhesions, and unplanned hysterectomy. A recent review, however, shows some of these risks have been mitigated with the wider adoption of laparoscopic myomectomy (42). The laparoscopic approach is limited by the size and location of the fibroid with some studies citing 15 cm as the upper limit of a single lesion no more than 3 lesions that are 5 cm or less (43). Additionally, myomectomies are limited to submucosal or subserosal lesions. Hysteroscopic myomectomy is the gold standard for managing submucosal fibroids, and have shown statistically significant improvement in addressing infertility related to this group of fibroids (44). Long-term follow-up of patients after myomectomy has shown almost 22% recurrence and reintervention rates necessitating a second surgery in 11 years (45).

Uterine artery occlusion

Uterine artery occlusion is another uterus-sparing procedure that aims to reduce fibroid symptoms by disrupting the vascular supply and inducing ischemia. The procedure can be performed laparoscopically as the primary intervention and it involves occluding the uterine arteries via permanent surgical clips or by thermocoagulation (46). It can also be performed trans vaginally with ultrasound and doppler guidance. The trans vaginal approach can involve placing temporary clips for a specified period of time to induce ischemia, although this approach was only investigated in a pilot study with operator-dependent success (47). In some studies, the procedure showed some short-term symptom improvement and reduction in fibroid size (46-48). One study showed reduction in fibroid size up to 76% at 10 months follow-up (46). A randomized trial comparing UAE and laparoscopic uterine artery occlusion found laparoscopic uterine artery occlusion to be inferior to UAE with regards to symptom recurrence rates, 48% vs. 17% respectively. Evaluation by contrast-enhanced magnetic resonance imaging (MRI) showed 100% of UAE patients had complete fibroid infarction vs. 23% of patients treated with uterine artery occlusion (48).

Non-surgical management

MRgHIUS

MRgHIUS is a uterine-preserving, non-invasive thermoablative modality used in the treatment of symptomatic UFs. The procedure utilizes focused high intensity ultrasound waves under MR guidance to deliver thermal energy and induce cell death and necrosis. It was approved by the Food and Drug Administration (FDA) to treat UFs in 2004 (49). Several studies have shown short-term symptomatic improvement with one study showing 71% and 51% of treated patients reaching targeted symptom reduction at 6 and 12 months, respectively (50). The PROMISe trial, a randomized, placebo-controlled trial also showed modest fibroid volume reduction of 18% in 12 weeks. However, inconsistency in early symptomatic improvement during the first 4 weeks suggested a placebo effect might account for some of the short-term symptom reduction (51).

The treatment response of individual fibroids is also variable and can be predicted based on magnetic resonance intensity of the fibroid relative to skeletal muscle and myometrium. The more hyperintense fibroids being less likely to respond (52).

Although minimal (53), the risk of thermal damage to adjacent structures is not zero (54). Additionally, there is inconsistent data regarding the effects on future pregnancy. Successful pregnancies have been reported after treatment (55,56). However, a review by Clark et al. reported a high rate of complications in 34 patients who were treated (57).

The size of the fibroid, and the depth the ultrasound waves need to penetrate are limiting factors along with technical standardization, a steep learning curve, sparse availability of the equipment and length of time required to treat can also be barriers to adoption of this treatment modality (58).

UAE

Background

In 1995, Drs. Ravina and Merland in Paris, France utilized UAE as a preoperative therapy to mitigate blood loss during myomectomies (59). While awaiting surgery, patients reported resolution of their symptoms prompting further investigation and publication of their experience. This became the first report in medical literature describing UAE as a therapy in managing symptomatic fibroids. Goodwin et al. reproduced these results in United States prompting interest in the procedure (60). Over the next 20 years, several studies evaluated and reported on safety and effectiveness of UAE in treatment of symptomatic UFs. Later, the Society of Interventional Radiology (SIR) and the American College of Obstetrics and Gynecology (ACOG) considered it a safe and effective treatment for symptomatic fibroids (61).

Despite its lower cost, shorter hospital stay, shorter time to return to baseline function and its uterine-preserving quality (62-65), studies have demonstrated that UAE utilization is significantly lagging behind surgical approaches (66,67) with racial disparities being a major driver of its underutilization (68-70).

Pre-procedural evaluation

The initial evaluation to assess treatment eligibility entails gathering a detailed medical history and performing a gynecological examination ideally by the primary care provider or gynecologist (71). A transvaginal pelvic ultrasound should then be obtained to assess for the presence and burden of UFs (14). Commonly, an interventional radiology referral is needed if the decision has been made to pursue UAE. The interventional radiologist evaluates the patient for potential contraindications prior to proceeding with the procedure.

Contraindications include viable active pregnancy, active endometritis, malignancy of the uterus/cervix, postmenopausal status with unknown etiology of bleeding, infarcted fibroid on MRI, fibroids smaller than 1 cm, cervical fibroid, and pedunculated fibroid (somewhat controversial) (72). Additionally, the presence of concurrent uterine adenomyosis should also be considered, as some believe this to be a cause of UAE failure. A literature review included in the 2014 SIR Guidelines for UAE has concluded that 72.5–94% of patients with both UFs and adenomyosis who underwent UAE still achieve symptomatic relief (73). Additionally, it is important to consider the existence of a pedunculated subserosal fibroid, characterized by a stalk diameter that is less than 50% of the fibroid’s greatest diameter. Although there are reports of necrosis of the stalk with detachment of the infarcted fibroid into the pelvis (74), later data revealed positive results of UAE for pedunculated fibroids, with a reduction in size exceeding 30% and no evidence of fibroid detachment or torsion (73).

The FDA reported that approximately 1 in 350 women who undergo hysterectomy or myomectomy for presumed symptomatic fibroids are found to have an underlying uterine sarcoma (75). A UAE, which will ideally reduce bleeding symptoms, carries a theoretical risk of masking symptoms of uterine malignancy. This risk indicates that patients would need to be up to date on their cancer screening before undergoing UAE.

Moreover, pre-procedural pelvic MRI and magnetic resonance angiography (MRA) are helpful studies for preprocedural planning (76). MRI plays a crucial role in diagnosing and mapping fibroids, ruling out other pelvic issues, and offering essential technical data for UAE planning. MRA serves as a comprehensive pre-treatment tool for assessing and mapping pelvic arterial anatomy, thus minimizing radiation exposure during the procedure, which is especially useful in women of reproductive age.

SIR and Cardiovascular and Interventional Radiological Society of Europe (CIRSE) recommend pre-procedural antibiotics given within 1 hour of procedural start time. The recommended antibiotic regimens are 1–2 g intravenous cefazolin, 900 mg clindamycin intravenous + 1.5 mg/kg gentamicin, 2 g ampicillin intravenous, 1.5–3 g ampicillin/sulbactam intravenous. Additionally, in women with hydrosalpinx, 100 mg doxycycline oral twice daily for 7 days should be administered following the procedure (77).

Furthermore, patients should be stratified by their bleeding and thrombosis risks before further recommendations on anticoagulation can be made (78). UAE is categorized as a ‘high-risk for bleeding’ by SIR. It is generally recommended that patients stop anticoagulation prior to undergoing this procedure. There are some exceptions to this recommendation for patients who have a high thrombotic risk, including CHA₂DS₂-VASc Score >7, presence of a mitral valve prosthesis, rheumatic valve disease, stroke or transient ischemic attack (TIA) within 6 months, venous thromboembolism (VTE) within 3 months, recurrent VTE, or VTE in the presence of a thrombophilia. In such cases of high thrombotic risk, the patient can be admitted and administered unfractionated heparin or be started on a low-molecular weight heparin bridge as an outpatient (78).

Anatomical considerations

If not pre-planned, anatomical variations of the uterine artery have potential to complicate the procedure. The uterine artery can arise directly from the internal iliac artery as the first branch in 5–6% of cases (79,80). More commonly the internal iliac artery bifurcates into an anterior and a posterior division in up to 77% of the general population with the uterine artery arising as one of the first 3 branches of the anterior division in 51% to 90% of cases (79,81). In up to 40% of cases, the uterine artery is a branch of a terminal internal iliac trifurcation, along with the inferior and superior gluteal arteries (79,81,82). It should be noted that the vaginal artery commonly shares a trunk with the uterine artery. The cervicovaginal artery can arise from the internal pudendal artery or the mid to distal portion of the uterine artery (83). There have been reports of the uterine artery arising as a branch of the umbilical artery, internal pudendal artery, or superior gluteal artery but those variations are rare. Uterine-ovarian artery anastomosis has been reported in up to 50% of cases and 3 main variations are described (81): the uterine artery as the main vascular supply of the ovary when the ovarian artery is absent, a direct communication of mid to distal portion of the uterine artery with ovarian artery, or an anastomosis of terminal branch of the ovarian artery with a uterine artery branch that is feeding a fibroid (81) (Figure 2).

Figure 2 Schematic illustration of 3 types of uterine blood supply from uterine and ovarian arteries. Type I includes intrauterine uterine-ovarian arterial anastomosis. Type II includes an anastomosis of terminal branch of the ovarian artery with a uterine artery branch that is feeding a fibroid. In type III, uterine artery supplies the uterus including fibroids as well as the ipsilateral ovary.

Intraprocedural considerations

UAE is commonly performed under conscious sedation. To achieve this level of sedation, the patient will need to be administered an anxiolytic and an analgesic concurrently. Midazolam is often the anxiolytic of choice, as it also has amnestic properties (84). Midazolam is administered intravenously and achieves sedation within 3 to 5 minutes. A narcotic, often IV fentanyl, is selected as analgesic. Both medications should be given in small doses and titrated up to achieve adequate sedation. Midazolam and fentanyl are often selected due to the short half-life and rapid onset, making them easily titratable and ideal for achieving the proper level of sedation. If the patient becomes overly sedated, reversal of the benzodiazepine can be achieved with flumazenil, and the opioid can be reversed with naloxone.

For additional pain control, a superior hypogastric nerve block may be performed before the procedure. One study demonstrated that patients were less likely to need opioids post-procedurally for pain control if they receive a preprocedural superior hypogastric nerve block (85). Additionally, the same study showed that the median length of stay in patients who had superior hypogastric nerve block was 2.2 hours, allowing for same day discharge.

There are several options for an access site at the start of the procedure. Classically, this procedure is performed through a single puncture site in the right common femoral artery (86). As this procedure will requires selection of bilateral uterine arteries, it is safe and feasible to access the bilateral common femoral arteries although a unilateral common femoral access would be sufficient to complete bilateral embolization successfully in majority of the cases. A single site randomized comparative trial with 57 patients demonstrated that accessing the bilateral femoral arteries at the start of the procedure resulted in shorter procedural time and lower radiation exposure to the patients without increased risk of complication (87). The operator may also opt for a transradial approach. One retrospective study of 29 cases demonstrated the feasibility and safety of this approach with a 100% success rate and no reported complications (88). A study comparing transradial and transfemoral approaches for UAE demonstrated similar technical and clinical outcomes and low rates of access site complications in women up to 178 cm height (89), and another single-center study of outpatient UAE via transradial access demonstrated safety of the approach using the same-day discharge protocol with low rates of patients returning to the hospital (90).

Once access has been established, the operator must perform an aortogram to establish the patient’s pelvic arterial anatomy. The internal iliac artery should be accessed with the catheter and another angiogram should be performed in both the anterior-posterior and oblique orientations to assess for the origin of the uterine artery (91). A microcatheter should be used to select the uterine artery distal to the cervicovaginal branches. After selection of the artery/branch feeding the fibroid, the embolic agent can be delivered until stasis (Figure 3). A large array of embolic agents may be used with different safety profiles (92). Commonly, 500–700 µm microspheres are employed due to their ease of injection without catheter obstruction and predictable occlusion levels. This particle size has been found to be optimal for arterial occlusion of the supply of fibroids with minimized risk of ovarian infarction in the case of presence of a utero-ovarian anastomosis. Other options for embolic include absorbable gelatine sponge dissolved in a solution of saline and radiopaque contrast, polyvinyl alcohol, glues, or liquid polymers (such as Onyx). The embolic agent should be slowly injected to reduce risk of reflux and non-target embolization (91). Embolization is usually considered complete when contrast continues to opacify the uterine artery after five heartbeats. This same process should be completed on the contralateral uterine artery. Once complete, the instruments are carefully removed from the arterial access and bleeding is controlled with manual pressure or a closure device depending on initial access location (86).

Figure 3 Schematic illustration of uterine fibroid embolization via a left femoral access.

Post-procedural outcomes

A validated disease-specific quality of life assessment questionnaire (UFS-QOL) has been developed to be used before and after therapy to gauge improvement (93).

The fibroid registry for outcomes data (FIBROID) is the largest study evaluating UAE outcomes. It enrolled over 3,000 patients over the course of 2 years (94). Analysis revealed a procedural technical success rate of 96.2% and unilateral embolization was the only technical factor that was associated with failure yielding a partial technical failure (94,95). Data from this study also highlighted sustainable fibroid symptom relief 1 and 3 years follow up with 95% of patients reporting improvement in HRQL at 1 year (96). Durability of UAE continued into the 3-year follow up with sustained improvements in HRQL and patient satisfaction with 85.7% of women agreeing they would recommend the procedure to a friend. The reintervention rate at 3 years was 14.4% with myomectomy in 2.8%, hysterectomy in 9.8% and repeat UAE in 1.8% (95). Factors predicting favorable outcome in the study were multiple, smaller submucosal fibroids and AUB as the main symptom, while older age was associated with a poorer outcome (95,96).

The safety, outcomes and cost effectiveness of UAE have been investigated in other large multicenter studies, some of which have compared UAE to surgery. The Ontario uterine embolization trial demonstrated successful symptomatic control with improvements in bleeding and urinary symptoms as well as uterine and dominant fibroid volume reductions, 35% and 42% respectively (97). Bilateral embolization success rate was 97% during the study (98). The study also found a positive correlation between increased operator experience and reduction in procedural time and radiation dose (98). The study also highlighted that a large proportion of patients sought alternatives to surgery for this disease and most of those patients consulted 3 gynecologists and endured 5 years of symptomatic fibroids before undergoing UAE (99).

The EMMY trial, comparing UAE with hysterectomy in treating symptomatic fibroids, reported significant and stable improvement in HRQL at 5- and 10-year follow up in the UAE and hysterectomy arms without significant difference between the groups (100,101). It also reported improvements in urinary and defecation function (101). At 10-year follow up, satisfaction rates were comparable with 78% in UAE group and 87% in hysterectomy group. The hysterectomy rate post successful UAE was 31% at 10 years (100).

The FEMME trial comparing embolization to myomectomy in treatment of fibroids showed significant improvement in HRQL in both groups. There was no significant difference in menstrual bleeding, AUB, pregnancy rates or impact on ovarian reserve at 4-year follow up. At 2-year follow up, myomectomy showed a more significant improvement in quality-of-life improvement, however there was no significant difference at 4 years (102).

The overall cost analysis of the financial medical expense burden favors UAE over surgical intervention for at least two thirds of patients, specifically those who are averse to surgery and are interested in uterine preserving therapy. The REST study showed although the initial cost analysis favors UAE, that initial benefit is counteracted in about a third of patients requiring reintervention post UAE (103). In a cost analysis, EMMY showed UAE is superior to hysterectomy with regards to cost burden over 24 months when incorporating the societal perspective in the form of missed work time and out of hospital expenses (104). Similarly in the HOPEFUL study, when factoring in quality of life related to conserving the uterus, UAE was associated with lower mean cost compared to hysterectomy (105).

Several factors have been identified as prognosticators of UAE failure or suboptimal clinical response. One study showed that lack of improvement in pain or AUB in 1 year had a hazard ration of 7.4 and 9.0, respectively for treatment failure (106). The same study also showed that dominant fibroid volume reduction was associated with decreased risk of treatment failure. Data from the EMMY trial showed patients with a single fibroid or small uterine volume had a higher risk of treatment failure (107). Another study showed post UAE hysterectomy rates were higher in unilateral UAE with a relative risk of 2.19 (108). Increased vascularity and number of lesions has been noted to be a predictor of success (109) while giant fibroids tend to not have successful outcomes (110). However, this was refuted in another review concluding treatment success was not influenced by number of lesions or the dominant fibroid’s size or location (111).

Procedural complications

Post-procedural pain is a common compilation. A variety of regiments including opioids, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), superior hypogastric nerve block, uterine artery lidocaine injection, or a patient-controlled analgesia (PCA) can be used for pain control. A systematic review of pain management protocols analyzed four different pain management protocols: opioids ± NSAIDs ± acetaminophen, opioids ± NSAIDs ± acetaminophen + nerve block, opioids ± NSAIDs ± acetaminophen + intrauterine artery lidocaine administration, and opioids ± NSAIDs ± acetaminophen + other. There were no statistically significant differences in mean pain score or time to discharge among the treatment groups (112).

There is an array of vascular access site complications that may occur in the early and delayed post-procedural setting. Major complications rates are less than 1% (113). Hematomas may occur at the vascular access site and are often managed conservatively unless uncontrolled or if the patient becomes anemic which would require intervention with transfusion. In the case of high femoral artery access, retroperitoneal hematomas rarely occur. Most can be managed with manual pressure, rarely requiring embolization with selective embolic or balloon tamponade (114). Pseudoaneurysms have been found to happen between 3.5% and 5.5% of all interventional arterial procedures. Some risk factors include long procedure times, use of large sheaths, obesity, and heavy arterial calcifications. Diagnosis can be made with Duplex ultrasound with high sensitivity and specificity. The majority (61%) of pseudoaneurysms less than 2 cm in size will resolve with conservative management: ultrasound-guided compression has a success rate up to 86%. Persistent pseudoaneurysms can often be treated with ultrasound-guided thrombin injection; requirement for surgical repair is rare. Arteriovenous fistulas (AVF) can occur in less than 1% of the cases and often heal spontaneously with conservative management. Rarely, persistent AVFs require management with coil embolization, vascular plugging, or stent grafting.

Treatment failure is certainly an area of concern. In a prospective study of 304 patients, 54 (23.3%) experienced recurrence of symptoms at some point during 10-year follow-up, 46 of whom underwent reintervention with hysterectomy, myomectomy or repeat UAE. Age younger than 45 years was the main risk factor for symptoms recurrence (115).

Other concerns include spontaneous abortion, infertility, ovarian failure, and premature menopause. In a randomized controlled trial, Mara et al. demonstrated comparable symptomatic control between UAE and myomectomy in short term. However, in those who tried to conceive after procedure, they observed more successful pregnancies (33/40 vs. 17/26) and labors (19/40 vs. 5/26) and fewer abortions (6/40 vs. 9/26) in the myomectomy group (116). With a lack of more rigorous research, the true infertility rate after UAE is unknown. A review of literature pooling the post-UAE pregnancy numbers reported a post-UAE pregnancy rate to be 38.3% (117).

A prospective cohort study of 36 women, aged 26–39 years, with normal ovarian reserve sampled serum FSH and estradiol levels at several intervals up to 60 months after UAE. These hormone levels remained within normal limits for all but two women during the study period, indicating that UAE is not associated with early ovarian failure (118). Another long-term prospective study found no causal effect between UAE and advancing age of menopause under the age of 45 years (119). Similarly, the REST trial showed no significant increase in risk of premature ovarian failure with UAE at 1 year compared to surgery (120). Likelihood of post-UAE amenorrhea has been reported to be dependent on age, with amenorrhea in women under 45 being a rare outcome (121). In cases where ovarian failure is a concern, occlusion of uteroovarian collateral vessels prior to UAE can assist with the prevention of non-target embolization (122).

Conclusions

UFs are the most common benign tumors in women. Despite progress in minimally invasive therapeutic approaches such as UAE, hysterectomy remains the most common treatment with significant racial preponderance in black women. Decreased fertility remains the main concern after endovascular approaches. However, data in this regard are still mixed and the actual infertility consequences of such treatments is yet to be elucidated. UAE is an effective minimally invasive, uterus sparing, and potentially fertility-preserving therapy for symptomatic UFs.

Acknowledgments

The authors thank Matthew Vos for designing the schematic illustrations.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-57/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-57/coif). J.J.M. reported consulting fees from Stryker. Y.J. reported receiving support for meeting attendance from American Roentgen Ray Society (ARRS) and patent issuance from US patent office. Y.J. also reported serving on the editorial board of the Journal of Vascular and Interventional Radiology (JVIR), and membership on the Society of Interventional Radiology (SIR) and comparative effectiveness committee (CER). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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