Dr. Itkin is a Clinical Instructor and Dr. Shlansky-Goldberg is an Associate Professor of Radiology in the Division of Interventional Radiology, University of Pennsylvania Medical Center, Philadelphia, PA.

Uterine fibroid embolization (UFE) is a widely practiced procedure for the treatment of symptoms due to uterine leiomyomata. Originally performed as uterine artery embolization (UAE) for the treatment of acute uterine bleeding, the majority of procedures are now performed for bleeding or bulk symptoms due to fibroids, hence the term UFE. Since the original description of the technique by Ravina, ¹ we have gained enormous knowledge about the impact of selectively embolizing both uterine arteries, demonstrating UFE to be an extremely safe and effective therapy for the treatment of symptomatic uterine fibroids.

Historical aspects

Prior to the discovery of UAE for the treatment of fibroids, embolotherapy for benign disease was reserved for bleeding complications associated with gynecologic procedures, obstetrical emergencies, and arteriovenous malformations. The first reports of percutaneous transcatheter embolization of postpartum hemorrhage and postoperative gynecological bleeding was in 1979. ² The first pelvic embolization specifically for the treatment of symptomatic uterine fibroids was performed in France initially as a treatment preceding myomectomy to reduce blood loss. ¹ At that time, Ravina et al ¹ discovered that many of the patients canceled their surgery due to almost complete disappearance of their symptoms. Goodwin et al ³ published the first U.S. results in 1997.

In October 2000, the Society of Interventional Radiology (SIR) performed a survey of its members performing UFE. ⁴ Information from 330 institutions revealed that approximately 10,500 procedures had been performed worldwide, including 8644 in the United States, at both academic and nonacademic sites in 47 states and the District of Columbia in addition to 17 foreign countries. The number of women currently treated worldwide probably has doubled since the last SIR survey.

Epidemiology

Uterine leiomyomata or fibroids are the most common tumor found in women. They are benign clonal tumors arising from the smooth-muscle cells of the uterus. Approximately 25% of premenopausal women suffer from fibroids, ⁵ while the overall prevalence of these tumors could be as high as 77%. ⁶ The incidence of fibroids in African-American women is three times that of Caucasian women. ⁷ Fibroids may occur at any age, but are most common in women over the age of 40 years. After menopause, fibroids usually regress in size due to the lack of hormonal stimulation, which may result in infarction.

Symptoms

More than 50% of the patients with fibroids are asymptomatic. ⁵ When present, there are usually three types of symptoms associated with fibroids: bleeding, pelvic pressure (pain, urine frequency), and infertility. The location of the leiomyoma is classified as subserosal, submucosal, or intramural and is probably more important than size in causing the symptoms (Figure 1). ⁸ However it may be difficult to determine its position within the wall of the uterus as the tumor increases in size. Prolonged and intensive cyclical menstrual bleeding (menorrhagia) is the most frequent clinical presentation of submucosal fibroids. Bulk symptoms are usually caused by serosal fibroids that compress the nearby pelvic structures, resulting in the associated symptoms: bladder (urinary frequency), sciatic nerve (pain), or bowel (constipation). Uterine fibroids may impact fertility, ⁹ usually due to a submucosal fibroid distorting the endometrial cavity. ¹⁰ In infertile women, uterine cavity distortion by fibroids was found in 56% of hysterectomy specimens. ¹¹

Diagnosis

The patient's clinical history is very important in evaluating patients for UFE. The typical patient is a premenopausal woman suffering from prolonged regular bleeding during menses without bleeding between periods (menorrhagia). Irregular or intermenstrual gynecological bleeding (menometrorrhagia) should raise the suspicion of another pathology. The differential diagnosis of vaginal bleeding includes fibroids, adenomyosis, endometrial sarcoma, polyps, and other endometrial disorders. An endometrial biopsy is generally recommended when the complaint is bleeding, but in cases of menometrorrhagia, it is essential to exclude endometrial carcinoma. The initial diagnosis is confirmed by magnetic resonance imaging (MRI) or ultrasound. MRI is advocated by many as the most reliable and reproducible modality. It allows for the differentiation of the fibroids from other pathological conditions, such as adenomyosis (Figure 2), potentially predicts outcome based on vascularity, ¹² and delineates precisely the fibroid's location within the uterus.

One concern in evaluating a patient for UFE is the risk of embolizing a leiomyosarcoma. In premenopausal women, the incidence of the leiomyosarcoma is very low with a rate of 0.13% to 0.29%. ¹³ A biopsy is not helpful to exclude this malignancy and it is almost indistinguishable from a leiomyoma on ultrasound or MRI. Unfortunately, a high growth rate of the uterine mass doesn't necessarily predict malignancy ¹⁴ ; however, symptoms such as fatigue and weight loss may raise suspicion. The risk of inadvertently embolizing a sarcoma is very small with only two cases reported in the literature. ^15,16 Both of these cases presented as therapeutic failures with a uterine mass that continued to grow after the embolization, making follow-up imaging important.

Uterine and ovarian artery anatomy

The main portion of the uterine artery can be divided into three parts. ¹⁷ The first part runs close to the lateral pelvic sidewall, the second part runs in the parametrium, and the third part, called the marginal artery, runs along the lateral margin of the uterus toward the uterine horn. The main branches from the uterine artery in the order of their branching are: the ureteric branch supplying the distal portion of the ureter (usually not visible); the cervico-vaginal branch supplying the vagina and cervix; the uterine intramural branches supplying the myometrium; and the terminal fundal branches supplying the fundus. In 9% of cases, the cervico-vaginal branch comes off of the internal iliac. Finally, the medial tubal and ovarian branches arise from the terminal uterine artery. In approximately 10% of cases, the blood to the uterine fundus is supplied by the ovarian arteries. Rarely, the ovarian artery may supply blood to most of or all of the uterus.

Generally the ovarian arteries arise from the ventral surface of the aorta in approximately 83% of cases, usually as a single origin but they may have multiple origins. ¹⁸ In 17% of cases, the ovarian arteries may arise from the renal arteries or other pelvic vessels. The blood supply to the ovaries comprises flow from the uterine artery from branches that create a tubal and ovarian arterial arcade and anastomose with the lateral tubal and ovarian branches from the ovarian artery. In 40% of cases, the ovarian artery solely supplies the ovary while there is a shared supply with the uterine artery in 30% of cases. In 10% of patients, the uterine artery is the main supply to the ovaries. The uterine artery supplies the fallopian tube in 60% of patients while there is shared supply in another 56% of cases. In only 4% of cases does the ovarian artery solely supply the fallopian tube. ^17,18 Knowledge of these anastomoses is important since they provide for the collateral blood flow that may result in the failure of percutaneous embolization or ovarian nontarget embolization.

Procedure­­technical aspects

Several different techniques utilizing a variety of catheters to access the uterine arteries have been described. ^19-22 Due to extensive intrauterine collateral flow, bilateral uterine artery embolization is necessary to achieve fibroid infarction. ^21,23 Catheterization is typically performed by the right common femoral artery approach with the use of a 4F or 5F Cobra catheter (Boston Scientific Corp., Watertown, MA) or Levin catheter (Cook Inc, Bloomington, IN) (Figure 3). Some practitioners use a coaxial microcatheter to access the uterine artery to reduce the potential for spasm. Spasm may result in nontarget embolization to the ovaries or in premature termination of the embolization.

Ipsilateral catheterization is commonly performed using the Waltman loop technique. As originally described by Waltman ²⁴ in 1973, the catheter is looped back over itself by selecting a suitable visceral vessel and pushing the catheter up into the aorta. This technique works well with braided catheters; however, based on our experience, newer hydrophilically coated catheters are more susceptible to kinking while forming the Waltman loop. We have described a modification of a Cope suture technique to form the Waltman loop to access the contra- and ipsilateral sides. ²⁵ Others use the "Roberts" catheter (Cook Inc., Bloomington, IN), which is specifically designed for UFE with a long reversed secondary curve that tapers from 5F to 3.8F. Spies et al ²⁶ advocate using a bilateral femoral approach to reduce the radiation dose to the ovaries by simultaneously injecting the embolic agent into both uterine arteries.

Embolic material

The main goal of the procedure is to embolize the perifibroid plexus where the median size of these arteries is approximately 500 µm. ²⁷ For that reason, most investigators use particles >350 µm. Several European groups advocate the use of the smaller 150 to 300 µm particles. ^21,28 Most reports describe the use of polyvinyl alcohol (PVA) as the embolic agent. The advantages of PVA are that it has been used safely as an embolic agent for more than 20 years and is relatively inexpensive. The main drawback of these particles is their propensity to aggregate in the syringe or catheter, causing catheter blockage or potentially proximal occlusions.

Recently, Embospheres (Biosphere Medical, Rockland, MA) particles have gained popularity. Their main advantage over PVA is a hydrophilic feature that prevents the aggregation and facilitates delivery of the particles.

Some authors advocate embolization with Gelfoam (Pharmacia & Upjohn Co., Kalamazoo, MI) since it is a temporary embolization agent. ²⁹ Because it allows reperfusion to the uterus after initial embolization, it has the theoretical benefit of potentially limiting some of the complications of UFE and may help maintain fertility in patients. Stancato-Pasik et al ³⁰ described a series of 12 patients who underwent embolization with Gelfoam and resumed normal menstruation; 3 of them eventually carried a pregnancy to term and had a normal delivery.

The end point of the embolization generally depends on the embolization material and personal experience of the operator (Figure 4). As a rule, the Embospheres propagate deeper than PVA because of the elastic features of the particle. For this reason, most researchers recommend a much less aggressive approach to embolization than the use of PVA. Moderate flow is maintained to the uterine vessels while achieving a "pruned tree" appearance to the fibroids. This is opposed to the "stagnant" flow that is usually achieved with PVA. ^19,31,32

Radiation exposure

Since UFE is done under fluoroscopic guidance, radiation exposure is a concern, especially in women who are of reproductive age. Several published studies demonstrated that the overall dose, 22.34 cGy, is comparable to the other diagnostic studies and far below the doses that are used for treatment of the pelvic malignancies (up to 3500 cGy). ³³ With proper collimation and the use of pulsed fluroscopy, the estimated absorbed ovarian dose could be decreased to 9.5 cGy (range 2.21 to 23.21 cGy). ²⁶

Pain control

Periprocedural pain control is of the utmost importance since it represents the major morbidity of the procedure. Pain generally starts early after the embolization and reaches the highest severity 24 to 48 hours after the embolization. Most pain protocols use a combination of opioids, such as a oxycodone derivative, and a nonsteroidal anti-inflammatory (NSAID), such as ibuprofen. Successful pain control potentially allows this procedure to be performed on an outpatient basis. Early studies attempting to perform UFE as an outpatient procedure reported that 15% of patients returned to the hospital for pain control. ³⁴ In a recent article by Siskin et al, ³¹ the authors reported 95.9% successful discharge after 8 hours of postprocedure observation. One should not use intra-arterial lidocaine in an attempt to reduce pain since it causes a large amount of spasm. ³⁵ Postembolization syndrome with severe pain, fever, and an elevation in the white blood count occurs in as many as 34% of patients. ¹⁹

Results

Two main measurable outcomes are reported in all published UFE studies: clinical (improvement of symptoms) and radiological (decrease of the fibroid and uterus sizes). Even though the change in size of the fibroids and uterus is a more objective measurement, the goal of the therapy is to improve clinical symptoms. Patients who have minimal change in the size of their fibroids and uterus will often have dramatic improvement in their symptoms.

The technical success rate of the procedure is very high: 84% to 100% (Table). ^{19-22,28,29,36-39} Difficulties in accessing the uterine artery or arterial spasm are the main causes of failure. Besides making it difficult to catheterize, uterine arterial spasm may also cause early proximal thrombosis of the uterine artery that may result in immediate recanalization causing procedural failures.

The fibroids and uterus decrease in size following the embolization (Figure 5). Overall shrinkage of the dominant fibroid is 40% to 70% and of the uterus is 40% to 60% (Table). It has been shown that the uterus continues to shrink over time. ^28,40

Fibroids vary considerably in their histologic composition. Some of them are extremely vascular with a significant cellular component and others are partially degenerated. Jha et al ¹² demonstrated that hypervascular fibroids by MRI criteria decrease in size more than those that are avascular, which suggests that the MRI vascularity pattern may help predict fibroid shrinkage after therapy.

The overall clinical response of UFE is close to 90% (Table). Menorrhagia is the most common indication for UFE and has the best response rate. In all published series, 81% to 100% of patients improve clinically. ^19,31 For bulk-related symptoms (bloating, pelvic pain, urinary frequency), the success rate is 61% to 100%. Some of the inconsistencies in these results may be due to the different ways that the outcomes were measured.

Lack of response to embolization may be due to perfusion to the fibroids by ovarian collaterals (Figure 6). As discussed, the ovarian artery may supply the uterus and fibroids in a small percentage of patients. For that reason, we complete each procedure with flush aortography with the tip of the catheter placed at the level of renal arteries. In cases of an enlarged ovarian artery, selective catheterization may be performed to demonstrate arterial supply to the fibroids. Some investigators advocate ovarian embolization if definite fibroid supply is demonstrated or if the patient's clinical symptoms do not improve. ^41,42 Ovarian embolization may increase the risk of ovarian failure.

The effect of the UFE on fertility is still under investigation. Ravina et al ⁴³ identified 12 pregnancies in 9 women in their series of 184 women who underwent UFE. Among the 12 pregnancies, there were 4 full-term and 3 premature deliveries, and 5 early miscarriages. Unfortunately, the authors didn't describe how many women tried to conceive. Due to the risk of ovarian failure, possible hysterectomy, and devascularization of the uterus, we generally do not recommend UFE for patients who desire pregnancy when surgical and medical options are available. If these other options have failed or are not possible, such as in a patient with numerous fibroids in whom a myomectomy cannot be performed, UFE may be offered.

Adenomyosis, which is ectopic growth of endometrial glands and stroma into endometrium, is less common and sometimes coexists with fibroids. Some investigators originally considered it responsible for UFE failure. ⁴⁴ However, in a recent study in which UAE was performed for 15 patients with adenomyosis, Siskin et al ⁴⁵ found that 92.3% of patients reported significant improvement of symptoms and quality of life at 1-year follow-up. This suggests that adenomyosis may be treated by UAE; although further information is needed.

Complications of UFE

The overall complication rate of UFE is very low. Currently there are 4 known deaths related to UFE: 2 have been reported in the literature ^46,47 and 2 unreported among >15,000 cases. ⁴⁸ Two are from pulmonary embolus and 2 from infection. This compares favorably to the mortality rate for hysterectomy performed for benign disease, which is 1 in 1600 operations. ⁴⁹ The mechanism of pulmonary embolism may be related to a derangement of the clotting cascade due to tissue necrosis. Some clinicians advocate leg pressure stockings to eliminate venous stasis, while others advocate the use of heparin to prevent deep venous thrombosis.

Complications related to the catheterization are extremely low, with < 1% reported throughout most of the studies (Table). Most of these complications are self-limited and do not require additional therapy. Hematoma is the most common complication but the incidence is difficult to estimate. Other rare reported complications include allergy to iodine contrast, ³⁹ pseudoaneurysm formation, and dissection. ²⁸

The more commonly reported complications are related to fibroid expulsion, uterine infection, and nontarget embolization. Fibroid expulsion is a common event after UFE, with up to a 5% rate in two large studies. ^21,39 The intrauterine necrotic fibroid tissue may become infected and cause significant morbidity. We recommend MRI for any women with suspected intracavitary sloughing of a fibroid, since it demonstrates whether the fibroid is detached from the wall and lying in the endometrial cavity near the cervix. Patients may expel the necrotic tissue without any help but often will require gynecologic assistance. Although patients will have a dramatic volume reduction with expulsion, suggesting that the process may accentuate their response to embolization, there remains a risk of hysterectomy if the debris cannot be removed or if the patient becomes septic.

Infection is another complication that is related directly to ischemia of the fibroids or uterus. Endometritis and pyometra are responsible for most postembolization hysterectomies, and this was the reason for 1 of the reported deaths. ⁴⁶

Nontarget embolization to the ovary is possible due to the ovarian collaterals from the uterine artery. Pelage et al ⁵⁰ identified the collaterals between the uterine artery and ovarian artery in 11% of the patients that underwent pelvic angiogram for a variety of reasons. In 5% of patients, the ovarian artery can be absent and the ovaries supplied solely from the uterine artery. It has been suggested that the embolization material passes into the ovarian artery through these tubal collaterals. This is supported by Ryu et al, ⁵¹ who demonstrated that 50% of the patients who had UFE had a decrease in ovarian Doppler flow.

Many patients may experience amenorrhea for 1 or 2 months after UFE. Most will have their periods resume. However, a few will go onto permanent amenorrhea; in most studies the incidence is <5% of cases. ^19,40,52 The etiology is probably nontarget embolization; however, other etiologies are possible, such as radiation. A higher rate of ovarian dysfunction is suspected in patients older than 45 years. Chrisman et al ⁵³ demonstrated that 15% of their 66 patients did not resume regular menses and all of them were older than 45 years of age. In the subgroup of patients who were >=45 years, 9 of 23 (43%) became menopausal. Spies et al ⁵⁴ conducted a study in which they measured follicle stimulating hormone (FSH) levels, an indicator of menopause, before and up to 6 months following UFE. They could not identify a statistically significant difference of the basal FSH change in the whole group, but when a subgroup analysis was performed for the patients aged 45 and older, 15% of patients had an increase in FSH into the perimenopausal range. These findings are not surprising, since the average age of menopause is 51 years. One could speculate that the ovaries in an older patient may be less tolerant of embolization.

While sexual dysfunction may be common after hysterectomy, ^55,56 there is only 1 report of a patient losing pelvic and clitoral orgasm after a successful UFE. ⁵⁷ The patient's orgasm eventually returned to baseline after a certain period of time. Trying to avoid embolization of the cervical-vaginal branch of the uterine artery may prevent this rare complication.

Comparison with surgical methods

There is only one reported prospective Phase II clinical trial that compares UFE using Embospheres with hysterectomy. ⁵⁸ The abstract was presented at the recent SIR annual meeting. The report demonstrated that UFE with Embospheres gave a similar improvement in the symptoms when compared with hysterectomy, but had the advantage of a faster recovery.

In a small nonrandomized retrospective study comparing myomectomy with UFE, ⁵⁹ 12% of the myomectomy patients required blood transfusion and 25% overall suffered from various complications while the UFE group had no complications or blood transfusion. Hwang et al ⁶⁰ demonstrated differences in complication rates of 19.4% versus 4.1% for the myomectomy and UFE groups, respectively. In addition, recovery was much faster in the UFE group. Future, prospective studies are needed to compare these two treatment modalities. The results from the prospective Boston Scientific Corp.­sponsored PVA UFE versus myomectomy study should be available soon.

In the future, a better understanding of the impact of UFE will be obtained from the large Fibroid Registry for Outcomes Data (FIBROID), sponsored by the Cardiovascular and Interventional Radiology Research and Education Foundation, the research affiliate of SIR. Its main goal is to establish the effectiveness and safety of UFE in a prospective longitudinal fashion.

Conclusion

Uterine artery embolization is a minimally invasive alternative for treatment of symptomatic fibroids. The success rate is excellent, with a low complication rate and a recovery time that is much shorter than conventional surgery. Although the experience of single-center small series makes it difficult to give accurate rates for many of these reported complications, the incidence appears to be low. In addition, further research must clarify the impact of UFE on fertility. We expect the FIBROID registry initiative to answer many of these questions and further support the advantages of using UFE for treating women with symptomatic fibroids. AR