Managing Fibroids: Medical and Surgical Options

SUMMARY:

Uterine leiomyomas are the most common solid neoplasm in women and occur in at least 70% of the population. Although leiomyomas are the most common indication for hysterectomy, there are many other management options, especially for patients who desire future childbearing or uterine preservation. This Practice Bulletin summary provides evidence based recommendation for medical, procedure, and surgical management of symptomatic leiomyomas

KEY POINTS:

Symptoms

• Prolonged or heavy menstrual bleeding
• Anemia
• Bulk symptoms such as pelvic pressure, urinary frequency, constipation
• Differences in race have been noted, with Black women experiencing clinically significant disease at an earlier age with larger uteri at diagnosis
  • Differences due to systemic racism and social determinants of health

Classification of Fibroids

Classification is based on FIGO system

• Submucosal fibroids
  • Type 0 is pedunculated intracavitary
  • Type 1 is less than 50% intramural
  • Type 2 is more than 50% intramural
  • Type 3 contacts the endometrium but 100% intramural
• “Other” fibroids
  • Type 4 is intramural
  • Type 5 is subserosal with more than 50% intramural
  • Type 6 is subserosal with less than 50% intramural
  • Type 7 is pedunculated subserosal
  • Type 8 is “other” but requires specification, i.e. cervical, parasitic

Diagnosis

• Transvaginal ultrasound is used as a screening test
• Sonohysterography can be used to identify and distinguish between type 0, type 1, and type 2 leiomyomas
• Hysteroscopy can be used to distinguish between type 2 and type 3 leiomyomas
• MRI
  • Can be used to distinguish between type 4 and 5 leiomyomas
  • Can aid with surgical planning, as well as determine vascularity and degeneration

Medical Management

• Expectant management can be considered in asymptomatic patients who do not desire intervention
• GnRH agonists (e.g., leuprolide) can be used for both bleeding symptoms and bulk symptoms as short term treatment of leiomyomas, or as a bridge to further treatment
  • These can facilitate the use of a minimally invasive surgical route, and are associated with an increased in preoperative hemoglobin level in patients
  • GnRH agonist use is typically limited to 6 months without add back therapy, and 12 months with add back therapy
  • Cessation of agonist leads to regrowth of fibroids within 6 to 9 months
  • Add-back therapy dosage typically 0.625 mg oral conjugated estrogen and norethindrone acetate 2.5 to 5.0 mg daily
• A 52 mg LNG-IUD can be used for the treatment of AUB-L, although there is a higher rate of expulsion
• Tranexamic acid can be used for the treatment of AUB-L
  • Dose (based on RCT cited in the guideline): 1.3 g per dose (two tablets, 650 mg each) three times daily at least 6 hours apart for up to 5 days per cycle over the course of six menstrual cycles
  • Begin treatment at the onset of heavy menstrual bleeding
  • Maximum daily dose used in study: 3.9 g
• Oral GnRH antagonists (elagolix or relugolix) can be used for treatment of AUB-L for up to 2 years | FDA limit of 24 month regimen due to risk for bone loss which may not be reversible | Add back therapy offsets hypoestrogenic effects, such as hot flashes, increased serum lipids, or bone mineral density loss
  • Elagolix: 1 capsule (elagolix 300 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) in the morning and 1 capsule (elagolix 300 mg) in the evening
  • Relugolix: 1 Fixed-dose combination tablet (relugolix 40 mg, estradiol 1 mg and norethindrone acetate 0.5 mg) once daily
• Combined and progestin only hormonal contraceptives can be considered for treatment of AUB-L, although there is limited data to support this
• Selective progesterone receptor modulators (mifepristone and ulipristal acetate) have some short-term benefits but are not approved in the US with daily use limited in Europe due to rare but serious liver injury

Surgical Management

• Uterine artery embolization (UAE) can be used for treatment of leiomyomas in patients who desire uterine preservation
  • These patients should be counseled about the limited data regarding future pregnancy outcomes
  • 2 to 5 years post-procedure, satisfaction rates are similar among UAE, myomectomy, and hysterectomy but post-UAE rates of re-intervention and further surgical intervention are 2 to 5 times higher (range from 15 to 38%)
  • Lower risk of blood transfusion, 1 to 2% rate of major complications, and higher rate of minor complications at 21 to 64%
• Laparoscopic radiofrequency ablation can be used as a minimally invasive treatment option for symptomatic leiomyomas for patients who desire uterine preservation however widespread access to techniques are limited
  • These patients should be counseled about the limited data regarding future pregnancy outcomes
  • Decreases uterine fibroid size up to 50 to 75% | Low rates of complications, both minor and major | No data on effect of uterine bleeding
• Endometrial ablation has insufficient evidence for use in AUB-L

Definitive Surgical Management

• Myomectomy allows fibroid removal in patients desiring their uterus
  • Risks include rate of recurrence (25% by 40 months) and procedural risks including blood transfusion (0 to 5%)
  • Re-intervention rate approximately 10 to 12% regardless of route of myomectomy (abdominal, robotic, laparoscopic)
  • Hysteroscopic myomectomy for Type 0, 1 and 2 fibroids have high efficacy with low risk of complications (1 to 3%) and low re-intervention rates (7% at 60 months)
• Hysterectomy is the definitive surgical management option for treatment of leiomyoma in patients who do not desire future childbearing or uterine preservation
  • Similar rates of complications between myomectomy and hysterectomy
  • The most minimally invasive route should be performed, with the vaginal approach being preferred
• If a patient desires uterine preservation or future pregnancy, myomectomy is recommended. If possible, a minimally invasive approach is preferred

Learn More – Primary Sources

ACOG Practice Bulletin 228 – Management of Symptomatic Uterine Leiomyomas

Tranexamic Acid Treatment for Heavy Menstrual Bleeding: A Randomized Controlled Trial

Management of Uterine Fibroids After the Withdrawal of Fibristal

Ulipristal Acetate: A New Treatment for Symptomatic Uterine Fibroids?

BACKGROUND AND PURPOSE: 

• Ulipristal Acetate is an oral selective progesterone receptor modulator 
  • 5-10 mg per day can decrease bleeding and the size of leiomyomas 
  • Studies were in performed in non-diverse populations and may not be generalizable to the US population  
• Simon et al. (Obstetrics & Gynecology, 2018) examined efficacy and tolerability of ulipristal acetate for the treatment of symptomatic uterine leiomyomas 

METHODS: 

• This was a phase 3, multicenter, randomized, doubleblind, double-dummy, placebo-controlled, parallel group study  
• Participants: premenopausal women, 18-50 years with  
  • Abnormal uterine bleeding 
  • One or more discrete leiomyomas 
  • Uterine size ≤20 weeks  
• Patients were assigned to the following groups 
  • 5 mg ulipristal 
  • 10 mg ulipristal 
  • Placebo once daily  
• Medications were taken for 12 weeks, followed by 12-week drug-free follow-up 
• Amenorrhea was defined as no bleeding for the last 35 consecutive days of treatment 
• Primary outcomes  
  • Proportion of patients who achieved amenorrhea (spotting permitted) during the last 35 consecutive days of treatment  
  • Time to amenorrhea during treatment 
• Secondary outcomes  
  • Proportion of patients who achieved amenorrhea by day 11 and did not report bleeding (spotting permitted) for the duration of treatment  
  • Change from baseline to end of treatment on the Revised Activities subscale of the Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire  
  • Questionnaire included questions pertaining to physical and social activites 

RESULTS: 

• 157 patients were randomized 
  • Demographics were similar between groups 
• Amenorrhea was achieved significantly greater number of individual in ulipristal groups (p<0.001) 
  • 5 mg ulipristal: 47.2% (97.5%, CI 31.6–63.2)   
  • 10 mg ulipristal 58.3% (97.5% CI 41.2–74.1)  
  • Placebo: 1.8% (97.5% CI 0.0–10.9)  
• Time to amenorrhea was shorter for both ulipristal doses compared with placebo (P<.001), and both doses of ulipristal resulted in improved quality of life compared with placebo (P<.001) 
• Improvement in anemia was seen at the end of treatment for patients treated with both ulipristal dose regimens 
• Ulipristal also improved health-related quality of life (both physical and social activities)  
• Common (≥5% in either ulipristal group) adverse events  
  • Hypertension 
  • Elevated blood CPK 
  • Hot flushes 

CONCLUSION: 

• The study population was diverse with a high proportion of obese women, which is more reflective of the US population than previous studies  
• A dose of 5 mg and 10 mg of Ulipristal was superior to placebo in rate of a time to amenorrhea in women with symptomatic uterine leiomyomas 
• Ulipristal is generally well tolerated 
• Not yet FDA approved – awaiting more safety data following reports of adverse events (liver damage) in Europe

Learn More – Primary Sources:  

Ulipristal Acetate for Treatment of Symptomatic Uterine Leiomyomas: A Randomized Controlled Trial 

High-Intensity Ultrasound for Fibroids – What are the Pregnancy Outcomes?

BACKGROUND AND PURPOSE:

• Ultrasound guided high-intensity focused ultrasound (HIFU) is an effective, non-invasive treatment for fibroids, but fertility and pregnancy effects are not well characterized
• Zou et al. (BJOG, 2017) evaluated the effect of high-intensity focused ultrasound (HIFU) ablation for uterine fibroids on pregnancy

METHODS:

• Retrospective Observational study (2011-2016)
• Cohort: Patients with uterine fibroids who wished to become pregnant and subsequently underwent a HIFU procedure

RESULTS:

• Data from 78 women were evaluated
• Total pregnancy rate was 19.2% (78/406) and average time to pregnancy was 5.6 months
  • Out of 80 pregnancies, 4 were IVF
• Of 78 patients who became pregnant
  • 9 had complicated primary or secondary infertility before the HIFU treatment
  • 13 had at least two miscarriages
• After the HIFU treatment, the average time to pregnancy was 5.6 ± 2.7 months
• There were 15 vaginal deliveries and 56 cesarean sections
  • Majority of cesarean sections were for social reasons
  • No evidence that HIFU affects mode of delivery
• 68 pregnancies were term and 3 cases were preterm (uncertain fetal status, PROM and decreased AFV), with an average gestational age of 38.1 weeks.
• There were 3 miscarriages (1 with low progesterone and 2 unexplained)
• There were no cases of fetal anomalies or perinatal/postpartum complications
• There were no cases of abnormal placentation or uterine rupture

CONCLUSION:

• The researchers did not find increase pregnancy complications with HIFU
• HIFU may be an approach to treat fibroids in women who are still interested in pregnancy, including those who have a history of infertility

Learn More – Primary Sources:

Pregnancy outcomes in patients with uterine fibroids treated with ultrasound-guided high-intensity focused ultrasound

Are Fibroids Associated with Miscarriage?

BACKGROUND AND PURPOSE:

• Data is conflicting as to whether uterine leiomyomas are associated with miscarriage
  • Studies often include women who are obtaining fertility treatment
• Sundermann et al. (Obstet Gynecol, 2017) examined the associated risk of spontaneous abortion and uterine leiomyomas in the general population

METHODS:

• Systematic review and meta-analysis
• Inclusion: Studies reporting risk of spontaneous abortion among pregnant women with  leiomyomas vs pregnant women without leiomyomas
• Exclusion: Studies that only included women seeking care for recurrent miscarriage, infertility, or assisted reproductive technologies
• Data was extracted and reviewed by two authors independently
• Primary outcome: Spontaneous abortion (definition varied across studies) among recognized pregnancies

RESULTS:

• 9 studies were included in the systematic analysis and 5 studies were used for the meta-analysis
• Pooled data for the meta-analysis included 21,829 women
• In the leiomyoma group, 11.5% has spontaneous abortion compared to 8.0% in the non-leiomyoma group
• Uterine leiomyomas were not associated with an increased risk of spontaneous abortion
  • Relative risk 1.16, 95% CI 0.80–1.52
  • Significant association was still absent even after adjusting for confounders

CONCLUSION:

• The presence of leiomyomas was not associated with increased risk of spontaneous abortion
• Prior studies showing an association did not always adjust for confounders
• This is the first association review that focused on a general risk population

Learn More – Primary Sources:

Leiomyomas in Pregnancy and Spontaneous Abortion: A Systematic Review and Meta-analysis