Fertility Sparing Management in Uterine Fibroids

Etiology

Fibroids develop as inappropriate yet benign growths of monoclonal uterine cells, specifically smooth muscle cells and fibroblasts.[3] Though pathogenesis typically occurs in the myometrium, fibroids can extend superficially from the uterine serosa from the pelvis into the lower abdomen and, on occasion, into the upper abdomen as well. Alternatively. they can arise from the myometrium and delve into the uterine cavity.

Epidemiology

Uterine fibroids may present at any age and in any community. However, prevalence varies significantly amongst different age groups and ethnicities. The prevalence of fibroids in women of reproductive age is estimated to be 20 to 40%.[4] In women presenting with infertility, 5 to 10% are determined to have uterine fibroids, and also they are found to be the sole factor affecting fertility in 2 to 4% of these women.[5][6] 

The incidence of fibroids increases with increasing age until menopause. The cumulative incidence of fibroids has been documented to be as high as 80% in black women and approximately 70% in white women. The incidence is higher among women in their fifth and sixth decade of life. Premenopausal women demonstrated a higher fibroid risk than post-menopausal women, likely due to the role of hormones in stimulating fibroid growth.

Studies have consistently shown a 3-fold increased risk of fibroids among black women compared to white women when controlled for other accepted risk factors. In addition, black women tend to develop uterine fibroids at a younger age, present with larger uteri at the time of diagnosis. They are more likely to suffer from blood-loss anemia compared to white women. This may be related to the fact that black women generally tend to have had earlier menarche compared to white women.[7]  Racial disparities observed are likely due largely to social determinants of health, including but not limited to access to care, job security, and adequate health insurance seen in the black community.   

Other risk factors for fibroids include early menarche, increased interval since last birth, obesity, diet, family history, and hypertension.[8] Notably, one study revealed that women with hypertension have a fivefold increased risk of developing fibroids compared to those without hypertension.[9]

The risk of fibroids decreases with an increasing number of term pregnancies, such that women having > 5 pregnancies have a quarter of the risk of women who had none.[10] The use of hormonal contraceptives and/or depot medroxyprogesterone acetate (DMPA) for any length of time has also been shown to be protective against fibroids.

Pathophysiology

The exact initiating factor of fibroid formation remains unclear, though prevailing theories highlight reproductive hormones, inherent abnormalities of the myometrium, and predisposing genetic variations as contributing factors.[11] Epidemiological studies also underscore the role of estrogen and progesterone since an increased incidence of fibroids has been found in premenopausal women, have undergone early menarche or DES exposure, or have an elevated BMI.  Perhaps the most striking evidence supporting this relationship is the tendency of fibroids to grow during early pregnancy and regress during the postpartum period or with the use of hormone-suppressing GnRH analogs.  Molecular studies help clarify this link. Myometrial cells with high levels of estrogen and progesterone receptors have been shown to stimulate the growth of adjacent fibroid stem cells in a paracrine fashion.[12] 

Other research models using leiomyoma xenografts were used to explore this molecular relationship have identified both estrogen and progesterone as necessary and interdependent for the growth of abnormal myocytes.[13] In addition, somatic mutations (i.e., MED12, HMGA1, and HMGA2) and inherited mutations (fumarate hydratase gene FH, somatic chromosomal rearrangements) have been identified as discernible genetic components that contribute to this fibroid pathogenesis.[14]

Histopathology

Fibroids are composed of monoclonal smooth muscle and fibroblast cells that have transformed at the microscopic level to abnormal cells.[15] These cells feature upregulated expression of progesterone receptors (predominantly the PR-a isoform) and estrogen receptors (mainly ER-a).[13][16] 

With the endocrinological influence of sex steroid hormones, these cells may grow into clinically detectable fibroids. Histological samples of fibroids demonstrate a significant extracellular matrix (ECM) composed of collagen, proteoglycan, and fibronectin adjacent to the disordered myometrium cells.[17][18] Fibroids are characteristically encapsulated by a thin layer of areolar tissue and compressed muscle fibers.

History and Physical

The diversity in size, location, and volume of fibroids is reflected in the diversity of their clinical presentation, which ranges from asymptomatic to intensely debilitating.  While most patients with fibroids are asymptomatic, approximately 25-30% of patients present with severe symptoms.[3] Moreover, the size and nature of fibroids are often dynamic, as they may involute, degenerate, become fibrotic, calcify, or even hemorrhage over time, and thus symptoms may evolve over time. 

 When fibroids present symptomatically, the most common complaints include AUB, pelvic pain/pressure, increased urinary frequency, constipation, and infertility.[19] Fibroids that arise from the submucosa are more likely to disrupt the contraction of endometrial vasculature and, as a result, may cause extensive bleeding, even when small.[20] Alternatively, large bulky fibroids that extend from the myometrium and/or serosal surface into the peritoneum are more likely to cause symptoms secondary to mass effect.[21] For example, large anterior fibroids tend to manifest with pelvic pressure and bladder symptoms, while posterior fibroids can lead to constipation.

Fibroids’ adverse effects on fertility are largely dependent on their location and ability to distort normal uterine and adnexal anatomy, thereby preventing gamete transport, embryo implantation, and/or the maintenance of early pregnancy.[22]   There is also significant evidence suggesting that fibroids alter endometrial receptivity, impair blood flow, and lead to chronic inflammation that creates a hostile environment for successful intrauterine pregnancy.[23][22]

On a bimanual exam, the examiner may palpate an enlarged, bulky, irregularly shaped uterus. If the fibroids are predominantly posterior, one may appreciate fullness in the posterior cul-de-sac with an anteriorly displaced cervix. An irregular contour or increased uterine size may not be appreciated in patients with small intramural or submucosal fibroids. Whether or not physical findings are significant, a patient with the symptoms described above is sufficient to warrant further evaluation.

Evaluation

The relationship of the leiomyoma with the uterine cavity is important for understanding symptoms and treatment options. Myomas are classified using the International Federation of Gynecology and Obstetrics (FIGO) classification system, which predominantly categorizes based on location (Figure 1).[24][25] There are three main categories: submucosal (FIGO 0, 1, 2), intramural (FIGO 3, 4, 5), subserosal (FIGO 6, 7), and other (e.g., cervical, parasitic) (FIGO 8). 

Transvaginal ultrasonography (TVUS) imaging remains the best tool for initial evaluation when fibroids are suspected.[26] With uterine size less than ten weeks gestation, transvaginal ultrasound has 95 to 100 percent sensitivity in detecting fibroids.[27] On TVUS, fibroids are typically described as well-circumscribed, concentric, hypoechoic masses with acoustic shadowing (figure 2).[28] 

Saline infusion sonohysterography (SIS) is also useful in evaluating the distinction between Type 1-3 fibroids as it provides a clearer picture of extension into the endometrial cavity (figure 3).[26] Suppose the distinction between Type 2 and Type 3 fibroids cannot be made on SIS. In that case, diagnostic hysteroscopy can be a useful tool to do so as it can characterize the extent of protrusion under direct visualization. However, hysteroscopy is less accurate in determining the size of the fibroid compared to ultrasound and SIS.[29] 

Magnetic resonance imaging (MRI) is the most effective imaging to detect the size and location of fibroids; however, given the cost of this modality, it is not routinely used and is instead useful for surgical planning since it can help identify vasculature, degenerating fibroids, location, and depth into the myometrium (figure 4).[2][30]

Treatment / Management

Medical Management

NSAIDs

NSAIDs are commonly used as first-line agents for the use of fibroid-related dysmenorrhea given their affordability, limited adverse effects, and availability.[31] Typically, ibuprofen (600 to 1800 mg daily) or naproxen (550 to 1100 mg daily) is given and advised to be taken 1 to 2 days before the onset of menstruation and through the duration of menstruation.[32] A Cochrane review showed that NSAIDs reduce heavy menstrual bleeding (HMB) compared to placebo. However, they are less effective compared to tranexamic acid, danazol, or LNG-IUD.[32](A1)

Combined Oral Contraceptives

Combined oral contraceptives work by preventing endometrial proliferation and have shown some benefits in improving fibroid-related heavy menstrual bleeding. However, there is no evidence to support their use for the relief of bulk symptoms.[33][31] In a randomized trial comparing the use of the levonorgestrel intrauterine device (LNG-IUD) and a low-dose combined oral contraceptive (COCs), COCs showed a decrease in menstrual blood loss. However, the LNG-IUD group had significantly less blood loss.[34] The use of progestin-only oral contraceptives is a reasonable option for patients with fibroid-associated heavy menstrual bleeding and contraindications to estrogen use. However, limited direct evidence supporting their benefit exists.(A1)

Levonorgestrel Intrauterine Device

Levonorgestrel IUDs (LNG-IUD) are currently FDA approved for the treatment of HMB, including fibroid-related uterine bleeding.[31] The LNG-IUD works via a local progesterone effect on the uterine cavity that induces endometrial decidualization, glandular atrophy, and desensitizing endometrial estrogen receptors rendering them less responsive.[35][36] The device has been clinically FDA-approved for five years, but recent studies demonstrate effectiveness for up to 7 years.[37] Around 20% of patients experience amenorrhea in the first year after insertion, which is the most common reason for removal.[38] Multiple studies have demonstrated that despite reducing fibroid-related menorrhagia, the LNG-IUD had no significant reduction in fibroid volume among premenopausal women.[39][34] Expulsion rates of IUDs seem to depend on fibroid size, with one study demonstrating a 15.4% expulsion rate in women with fibroids >3 cm compared to a rate of 6.3% in those with fibroids <3 cm, regardless of fibroid type.(A1)

Gonadotropin-Releasing Hormone (GnRH) Agonists

Gonadotropin-Releasing Hormone (GnRH) agonists are peptide analogs of the GnRH molecule that act as agonists at the GnRH receptor in the pituitary gland.  Their initial activation at the GnRH receptor causes a flare effect, temporarily increasing serum gonadotropins and downstream sex hormone concentrations. Prolonged activation of the GnRH receptor, typically following 2-4 weeks of continuous therapy, leads to involution or downregulation of the receptor, thereby suppressing pituitary function leading to hypoestrogenism.[40] GnRH agonists have a diverse array of clinical applications. Regarding symptomatic fibroid management, they are used for short-term treatment of AUB, typically inducing a state of amenorrhea, and help improve symptoms of uterine enlargement. Given their side effect profile with long-term use, GnRH agonists are meant to be utilized as a bridge therapy prior to surgical or interventional procedures or natural menopause.[2] Leuprolide acetate, the most studied and most frequently administered GnRH agonist for fibroid therapy, is given as an intramuscular depot injection, either as a monthly injection of 3.75 mg for up to three months or an 11.25 mg 3-month formulation as a single dose.

GnRH agonists are often used to decrease uterine volume prior to surgical therapy, which may ultimately allow for a more minimally invasive surgical approach. In a recent Cochrane review, GnRH agonists were shown to reduce uterine volume by 175ml and fibroid volume by 155 ml compared to placebo controls. The same review demonstrated GnRH agonist benefit in increasing preoperative hemoglobin by an average of 0.88 g/dL, decreasing intraoperative blood loss, and decreasing postoperative complications.[41](A1)

With prolonged therapy, there is a risk of chemically induced menopause leading to vasomotor symptoms, bone loss, vaginal atrophy/dryness, and unfavorable changes to lipid profile.[2] If therapy is to exceed six months, it is important to start hormone add-back therapy with estrogen and progesterone, which can prolong acceptable treatment to an additional six months (for a total of 12 months of therapy).[42]

Gonadotropin-Releasing Hormone (GnRH) Antagonists

Elagolix and relugolix are oral, non-peptide, GnRH antagonists that function by reversible, dose-dependent suppression of GnRH, thereby suppressing gonadotropins and ovarian sex hormones and leading to a hypoestrogenic state.[43] These medications have both been recently FDA-approved (elagolix in 2020 and relugolix in 2021) for the use of HMB related to fibroids. An advantage of these medications is they are formulated with hormone-add back therapy. Elagolix comes co-packaged with two capsules; one containing elagolix 300 mg plus estradiol 1 mg plus norethindrone 0.5 mg taken in the morning and the other capsule containing elagolix 300mg alone taken at night.[44] Relugolix is also a combined formulation consisting of relugolix 40 mg plus estradiol 1mg plus norethindrone acetate 0.5 mg; however, it is only a single daily dose.[45] Both treatments are FDA approved for 24 months of use.

Regarding efficacy, elagolix has been shown to be efficacious in reducing fibroid-related bleeding. In two recent identical double-blinded, randomized, placebo-controlled, 6-month phase III trials (trials UF1 and UF2), 68.5% of 206 women in UF-1 and 76.5% of 189 women in UF-2 receiving elagolix + add back therapy achieved the primary endpoint of reduced menstrual blood loss to less than 80 mL during the final month of treatment and at least a 50% reduction in menstrual blood loss compared to baseline. In those who received elagolix alone (without add-back therapy), the same primary endpoint was met in 84.1% of 104 women in UF-1 and 77% of 95 women in UF-2.[43] 

In a subsequent extension phase III trial, when therapy was given for an additional six months (total of 12 months of treatment), more than half of the participants demonstrated amenorrhea showing a significant improvement in quality of life.[44] The most common side effects of elagolix were hot flushes (7%) and headaches (5.5%). With prolonged therapy, the bone mineral density of the lumbar spine was reduced by 1.5%; however, the reduction was improved to only 0.6% when measured one year following completion of treatment.

Following the elagolix trials, the protocol was replicated for two international, randomized, double-blind placebo-controlled, 24-week, phase 3 trials for the study of relugolix. The relugolix trials demonstrated a reduction of menstrual blood loss in 71 to 80 % of participants compared to placebo and resulted in a significant decrease in pain, anemia, bulk-related symptoms, and uterine volume.[45] Moreover, relugolix was shown to preserve bone mineral density. The most common adverse effects of relugolix combination therapy were hot flashes and hypertension.

Selective Progesterone Receptor Modulators (SPRMs)

SPRMs are a class of synthetic steroids that bind to progesterone receptors and have tissue-specific antagonist effects of varying degrees.[46] Specifically, Ulipristal Acetate (UPA) binds to the pituitary gland, endometrium, and uterine fibroids to elicit actions that have been beneficial in managing uterine fibroids. At the level of the pituitary, UPA inhibits ovulation and induces amenorrhea. At the level of the endometrium, UPA prevents endometrial proliferation and decreases uterine bleeding. UPA also binds progesterone receptors that are abundant within the fibroids themselves to decrease cellular proliferation and increase apoptosis, ultimately reducing the size of the fibroids. Of note, SPRMs lead to histologic changes in the endometrium, referred to as progesterone receptor modulator-associated endometrial changes (PAECs), which are reversible and are not associated with malignancy.[46][47] (A1)

Clinical efficacy in the reduction of AUB-L and fibroid volume has been demonstrated in the European-based PEARL trials.[48][49] UPA is currently not approved in the United States for the treatment of fibroids. UPA use outside the United States is limited due to the rare side effect of severe liver injury.(A1)

Aromatase Inhibitors

Letrozole is a reversible non-steroidal competitive aromatase inhibitor that works by inhibiting the conversion of androgens into estrogens. Studies have demonstrated that uterine fibroid tissue over-expresses aromatase. Thus, aromatase inhibitors reduce the local production of estrogen from the fibroid itself, thereby preventing further fibroid proliferation and assisting in fibroid volume reduction.[50][51] Letrozole can be administered orally 2.5 to 5 mg/day for 12 weeks. One trial of 70 participants demonstrated a reduction in fibroid volume by 46% after 12 weeks of treatment; however, there was no significant difference compared to GnRH agonists.[52] Another study demonstrated a decreased operative time and intraoperative blood loss when letrozole was used preoperatively for 12 weeks.[53] Letrozole is not currently FDA approved for symptomatic fibroids; however, it has been used off-label for this purpose. Most reported adverse effects are hot flashes and bone mineral density loss with prolonged use.[52](A1)

Surgical Management

Myomectomy is the surgical removal of uterine fibroids via hysteroscopic, laparoscopic, or abdominal surgery. Common indications for myomectomy include AUB with or without a history of symptomatic anemia, bulk-related symptoms such as urinary urgency, frequency, hydronephrosis, constipation, infertility, prevention of obstetrical complications, and in some cases, for the evaluation of potential malignancy. Establishing the type (location), size, and quantity of fibroids using the modalities described above is a crucial step in a patient’s evaluation that guides the optimal excision strategy.    

Hysteroscopic Myomectomy

Hysteroscopic myomectomy (HSC-M) is a minimally invasive approach to fibroid removal with high success rates and low risk for complications in the appropriately selected patient (figure 5).  The feasibility of performing a successful HSC-M is largely dependent on the type and size of the existing fibroids. HSC-M has shown to be most successful in resecting Type 0 and Type I fibroids.[54] Complete resection rates of Type 0 and Type I fibroids range from 96 to 97% and 86 to 90%, respectively.[54] 

HSC-M can be used for type 2 fibroids; however, this often involves repeat procedures due to the lower complete resection rate of 61 to 83%. The type of fibroid also correlates to operative time and the amount of distention fluid absorbed during the procedure. The deeper the penetration of the fibroid into the myometrium, the greater the volume of fluid absorbed (type 0: 450 ml, type I: 957 ml, type II: 1682ml).[55] Patients with fibroids >3 cm and/or with two or more fibroids present have the highest risk of needing a repeat procedure.[56] The overall rate of incomplete resection is approximately 5 to 17%.[57]

 HSC-M has a 94.4% success rate, defined as improved quality of life (QoL) scores and resolution of symptoms.[58][59] One of the biggest advantages of HSC-M is the benefits that come with a minimally invasive approach, such as minimal recovery time, minimal need for opioids, minimal postoperative restrictions, sooner return to daily activity, and decreased perioperative morbidity.[60] Patients typically report a major improvement in symptom severity and quality of life within 6-12 weeks of surgery.[60] (B2)

Regarding fertility, a 2009 study of infertile women with submucosal fibroids by Pritts et al. found that women who underwent submucosal myomectomy were twice as likely to become pregnant than women who did not undergo myomectomy (RR 2.03, CI 1.08–3.82).[61] Another study investigating conception rates up to 3 years after hysteroscopic myomectomy found a 49% conception rate after resection of type 0 fibroids and 33% after resection of type I fibroids.[62](A1)

HSC-M is overall a very safe procedure with a complication rate of <1%.[63] The most common complication with hysteroscopy is uterine perforation at a rate of 0.76%, which most frequently occurs during uterine entry. This is also the most common reason for excessive bleeding during the procedure.  Other complications of HSC-M are associated with excess fluid absorption of the distention medium, which can occur during complicated resections with large or multiple fibroids that prolong the procedure.[64](B2)

Laparoscopic Myomectomy

Laparoscopic myomectomy (LSC-M) is a minimally invasive surgical approach to remove symptomatic fibroids of type 2 through 8. Location, size, and the number of fibroids are all important determinants for the success of the surgery and reducing recurrence.

LSC-M provides an 80% success rate in the relief of symptoms, similar to abdominal myomectomy. However, it comes with significantly fewer complications.[65] Furthermore, LSC-M shares the benefits of a minimally invasive approach providing patients with shorter recovery time and fewer complications. One study looking specifically at the short-term quality of life post-LSC-M demonstrated a median 20-day shorter time to return to work and a 1-week shorter time to return to normal activity than abdominal myomectomy.[60] (B2)

In another study looking at outcomes immediately post-op, patients who underwent laparoscopic myomectomy had less post-op pain at the 6-hour and 48-hour mark, a 50% lower chance of perioperative fever, and shorter hospitalization compared to those who underwent abdominal myomectomy.[66](A1)

Risk of complication during LSC-M is increased in patients with fibroids >5 cm, >3 total fibroids, and in those with intramural and intraligamentous fibroids.[67] Complications include hemorrhage, fever/infection, bowel or bladder injury, conversion to laparotomy, and adhesive disease.  A large multicenter study looking at over 2000 cases demonstrated a total complication rate of 11.1% (n=225), of which 9.1% were minor complications and 2.02% were major complications.  The most common minor complications were fever of unexplained origin (5.1%) and urinary tract infections (3.4%). Among the major complications were hemorrhage (0.7%), hematoma (0.48%), bowel injury (0.04%), and post-op kidney failure (0.04%).[67] (B2)

Conversion to laparotomy is overall a rare event. In a study looking at over 700 intended laparoscopic myomectomies, only seven had to be converted to an abdominal open approach.[68] Risk factors for conversion to abdominal myomectomy include the size of fibroids (5 cm on ultrasound), intramural type fibroids, anterior fibroids, and preoperative use of GnRH agonists, and elevated BMI.[69] Long-term complications of surgery include adhesive disease (36-66%) and recurrence of fibroids.[70][71][72](A1)

It is worth mentioning the use of robot-assisted laparoscopic myomectomy (RLSC-M), which has grown in popularity amongst many minimally invasive gynecologic surgeons in recent years. Preference for the use of either technique is based on the surgeon’s skill level in using the conventional vs. robotic approach in handling complex cases. Surgeons tend to prefer RLSC-M in cases that involve ≥10 fibroids ≤ 7 cm or in patients with obesity due to improved visibility.[73] The most significant difference between the two techniques is conversion to abdominal myomectomy. In a systematic review and meta-analysis looking at over 2000 patients, laparoscopic myomectomy was associated with a 4.5 times increased risk of conversion to abdominal myomectomy compared to robot-assisted laparoscopic myomectomy.[74] (B2)

Regarding outcomes and complications, a meta-analysis of eight retrospective trials comparing the two techniques demonstrated no significant difference in complications, operative time, length of hospital stays, and postoperative fertility.[75] Given these subtle differences and the increased costs associated with robotic-assisted laparoscopy, there is no significant indication for choosing it over LSC-M. With both approaches, the failure rate remains comparably low.[76](A1)

Abdominal Myomectomy   

Abdominal myomectomy (ABD-M) is a major surgical procedure typically reserved for complex cases where a minimally invasive approach is contraindicated or in failed intended laparoscopy cases. Similar to LSC-M, an abdominal myomectomy is best used for symptomatic intramural and subserosal fibroids.

In a retrospective cohort study looking at 30 patients who underwent ABD-M, overall symptoms improved in 90% of patients, and 79% of patients were satisfied with their choice of the procedure.[65] With regards to fertility outcomes, a Cochrane review demonstrated no difference between LSC-M and ABD-M.[77] When looking at the difference in operative time, Barakat et al. demonstrated that ABD-M is associated with a shorter operative time of 126 minutes, compared to 155 and 181 minutes with LSC-M and RLSC-M, respectively.[78] Another benefit is the lower risk of recurrence with ABD-M eight years post-procedure (63.4% vs. 76.2%) compared with LSC-M.[79] This is likely due to the ability to identify and remove sub-centimeter-sized fibroids more easily with an ABD-M approach. (A1)

Despite the similar outcomes in symptom reduction, fertility, and benefits in operative time, ABD-M is associated with significant morbidity. Blood loss is significantly higher with ABD-M compared to its minimally invasive alternatives, with an average of 200 mL blood loss during ABD-M compared to 150 ml and 100 ml in LSC-M and RLSC-M, respectively.[78] A systematic review and meta-analysis performed by Chen et al. demonstrated that ABD-M caused a longer duration of post-op ileus and increased length of hospital stay.[80] A Cochrane review concluded that pain was increased at the 6-hour and 48-hour mark after an ABD-M compared to LSC-M. This review also found a 50% increased risk of postoperative fever in patients who received ABD-M compared to LSC-M.[66] Due to the higher rate of surgical complications compared to its minimally invasive counterparts, patient selection for ABD-M and preoperative optimization are paramount.(A1)

Myomectomy for Improving Fertility 

Many studies have demonstrated a clear relationship between uterine fibroids and infertility; however surgical management of fibroids for the sole purpose of improving fertility (i.e., in otherwise asymptomatic patients) is less clear cut and largely depends on the location of the fibroids.

Fibroids that distort the uterine cavity, i.e., submucosal fibroids (FIGO Type 0-2), strongly influence reproductive outcomes.[81] In one systematic review and meta-analysis of 23 randomized controlled trials evaluating pregnancy outcomes of infertile women with and without SM fibroids, women with SM fibroids had a significantly reduced rate of implantation (RR=0.283), clinical pregnancy (RR=0.363), and ongoing pregnancy/live birth rate (RR=0.318). Furthermore, women with SM fibroids have increased rates of spontaneous abortion.[82][61] Evidence suggests that cavity-distorting myomas should be surgically removed to improve reproductive outcomes even if the patient is otherwise asymptomatic.[81] A prospective study of 181 infertile women with a solitary fibroid <4 cm compared pregnancy outcomes in those who underwent myomectomy vs. those who underwent expectant management. In patients with submucosal fibroids (n=52), those who underwent submucosal myomectomy had a clinical pregnancy rate of 43% compared to 27% in the expectant management group after one year of enrollment (p < .05).[83] At this time, there is insufficient evidence to suggest that HSC-M for submucosal fibroids reduces miscarriage rates.[81](A1)

The negative impact of intramural (IM) fibroids on fertility outcomes has been demonstrated in multiple studies. However, limited data suggest whether or not the removal of the intramural fibroids improves these outcomes. In general, women with intramural fibroids have a lower implantation rate, clinical pregnancy, and ongoing pregnancy/live birth.[82][61] One of the largest prospective cohort studies investigating the success of in vitro fertilization (IVF) in women with and without fibroids showed that in women with intramural fibroids ≤ 5 cm (mean size 2.3 cm), the clinical pregnancy rate per embryo transfer was 23.3% compared to 34.1% in women without fibroids.[84] (A1)

An RCT of 181 women with a solitary fibroid < 4 cm and at least one year of infertility showed that myomectomy was not associated with an improved clinical pregnancy rate in women with intramural fibroids (n=23, 56.5%, NS).[83] On the other hand, a prospective, nonrandomized cohort study of 318 women with unexplained infertility or recurrent pregnancy loss showed that women who underwent LSC-M had higher birth rates than those with fibroids who did not undergo LSC-M (42% [44/106] vs. 11% [12/106], P <.001, respectively).[85] In summary, myomectomy for intramural fibroids does not necessarily guarantee the resolution of infertility. However, there is fair evidence to support that it does not impair reproductive outcomes. If a patient with large intramural fibroids has failed multiple IVF cycles, myomectomy should be strongly considered. Ultimately, the decision to undergo myomectomy for intramural fibroids should result from a shared decision-making process between the patient and her surgeon.  (B2)

Studies looking at subserosal (SS) fibroids suggest they do not play a role in infertility and thus do not need to be removed to improve reproductive outcomes.[82][61](A1)

Alternative Procedural Treatment Modalities

Uterine Artery Embolization (UAE)

Uterine artery embolization (UAE) is a percutaneous transcatheter embolization technique that occludes the cervicovaginal branch of both uterine arteries to deprive fibroids of their blood supply leading to degeneration [76] (figure 6). Ideal candidates for this approach are patients with heavy menstrual bleeding (HMB) caused by intramural fibroids who are either resistant to or not ideal candidates for surgery. 

In a study looking at ten-year follow-up after UAE, 62% of patients reported their HMB had resolved at two years, which increased to 83% at five years post-procedure. Overall, 78% of patients reported they were very satisfied with the treatment at the ten-year mark.[86] UAE is associated with decreased risk for transfusion, shorter hospital stays, and quicker return to baseline functioning.[87][88](A1)

Although the UAE can provide relief for many patients and avoid surgery-associated risks, studies have shown that as many as 19-38% of patients undergo reintervention for persisting symptoms.[89] Over five years, the rate of re-intervention requiring hysterectomy was 28%.[90] Major complications occur about 1 to 12% of the time and include rehospitalization, ovarian failure, pulmonary embolism, and unplanned hysterectomy.[91] (A1)

Minor complications include fever, pain, nausea, pelvic infection, postembolization syndrome, and vaginal discharge. There is conflicting data regarding reproductive outcomes after UAE compared to myomectomy. Overall, UAE is not the ideal treatment option for patients who desire future fertility due to a potential post-procedure decline in ovarian reserve and increased risk of pregnancy-related complications. Regarding pregnancy-related complications, UAE for uterine fibroids is associated with an increase of miscarriage (35.2% versus 16.5%; OR, 2.8; 95% CI, 2.0–3.8), cesarean delivery (66% versus 48.5%; OR, 2.1; 95% CI, 1.4–2.9), and postpartum hemorrhage (13.9% versus 2.5%; OR, 6.4; 95% CI, 3.5–11.7) compared to expectant management.[92](A1)

Magnetic Resonance–guided Focused Ultrasound Surgery (MRgFUS)

Magnetic resonance-guided focused ultrasound surgery is a form of therapy that involves continuous waves of ultrasound energy over a 3 to the 5-hour period under magnetic resonance guidance. Eventually, the goal is to heat the entire fibroid to >57 degrees C for at least 1 second to induce coagulative necrosis.[76][93] Fibroids that possess a high T2-weighted signal intensity are more likely to be responsive to the treatment.[94] MRgFUS is a minimally invasive approach with very minimal recovery time, low radiation exposure and provides symptomatic treatment serving as a great option for patients who are opposed to surgery.

A study performed by Funaki et al. looking at 91 women over 24 months who underwent MRgFUS demonstrated a mean reduction in the volume of 36.5% at six months and 39.5% at 24 months.[95] Another study looking at 12-month follow-up showed an 86%, 93%, and 88% at 3, 6, and 12 months, respectively.[96] In patients with primarily intramural myomas >3cm and uteri size < 24 weeks of gestation, MRgFUS decreased the percentage of patients reporting excessive bleeding from 69 to 31% and relieving pressure symptoms in 49% of patients.[97] There is limited research regarding reproductive outcomes after MRgFUS, with most data coming from a few case reports and small case series.  Existing data is reassuring, with one case series describing 54 pregnancies in 51 women after MRgFUS.[98] More studies are needed to determine whether MRgFUS should be recommended for patients seeking future fertility.(A1)

The overall complication rate with MRgFUS is low at about 13.1% in a study that looked at 150 women who underwent the procedure. However, only one of these was a major complication (deep vein thrombosis).[96] In the same study, 7.4% of patients required treatment for fibroid-related symptoms at one year following the procedure. Other side effects of the therapy involve skin burns, nerve damage, necrosis of non-targeted tissue, bone heating, and venous thrombosis due to prolonged immobility.[76][97][99] (B2)

Ultrasound-guided Radiofrequency Ablation (Laparoscopic RFA)

Radiofrequency ablation (RFA) is a therapy that involves applying energy via ultrasound which utilizes direct thermal conduction to induce coagulative necrosis in tissue.[100] The technique now includes using laparoscopic guidance using a laparoscopic transducer allowing direct placement of the radiofrequency ablation tip directly into the fibroid.

In a prospective international trial observing a cohort of 135 women with fibroids and HMB, menstrual blood loss decreased from baseline levels by 38.3 months, and fibroid volume decreased by 45.1% at the 1-year mark. Furthermore, symptom severity scores improved significantly along with the quality of life, and 94% of women reported satisfaction with the procedure.[101] Another study of 31 women had improved symptom severity scores by 82% and a mean reduction of uterine volume from 194.4 cm to 113.2 cm at one year.[102] (B2)

There is very limited data on fertility and pregnancy after RFA. There is documentation of 15 pregnancies in 13 patients yielding 13 live births after RFA for fibroids.[100] In addition, a case series of 30 pregnancies by Berman et al. demonstrated 26 full-term live birth and four pregnancy losses.[103] Current trials are beginning to include more patients desiring fertility, given that RFA causes minimal myometrial damage. However, no definitive conclusions can be drawn about pregnancy outcomes and pregnancy-related risks.(B2)

A meta-analysis regarding the rate of surgical reintervention after RFA was 4.2%, 8.2%, and 11.5% at 1, 2, and 3 years, respectively.[104] The Halt trial looked at the 3-year outcome of RFA in 104 patients and reported a reintervention rate of 11% (14 patients) which included 11 hysterectomies, two laparoscopic myomectomies, and 1 UAE.[105] The incidence of complications and adverse effects remains inconsistent across studies.(A1)

Differential Diagnosis

The differential diagnosis for uterine fibroids includes conditions that lead to a similar symptom profile of uterine enlargement (e.g., bulk symptoms), HMB, infertility, and/or dysmenorrhea. The main diagnoses to consider when evaluating a patient for these symptoms are pregnancy, adenomyosis, benign or malignant uterine neoplasms, endometrial carcinoma, and uterine leiomyosarcoma.

Adenomyosis often presents with an enlarged uterus, HMB, and dysmenorrhea. However, there are a few factors that can help in discerning between the two. Typically, the uterus is described to be smooth, globular, and boggy. However, this can be difficult to distinguish from fibroids. One of the main differentiating tools is transvaginal ultrasonography.[26] Features that support adenomyosis on ultrasound are asymmetric myometrial thickness, heterogeneous myometrium, heterogenous cysts, and sub endometrial echogenic linear striations (figure 7).[106][107]

A fibroid is typically well-circumscribed, whereas adenomyomas are more ill-defined. Adenomyomas are also more difficult to excise than fibroids. Thus suspicion of an adenomyoma might not be discovered until excision is attempted.[108] Ultimately, the gold standard for diagnosis is pathology, and an official diagnosis cannot be made solely with imaging.

Uterine leiomyosarcoma is a malignant neoplasm that is important to consider in the differential for uterine fibroids. They commonly present as fibroids with abnormal vaginal bleeding and a rapidly enlarging uterus. It is important to consider this differential in any post-menopausal women with rapidly enlarging uterine fibroids, as a correct preoperative diagnosis occurs less than 50% of the time. This should prompt further evaluation with hysterectomy without morcellation because the only way to exclude uterine leiomyosarcoma is through excision and pathologic examination.[109]

Endometrial carcinoma is another important differential to rule out when evaluating a patient with uterine bleeding, pain, and enlarging uterus.[110] On transvaginal ultrasound, endometrial carcinoma is typically described as irregular endometrial margins, a polypoid intrauterine mass, intrauterine fluid collection, and in more advanced disease, frank myometrial invasion from the endometrium. The use of color doppler to distinguish benign lesions from malignant is still controversial, and ultimately the diagnosis can only be made by pathologic examination.[111]

Prognosis

The overall prognosis of patients depends on the size and number of fibroids and the treatment modality they choose. Comparing Options For Management: Patient-centered results for Uterine Fibroids (COMPARE-UF), a prospective nationwide registry that looked at the short-term interval follow-up after different routes of myomectomy in 1206 women, showed that regardless of the type of myomectomy, all had improvement in short-term health-related quality of life and symptom severity score improvement. Return to usual activity averaged at 0 days in HSC-M patients compared to 21 and 28 days for laparoscopic and abdominal myomectomy, respectively.[60]

Some notable risk factors for fibroid recurrence include age less than 35.5 years, two or fewer fibroids at time of surgery, size of the uterus less than 13 weeks of gestation, and no childbearing after surgery.[112] At eight years post-operation, ABD-M has a 63.4% risk of fibroid recurrence compared to 76.2% after LSC-M.[79] Reintervention rates range from 19 to 38% after UAE and as high as 54% after MRgFUS.[89][58]

For those patients who become pregnant following myomectomy, delivery modality and timing of delivery recommendations are dependent on factors as the type of fibroid removed, number and location of incisions on the uterus, and if hysterotomy was made. The main concern in pregnancy in patients with a non-low transverse scar on the uterus, especially those with a mid-vertical or trans-fundal uterine scar, is the risk of uterine rupture, which is as high as 10%. Although published data is limited, the risk of uterine rupture after myomectomy is reportedly closer to 1%, similar to the risk of a trial of labor after cesarean section with successful vaginal delivery being achieved in about 90% of patients.[113] 

According to the Society of Maternal-Fetal Medicine (SMFM), patients with a prior myomectomy with entry into the uterine cavity should undergo a scheduled cesarean delivery between 37-38 weeks gestation. If extensive trans-fundal scarring is suggested from the myomectomy operative report, delivery should be considered between 36 and 37 weeks gestation.[114]

Complications

Every medical intervention has a side effect profile, and every IR or surgical intervention has its associated risks, as described in detail above. Counseling patients on the adverse effects of medications such as altered bleeding profile and medication-induced menopause are worth mentioning to patients when they are deciding on treatment modality. Informing patients about the risks of bleeding, infection, injury to nearby organs, scarring, and failed treatment are all important to mention when consenting a patient for surgery or alternative procedure. Although the overall risk of hysterectomy for uncontrolled intraoperative bleeding is fewer than 1 out of 100 women, it is especially important to mention this risk to patients, particularly in women with multiple large fibroids.