Introduction

Uterine leiomyomas, also known as myomas or fibroids, are the most common benign uterine tumors in women of reproductive age, occurring in 20–25% of women . Fibroids develop from a single myometrial smooth muscle cell and are therefore classified as a clonal disease caused by a disruption in the hormonal receptors . Depending on localization, the symptoms vary in frequency and severity, and include anemia caused by heavy bleeding, bulk-related symptoms, pelvic pain, pressure, dysmenorrhea, infertility, and reduced quality of life .

During the 1970s, hysterectomy was the treatment of choice for symptoms caused by fibroids such as menorrhagia, anemia, and abdominal and pelvic pain. Hysterectomy represents still an important treatment with 600,000 operations performed annually in the United States and Canada, most commonly because of uterine myomas, but is an unacceptable treatment for many women desiring uterine preservation . Depending on the underlying cause, maintaining the uterus is of main importance in patients with fibroids, not just for reproduction, but also to avoid ‘‘radical’’ surgery.

Over the last 30 years, advances in technology have promoted different pathways of treatment, leading to less invasive techniques .

The target of these treatments is to achieve good results in terms of fertility, bulk-related symptoms, and menstrual disorders, without the great invasiveness of the previous procedures and without the unattractive side effects of the medical therapy.

Myomectomy, particularly hysteroscopic myomectomy, is the treatment of choice for submucous fibroids in reproductive age women and can increase the chance of pregnancy and live birth . Laparoscopic myomectomy is instead the treatment of choice in case of other localizations such as intramural or subserous fibroids. However, myomectomy is associated with risk and adverse outcomes such as hemorrhage, conversion to hysterectomy, uterine rupture, and abnormal placentation in following pregnancies. Conversely, non-excisional alternative techniques cannot provide a histological confirmation of the disease, with the risk of missing an underlying malignancy. The possibility of inadvertent treatment of malignant disease, thus delayed diagnosis and worsened prognosis exists with all non-excisional therapies for uterine leiomyomas .

In fact, laparoscopic myomectomy and uterine artery embolization (UAE) are the most commonly used therapies, but alternative treatments and less invasive procedures are under development .

Uterine Artery Embolization

UAE has been developed in recent times in a variety of clinical settings including postpartum hemorrhage, bleeding after cesarean section, and bleeding following gynecological surgery treatment of arterial venous malformations of the genital tract as well as gestational trophoblastic disease. Ravina has first used this technique in 1995 to treat uterine fibroids . Since then, the UAE has been further developed, thanks to the new technologies in the field of Interventional Radiology; a prospective randomized trial demonstrated its efficacy in treating symptomatic fibroids, thus establishing this technique as a validated alternative to surgery .

The goal of the technique is the occlusion or marked reduction in blood flow to the fibroids causing selective ischemic necrosis acting at arteriolar level minimizing the uterine damage .

UAE is usually performed by an interventional radiologist where the arterial access is obtained at the level of the femoral artery. The access can be ether mono- or bilateral; the monolateral approach reduces complications due to arterial puncture but exposes the patient to a fluoroscope for a longer duration .

A 4-5F catheter or microcatheter is inserted into the uterine artery, and then the embolic agent is released. Several types of embolic agent are available in market (polyvinyl alcohol (PVA) particles, PVA microspheres, tris-acryl gelatine (TAGM), acrylamido PVA microspheres, or gelfoam) with size ranging from 350 to 900μ. Despite a trend toward a greater reduction using TAGM, a recent meta-analysis reported no significant differences when comparing embolic materials .

Both magnetic resonance imaging (MRI) and ultrasound are suitable for preoperative assessment of localization, number, and dimension of the myomas. MRI has been demonstrated to be superior to both trans-abdominal and trans-vaginal ultrasonography in terms of reproducibility, and provides considerable additional information on viability of the fibroids, the concomitant presence of adenomyosis, or other pathologies that may change patient management . The possibility of administering gadolinium intravenously may also facilitate UAE through the mapping of pelvic vasculature giving additional information on the viability of the fibroids that may predict the responsiveness to embolization .

Despite encouraging results and good tolerability of the procedure, case selection and a good preoperative workup remains crucial to avoid complications and for resolution of symptom.

UAE should be reserved for patients with symptomatic fibroids, who wish to preserve their uterus and who would be otherwise advised to undergo surgical treatment .

Absolute contraindications to perform a UAE include severe vascular disease limiting the access, radiographic contrast media allergy, and impaired renal function as well as a pregnancy state, active infections, and suspicion of malignancies of both uterus and ovaries, while the relative ones are desire for future fertility and in some cases, fibroid localization .

A recent review reported a case series of 13 sarcomas accidentally treated with UAE and a poor responsiveness to the procedure as well as regrowth has been noticed . Although the treatment of an occult leiomyosarcoma with embolization does not seem to spread the disease, the delayed surgical treatment may worsen the prognosis. When a suspicion arises, an MRI scan will indicate malignancy by increased and diffuse heterogeneous signal intensities, irregular contours, evidence of degenerated areas, and early enhancement .

An early failure in clinical response should be better investigated for no further delay of the diagnosis; a persistent early enhancement with lack of size reduction indicates an insufficient embolization but also raises suspicion of the presence sarcomas, and a surgical removal should be considered.

UAE demonstrated good effectiveness in treating fibroid-related symptoms and was advantageous in terms of blood loss, hospital stay, and resumption to normal activities when compared to laparotomic hysterectomy; in a 5-year period, the expected rate of hysterectomy is reported to be approximately 80% .

The procedure seems to alleviate metrorrhagia and bulky symptoms in 80–90% of the patients with 50–60% shrinkage of tumor at 1 year .

In 2003, Pron et al. reported one of the largest series with 83% of the women showing improvement in menorrhagia and 77% in dysmenorrhea; 86% had reduced urinary frequency and a 33% mean reduction in size of the myoma . A preoperative MRI may help predicting the responsiveness to embolization, and a recent study showed that fibroids with lower T1 signal intensity or stronger gadolinium enhancement tend to undergo a greater volume reduction .

Despite a good short-term efficacy, women treated with UAE are more likely to undergo further intervention and the risk is estimated to be about 15–20% after a successful embolization . The post-procedure outcome seems to be related to the completeness of fibroid infraction at MRI in three studies and the re-intervention rate is reported up to 50% at 5 years in case of incomplete infarction .

When selecting a patient for UAE, a possible relative contraindication could be the presence of a pedunculated submucosal myoma as well as previous internal iliac or uterine artery occlusion or a recent GnRH (gonadotropin-releasing hormone) analog administration .

The indication to UAE in the case of pedunculated fibroids that present a stalk 50% narrower than the tumor remains controversial. Even though few series reported the treatment of pedunculated myomas as safe, the embolization may cause torsion of the fibroid with subsequent separation of the tumor from the uterus or a septic complication requiring surgical removal .

In addition, the presence of pedunculated submucosal fibroids, either isolated or associated with others, is related to an increased number of complications such as vaginal discharge, pain, abnormal uterine bleeding, and fever; hence, the possibility of a hysteroscopical removal should be evaluated before the embolization .

Furthermore, the dimension of the fibroids has been reported in early reports as the possible factor leading to unfavorable outcomes following UAE; however, a recent study reported the feasibility of the technique on fibromas of size >10 cm without sensitive increment in the complication rates .

The patient’s wish for future fertility is another relative contraindication as the lack of data in the current literature cannot ensure a good pregnancy outcome. In the case of impaired fertility due to fibroids, myomectomy remains the gold standard. A recent prospective randomized trial comparing UAE versus myomectomy demonstrated a more favorable outcome in the case of surgical removal with a higher pregnancy rate (50% vs. 78%), higher delivery rate (19% vs. 48%), and a lower abortion rate (64% vs. 23%) . The reduced pregnancy rates can be attributed to uterine cavity abnormalities and a negative impact on the ovarian reserve following embolization.

In a study on uterine cavity abnormalities including 127 patients, an hysteroscopy was performed 6–9 months after the procedure detected a normal uterine cavity in only 40% of cases, while the majority reported tissue necrosis and others with synechiae, intracavitary protrusion of the myoma, and fistula between the myoma and the uterine cavity . Although few small series reported uncomplicated pregnancies, data are debatable and those cavity abnormalities may impair the pregnancy outcomes .

Goldberg et al. reported a series of 34 pregnancies following UAE. Spontaneous abortion rate was 32%, the postpartum hemorrhage rate 9%, the premature delivery rate 22%, the malpresentation rate 22%, and the rate of cesarean delivery 65% . Moreover, the Ontario UFE multicenter trial reported 19 pregnancies in 167 patients who wished to conceive, with two cases of placenta accreta and one membranous placenta .

Women should be aware of the lack of data on potential risk for pregnancy outcomes and placental complications . Furthermore, a potential risk for the ovarian function has been reported in up to 10% of patients; patients of age >45 years are more likely to experience post-embolization ovarian failure .

The rate of major complications following UAE is reported between 1% and 2%; infections, bleedings, and hematomas at the groin femoral artery puncture site; allergic or anaphylactic reactions to the iodinated contrast dye; and incomplete uterine artery occlusion as well as inadvertant embolixation of non-target organs are some major complications .

During hospitalization, most of the patients will experience abdominal pain, and special attention should be paid to establish a pain protocol. The intensity of pain do not seem to be related number, size, clinical outcomes, or embolic agents. Up to 40% of the patients experience a self-limiting post-embolization syndrome that is resolved in 48 h; it is characterized by diffuse abdominal pain, nausea, vomiting, low-grade fever, and leukocytosis. The pain is caused by the ischemic necrosis of the fibroid and it is usually resolved within few days; however, in 5–10% of the patients, it persists over 2 weeks, with 2% undergoing a hysterectomy within 6 months .

Another possible complication following UAE is the risk of infections, fever, and sepsis, which is reported in 1–1.8% of the patients. The infections include pyometria, endomyometritis, salpingitis, tuboovarian abscess, and infected myomas, and the most common agent is the Escherichia coli. .

In the case of persisting pain post embolization, uterine infection should always be ruled out and a delayed diagnosis may lead to unfavorable outcomes. Five patients died after undergoing UAE, two from septic shock .

The efficacy of prophylactic antibiotics is still under debate, and their routine use is not recommended; however, they should be reserved for those patients at high risk of infection according to the guidelines .

Thus, it can be concluded that UAE is a safe and effective technique; it should be suggested as an alternative to surgery to those patients affected by symptomatic fibroids, who wish to preserve their uterus without the aim of childbearing. However, these patients should be advised about the risk of re-intervention and possible complications.

Uterine Artery Embolization

UAE has been developed in recent times in a variety of clinical settings including postpartum hemorrhage, bleeding after cesarean section, and bleeding following gynecological surgery treatment of arterial venous malformations of the genital tract as well as gestational trophoblastic disease. Ravina has first used this technique in 1995 to treat uterine fibroids . Since then, the UAE has been further developed, thanks to the new technologies in the field of Interventional Radiology; a prospective randomized trial demonstrated its efficacy in treating symptomatic fibroids, thus establishing this technique as a validated alternative to surgery .

The goal of the technique is the occlusion or marked reduction in blood flow to the fibroids causing selective ischemic necrosis acting at arteriolar level minimizing the uterine damage .

UAE is usually performed by an interventional radiologist where the arterial access is obtained at the level of the femoral artery. The access can be ether mono- or bilateral; the monolateral approach reduces complications due to arterial puncture but exposes the patient to a fluoroscope for a longer duration .

A 4-5F catheter or microcatheter is inserted into the uterine artery, and then the embolic agent is released. Several types of embolic agent are available in market (polyvinyl alcohol (PVA) particles, PVA microspheres, tris-acryl gelatine (TAGM), acrylamido PVA microspheres, or gelfoam) with size ranging from 350 to 900μ. Despite a trend toward a greater reduction using TAGM, a recent meta-analysis reported no significant differences when comparing embolic materials .

Both magnetic resonance imaging (MRI) and ultrasound are suitable for preoperative assessment of localization, number, and dimension of the myomas. MRI has been demonstrated to be superior to both trans-abdominal and trans-vaginal ultrasonography in terms of reproducibility, and provides considerable additional information on viability of the fibroids, the concomitant presence of adenomyosis, or other pathologies that may change patient management . The possibility of administering gadolinium intravenously may also facilitate UAE through the mapping of pelvic vasculature giving additional information on the viability of the fibroids that may predict the responsiveness to embolization .

Despite encouraging results and good tolerability of the procedure, case selection and a good preoperative workup remains crucial to avoid complications and for resolution of symptom.

UAE should be reserved for patients with symptomatic fibroids, who wish to preserve their uterus and who would be otherwise advised to undergo surgical treatment .

Absolute contraindications to perform a UAE include severe vascular disease limiting the access, radiographic contrast media allergy, and impaired renal function as well as a pregnancy state, active infections, and suspicion of malignancies of both uterus and ovaries, while the relative ones are desire for future fertility and in some cases, fibroid localization .

A recent review reported a case series of 13 sarcomas accidentally treated with UAE and a poor responsiveness to the procedure as well as regrowth has been noticed . Although the treatment of an occult leiomyosarcoma with embolization does not seem to spread the disease, the delayed surgical treatment may worsen the prognosis. When a suspicion arises, an MRI scan will indicate malignancy by increased and diffuse heterogeneous signal intensities, irregular contours, evidence of degenerated areas, and early enhancement .

An early failure in clinical response should be better investigated for no further delay of the diagnosis; a persistent early enhancement with lack of size reduction indicates an insufficient embolization but also raises suspicion of the presence sarcomas, and a surgical removal should be considered.

UAE demonstrated good effectiveness in treating fibroid-related symptoms and was advantageous in terms of blood loss, hospital stay, and resumption to normal activities when compared to laparotomic hysterectomy; in a 5-year period, the expected rate of hysterectomy is reported to be approximately 80% .

The procedure seems to alleviate metrorrhagia and bulky symptoms in 80–90% of the patients with 50–60% shrinkage of tumor at 1 year .

In 2003, Pron et al. reported one of the largest series with 83% of the women showing improvement in menorrhagia and 77% in dysmenorrhea; 86% had reduced urinary frequency and a 33% mean reduction in size of the myoma . A preoperative MRI may help predicting the responsiveness to embolization, and a recent study showed that fibroids with lower T1 signal intensity or stronger gadolinium enhancement tend to undergo a greater volume reduction .

Despite a good short-term efficacy, women treated with UAE are more likely to undergo further intervention and the risk is estimated to be about 15–20% after a successful embolization . The post-procedure outcome seems to be related to the completeness of fibroid infraction at MRI in three studies and the re-intervention rate is reported up to 50% at 5 years in case of incomplete infarction .

When selecting a patient for UAE, a possible relative contraindication could be the presence of a pedunculated submucosal myoma as well as previous internal iliac or uterine artery occlusion or a recent GnRH (gonadotropin-releasing hormone) analog administration .

The indication to UAE in the case of pedunculated fibroids that present a stalk 50% narrower than the tumor remains controversial. Even though few series reported the treatment of pedunculated myomas as safe, the embolization may cause torsion of the fibroid with subsequent separation of the tumor from the uterus or a septic complication requiring surgical removal .

In addition, the presence of pedunculated submucosal fibroids, either isolated or associated with others, is related to an increased number of complications such as vaginal discharge, pain, abnormal uterine bleeding, and fever; hence, the possibility of a hysteroscopical removal should be evaluated before the embolization .

Furthermore, the dimension of the fibroids has been reported in early reports as the possible factor leading to unfavorable outcomes following UAE; however, a recent study reported the feasibility of the technique on fibromas of size >10 cm without sensitive increment in the complication rates .

The patient’s wish for future fertility is another relative contraindication as the lack of data in the current literature cannot ensure a good pregnancy outcome. In the case of impaired fertility due to fibroids, myomectomy remains the gold standard. A recent prospective randomized trial comparing UAE versus myomectomy demonstrated a more favorable outcome in the case of surgical removal with a higher pregnancy rate (50% vs. 78%), higher delivery rate (19% vs. 48%), and a lower abortion rate (64% vs. 23%) . The reduced pregnancy rates can be attributed to uterine cavity abnormalities and a negative impact on the ovarian reserve following embolization.

In a study on uterine cavity abnormalities including 127 patients, an hysteroscopy was performed 6–9 months after the procedure detected a normal uterine cavity in only 40% of cases, while the majority reported tissue necrosis and others with synechiae, intracavitary protrusion of the myoma, and fistula between the myoma and the uterine cavity . Although few small series reported uncomplicated pregnancies, data are debatable and those cavity abnormalities may impair the pregnancy outcomes .

Goldberg et al. reported a series of 34 pregnancies following UAE. Spontaneous abortion rate was 32%, the postpartum hemorrhage rate 9%, the premature delivery rate 22%, the malpresentation rate 22%, and the rate of cesarean delivery 65% . Moreover, the Ontario UFE multicenter trial reported 19 pregnancies in 167 patients who wished to conceive, with two cases of placenta accreta and one membranous placenta .

Women should be aware of the lack of data on potential risk for pregnancy outcomes and placental complications . Furthermore, a potential risk for the ovarian function has been reported in up to 10% of patients; patients of age >45 years are more likely to experience post-embolization ovarian failure .

The rate of major complications following UAE is reported between 1% and 2%; infections, bleedings, and hematomas at the groin femoral artery puncture site; allergic or anaphylactic reactions to the iodinated contrast dye; and incomplete uterine artery occlusion as well as inadvertant embolixation of non-target organs are some major complications .

During hospitalization, most of the patients will experience abdominal pain, and special attention should be paid to establish a pain protocol. The intensity of pain do not seem to be related number, size, clinical outcomes, or embolic agents. Up to 40% of the patients experience a self-limiting post-embolization syndrome that is resolved in 48 h; it is characterized by diffuse abdominal pain, nausea, vomiting, low-grade fever, and leukocytosis. The pain is caused by the ischemic necrosis of the fibroid and it is usually resolved within few days; however, in 5–10% of the patients, it persists over 2 weeks, with 2% undergoing a hysterectomy within 6 months .

Another possible complication following UAE is the risk of infections, fever, and sepsis, which is reported in 1–1.8% of the patients. The infections include pyometria, endomyometritis, salpingitis, tuboovarian abscess, and infected myomas, and the most common agent is the Escherichia coli. .

In the case of persisting pain post embolization, uterine infection should always be ruled out and a delayed diagnosis may lead to unfavorable outcomes. Five patients died after undergoing UAE, two from septic shock .

The efficacy of prophylactic antibiotics is still under debate, and their routine use is not recommended; however, they should be reserved for those patients at high risk of infection according to the guidelines .

Thus, it can be concluded that UAE is a safe and effective technique; it should be suggested as an alternative to surgery to those patients affected by symptomatic fibroids, who wish to preserve their uterus without the aim of childbearing. However, these patients should be advised about the risk of re-intervention and possible complications.