Background and Objectives for the Systematic Review
Most women will develop one or more uterine fibroids (i.e., leiomyomata), benign smooth muscle tumors of the uterus, during their reproductive lifespan.1 In the United States, an estimated 26 million women between the ages of 15 and 50 have uterine fibroids.1-4 More than 15 million of them will experience associated symptoms or health concerns.5,6 A disproportionate number of black women are among those with symptoms in part due to earlier age at onset of fibroids with larger and more numerous tumors.1-3,7,8
The etiology of uterine fibroids is not well understood, and a variety of factors including race/ethnicity, parity, and age at menarche have been examined. Health effects range from profound bleeding and anemia, to pelvic pressure or pain, urinary frequency, abnormal bowel function, and pain with intercourse, as well as concerns about influence on fertility and pregnancy outcomes.9
Fibroids are prevalent and symptoms are common among women with fibroids, creating considerable personal and societal costs including diminished quality of life, disruption of usual activities and roles, lost work time associated with symptoms, and substantial healthcare expenditures. Across types of interventions, direct annual healthcare costs in the United States are projected to exceed $9.1 billion. Lost wages, productivity, and short-term disability are estimated to total more than $5 billion, perhaps as much as $17 billion, with roughly $4,624 in costs per women in the first year of diagnosis.10,11
Discussion of options for management of symptomatic fibroids is among the most frequent conversations in gynecology and primary care and is the most common cause for consideration of gynecologic surgical intervention.12,13 The nature of those discussions is also fundamentally shaped by future reproductive goals and desire to retain fertility.14,15
Though hysterectomy and myomectomy by a variety of routes are frequently used, perhaps with insufficient consideration of alternative treatment prior to surgery,16 the range of fibroid-specific treatments including interventions like extended medical management with ulipristal acetate, magnetic resonance image-guided focused ultrasound (MRgFUS), uterine artery embolization, radiofrequency volumetric thermal ablation, and techniques for myolysis are increasingly generating comparative effectiveness data7,9 as is the clinical trials literature about improving bleeding symptoms.17 Furthermore, as the literature evolves, including larger studies of stronger design with longer followup, a clearer picture of anticipated outcomes is likely to emerge.
No medications have been specifically approved by the U.S. Food and Drug Administration (FDA) for treatment of fibroid symptoms, though several medications are used off-label (see Table A-1). The FDA has approved a number of devices to treat uterine fibroids including MRgFUS systems and power morcellators (see Table A-2), though it has issued safety communication for laparoscopic uterine power morcellation.18
Across treatment modes attention should be paid to the influence of the characteristics of individual women and their fibroids in predicting outcomes and judging whether differing interventions are differentially influenced by such factors as fibroid size, location, and the patient's contraceptive choices or age. Women desire a broad range of treatment options that suit their life circumstances and future reproductive desires. Therefore, it is crucial for women, their care providers, and those who guide policy decisions to have timely, accurate information about the effectiveness of treatments and the associated risks.
What this review will add to the body of literature
The quantity and quality of research on fibroid management has steadily improved in recent years. It should now be feasible, and most informative to guiding care, to restrict a review to randomized clinical comparisons of effectiveness, including medical management versus surgical, rather than restricting comparisons only to abdominal hysterectomy. Specifically this review will address the recent visibility and uncertainty about the harms of morcellation of fibroids during minimally invasive procedures, as an explicit element of risk of harm.
The Key Questions evolved from the EPC team discussions, expert input, and reviewer comments during the topic refinement period. The Key Questions reflect the unmet need for a relevant synthesis of evidence from prospective randomized controlled trials on the relative benefits and harms of surgical, procedural, and medical interventions to manage uterine fibroids. In addition, the Key Questions address the potential harms associated with morcellation, as well as an exploration of patient and tumor characteristics that may predict success or adverse events in patients considered for morcellation.
Key Question 1
What is the comparative effectiveness (benefits and harms) of treatments for uterine fibroids, including comparisons among and within these interventions?
- Hysterectomy via abdominal, vaginal, laparoscopic, or robotic approach
- Myomectomy via laparotomy, laparoscopy, hysteroscopy, or robotic approach
- Uterine artery embolization including ligation and occlusion
- Ablative procedures (e.g., MRgFUS, cryoablation)
- Progestin-containing intrauterine devices
- Medications to improve or resolve symptoms or reduce size of fibroids
- Expectant management or placebo
Key Question 2
Does treatment effectiveness differ by patient or fibroid characteristics (e.g., age, race/ethnicity; symptoms; vascular supply to fibroids; menopausal status; or number, size, type, location, or total volume of fibroids)?
Key Question 3
What is the risk of cancer dissemination from morcellation of uterine fibroids at the time of myomectomy or hysterectomy?
Key Question 4
Does risk of cancer dissemination from morcellation differ by patient or fibroid characteristics (e.g., age; race/ethnicity; symptoms; menopausal status; imaging characteristics; vascular supply to fibroids; or number, size, type, location, or total volume of fibroids)?
Public Comments and Changes to Posted Key Questions
The draft Key Questions were posted for public comments (6/23/15 – 7/13/15). Comments did not necessitate any significant changes to the Key Questions, review scope, or inclusion criteria. Minor changes included the addition of fibroid type and location as a characteristic of interest in Key Question 2 and Key Question 4. Additionally, public comments noted the need to assess effectiveness of morcellation in addition to harms. This comment did not require changes to the Key Questions as literature addressing Key Question 1 would include benefits of morcellation.
PICOTS for Key Questions
|PICOTS||Criteria and Key Question(s)|
|Abbreviations: KQ=key question|
|Population||Women who are being treated for uterine fibroids (KQs 1-4)|
|Outcomes||1. Intermediate outcomes (KQ 1)
2. Final health outcomes (KQ 1)
3. Adverse effects / Harms (KQs 1, 3)
|Timing||Any length of followup (KQs 1-4)|
|Setting||Clinical setting in countries with health care systems similar to the U.S. (defined as inclusion as a Very High Human Development country on the United Nations Development Programme Human Development Index (KQs1-4).
Countries include: Albania, Algeria, Andorra, Antigua and Barbuda, Argentina, Armenia, Australia, Austria, Azerbaijan, Bahamas, Bahrain, Barbados, Belarus, Belgium, Belize, Bosnia and Herzegovina, Brazil, Brunei Darussalam, Bulgaria, Canada, Chile, China, Colombia, Costa Rica, Croatia, Cuba, Cyprus, Czech Republic, Denmark, Dominica, Dominican Republic, Ecuador, Estonia, Fiji, Finland, France, Georgia, Germany, Greece, Grenada, Hong Kong, China (SAR), Hungary, Iceland, Iran (Islamic Republic of), Ireland, Israel, Italy, Jamaica, Japan, Jordan, Kazakhstan, Korea (Republic of), Kuwait, Latvia, Lebanon, Libya, Liechtenstein, Lithuania, Luxembourg, Malaysia, Malta, Mauritius, Mexico, Montenegro, Netherlands, New Zealand, Norway, Oman, Palau, Panama, Peru, Poland, Portugal, Qatar, Romania, Russian Federation, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Saudi Arabia, Serbia, Seychelles, Singapore, Slovakia, Slovenia, Spain, Sri Lanka, Suriname, Sweden, Switzerland, Thailand, The former Yugoslav Republic of Macedonia, Tonga, Trinidad and Tobago, Tunisia, Turkey, Ukraine, United Arab Emirates, United Kingdom, United States, Uruguay, Venezuela
The analytic framework illustrates the population, interventions, outcomes, and adverse effects that guide the literature search and synthesis.
The methods for this systematic review will follow the AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews19 and the PRISMA-P20 statement checklist. The protocol is registered in Prospero (CRD42015025929).
Inclusion and Exclusion of Studies in the Review
This review will include studies evaluating medical and surgical treatments to treat fibroids (asymptomatic or symptomatic) in women of any age. There is some literature about the relationship of imaging findings and symptom profiles, but the correlation is not tight. Women with large fibroids may experience minimal symptoms while women with small fibroids may have significant symptoms. Diagnostic accuracy and sequencing of care are outside of the scope of this review. Ongoing observational studies such as COMPARE21 will provide data about sequencing of treatments when completed. We do not anticipate that current studies can offer meaningful data to address a sequencing question.
The review will focus on interventions to treat fibroids directly. Prior reviews have reported on the effectiveness preoperative adjunctive treatments such as gonadotropin-releasing hormone (GnRH) agonists or cell savers. Such approaches are generally well accepted in practice. This review will not include studies that evaluate the effectiveness of preoperative or adjunctive interventions to minimize blood loss or otherwise improve operative outcomes.
Randomized controlled trials are best suited to provide data for comparative effectiveness and there has been substantial growth in the variety and sophistication of trials since the prior review. Therefore, eligible studies for Key Question 1 and Key Question 2 must be randomized trials evaluating the benefits or harms of a medical, procedural, or surgical intervention compared with an inactive control, including expectant management, or alternate intervention. We will include nonrandomized cohort studies and observational studies to address Key Question 3 or Key Question 4.
Key Question 1 and Key Question 2 focus on comparative effectiveness for final outcomes. Eligible studies must report one or more patient-centered outcome (e.g., symptom improvement, blood loss, pain, quality of life). Studies reporting only outcomes related to healthcare delivery (e.g., costs, access) will not be included. Cost data are linked with operative time and clinician skill sets, which may be affected by a number of factors. Older cost data also have limited utility. Studies reporting only intermediate outcomes will not be included.
A preliminary assessment of the published literature on uterine fibroid treatment suggests that limiting the search to studies published in or after 1985 does not omit critical literature. We summarize the inclusion criteria in Table 2.
|Population||Women with uterine fibroids (KQs 1-4)|
Searching for the Evidence
To ensure comprehensive retrieval of relevant studies, we will search MEDLINE via PubMed, the Cumulative Index to Nursing and Allied Health (CINAHL), EMBASE, and the Cochrane Library to identify relevant publications. We will use the search strategies presented in Tables A-3 and A-4 of the Appendix. The search and selection literature sources may be refined following discussions with Technical Experts. The final search strategies will be peer reviewed by an independent information specialist. We will use a date limit of 1985 for the search of indexed literature. We will conduct literature search updates periodically during preparation of the review and will conduct a final literature search update at the time of peer review of the draft report. We will screen and include relevant studies with each update. We will also incorporate relevant, eligible studies identified by peer reviewers or public commenters.
We will search web sites of organizations likely to conduct research, issue guidance, or generate policies relevant to management of uterine fibroids (Table A-5 in the Appendix). We will search government and regulatory agency web sites for information on morcellation. We will search ClinicalTrials.gov for information about relevant ongoing trials and to confirm that we have obtained available publications of results from completed trials.
We will carry out hand searches of the reference lists of recent systematic reviews or meta-analyses of therapies for uterine fibroids. The investigative team will also scan the reference lists of articles that are included after the full-text review phase for studies that potentially could meet our inclusion criteria.
Scientific Information Packets
The Scientific Resource Center (SRC) will request information from stakeholders, including Scientific Information Packets (SIP) and regulatory information on medications, procedures, and devices used to treat uterine fibroids. We have listed known pharmaceutical companies (Table A-1) and device manufacturers (Table A-2) in the Appendix. We will compare the information in the SIPs with the biomedical literature and grey literature retrieval. We will extract information from the SIPs that is not already captured by published study results or other sources. We will apply the same inclusion and exclusion criteria relevant to Key Questions to studies identified via SIPs.
We will develop forms for screening and preliminary data extraction. The form used at the abstract screening level will include basic questions to determine study eligibility based on the exclusion and inclusion criteria. The forms used for the full-text screening level will include additional questions to identify studies that meet all the inclusion criteria. The forms will also include questions to assist in preliminary grouping of the eligible studies by Key Question.
We will review the titles and abstracts of all publications identified through our searches against our inclusion/exclusion criteria. To be excluded, publication abstracts must be reviewed and excluded independently by two members of the investigative team. When differences between the reviewers arise, we will err on the side of inclusion.
Retrieving and reviewing articles
We will retrieve and review all articles that meet our predetermined inclusion criteria from abstract screening or for which we have insufficient information to make a decision about eligibility. Each article will be reviewed for eligibility independently by two members of the investigative team. Differences between the reviewers will be adjudicated by a senior team member or via team discussion. We will use the same screening forms and inclusion/exclusion criteria to assess eligibility of citations recommended by peer and public reviewers and for the literature retrieved by updated literature searches. If we are unable to resolve a discrepancy in the reporting of data from a publication we may contact study authors for additional information or clarification.
We will develop a simple categorization scheme for coding the reasons that articles at full review are excluded. We will record exclusion codes in an EndNote® (Thomson Reuters, New York, NY) bibliographic database and will compile a list of excluded papers and exclusion reasons in the report. We will deposit data used in a meta-analysis into the Systematic Review Data Repository (SRDR).
We will create data extraction forms to collect detailed information on the study characteristics, intervention(s), comparator(s), arm details, reported outcomes and outcome measures, and risk of bias assessment. We will pilot test the data entry forms. We will upload the extracted data to the Systematic Review Data Repository (SRDR).
For studies that meet the eligibility criteria from the full-text review assessment, we will extract study characteristics (e.g., study design, year, setting, funding source, etc.); patient characteristics (e.g., age, race/ethnicity, symptom status, treatment history); operational definition of fibroid; diagnostic modality (e.g., imaging, symptom record); intervention description and characteristics; outcomes of interest reported; operational definition of each outcome; results; and length of followup.
We will extract additional information, when reported, to assess whether the effectiveness of interventions differ by patient or fibroid characteristics. Examples include: baseline characteristics of the patients (e.g., age, menopausal status; symptom status) and fibroid characteristics (e.g., size, volume, location, type, and vascularity).
We will prespecify the harms that we will extract and will use consistent and precise terminology for reporting data on harms to the degree the literature includes operational definitions.22 We will check sources other than published literature (e.g., FDA, clinical trial data from device manufacturers or pharmaceutical companies via SIPs) for additional information on harms.
Assessment of Methodological Risk of Bias
We will evaluate the methodologic risk of bias of individual studies. We will use the criteria and established tools described in the Methods Guide for Effectiveness and Comparative Effectiveness Reviews.23 Two senior investigators will assess each included study independently. Disagreements will be resolved through discussion.
We will use prespecified questions1 from Table 4 in "Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions"23 to assess risk of bias of randomized controlled trials. We will use an adapted version of the McMaster Quality Assessment Scale of Harms tool to assess harms reporting.23,24 We will enumerate the risk of bias assessments and source of bias for all studies. Depending upon the quantity and size of the sources for the data, we may attempt to establish thresholds to assess overall high, medium or low risk of bias.25
We may limit the report of key findings from studies assessed as high risk of bias to summary tables. We may include in the analysis high of risk of bias studies that have a large sample size or that evaluate outcomes not addressed in other studies.
1from Table 4 in "Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions".23
We will provide a qualitative and quantitative synthesis of studies meeting our review criteria. We will summarize data related to symptom status and prioritize patient-reported measures. We collected a list of outcomes from a prior review of relevant studies and prioritized that list to establish a core minimum set of outcomes for quantitative analyses. We identified patient-centered outcomes including bleeding, pain, other symptom resolution, need for subsequent treatment, and quality of life, as those of greatest priority.
We anticipate performing a meta-analysis to describe the effects of treatment decisions on outcomes including likelihood of maintaining fertility or needing additional treatment, including, ultimately, hysterectomy. The specific meta-analysis or meta-regression will depend on the data available. In particular, we hope to estimate probabilities of an outcome associated with potential trajectories of care for women under differing circumstances (e.g., likelihood of progressing to increasingly invasive options, particularly hysterectomy).
We will refine our analytic approach as we gather more data on the available literature. It is likely that analyses will be combined using a Bayesian hierarchical mixed effects model. Hierarchical random effects allow results from individual studies to be partially pooled, meaning that each study can contribute to inference in the meta-analysis without assuming that the set of studies are identical. These random effects will allow estimates of overall (population) effects as well as an estimate of the variance of the effect across studies, after controlling for available study-level covariates.
Quantifying study-level heterogeneity via random effects is preferable to the use of an arbitrary variance cutoff value or statistical tests for heterogeneity, such as Q statistics or I2 scores. The decision of whether to partially pool a set of studies using random effects depends not on how heterogeneous their outcomes are, but rather, whether they can be considered exchangeable studies from a population of studies of the same phenomenon. This should be determined based on the design and quality of the studies, independently of the studies' relative effect sizes.
Many fibroid studies have small sample sizes, which limit the ability of a study to overcome differences in baseline characteristics and variability of outcome reporting. Some differences among study populations may be accounted for in the model by adjusting for factors such as age distribution, demographic attributes, and the prevalence of concomitant conditions in the study sample. Newer approaches to random effects meta-analysis, such as latent Dirichlet process and Gaussian process models, allow for robust (e.g., non-parametric) estimates of variation that do not rely on the assumption of normally distributed random effects. This permits us to account for "outlier" studies in the meta-analytic model without either discarding them unnecessarily or allowing them to influence meta-estimates disproportionately.
Analysis of subgroups will be done formally, within a statistical model, or by stratifying results and organizing the report in such a way that end users are provided with overall outcomes data and information specific to subgroups defined by factors such as menopausal status or fibroid size that can be easily identified and stand alone as needed.
Subgroup analysis may be used to evaluate the intervention trajectory in a defined subset of the participants in a trial, or in complementary subsets. Subgroup analysis can be undertaken in a variety of ways, from completely separate models at one extreme, to simply including a subgroup covariate in a single model at the other, with multilevel and random effects models somewhere in the middle. Generally, trial sizes are too small for sub-group analyses within individual studies to have adequate statistical power.
Meta-regression models describe associations between the summary effects and study-level data; that is, it describes only between-study and not between-patient variation. We will use multilevel models, which boost the power of the analysis by sharing strengths across subgroups for variables where it makes sense to do so, or subgroup analysis (with random effects meta-analysis) to explore heterogeneity if there are a sufficient number of studies.
Grading the Strength of Evidence for Major Comparisons and Outcomes
We will use explicit criteria for rating the overall strength of the evidence for intervention-final outcome pairs for which the overall risk of bias is not overwhelmingly high. We will use established concepts of the quantity of evidence (e.g., numbers of studies, aggregate ending-sample sizes), the quality of evidence (from the quality ratings on individual articles), and the coherence or consistency of findings across similar and dissimilar studies and in comparison to known or theoretically sound ideas of clinical or behavioral knowledge.
We will assess strength of evidence as stipulated in the Effective Health Care Program's Methods Guide for Effectiveness and Comparative Effectiveness Reviews updated strength of evidence guide.25 Current guidance on strength of evidence evaluation emphasizes the following major domains: study limitations (low, medium, high level of limitation), consistency (inconsistency not present, inconsistency present, unknown, or not applicable), directness (direct, indirect), precision (precise, imprecise), and reporting bias (present, undetected). Intervention-outcomes pairs will be given an overall evidence grade based on the ratings for the individual domains.
The assessment of the study limitations domain will be derived from the risk of bias of the individual studies that addressed the Key Question and specific outcome under consideration. The domains of consistency and precision will be assessed based on the direction and variation of the estimates. We will assess reporting bias of randomized controlled trials by examining outcomes of trials as reported in resources such as ClinicalTrials.gov to determine if prespecified outcomes are not reported in the published literature. We assign an overall grade (high, moderate, low or insufficient) for the strength of evidence for each key outcome (Table 4).
|High||We are very confident that the estimate of effect lies close to the true effect for this outcome. The body of evidence has few or no deficiencies. We believe that the findings are stable, i.e., another study would not change the conclusions.|
|Moderate||We are moderately confident that the estimate of effect lies close to the true effect for this outcome. The body of evidence has some deficiencies. We believe that the findings are likely to be stable, but some doubt remains.|
|Low||We have limited confidence that the estimate of effect lies close to the true effect for this outcome. The body of evidence has major or numerous deficiencies (or both). We believe that additional evidence is needed before concluding either that the findings are stable or that the estimate of effect is close to the true effect.|
|Insufficient||We have no evidence, we are unable to estimate an effect, or we have no confidence in the estimate of effect for this outcome. No evidence is available or the body of evidence has unacceptable deficiencies, precluding reaching a conclusion.|
Two senior staff will independently grade the body of evidence; disagreements will be resolved as needed through discussion or third-party adjudication. We will record strength of evidence assessments in tables, summarizing results for each outcome. When no studies are available for an outcome or comparison of interest, we will grade the evidence as insufficient.
We will assess the applicability of findings reported in the included literature to the general population of women with uterine fibroids by determining the population, intervention, comparator, and setting in each study and developing an overview of these elements for each intervention category.
We anticipate that areas in which applicability will be especially important to describe will include racial/ethnic variability, availability of treatment options, desired fertility status, fibroid characteristics such as size, volume, type, location, and number.
- Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003 Jan;188(1):100-7. PMID: 12548202
- Wise LA, Palmer JR, Stewart EA, et al. Age-specific incidence rates for self-reported uterine leiomyomata in the Black Women's Health Study. Obstet Gynecol. 2005 Mar;105(3):563-8. PMID: 15738025
- Laughlin SK, Baird DD, Savitz DA, et al. Prevalence of uterine leiomyomas in the first trimester of pregnancy: an ultrasound-screening study. Obstet Gynecol. 2009 Mar;113(3):630-5. PMID: 19300327
- Monte LM ER. Fertility of Women in the United States: June 2012. Current Population Reports. 2014:P20-575.
- Myers ER BM, Couchman GM, et al. Management of uterine fibroids (Evidence Report/Technology Assessment No. 34, contract 290-97-0014 to the Duke Evidence-based Practice Center). AHRQ Publication No 01-E052 Rockville, MD: Agency for Healthcare Research and Quality. July 2001
- Wegienka G, Baird DD, Hertz-Picciotto I, et al. Self-reported heavy bleeding associated with uterine leiomyomata. Obstet Gynecol. 2003 Mar;101(3):431-7. PMID: 12636944
- Stewart EA. Uterine fibroids. Lancet. 2001 Jan 27;357(9252):293-8. PMID: 11214143
- Huyck KL, Panhuysen CI, Cuenco KT, et al. The impact of race as a risk factor for symptom severity and age at diagnosis of uterine leiomyomata among affected sisters. Am J Obstet Gynecol. 2008 Feb;198(2):168 e1-9. PMID: 18226615
- Segars JH, Parrott EC, Nagel JD, et al. Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations. Hum Reprod Update. 2014 May-Jun;20(3):309-33. PMID: 24401287
- Hartmann KE, Birnbaum H, Ben-Hamadi R, et al. Annual costs associated with diagnosis of uterine leiomyomata. Obstet Gynecol. 2006 Oct;108(4):930-7. PMID: 17012456
- Cardozo ER, Clark AD, Banks NK, et al. The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol. 2012 Mar;206(3):211.e1-9. PMID: 22244472
- Wechter ME, Stewart EA, Myers ER, et al. Leiomyoma-related hospitalization and surgery: prevalence and predicted growth based on population trends. Am J Obstet Gynecol. 2011 Nov;205(5):492 e1-5. PMID: 22035951
- Whiteman MK, Hillis SD, Jamieson DJ, et al. Inpatient hysterectomy surveillance in the United States, 2000-2004. Am J Obstet Gynecol. 2008 Jan;198(1):34 e1-7. PMID: 17981254
- Gliklich R, Leavy M, Velentgas P, et al. Identification of Future Research Needs in the Comparative Management of Uterine Fibroid Disease. AHRQ Publication No. 11-EHC023-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
- Zimmermann A, Bernuit D, Gerlinger C, et al. Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. BMC Womens Health. 2012;12:6. PMID: 22448610
- Corona LE, Swenson CW, Sheetz KH, et al. Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative. Am J Obstet Gynecol. 2014 Dec 23PMID: 25542564
- Hartmann KE, Jerome RN, Lindegren ML, et al. Primary Care Management of Abnormal Uterine Bleeding. Rockville (MD); 2013.
- Center for Devices and Radiological Health. Laparoscopic Uterine Power Morcellation in Hysterectomy and Myomectomy: FDA Safety Communication, Updated [WebContent]. US Department of Health and Human Services, Food and Drug Administration; Issued: Nov 24, 2014. Available at http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm424443.htm.
- Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality; January 2014. www.effectivehealthcare.ahrq.gov.
- Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 2015-01-02 22:52:22;349:g7647. PMID: 25555855
- Comparing Options for Management: Patient-Centered Results for Uterine Fibroids (COMPARE-UF). Patient-Centered Outcomes Research Institute (PCORI). Evan R. Myers (Principal Investigator). Funding administered by the Agency for Healthcare Research and Quality: 2014. http://www.pcori.org/research-results/2014/comparing-options-management-patient-centered-results-uterine-fibroids-compare
- Chou R, Aronson N, Atkins D, et al. AHRQ series paper 4: assessing harms when comparing medical interventions: AHRQ and the effective health-care program. J Clin Epidemiol. 2010 May;63(5):502-12. PMID: 18823754
- Viswanathan M, Ansari MT, Berkman ND, et al. Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 12-EHC047-EF. Rockville MD: Agency for Healthcare Research and Quality; March 2012. www.effectivehealthcare.ahrq.gov/
- Santaguida P, Raina P. McMaster Quality Assessment Scale of Harms (McHarm) for primary studies: Manual for use of the McHarm.
- Berkman ND, Lohr KN, Ansari MT, et al. Grading the strength of a body of evidence when assessing health care interventions for the effective health care program of the Agency for Healthcare Research and Quality: An update. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 13(14)-EHC 130-EF. Rockville, MD: Agency for Healthcare Research and Quality; November 2013. www.effectivehealthcare.ahrq.gov
Definition of Terms
|ACOG||American College of Obstetricians and Gynecologists|
|AHRQ||Agency for Healthcare Research and Quality|
|CAM||Complementary and alternative medicine|
|CER||Comparative Effectiveness Review|
|CINAHL||Cumulative Index to Nursing and Allied Health|
|COMPARE-UF||Comparing Options for Management: Patient-Centered Results for Uterine Fibroids|
|EPC||Evidence-based Practice Center|
|FDA||Food and Drug Administration|
|FIGO||International Federation of Gynecologists and Obstetricians|
|GnRH||Gonadotropin releasing hormone|
|MRgFUS||Magnetic resonance guided focused ultrasound|
|NSAID||Non-steroidal anti-inflammatory drug|
|PICOTS||Population, Intervention, Comparators, Outcomes, Timing, Setting|
|RCOG||Royal College of Obstetricians and Gynaecologists|
|RCT||Randomized controlled trial|
|SERM||Selective estrogen receptor modulator|
|SPRM||Selective progesterone receptor modulator|
|SIP||Scientific information packet|
|TEP||Technical Expert Panel|
|TOO||Task Order Officer|
|WHO||World Health Organization|
Summary of Protocol Amendments
If we need to amend this protocol, we will give the date of each amendment, describe the change, and give the rationale in this section. Changes will not be incorporated into the protocol.
Review of Key Questions
AHRQ posted the key questions on the Effective Health Care Website for public comment. The EPC refined and finalized the key questions after review of the public comments, and input from Key Informants and the Technical Expert Panel (TEP). This input is intended to ensure that the key questions are specific and relevant.
Key Informants are the end users of research, including patients and caregivers, practicing clinicians, relevant professional and consumer organizations, purchasers of health care, and others with experience in making health care decisions. Within the EPC program, the Key Informant role is to provide input into identifying the Key Questions for research that will inform healthcare decisions. The EPC solicits input from Key Informants when developing questions for systematic review or when identifying high priority research gaps and needed new research. Key Informants are not involved in analyzing the evidence or writing the report and have not reviewed the report, except as given the opportunity to do so through the peer or public review mechanism.
Key Informants must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their role as end-users, individuals are invited to serve as Key Informants and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.
Technical Experts constitute a multi-disciplinary group of clinical, content, and methodological experts who provide input in defining populations, interventions, comparisons, or outcomes and identify particular studies or databases to search. They are selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicting opinions are common and perceived as health scientific discourse that results in a thoughtful, relevant systematic review. Therefore study questions, design, and methodological approaches do not necessarily represent the views of individual technical and content experts. Technical Experts provide information to the EPC to identify literature search strategies and recommend approaches to specific issues as requested by the EPC. Technical Experts do not do analysis of any kind nor do they contribute to the writing of the report. They have not reviewed the report, except as given the opportunity to do so through the peer or public review mechanism.
Technical Experts must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals are invited to serve as Technical Experts and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.
Peer reviewers are invited to provide written comments on the draft report based on their clinical, content, or methodological expertise. The EPC considers all peer review comments on the draft report in preparation of the final report. Peer reviewers do not participate in writing or editing of the final report or other products. The final report does not necessarily represent the views of individual reviewers. The EPC will complete a disposition of all peer review comments. The disposition of comments for systematic reviews and technical briefs will be published three months after the publication of the evidence report.
Potential Peer Reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Invited Peer Reviewers may not have any financial conflict of interest greater than $10,000. Peer reviewers who disclose potential business or professional conflicts of interest may submit comments on draft reports through the public comment mechanism.
EPC Team Disclosures
EPC core team members must disclose any financial conflicts of interest greater than $1,000 and any other relevant business or professional conflicts of interest. Related financial conflicts of interest that cumulatively total greater than $1,000 will usually disqualify EPC core team investigators.
Role of the Funder
This project was funded under Contract No. HHSA 290-2015-00003I from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The Task Order Officer reviewed contract deliverables for adherence to contract requirements and quality. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
|Drug Class||Drug Name, Brand/Other Names||Labeled Indications||Company Name and Location|
|GnRH Agonists||Cetrorelix Acetate, Cetrotide®||
||Merck Serono (EMD Serono, Inc.), Rockland, MA, USA|
|Goserelin Acetate, Zoladex®||
||AstraZeneca Pharmaceuticals, Wilmington, DE, USA|
|Leuprolide Acetate, Eligard®, Lupron Depot®, Lupron®, Viadur®||
||AbbVie, Chicago, IL, USA|
|Triptorelin Pamoate, Trelstar Depot®, Trelstar LA®, Trelstar®||
|Buserelin, Suprefact®, CinnaFact®, Metrelef®||Not available in the US||Sanofi-Aventis, Laval, Quebec, Canada|
|Progesterone Antagonists/Agonists||Mifepristone, Mifeprex®, RU-486||
||Danco Laboratories, New York City, USA|
|Ulipristal Acetate, Ella®||
|Estrogen Receptor Antagonists/ SERM||Fulvestrant, Faslodex®||
||AstraZeneca, Wilmington, DE, USA|
|Raloxifene Hydrochloride, Evista®||
||Eli Lilly and Company, Indianapolis, IN, USA|
|Other||Levonorgestrel-releasing intrauterine system, Mirena®, LNG-IUS||
||Bayer Healthcare Pharmaceuticals, Inc, Whippany, NJ, USA|
|Lynestrenol||Not approved for use in US||NAARI AG, Switzerland|
|Tibolone, Livial||Not available in the US||Merck Sharp & Dohme Limited, Hertfordshire, UK|
|Aromatase inhibitors||Not FDA approved for treatment of uterine leiomyoma|
|Cook Tissue Morcellator||Cook Urological Inc.|
|Coring Morcellator||Cook Urological Inc.|
|Gyncare Morcellex Tissue Morcellator||Ethicon Inc.|
|Gynecare Laparoscopic Morcellator||Ethicon Inc.|
|Gynecare Morcellex Tissue Morcellator Models Mx0100 And Mx0100r||Ethicon Inc.|
|Femrx Morcellator System||Gynecare Innovation Center|
|Pks Plasma Morcellator Models 962000pk 3620pk||Gyrus Acmi Inc.|
|Lasersonics Tissue Morcellator Set||Heraeus Surgical Inc.|
|Ksea Sawahle Electromechanical Morcellator||Karl Storz Endoscopy|
|Kse Steiner Electromechanic Morcellator||Karl Storz Endoscopy-America Inc.|
|Ksea Rotocut G1 Electromechanical Morcellator||Karl Storz Endoscopy-America Inc.|
|Ksea Sawahle Electromechanical Morcellator||Karl Storz Endoscopy-America Inc.|
|Ksea Steiner Electromechanic Morcellator||Karl Storz Endoscopy-America Inc.|
|Ksea Steiner Electromechanic Morcellator||Karl Storz Endoscopy-America Inc.|
|Coherent Tissue Morcellator Kit And Accessories||Lumenis Inc.|
|Lumenis Versacut Tissue Morcellator System||Lumenis Inc.|
|Versacut + Tissue Morcellator||Lumenis Ltd.|
|Morce Power Plus And Variocarve Morcellator||Nouvag Ag|
|Riwo Cut-Morcellator Existing Of Knife/Cutting Sleeve/Protection Sleeve/Claw Grasping Forceps||Richard Wolf Medical Instruments Corp.|
|Iur Reciprocating Morcellator Model # 7210517||Smith & Nephew Inc.|
|Truclear Morcellation System And Truclear Morcellators||Smith & Nephew Inc.|
|Truclear Morcellator System||Smith & Nephew Inc.|
|Trokamed Morcellator||Trokamed Gmbh|
|Ablative Devices||ExAblate 2000||General Electric Medical Systems|
|VizAblate not FDA-approved for use in the U.S.)||Gynesonics|
|Thermachoice Thermal Balloon Ablation system||Gynecare, Inc|
|NovaSure Impedance Controlled Endometrial Ablation System||Hologic Corporation; Cytyc Corporation|
|Her Option||American Medical Systems, Inc|
|Hydro ThermAblator System||Boston Scientific Corporation|
|Artery Occlusion||Doppler-Guided Uterine Artery Occlusion (DUAO) Device (Gynecare Gynocclude D-UAO)||Ethicon|
|Microspheres for Embolization||Embosphere®||Merit Medical Systems|
|Hysteroscopic and/or Laparoscopic||da Vinci Surgical System||Intuitive Surgical|
|MyoSure Hysteroscopic Tissue Removal System (Hysteroscopic)||Hologic|
|Notes: “Drug therapy”[mh] includes hormone therapy; “Surgical procedures, operative”[mh] includes ultrasound ablation, embolization, and hysterectomy|
|#1||((leiomyoma[mh]) OR (fibroma[mh] AND (uterine diseases[mh] OR uterus[mh])))||17559|
|#2||(Uterine[tiab] AND (fibroma*[tiab] OR fibroid*[tiab] OR leiomyoma*[tiab] OR myoma*[tiab] OR fibromyoma*[tiab])) OR (submucous fibroid*[tiab] OR submucosal fibroid*[tiab] OR Intramural fibroids [tiab]) NOT medline[sb]||964|
|#3||#1 OR #2||18503|
|#4||(((((("Mifepristone"[Mesh] OR "ulipristal"[Supplementary Concept]) OR "Anti-Inflammatory Agents, Non-Steroidal"[Mesh]) OR "Antifibrinolytic Agents"[Mesh]) OR "Goserelin"[Mesh]) OR "cetrorelix"[Supplementary Concept]) OR "Selective Estrogen Receptor Modulators"[Mesh]) OR "Levonorgestrel"[Mesh]||85952|
|#5||therapy[sh:noexp] OR drug therapy[mh] OR drug therapy[sh] OR complementary therapies[mh] OR Treatment outcome[mh]||4541911|
|#6||(Mifepristone[tiab] OR Ulipristal acetate[tiab] OR NSAID[tiab] OR antifibrinolytic[tiab] OR Goserelin[tiab] OR cetrorelix acetate[tiab] OR Selective estrogen receptor modulators[tiab] OR SERM[tiab] OR mirena[tiab] OR lng-ius[tiab] OR levonorgestrel-releasing intrauterine system[tiab]) NOT medline[sb]||1474|
|#7||#4 OR #5 OR #6||4578967|
|#8||surgery[sh] OR surgical procedures, operative[mh] OR embolization, therapeutic[mh]||3041828|
|#9||(Hysterectomy[tiab] OR myomectomy[tiab] OR emboliz*[tiab] OR ablation[tiab] OR ultrasound[tiab] OR uterine artery occlusion[tiab] OR Uterine artery embolization[tiab] OR UAE[tiab]) NOT medline[sb]||31999|
|#10||#8 OR #9||3073791|
|#11||#3 AND #7||3830|
|#12||#3 AND #10||8878|
|#13||#11 OR #12||10114|
|#2||morcellat* AND uterine||256|
|#4||("Electrosurgery/adverse effects"[Mesh]) OR "Uterine Myomectomy/adverse effects"[MeSH] OR morcellat*||1251|
|#5||("Electrosurgery/adverse effects"[Mesh] AND uterine) OR "Uterine Myomectomy/adverse effects"[MeSH] OR morcellat*||737|
|American College of Obstetricians and Gynecologists||http://www.acog.org/|
|American Association of Gynecologic Laparoscopists||https://www.aagl.org/|
|Society of Interventional Radiologists||http://www.sirweb.org/|
|Society of Gynecologic Surgeons||http://www.sgsonline.org/|
|American Institute for Ultrasound in Medicine||http://www.aium.org/|
|Food and Drug Administration||http://www.fda.gov/|
|European Medicines Agency||http://www.ema.europa.eu/ema/|
|National Health Service / National Institute for Health and Care Excellence||https://www.nice.org.uk/|