The Lublin Protocol of the Uterine Arteries Embolization in the Treatment of Symptomatic Uterine Fibroids

Uterine fibroids are benign tumors originating from smooth muscle tissue, constituting uterine muscle stroma. They are monoclonal tumors, consisting of a large amount of extracellular substance containing collagen, fibronectin, and proteoglycans. The fibroids are surrounded by a thin pseudocapsule made of compressed muscle fibers, collagen fibers, neurofibers, and blood vessels^1,2. The pathophysiology of myomas is not entirely understood but seems to rely mainly on monoclonal proliferation caused by selective and tissue-specific epigenetic changes³. No single gene was found to cause uterine fibroids. However, the presence of rare uterine fibroid syndromes, such as multiple cutaneous and uterine leiomyomatosis, has been attributed to a gene that codes for fumarate hydratase, a mitochondrial enzyme involved in the Krebs cycle⁴. The presence of chromosome 7 deletions and translocations in chromosomes 7, 12, and 14, which occur in 50% of fibroids, seems to be secondary rather than primary^5,6,7.

The regulators of the growth of uterine fibroids are steroid hormones produced by ovaries (estrogens and progesterone), growth factors, angiogenesis, and apoptosis. Risk factors for the development of uterine fibroids have also been identified, including age, early menarche, African-American race, heredity, nulliparity, obesity, polycystic ovary syndrome, diabetes, hypertension, vitamin D deficiency, use of soybean milk, alcohol, and caffeine consumption⁸.

Uterine fibroids are the most common benign tumors of reproductive organs in women. These tumors were first described in 1793 by Matthew Baillie at St George's Hospital in London. Available epidemiological data do not accurately specify the incidence of uterine fibroids, as their large proportion remain undiagnosed. It is estimated that uterine fibroids occur in 5.4% to 77% of all patients. Their prevalence is higher in the United States than in Europe, the probable cause being racial differences⁸.

Among women in the childbearing age, approximately 30% of myomas may give clinical symptoms in the form of abnormal uterine bleeding, resulting in inadequate blood supply in patients⁹. In most cases, patients have more than one myoma, which are spherical lesions located in the uterus. Their dimensions and location may vary. In 90% of the cases, they are located in the body of the uterus. Their diameter can be from several millimeters to 20 cm¹⁰.

The FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) classification divides them into groups from 0–8 depending on the proximity of the endometrium (lower the number, closer will be the endometrium) (Figure 1)¹¹. In about 50%–75% of the cases, fibroids are asymptomatic. The most common symptoms of uterine fibroids are profuse menstrual bleeding, abnormal uterine bleeding, and pressure symptoms. Myomas are associated with about 10% of the cases of infertility, and in 1%–3% they are the only cause¹². Asymptomatic uterine fibroids usually undergo only a regular medical control, whereas symptomatic fibroids are an indication for treatment¹³.

The treatment methods for uterine fibroids that are currently used include surgical treatment, pharmacological therapy, and minimally invasive procedures^{13,14,15,16,17,18}. Surgical treatment includes myomectomy (abdominal and hysteroscopic) and hysterectomy. Both myomectomy and hysterectomy have a positive impact on the quality of life¹⁹. Hysterectomy is associated with irreversible loss of fertility; thus, many women seek other treatment options²⁰.

Abdominal myomectomy allows for the preservation of fertility. Depending on the size and number of fibroids, as well as the experience of the surgeon, this procedure can be performed via laparotomy or laparoscopy. Although hemorrhages are less common than in hysterectomy, overall morbidity is similar. Hysteroscopic myomectomy is a safer, less invasive method than abdominal myomectomy and allows the treatment of submucous fibroids (FIGO 0). Subsequent hysteroscopic procedures may be necessary to completely remove larger type-2 fibroids²¹.

Levonorgestrel releasing intrauterine devices are an effective treatment for heavy menstrual bleeding, but they do not reduce the size of the fibroids. Their use is limited in patients with the deformed uterine cavity. GnRH analogues are mainly used as a pre-operative agent to reduce the size of fibroids and perioperative blood loss. They also reduce the percentage of vertical incisions during hysterectomy and myomectomy while increasing the possibility of a vaginal procedure²⁰.

In the short term, selective progesterone receptor modulators reduce the myoma volume and induce amenorrhea. However, the long-term efficacy and safety require further research. Along with aromatase inhibitors, there may be other options for pre-operative treatment of anemia and reduction of the myoma volume²². Some studies suggest that vitamin D may slow down or prevent the growth of fibroids and the onset of symptoms²³.

New methods using 2-methoxyestradiol combined with nanoparticles are also under development²⁴. Minimally invasive methods used in the treatment of fibroids include uterine artery embolization (UAE), magnetic resonance-guided focused ultrasound surgery (MRgFUS), laparoscopic uterine artery occlusion (LUAO), and radiofrequency myolysis^14,25. Ultrasound-guided High-Intensity Focused Ultrasound (US-HIFU) is a new, still experimental, minimally invasive method^26,27.

Methods of therapeutic vascular occlusion and blocking the blood supply to the uterus were mentioned over 120 years ago. In 1894, Kelly presented the ligation of internal iliac arteries during an oncological hysterectomy to control intractable pelvic bleeding, which at that time was a common complication after the surgical procedure²⁸. Then, Sack (1973) described the effective use of the same technique in the treatment of massive postpartum hemorrhage after forceps delivery. In both cases, hemostasis was achieved without hysterectomy²⁹. In 1979, Heaston et al. and Brown et al., independently described embolization of the pelvic arteries using absorbable gelatin sponges to control postpartum hemorrhage^30,31.

UAE was first used as a treatment method for symptomatic uterine fibroids in 1991 in France³². It was initially used to reduce blood loss after myomectomy. In 1995, Ravina et al. proposed this procedure as the primary treatment method for symptomatic uterine fibroids³³. In the United States, uterine artery embolization was successfully performed in 1997³⁴.

The growing interest in uterine preservation in women with symptomatic fibroids put UAE at the forefront of minimally invasive fibroids treatment^{14,18,35,36,37}. In 2000, the Joint Working Party of the Royal College of Obstetricians and Gynecologists and The Royal College of Radiologists was created to issue guidelines on UAE. At that time, UAE was considered to be an experimental method (less than 7,000 procedures performed worldwide). Since the guidelines were published, more than 100,000 UAE procedures have been performed worldwide. Also, five randomized controlled trials have been carried out, comparing the UAE with other surgical procedures. Research results indicate that UAE is highly effective in the short-to-medium term (up to a few years) with a low risk of medium (e.g., uterine infection) and serious (life-threatening) complications^38,39. In randomized studies, shorter hospitalization times, faster recovery, and return to daily activities speak in favor of UAE. Surgical procedures proved to be cheaper and less frequently required re-intervention while maintaining statistical significance³². This procedure is currently a widely accepted method of treatment for symptomatic uterine fibroids and has been recognized as such by the National Institute for Health and Clinical Excellence (NICE) in the guidelines for heavy menstrual bleeding⁴⁰.

Currently, there are 11 recommendations regarding the use of UAE in the treatment of symptomatic uterine fibroids, created by scientific societies from Europe, North America, and Australia. In most cases, the recommendations are consistent while the divergence concerns two discrepancies. The first is whether pedunculated submucosal (FIGO 0) and subserosal (FIGO 7) myoma are contraindications for UAE. The second is whether women declaring future pregnancy should be qualified for this procedure⁴¹. The American College of Obstetricians and Gynecologists (ACOG) (2008) presented an interesting guideline for the treatment of uterine fibroids. Based on consistent scientific evidence (Level A), the ACOG defined UAE as an effective and safe method for appropriately qualified women who wish to preserve the uterus with typical indications for the treatment of fibroids. At the same time, the ACOG recommendations emphasized the need for close cooperation between gynecologists and interventional radiologists. In the published guidelines, the ACOG recognized the desire to preserve fertility as the only contraindication (relative)⁴².

One of the latest recommendations was issued in 2013 by the Royal College of Obstetricians and Gynecologists (RCOG) and in 2015 by the Society of Obstetricians and Gynecologists of Canada (SOGC)⁴¹. In the remaining part of this article, the authors will use the above recommendations. According to the guidelines of RCOG and SOGC, any patient with symptomatic myomas can be a candidate for embolization, provided there are no contraindications and the benefits of the procedure (resolution of symptoms) outweigh the risk of complications. It should be noted that the embolization of uterine fibroids as a minimally invasive procedure carries a negligible number of serious complications. Hence, the benefits in most cases outweigh the risk of complications^14,32,43.

An appropriate patient qualification is of crucial importance for high clinical effectiveness and prevention of complications after UAE. The main indication for UAE is symptomatic uterine fibroids, resulting in heavy menstrual bleeding, dysmenorrhea, pain, dyspareunia, and other adverse effects on the urinary or gastrointestinal tract. It is necessary to differentiate fibroids from adenomyosis or fibroids co-existing with adenomyosis because, in such a situation, UAE is less effective and requires modification of the procedure technique^{14,32,43,44,45,46,47}. Specific indications for performing the UAE procedure in women with symptomatic uterine fibroids include refusal of surgery, no consent for blood transfusion, and previously failed uterine fibroids surgery.

In the above indications, UAE should be treated as an alternative to surgical treatment. However, patients should be advised that in a small number of cases, complications after the procedure may result in the need for a surgical intervention^14,32,43. According to the RCOG guidelines, the use of UAE in a situation in which myoma is a probable cause of infertility requires special care and proper assessment of a gynecologist specializing in the treatment of infertility and assisted reproduction. Infertility due to the presence of fibroids is not absolute, and many women will become pregnant without any intervention. Therefore, it is reasonable to exclude other possible causes of infertility, including assessment of the male partner^14,32,43.

Thus, according to the recommendations of RCOG and SOGC, the candidates should be women with symptomatic uterine fibroids in whom pathologies in the pelvis with fibroid-like clinical symptoms have been excluded^41,43.

Absolute contraindications to this procedure include current or recent genital infection, diagnostic doubts due to clinical factors or inadequate imaging, asymptomatic fibroids, viable pregnancy, and contraindications for the use of radiological contrast agents.

Relative contraindications include pedunculated submucosal (FIGO 0) and subserosal (FIGO 7) fibroids, which theoretically may detach from the endometrium due to peduncle necrosis, in rare cases resulting in sepsis. In these cases, UAE should only be considered if hysteroscopic or laparoscopic removal of pedunculated myoma before the procedure is planned.

Despite the fact that current literature suggests that the size of the myoma is not a contraindication by itself, experience shows that extreme caution is required when qualifying patients with large myomas (especially associated with compression symptoms) for UAE, as the reduction in volume may be insufficient to relieve symptoms and meet patient expectations^14,32,43,48.

There are many reports of successful pregnancy after UAE, but existing evidence does not fully support its use as an alternative to pharmacological or surgical treatment (myomectomy) in young women⁴⁹. Therefore, this procedure should be used with great caution in women who declare a desire to become pregnant (as there is a lower pregnancy rate, a higher miscarriage rate, uterine rupture, placenta accreta, and adverse pregnancy outcomes after UAE than after myomectomy)^{32,50,51,52,53,54,55}. As gynecologists, we do not recommend UAE for women seeking pregnancy. For us, it is a relative contraindication, provided that there are additional indications for UAE, such as refusal for surgery or blood transfusions, where the lack of treatment may be life-threatening.

According to RCOG guidelines, the desire to preserve or improve fertility in young women with symptomatic uterine fibroids is a relative contraindication to UAE³². In contrast, SOGC guidelines recommend that in similar cases UAE should not be proposed as a treatment option for fibroids, because safety and effectiveness in such women have not been established^14,43. A similar point of view is represented by other scientific societies, including American Society for Reproductive Medicine (ASRM), American College of Obstetricians and Gynecologists (ACOG), American College of Radiology (ACR), Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG) and others, citing improved fertility outcomes after myomectomy^41,43,56. UAE has been recommended only by NICE for women seeking to maintain or improve fertility, especially with features unfavorable to myomectomy (multiple fibroids)⁵⁷.

Generally, the procedures of UAE could be performed at any stage of the menstrual cycle³². However, assuming that there is no ideal method to exclude pregnancy at the stage of fertilization or implantation, in order to exclude early pregnancy, in our center, it is performed until the 10th cycle day. In most cases, patients are admitted to the gynecology ward on the day of the procedure. Admitting a patient to the vascular surgery ward is permissible if appropriate examinations and gynecological consultation are provided. A gynecologist and an interventional radiologist perform qualification for embolization of fibroids. Gynecological qualification includes medical history, examination, an ultrasound assessment of the reproductive organ and the myoma type. In addition, to exclude any malignancy within the uterus, a cervical (PAP) smear and endometrial biopsy are necessary. In cases where the ultrasound scan of the ovaries is questionable, ROMA test (Risk of Ovarian Malignancy Algorithm) is necessary.

A separate issue requiring discussion is uterine sarcoma, in particular leiomyosarcoma (LMS), which accounts for 70% of these uterine tumors. The prevalence of LMS in patients operated on for myoma is low and is estimated at 0.13%–0.29%^58,59. The increase in the incidence of LMS is observed in women over 40 years of age. LMS is difficult to diagnose before treatment as it may resemble benign fibroids⁶⁰. Most LMSs are unrelated to pre-existing fibroids, and there is no evidence of an association of LMS with uterine fibroids⁶¹. Both uterine fibroids and LMS tend to grow rapidly. Thus, the size or growth rate is not a risk factor for a malignant uterine tumour⁶⁰.

Currently, there are no reliable laboratory or imaging tests that would allow us to clearly identify leiomyosarcoma and differentiate it from leiomyoma^60,62. The sensitivity of endometrial biopsy in the diagnosis of leiomyosarcoma is 86%. Thus, a negative biopsy result does not exclude the existence of a malignant uterine tumor. Contrast-enhanced MRI is currently the optimal diagnostic method for uterine tumors. The sensitivity of this test in the diagnosis of LMS is 94%⁶⁰.

As already mentioned, the above tests do not exclude 100% of malignant uterine tumors. Therefore, there is a slight risk of prolonging the diagnosis of LMS after treatment, without the possibility of histopathological verification of the uterine tumor. The patient should be informed about this during the qualification for UAE.

Performing a complete blood count (CBC) and coagulation tests (INR, APTT), renal panel (creatinine, urea), thyroid-stimulating hormone (TSH), the concentration of anti-Mullerian hormone (AMH) (recommended) or the follicle-stimulating hormone (FSH) at follicular phase, C-reactive protein (CRP), general urine test, and vaginal smear (aerobic vaginal culture) make it possible to assess and avoid potential post-embolization complications (infections, iatrogenic ovarian damage, intensification of previous renal impairment after Gadolinium-based contrast agents, thyrotoxicosis in cases of hyperthyroidism after an iodine-based contrast agent)^63,64. Please note that FSH testing is not recommended under the age of 40, as FSH is not a sensitive indicator of changes in ovarian reserve in young women^50,65.

An interventional radiologist qualifies patients for the procedure based on medical history and magnetic resonance imaging (MRI). While gathering medical history, the benefits and possible complications, as well as the procedure itself, should be discussed with the patient. Patient's expectations regarding UAE should also be discussed. MRI aims to exclude other pathologies of the reproductive organ and adjacent structures as well as assessing the morphology and location of fibroids and anatomy for the technical feasibility of the procedure^35,36,37,57.

UAE aims to completely block the vasculature of all myomas while maintaining the blood supply to the uterus, ovaries, and surrounding tissues within the pelvis. The technical aspects of UAE are still evolving to some extent.

The embolization of uterine arteries is performed by interventional radiologists with appropriate competence in the field of intravascular embolization. The procedure is carried out under fluoroscopy guidance. It involves the percutaneous insertion of a vascular catheter from the puncture in the inguinal region into the femoral artery, the aorta, the internal iliac artery, up to the uterine artery. After placing the catheter deep in the uterine artery and achieving a stable position, the embolization agent mixed with contrast is injected under fluoroscopic control in such a way as to avoid reflux and "non-target" embolization. The vascular bed of myomas is closed using particles of 500–900 µm depending on the type of embolization material—usual sizes are 700 µm. Embolization is continued until stasis blood flow is achieved. At the end of the procedure, the catheter is removed, and the vascular access site is secured with manual pressure and dressing or mechanical closer. The procedure lasts for approximately 0.5–1.0 h. The mean ionizing radiation dose absorbed by the ovary during UAE ranges from 0.04–0.22 (Gy: gray) and mean estimated effective dose ranges from 22–34 (mSv: millisievert). Mean fluoroscopic time is about 22 min^66,67.

The vasculature of most fibroids comes from the uterine arteries. Only about 5%–10% of fibroids are additionally supplied by ovarian arteries. Arterial uterine anastomoses occur in about 10% of cases, while utero-ovarian in 10%–30%. Cutting off the blood supply to the embolized tissues causes ischemic necrosis, followed by hyaline degeneration or coagulative necrosis. This process takes several months^68,69.

The effectiveness of UAE depends on the resolution of symptoms or the degree of their reduction. For the treatment of excessive menstrual bleeding, pelvic pain, and pressure symptoms, the clinical effectiveness index for UAE is 81%–96%, 70%–100%, and 46%–100%, respectively. Within 3–6 months after the procedure, the observed reduction in the volume of fibroids was 25%–60%^33,70,71,72. The mean diameter reduction of the myoma was 2.2 cm⁵⁷.

The reduction in the volume of fibroids does not always correlate with the resolution or reduction of clinical symptoms. In long-term follow-up after UAE, more than 70% of patients reported resolution or significant reduction of clinical symptoms within 5 years after the procedure, while 16%–23% of them required re-intervention^73,74.

In assessing the early UAE effect, authors of this publication propose the use of three-dimensional (3D) ultrasound, using Virtual Organ Computer-aided AnaLysis (VOCAL), performing measurements of vascular indices: vascularization index (VI), flow index (FI), and vascularization flow index (VFI)⁷⁵.

Post-embolization pain is an early (lasting about 24 h) expected after-effect of successful UAE (not to be confused with a complication) and should be actively treated. This clinical symptom is caused by the release of tissue breakdown products of ischemic myoma. The treatment includes adequate pain control, hydration, and possible antibiotic therapy^32,43. Epidural anesthesia (EA) maintained for 24 h after the procedure significantly reduces pain to a completely acceptable level, but at a higher cost and increased risk of complications compared to Patient-Controlled Analgesia (PCA)⁷⁶.

Other approaches are also available in post-embolization pain management reviews. It is worth mentioning the use of mixtures of pain medications with polyvinyl alcohol molecules and electroacupuncture anesthesia during UAE. Both methods were intended to limit the number of UAE procedures performed in a hospital setting^77,78. We do not use these methods in our and cooperating centers.

The early complications of UAE are usually local complications associated with the angiography procedure. This group of adverse events is rare (they occur in less than 1% of cases) and relates mainly to groin hematoma, arterial thrombosis, arterial dissection and pseudo-aneurysm, allergic reactions to contrast agents, a spasm in the uterine artery caused by manipulation of the catheter in the vessel during the procedure (treated as a temporary event after a few minutes pass and the procedure can be continued, if the spasm persists, Verapamil (2.5–5 mg) or Nitrate (100–150 µg) intraarterially could be given) and "non-target" embolization^32,37,38.

There have also been several reports of "non-target" embolization of other pelvic organs and their subsequent ischemia. This complication can occur as a result of poor execution of the procedure, as well as due to the presence of anastomoses and anatomical variants of the pelvic vasculature. A special case of non-target embolization is ovarian damage that results from anastomoses between the vessels of the uterus and the ovaries in some patients^79,80.

The consequence of myoma necrosis is a post-embolization syndrome occurring within 30 days of the procedure in approximately 10%–15% of patients. The symptoms of this syndrome, which may occur together or individually, include nausea, vomiting, malaise, low-grade fever, lower abdominal pain, and elevated leukocyte levels. This is usually a self-limiting syndrome that usually disappears within 10–14 days. Analgesics and anti-inflammatory drugs are used to treat this complication³². It is important to differentiate the symptoms of a post-embolization syndrome with more serious complications such as sepsis. This is especially true in cases where the mentioned symptoms last longer than two weeks^32,37,38.

Infection is potentially the most serious complication after UAE, and it occurs in about 0.5% of cases^32,38. In a case of persistent, high fever (38.5 °C and above) for 24–48 hours and hard and painful abdomen, a sepsis should be suspected. In this case, treatment may not only require the use of antibiotic therapy, but also the need to remove the uterus. In the latter case, in less than 1% of cases, it may pose a threat to the patient's life. Sepsis is more common when UAE is performed on a large uterus (over 20 cm or when the diameter of a single myoma is larger than 9 cm, and also in the case of coexistence of large submucous fibroids)^37,38.

A late complication after UAE (more than 30 days after the procedure), occurring after embolization of submucous fibroids, is the excretion of demarked, necrotic fragments of fibroids through the cervical canal. It happens in about 10% of cases^32,81,82. Approximately 16% of women, after UAE, may have abundant vaginal discharge for several weeks up to many months as a result of the excretion of necrotic fibroids from the uterus⁸³. After the UAE procedure, a significant shortening of menstruation and a decrease in its abundance is observed, which is considered a beneficial effect of this procedure. However, complete amenorrhea is treated as the effect of post-embolization ovarian failure^50,84.

Amenorrhea after UAE is usually transient and limited to a few cycles. Permanent amenorrhea occurs in about 15% of women over 40 years of age and in about 1% of women under this age, causing symptoms of premature menopause. In our own research, a decrease in fertility in young women (33–40 years) as a result of the reduction of the ovarian reserve was found⁶⁵. It is estimated that about 85% of women who report amenorrhea after UAE are over 45 years old⁸⁵. It has been argued that the reason for the increase in the incidence of amenorrhea in older women is due to the reduced ovarian reserve and greater sensitivity of ovarian tissue to ischemia caused by "non-target" embolization⁸⁶.

The UAE procedure also affects the sexual function of women undergoing the procedure. Improvement of sexual function after UAE was reported by 26% of women, deterioration was found in 10%, and unchanged in the remaining 64% of women. A possible cause of sexual dysfunction is abnormal vasculature of the clitoris, cervix, and corpus uteri as a result of the UAE procedure⁷⁴.