Key Research Questions

The EPC addressed nine key research questions:

1. What are the risks and benefits of hysterectomy and myomectomy in the treatment of symptomatic and asymptomatic fibroids?
2. What are the risks associated with single vs. multiple myomectomies? (i.e., Do women with a solitary clinically apparent fibroid have different outcomes after surgical management than women with multiple fibroids?)
3. Who are appropriate candidates for each procedure?
4. What is the incidence of need for additional treatment after myomectomy or other uterus-sparing interventions?
5. Does additional treatment result in significantly increased morbidity? (i.e., Is the overall risk of adverse outcomes greater with uterus-conserving therapy because of recurrence or persistence resulting in additional therapy with associated risks, compared with immediate definitive therapy such as hysterectomy?)
6. What are the risks and benefits of nonsurgical treatment?
7. What are the costs associated with effective surgical and nonsurgical treatments? (This question was expanded to include other invasive therapies such as uterine artery embolization.)
8. Do risks and benefits differ by race, ethnicity, age, interest in future childbearing, etc.?
9. What are the effects of surgical management of uterine fibroids, especially hysterectomy, on the aging process?

Interventions Assessed

Interventions considered include:

• No intervention ("watchful waiting").
• Medical therapies:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Oral contraceptive pills (OCPs).
  • Progestational agents.
  • Other oral agents identified in a literature search (e.g., mifepristone, tibolone, herbal preparations).
  • Gonadotropin-releasing hormone (GnRH) agonists (both as primary therapy and as an adjunct to myomectomy or hysterectomy).
• Invasive therapies:

  • Uterine artery embolization.
  • Coagulation using cautery or laser.
  • Myomectomy.
  • Hysterectomy.

In addition, the EPC reviewed the available evidence on the following strategies for managing asymptomatic fibroids:

• No intervention.
• Prophylactic myomectomy.
• Prophylactic hysterectomy.

The EPC did not attempt to evaluate systematically the evidence on the relative benefits, risks, and costs of different technical approaches to either the diagnosis and followup of fibroids (such as clinical examination, ultrasound, or magnetic resonance imaging) or surgical procedures (e.g., comparing a laparoscopic to an abdominal myomectomy). Although these questions are clearly important, each topic in itself is large and complex enough to warrant a formal systematic review.

Patient Population and Settings

The primary population of interest is women between the ages of 20 and 55 years with symptomatic or asymptomatic uterine fibroids. Separate reviews were performed for women of different racial and ethnic backgrounds, ages (especially perimenopausal women), and plans for future childbearing.

The principal practice settings considered were offices of ob-gyns, offices of other primary care providers, ambulatory surgical centers, interventional radiology suites, and acute care hospitals (for inpatient surgical procedures).

Outcomes Considered

Outcomes considered varied depending on the study and the question being addressed. Data recorded on the abstraction forms included:

• Anatomical/physiological outcomes (change in uterine size, fibroid size, hemoglobin, or hematocrit).
• Symptomatic outcomes (change in symptoms of bleeding, cyclic pain, or non-cyclic pain).
• Pregnancy-related outcomes (pregnancy rates, live-birth rates, pregnancy complications).
• Quality-of-life measures.
• Adverse outcomes (side effects and complications of treatment, development of new symptoms).
• Need for additional treatment after uterus-conserving therapy.
• Resource use (length of stay, medical costs, time lost from work or usual activities).

Literature Sources

The primary sources of literature were the following databases (with search years shown in parentheses): MEDLINE (1975-February 2000), HealthSTAR (1975-February 2000), CINAHL (1983-February 2000), CancerLit (1983-February 2000), the Cochrane Library (Issue 3 1999), and EMBASE (1980-January 2000). Searches of these databases were supplemented by secondary searches that included E-mail subscriptions for announcements of newly published journal articles and thorough searching of the reference lists of all included articles and review articles.

The initial search was performed in MEDLINE (and then duplicated in the other databases) and limited to articles in the English language and with human subjects. A previously validated search strategy was used that identifies three subsets:

1. High specificity for randomized controlled trials (RCTs), using terms like "randomized."
2. Moderate specificity, using terms like "blinding."
3. Low specificity, using terms such as "followup studies."

All searches included:

• The MeSH terms "uterine neoplasms," "leiomyoma," "hysterectomy," "hysterectomy, vaginal," and "surgical procedures, laparoscopic."
• Text terms (truncated) for "fibroid," "uterine and leiomyoma)," "hysterectomy," and "myomectomy."

The overwhelming majority of RCTs identified by this initial search examined the use of gonadotropin-releasing hormone (GnRH) agonists, frequently as adjunctive treatment prior to surgery. The remainder of the citations identified were either uncontrolled case series, case series with historical or nonrandomized controls, case-control studies, or in a few instances, prospective cohort studies. A subsequent search (performed initially in EMBASE and then duplicated in MEDLINE and the other databases) was targeted to surgical interventions and included other, less robust study designs. Finally, because few of the targeted articles on hysterectomy and fibroids provided data relevant to question 9 (on the effects of hysterectomy on the aging process), the EPC performed an additional search on hysterectomy without limiting studies to those including patients with fibroids.

Screening of Articles

Empirical study designs considered included controlled trials, prospective trials with historical controls, prospective or retrospective cohort studies, case-control studies, and medium to large case series (n = 20). Studies of these types and review articles were included if they met the following criteria:

• The study population included women with uterine fibroids.
• Data were relevant to one or more of the key questions described above.
• Information was presented on health outcomes, health services use, and/or health care costs for the management of uterine fibroids.

Exclusion criteria were as follows:

• The article was not original research or relevant review.
• The patient population did not include women with uterine fibroids.
• The study design was a single case report.
• The study design was a small case series with fewer than 20 subjects.

For studies on the effects of hysterectomy on aging (question 9), the EPC expanded the inclusion criteria to include studies of all hysterectomies for benign disease, even if the patient population did not include women with fibroids or results were not reported separately for patients with fibroids.

The searches yielded 1,084 articles. Abstracts from these articles were reviewed against the inclusion/exclusion criteria by five physician investigators. A team of two physicians reviewed each abstract; when no abstract was available, the title, source, and MeSH words were reviewed. Articles were included if requested by one member of the review team. At the full-text screening stage, each article was independently reviewed by two physicians, and disagreements were resolved through discussion. Articles on the effects of hysterectomy on aging were identified by a separate search and were reviewed by a single reviewer with a special interest in gynecological surgery and the aging process.

Data Abstraction Process

Teams of two physicians performed the data abstraction for articles identified by the main searches. For each included article, one physician completed the data abstraction form, and the other served as over-reader. The physician responsible for the primary abstraction also entered data on relevant outcomes and results into a Microsoft® Word® document. The information from the data abstraction form and the corresponding outcomes and results data were then merged into the evidence table format. The data abstraction assignments were made based on the physicians' clinical interests and expertise.

Again, data on outcomes of hysterectomy that did not explicitly focus on patients with fibroids were not subject to the same level of review. A single reviewer was responsible for selecting articles and assessing their relevance. Because the majority of these articles did not explicitly focus on women with fibroids, they were not abstracted into the evidence tables.

Criteria for Evaluating Article Quality

The majority of the evidence was not of the highest quality according to published grading systems, such as that used by the U.S. Preventive Services Task Force in its evaluation of preventive services or by the American College of Obstetricians and Gynecologists (ACOG) in its Practice Bulletins. In these and most other systems, randomized trials done with rigorous methodology are judged to be of the highest quality, followed by prospective cohort studies. Very few of the identified articles were of these types.

Dismissing this literature entirely would have severely limited the investigators' ability to make any inferences at all. In fact, some study designs, such as large cohort studies or retrospective reviews of administrative data, may be better suited to certain questions, such as those concerning disease incidence or resource use. On the other hand, the quality of these studies clearly varies widely. Therefore, each study was evaluated for factors affecting internal and external validity.

For internal validity, these criteria were:

• Randomized allocation to treatment, and appropriate methods for randomization.
• Adequate description of patients and controls.
• Adequate description of length of followup, loss to followup, and dropout rates.
• Recognition and discussion of important statistical issues.

For external validity, these criteria were:

• Information about age, racial/ethnic background, pregnancy history, and prior surgical history.
• Adequate description of uterine or fibroid size, fibroid location, and fibroid number.
• Adequate description of baseline symptoms.
• Adequate description of timing of outcomes measurement.
• Adequate description of methods used for outcomes measurement.
• Description of the validity and reliability of outcomes measures.
• Adequate description or reference to clinical care provided to subjects.
• Use of standard, validated measures.

Additional Data Sources

The EPC used two additional data sources, primarily to address questions of costs and racial differences:

1. The Nationwide Inpatient Sample (NIS). The NIS is maintained by the Agency for Healthcare Research and Quality (AHRQ). This database contains administrative discharge data from over 1,000 hospitals in 22 States, representing a stratified sample of 20 percent of U.S. hospitals. The NIS provided supplemental data on frequency and resource use for hysterectomy and myomectomy by age and race (question 7, on cost and question 8, on age and race). These data from the sampled hospitals were converted to national estimates using the weighting variables provided by AHRQ. To assess differences in the proportion of white and black women undergoing each procedure, logistic regression was performed using myomectomy versus hysterectomy as the dependent variable and race as the main independent variable and controlling for age, payer type, and median income.
2. Data from Duke University Medical Center. Data on hospital costs and clinical characteristics affecting cost and complications of patients undergoing myomectomy were obtained from Duke University Medical Center. Records for patients undergoing abdominal myomectomy at Duke University Medical Center between July 1, 1993, and June 30, 1998, were identified using the hospital's cost-accounting system. Data on each patient's age, race, length of stay, insurance status, ZIP code, attending physician, and hospital costs were available from the abstracted discharge data. After the appropriate records were identified, trained abstractors reviewed the charts to collect additional clinical information. Multivariate analysis was used to determine the effects of multiple patient characteristics on outcomes using linear regression for continuous outcomes (length of stay and costs) and logistic regression for dichotomous outcomes (transfusions and complications).

Decision Model

The EPC constructed a Markov model incorporating 11 possible health states:

1. Asymptomatic fibroids, defined as having clinically detectable fibroids, but without symptoms attributable to their presence.
2. Symptomatic fibroids, without side effects/complications of therapy.
3. Symptomatic fibroids, with side effects/complications of therapy.
4. Improved symptoms, with no side effects/complications.
5. Improved symptoms, with side effects/complications.
6. No symptoms, without side effects/complications, defined as having symptoms prior to treatment but experiencing complete relief after treatment with no side effects or complications attributable to therapy.
7. No symptoms, with side effects/complications, defined as having symptoms prior to treatment with complete relief after treatment but with side effects or complications attributable to therapy.
8. Uncomplicated pregnancy (no complications attributable to fibroids).
9. Complicated pregnancy (complications attributable to fibroids).
10. Menopause.
11. Death.

Data needed to estimate transition probabilities were identified. Because data on many of the probabilities were unavailable, a simplified analysis comparing outcomes of hysterectomy, myomectomy, and no treatment in women of different ages was performed.