Chapter  154:  Management of Uterine Fibroids: An Update of the Evidence

KQ 1: Incidence and Prevalence of Uterine Fibroids

Two studies provided weak evidence (limited number of studies) on the incidence and prevalence of uterine fibroids. One study used randomly selected participants from a prepaid urban health plan with 50 percent black membership to report ultrasound-confirmed incidence for premenopausal women and medical records and self-report for postmenopausal women for a cumulative incidence rates by age 50 of nearly 70 percent among white women and more than 80 percent among black women. Another study reported an incidence rate of 2.97 for every 100 person-years from a black nationwide U.S. sample. The literature provides no guidance on the overall burden of disease posed by uterine fibroids.

KQ 2: Outcomes of Treatment of Uterine Fibroids for Symptoms

Studies provided information on effectiveness more commonly than on adverse outcomes. We summarize data on adverse outcomes when available below.

Expectant Management. We identified no literature to document the natural history of uterine fibroid incidence, growth, symptomatology, use of clinical care, or outcomes when women choose watchful waiting over intervention.

Pharmaceutical Management. GnRH agonists. Of the 19 studies that we reviewed for pharmaceutical management of fibroids, 13 (7 RCTs) addressed the effect of GnRH agonists. Eight of these studies provided moderate evidence (consistent effects and strong design but small sample sizes) that GnRH agonists were effective in decreasing overall uterine size when used either as preoperative treatment or as an alternative to surgery. Another subset (six studies) on hemoglobin levels provided weak evidence of increases in hemoglobin levels by 0.9 g/dL to 5.2 g/dL after treatment and before surgery.

Three studies provided weak evidence (limited number of studies, inconsistent effects) on the effect of GnRH agonists on symptom relief. A small nonrandomized study reported relief from hot flashes among women receiving tibolone and a GnRH agonist. The other two studies found that raloxifene was not effective in reducing fibroid symptoms compared with placebo.

Progestins. A small randomized controlled trial (RCT) presented weak evidence of reduction in fibroid size among women receiving lynestrenol compared with women receiving leuprolide acetate.

Mifepristone. One study (weak evidence) comparing two doses of mifepristone reported significant reductions in uterine size and menstrual blood loss from baseline values in both groups but no differences between the dose groups, suggesting that the lower dose is sufficient.

Estrogen Receptor Modulators and Antagonists. Three trials provided weak evidence (limited number of studies, inconsistent effects) comparing raloxifene with placebo; two reported a significant reduction in uterine and fibroid size compared with baseline values for postmenopausal women on raloxifene and an increase in uterine and fibroid size for premenopausal women on raloxifene. A fourth study was a five-arm trial of poor quality comparing three different doses of the estrogen receptor antagonist fulvestrant with goserelin and a placebo. Goserelin significantly reduced fibroid growth and endometrial thickness compared with placebo and fulvestrant, but fulvestrant did not significantly alter fibroid volume or endometrial thickness compared with placebo.

Uterine Artery Embolization (UAE). Twenty-three studies examined short- and long-term outcomes following UAE. Of these, six studies (one RCT) compared UAE with either hysterectomy or myomectomy. They yielded evidence of moderate strength (consistent effects but weak design) suggesting shorter procedure (operative) times and shorter lengths of hospital stay for UAE than for hysterectomy or myomectomy. However, they provided only weak evidence (either no significant differences or inconsistent direction of effect) about the impact of UAE on complications and symptom relief.

The remaining studies were case series or cohort studies, of poor or fair quality, with sample sizes ranging from 46 to 3,140. They do not provide consistent definitions or time points for measuring key outcomes such as complications. The largest case series on UAE reported an in-hospital complication rate of 2.7 percent, (0.6 percent rate of major events), and a postdischarge complication rate of 26.1 percent (4.1 percent rate of major events).

Only one study examined rates of subsequent interventions for UAE and another procedure. It reported statistically significant higher rates of subsequent interventions with UAE than with myomectomy (29 percent versus 3 percent) in followup ranging from 3 to 5 years. Another study reported a subsequent intervention rate of 20 percent at 5 years. The value of this information is limited by the lack of comparable data for other types of treatment.

Endometrial Ablation. We found only three studies, all of poor quality, about endometrial ablation, which is used to treat bleeding symptoms. Of these, two combined ablation with hysteroscopic resection (retrospective case series) and one evaluated ablation only (prospective case series). These publications poorly document operative and longer-term outcomes; they lack enough common data elements to permit any substantive summary of findings.

Magnetic Resonance Imaging (MRI) Guided Focused Ultrasound. The strength of evidence about MRI-guided ultrasound ablation of fibroids is weak, although we identified one carefully conducted prospective case series. Overall, the study suggested reasonable tolerance (16 percent of women reported severe pain at some point during the treatment and 8 percent reported severe to moderate pain after the procedure), improvement in quality of life (71 percent improved), and modest change in fibroid size (13 percent decrease). During more than a year of followup, 11 percent of women experienced worsened symptoms; 28 percent elected further treatment including myomectomy and hysterectomy.

Myomectomy. The strength of evidence overall is weak because of the predominance of weak study designs, the restricted scope of outcomes studied, and the limited quality of measurements in the few studies of stronger design.

Abdominal Myomectomy. The abdominal myomectomy literature comprised 13 studies of small to modest size. Transfusion risk in the eight studies that reported it varied widely, from 5 percent to 21 percent, with higher risk in studies in less specialized surgical settings. Among women for whom myomectomy had been the original plan, 3 percent to 4 percent required intraoperative conversion to hysterectomy. Wound healing complications affected 2 percent to 4 percent of women receiving abdominal myomectomy.

In four studies that assessed symptoms, most women reported improvements in symptoms such as bleeding, pressure, and pain, for which they sought care, although the degree of improvement varied by symptom. Recurrence of fibroids likely affected more than 18 percent of women and may have been as high as 62 percent within 3 to 4 years after surgery.

Laparoscopic Myomectomy. Transfusion ranged from <1 percent to 8 percent in 11 of 16 studies that reported. A single study provided direct comparison between abdominal and laparoscopic myomectomy, reporting statistically significant lower risk among those having laparoscopic procedures. Conversion to open procedures occurred in approximately 9 percent of women; a small proportion had an immediate hysterectomy. Length of stay in the hospital is shorter after laparoscopy than after abdominal procedures, and wound healing complications are rare. Recurrence of fibroids ranged from 13 percent to 27 percent, and 7 percent to 12 percent of women had additional surgery over the first few years after myomectomy, Although these operative risks appear similar to those for abdominal myomectomy, we found no direct comparisons with power adequate to compare long-term outcomes between laparoscopic and abdominal myomectomy.

Hysteroscopic Myomectomy. Across five studies with 2,061 participants, we found little detail about operative complexity and complications. The risk of perforations of the uterus (two studies) was consistent with the often clinically cited rate of 1 in 100. Repeat procedures and subsequent surgery affect 2 percent to 20 percent of women in the years immediately after hysteroscopic myomectomy. In these studies > 80 percent of women reported good outcomes as defined by self-report of “control of bleeding.”

Hysterectomy. Seventeen studies (eight RCTs) of poor and fair quality provided weak evidence on outcomes of hysterectomy, comparisons of types of hysterectomy, and modifiers of hysterectomy.

Outcomes. The hysterectomy literature is limited largely to short-term outcomes such as operative time, length of stay, and complications. Most studies reporting on comparative studies of hysterectomy either did not have sufficient sample sizes to derive estimates of risks of individual operative or postoperative complications or were not of generalizable practice settings.

Long-term outcomes are similarly limited to small studies of comparisons between treatments. These studies did not have sufficient sample sizes to derive estimates of long-term outcomes.

Comparisons of Types of Hysterectomy. In three studies comparing vaginal to abdominal hysterectomy, the most consistent finding was shorter average hospital stay (by 1 to 2 days) for patients undergoing vaginal procedures. Rates of transfusion and intraoperative complications were generally comparable; in one cohort study the combined rate of postoperative complications was significantly higher in women undergoing abdominal hysterectomy.

The two studies reporting on laparoscopically assisted vaginal hysterectomy (LAVH) and abdominal hysterectomy demonstrated improved outcomes for LAVH on a limited set of perioperative outcomes, namely hospital stay, convalescence, and use of analgesia.

The only study comparing outcomes of LAVH and vaginal hysterectomy reported significantly longer hospital stay and higher rates of total perioperative complications among women undergoing LAVH.

Complementary and Alternative Medicine. A single study of poor quality provided weak evidence favoring traditional Chinese medicine over standard medical management. Differences in degree of motivation between treatment arms may have potentially biased the results.

KQ 3: Outcomes of Treatment of Uterine Fibroids for Other Reasons

The sole clinical trial comparing surgical intervention with no intervention to improve fertility (in the absence of assisted reproductive technology) supported benefit from removing fibroids that have a submucosal component. This benefit was substantial (>15 percent absolute increase in the proportion of women becoming pregnant); the trial was limited, however, by small study size, to reporting only ability to conceive and not other pregnancy outcomes. The 10 studies we identified provided weak evidence that was insufficient to assess risk of pregnancy complications related to myomectomy. Uterine rupture was rare (1 in 314 births); all studies combined are underpowered to estimate risk accurately.

We found no evidence on the effects of treatment to prevent further fibroid growth among asymptomatic women. However, concerns about further growth during the postmenopausal period limit the use of hormone replacement therapy to treat postmenopausal symptoms. Moderate evidence from three studies indicated that menopausal hormone therapy had no effect on fibroid size; one reported a higher rate of uterine growth with the percutaneous-oral schedule of hormone replacement therapy than with a single oral combination of oestradiol valerate and cyproterone acetate.

KQ 4: Costs of Fibroid Treatment

Three studies report on UAE, either on its own or in comparison with other interventions. They do not suggest cost savings for UAE; rather, they demonstrate comparable or higher costs of UAE, despite shorter length of stay.

Our analysis of Healthcare Cost and Utilization Project data showed that the average costs of uterine fibroid treatment increased by almost 30 percent between 1997 and 2004. In 1997 the average inpatient costs were $11,978 (adjusted to 2004 dollars); by 2004 the average costs had increased to $15,405. During the same period, the average length of stay dropped from 2.9 days to 2.6 days.

The source of increase in costs is unclear; possible explanations include higher professional costs with procedures such as UAE and overall increase in health care costs. We found no information comparing average costs of procedural interventions with pharmaceutical treatments.

KQ 5: Modifiers of Outcomes

In eight studies, larger and more numerous fibroids often predict worse outcomes for several uterine fibroid procedures other than UAE (seven studies), for which the evidence is unclear. Eight studies addressed patient health characteristics or provider characteristics as modifiers of outcomes; they suggested that greater provider experience predicts fewer adverse events. For UAE, three studies demonstrated that a history of previous procedures predicts a higher risk of failure and adverse events.

KQ 6: Comparisons of Treatments

The majority of comparative studies (8 of 10) compared UAE with hysterectomy or myomectomy. They reported procedure time and length of stay favoring UAE. However, the inconsistency of the direction of effect for complications and the absence of information on longer-term outcomes suggested that this evidence base is inadequate to comment on the relative risks and benefits of UAE versus hysterectomy or myomectomy. Only one study addressed the need for further invasive therapy; it reported a much higher risk of hysterectomy, myomectomy, or repeat UAE in the UAE group than in the myomectomy group.

One study comparing abdominal hysterectomy with abdominal myomectomy reported no difference in the only outcome considered (febrile morbidity). Another study, comparing Chinese traditional medicine with conventional therapy, as discussed earlier in this summary, provides weak evidence (weak design, potential bias) favoring traditional Chinese medicine.

KQ 7: Geographic Variation in Treatment

We found no study on geographic variation in treatment within the United States. Studies in our systematic review were generally conducted in academic medical centers, and we could not assess the generalizability of their patterns of care with the broader population from which they were drawn.

Key Questions

The first Agency for Healthcare Research and Quality (AHRQ) systematic review on the management of uterine fibroids was published in January 2001.³⁰ That review found that the overall quality of the literature on the management of fibroids was poor, with almost no evidence to support the effectiveness of commonly recommended medical treatments. The review found consistent evidence from randomized trials that preoperative use of GnRH agonist therapy reduced estimated blood loss and may facilitate the surgical approach by reducing uterine size. The review also found that the outcomes of hysterectomy up to 2 years after surgery are favorable for most symptomatic women, although up to 12 percent of women develop new symptoms after surgery. The review did not attempt to deduce the clinical significance of these outcomes compared with outcomes of myomectomy, medical therapy, or no intervention, because of significant differences in the severity of preintervention disease. The prior review found almost no data to allow estimation of the overall costs of fibroids to the economy.

Since then, new treatment approaches, such as uterine artery embolization and ablation of fibroids via ultrasound guided by magnetic resonance imaging (MRI), have become available for management of uterine fibroids. More recent publications have also expanded the evidence base and may better reflect the variety of currently available medical management resources and the range of surgical interventions in use. New direct comparisons of different types of management approaches, as well as new research with longer lengths of followup of participants, have also become available.

The American College of Obstetricians and Gynecologists (ACOG) (the partner for this evidence report) proposed an update to the 2001 systematic review. ACOG developed the initial scope of this review; AHRQ forwarded it to the RTI International-University of North Carolina Evidence-based Practice Center (RTI-UNC EPC). The original work assignment proposed eight provisional questions for review; they recapitulate those of the original review.

The RTI-UNC EPC revised the proposed questions after discussions with internal technical staff, AHRQ staff, ACOG, and our Technical Expert Panel (TEP, see below). We aimed to allow a cross-walk between the 2001 report and this update while expanding the modalities considered and regrouping questions to result in chapters that better conform to the clinical care concerns confronting women and their care providers. The final seven key questions (KQs) are listed below.

KQ 1. What is the incidence and prevalence of uterine fibroids, as estimated in representative U.S. populations through use of diagnostic imaging or histology to document uniformly the presence or absence of fibroids? Among women with symptomatic fibroids, what are the incidence, type, and severity of symptoms?

KQ 2. Among women with symptomatic fibroids (e.g., anemia, problem bleeding patterns, bulk symptoms, pain, dyspareunia), what are the short- and long-term outcomes of the following treatment approaches or combinations of treatment approaches:

• 1

  expectant management without intervention?

• 2

  medical (pharmaceutical) management (including oral contraceptives, menopausal hormone therapy, GnRH agonist therapy, antiprogestins, progesterone-containing IUDs, and nonsteroidal anti-inflammatory drugs)?

• 3

  uterine artery embolization?

• 4

  endometrial ablation (with or without myomectomy)?

• 5

  in situ destructive techniques (MRI-guided focused ultrasound and cryotherapy)?

• 6

  myomectomy (abdominal, laparoscopic, and hysteroscopic)?

• 7

  hysterectomy (abdominal, laparoscopic, vaginal)?

• 8

  complementary and alternative therapies including acupuncture?

KQ 3. Among women with fibroids (symptomatic or asymptomatic), what are the short- and long-term outcomes of these treatment approaches when used with the objective of:

• a

  enhancing fertility?

• b

  reducing adverse pregnancy outcomes?

• c

  preventing further growth?

• d

  ruling out uterine malignancy?

KQ 4. What are the costs associated with fibroids care?

KQ 5. Are the short- and long-term outcomes of these treatment approaches (including risk of fibroid recurrence) modified by age, race or ethnicity, parity, breastfeeding, contraceptive choices, body habitus, insulin resistance, concurrent medical conditions such as diabetes, hormone replacement status, or other factors?

KQ 6. Where direct comparisons have been made between or among the treatment modalities of interest, which modalities achieve superior outcomes with respect to benefits, short- and long-term risks, quality of life, and costs?

KQ 7. Do rates of use of these treatments for fibroids vary geographically in the United States?

Organization of This Evidence Report

Chapter 2 describes our methods, including our search strategies and inclusion/exclusion criteria; we also document our approach to grading the quality of articles and rating the strength of evidence. In Chapter 3, we present the results of our literature search and synthesis of retained articles by key question. Specifically, we address KQs 1, 2, 3, and 4, as they directly draw upon evidence. Chapter 4 further discusses the findings and addresses KQs 5, 6, and 7, as they are further analyses of the evidence presented in Chapter 3. Chapter 4 also presents our conclusions, and offers recommendations for future research.

Our references and included studies follow Chapter 4. Appendices include a detailed description of our search strings (Appendix A ^*), data collection forms (Appendix B ^*), detailed evidence tables (Appendix C ^*), excluded studies (Appendix D ^*), and acknowledgments (Appendix E ^*). Appendixes and evidence tables cited in this report are provided electronically at http://www.ahrq.gov.

Technical Expert Panel (TEP)

We identified technical experts in the field of fibroid evaluation and treatment to provide assistance throughout the project. The TEP (see Appendix E ^*) was expected to contribute to AHRQ's broader goals of (1) creating and maintaining science partnerships as well as public-private partnerships and (2) meeting the needs of an array of potential customers and users of its products. Thus, the TEP was both an additional resource and a sounding board during the project. The TEP included seven members serving as technical or clinical experts, including an ACOG representative. To ensure robust, scientifically relevant work, we called on the TEP to provide reactions to work in progress and advice on substantive issues or possibly overlooked areas of research. TEP members participated in conference calls and discussions through e-mail to:

• Refine the analytic framework and key questions at the beginning of the project;

• Discuss the preliminary assessment of the literature, including inclusion/exclusion criteria; and

• Provide input on the information and categories included in evidence tables.

Because of their extensive knowledge of the literature, including numerous articles authored by TEP members themselves, and their active involvement in professional societies and as practitioners in the field, we also asked TEP members to participate in the external peer review of the draft report.

Inclusion and Exclusion Criteria

Our inclusion and exclusion criteria are documented in Table 1. As noted in Chapter 1, this is an update of a systematic review originally published by the Agency for Healthcare Research and Quality (AHRQ) in 2001. Largely for that reason, we limited our searches to articles published in or after February 2000 through August 2006. We also restricted our searches to developed countries so that we could have data generally comparable to the standard of care in the United States.

We excluded studies that (1) were published in languages other than English (given the available time and resources); (2) did not report information pertinent to the key clinical questions; (3) had fewer than 40 subjects for randomized controlled trials (RCTs) or nonrandomized cohorts with comparisons or fewer than 100 subjects for case series; and (4) were not original studies.

For most of our key questions, the relevant population consists of women with fibroids. For KQ 3a and 3b, however, the relevant population is a subset of women with treatment for fibroids. For KQ 3a, on outcomes of treatment for enhancing fertility, and KQ 3b, on outcomes of treatment to reduce adverse pregnancy outcomes, the relevant subpopulation is women with treatment for fibroids who are attempting to get pregnant. For these two subquestions, we applied our sample size criterion to the relevant subpopulation of interest. To illustrate this strategy: assume that a publication about a cohort of 80 women with and without prior myomectomy reported treatment outcomes and 30 pregnancies but that it did not report the number of women trying to conceive. We would exclude this publication from KQ 3a and 3b (the section on enhancing fertility) but include it in KQ 2 (the section on treatment outcomes).

We included studies that did not provide a denominator (number attempting conception) but had sufficient pregnancies to infer that the denominator exceeded our size cutoff. To illustrate, we included case series examining the effect of assisted reproductive technologies on pregnancies that did not report the number attempting conception, if number of pregnancies was 100 or higher.

Our definitions of study design appear in Appendix B ^*.

Literature Search and Retrieval Process

Databases. We used multifaceted search strategies to include current and valid research on the KQs, which we applied to three standard electronic databases—MEDLINE^®, Cochrane Collaboration resources, and Embase. We also hand-searched the reference lists of relevant articles to make sure that we did not miss any relevant studies. We consulted with our Technical Expert Panel (TEP) about any studies or trials that are currently under way or that may not be published yet.

Search Terms. Based on the inclusion/exclusion criteria above, we generated a list of Medical Subject Heading (MeSH) search terms (Table 2 and Appendix A ^*). Our TEP also reviewed these terms to ensure that we were not missing any critical areas, and this list represents our collective decisions as to the MeSH terms used for all searches.

Our searches on EMBASE and Cochrane used the search term “Leiomyoma OR Fibroid^*” and retrieved 3 and 52 citations, respectively, that had also been identified by our MEDLINE^® searches. Peer reviewers suggested an additional eight citations.

Figure 2 presents the yield and results from our searches, which we conducted from March through August 2006. Beginning with a yield of 1,991 articles, we retained 124 articles covering 107 studies that we determined were relevant to address our KQs and met our inclusion/exclusion criteria (Table 1). We reviewed titles and abstracts of the articles against the basic inclusion criteria above; we retained relevant articles, all published after our search cutoff date of February 2000, and used them as appropriate in the discussion in Chapter 4.

Article Selection Process. Once we had identified articles through the electronic database searches, review articles, and bibliographies, we examined abstracts of articles to determine whether studies met our criteria. Two reviewers separately evaluated the abstracts for inclusion or exclusion, using an Abstract Review Form (Appendix B ^*). If one abstractor concluded that the article should be included in the review, we retained it. The group included three physicians (Katherine Hartmann, MD, PhD, Scientific Director, Gretchen Stuart, MD, and Nicole Rankins, MD), one senior health services researcher (Meera Viswanathan, PhD, Study Director), and two junior health services researchers (Nikki McKoy, BS, and Patricia Thieda, MS).

Of this entire group of 1,991 articles, 201 required full review because of missing or uninformative abstracts. For the full article review, one reviewer read each article and decided whether it met our inclusion criteria, using a Full Text Inclusion/Exclusion Form (Appendix B ^*). Reasons for article exclusion are listed in Appendix D ^*.

Development of Evidence Tables and Data Abstraction Process

The staff members who conducted this systematic review jointly developed the evidence tables. We designed the tables to provide sufficient information to enable readers to understand the studies and to determine their quality; we gave particular emphasis to essential information related to our KQs. We based the format of our evidence tables on successful designs that we have used for prior systematic reviews; we incorporated some elements of the tables in the prior review on uterine fibroids.³⁰

We trained abstractors by having them abstract several articles into evidence tables and then reconvening as a group to discuss the utility of the table design. The abstractors repeated this process through several iterations until they decided that the tables included the appropriate categories for gathering the information contained in the articles.

All team members shared the task of initially entering information into the evidence tables. Another member of the team also reviewed the articles and edited all initial table entries for accuracy, completeness, and consistency. The two abstractors reconciled all disagreements concerning the information reported in the evidence tables. The full research team met regularly during the article abstraction period and discussed global issues related to the data abstraction process.

The final evidence tables are presented in their entirety in Appendix C ^*. Studies are presented in the evidence tables alphabetically by the last name of the first author. A list of abbreviations and acronyms used in the tables appears at the beginning of that appendix.

Quality Rating of Individual Studies

Rating the Quality of Individual Articles. We developed our approach to assessing the quality of individual articles based on the prior review on management of uterine fibroids conducted by the Duke EPC;³⁰ the rationale is that we wished to preserve as much consistency as appropriate between that review and this update. The original review assessed each study on a range of factors affecting internal and external validity and generally assigned “+” scores when studies met criteria, and “-” scores when studies did not, but it did not aggregate those factors into a single score. We made minor modifications to that earlier quality assessment list to allow us to construct an aggregate score; our final set of criteria is described below. Our final assessment of quality is based largely on the prior review, presented below in double-indented text, with our modifications, presented in regular text. We included citations from the prior review in the text below but recoded them to follow in numerical sequence in our own text and reference list.

Internal Validity. The criteria for assessing internal validity were as follows:

Randomized Allocation to Treatment. We modified the approach to this variable by combining randomization and method of randomization into a single criterion with a three-point scale. We employed the same rationale to evaluate this criterion, as follows (Matchar et al., 2001, pp.36–37):³⁰

• Rationale: By randomly assigning groups to the intervention of interest, other factors that may confound the results are equally distributed between groups (assuming a large enough sample size). This equal distribution minimizes the chances of over- or underestimation of treatment effect based on unequal distribution of confounding factors.

If randomized, we evaluated the study for randomization methods, using the rationale described in Matcher et al., 2001, p.37:³⁰

• Rationale: “Pseudo-randomization” methods may be susceptible to bias, as demonstrated by evidence of unequal distribution of subject characteristics³⁵ and larger effect sizes compared with studies using more rigorous methods.³⁶ In addition, methods of allocation concealment are also important in preventing bias (e.g., use of prepared sealed envelopes).

We combined these elements into a single operational definition, as described below:

• Operational definition: Criterion met if randomization methods were not susceptible to bias, such as computer-generated numbers in sealed envelopes (+). Criterion not met by studies that either used methods more prone to bias, such as alternate medical record numbers, or did not describe randomization methods or methods of allocation concealment (-). Criterion not applicable if treatment was not randomly allocated (NA).

We added a criterion to measure blinding.

Blinding.

• Rationale: Blinding, also known as masking, refers to the concealment of treatment allocation from the care provider, the assessor, and the patient. In certain trials, particularly surgical trials, masking the patient or the surgeon from the treatment allocation can be challenging or impossible. Similarly, masking the assessor assigned to record immediate postprocedural outcomes such as wound healing can also be difficult. Nevertheless, when possible, masking prevents expectations from influencing findings.

• Operational definition: Criterion met if at least assessors were blinded (+). Criterion not met if care provider, assessor, or patient were not blinded (-). Criterion not applicable if treatment was not randomly allocated or blinding was not possible (NA).

For adequate description of patients and controls, we relied on the scoring used by the prior review (Matcher et al., 2001, p.37).³⁰ Unless otherwise specified, we followed the prior review's practice of assigning a ‘+’ for studies that met the criterion or ‘-’ for studies that did not meet the criterion:

Adequate Description of Patients and Controls.

• Rationale: Patient characteristics that might affect outcomes (such as obesity, prior surgery, or medical comorbidities) are likely to differ between two interventions. If these differences are not characterized, then erroneous conclusions may be drawn. For example, comparison of outcomes from a series of laparoscopic appendectomies with those from concurrent open appendectomies found better outcomes with the laparoscopic procedure.³⁷ These differences were not seen when the same group performed a randomized trial, a finding attributable to differential patient selection criteria in the nonrandomized study.³⁸

• Operational definition: Criterion met if (a) inclusion and exclusion criteria for participation in the study were described or (b) for nonrandomized studies, description of the rationale for selecting a particular intervention was given. Criterion not met if (a) inclusion/exclusion criteria were not described or (b) description of the rationale for selection of the interventions was not given (e.g., a nonrandomized comparison of concurrent laparoscopic and abdominal myomectomies that did not describe why patients received one or the other procedure).

We modified our reporting of the item on description of patient and control to account separately for missing versus inadequate inclusion and exclusion criteria. We assigned a ‘-’ score (negative) to studies with no description of inclusion and exclusion, a ‘+’ score to studies unable to control or account for confounding factors, and a ‘++’ score to studies able to control and account for confounding factors in patient selection through clear inclusion and exclusion criteria.

We did not include the prior review's item on description of loss to followup as an additional internal validity criterion, because we accounted for loss to followup in internal validity and appropriateness of length of followup in evaluating external validity. We retained other aspects of the prior review's internal validity assessment as follows:^{30 (p38)}

Description of Loss to Followup.

• Rationale: Failing to account for patients lost to followup may lead to erroneous conclusions, especially if the loss to followup is related to either the underlying disease or the intervention (e.g., patients seeking care elsewhere because of continuing symptoms or unacceptable side effects of treatment).

• Operational definition: Criterion met if (a) loss to followup was explicitly reported, (b) number of subjects for whom data were presented was equal to number of subjects receiving intervention at start of study, or (c) for studies reporting only hospital-based outcomes, number of missing charts or records was reported. Criterion not met if loss to followup was not reported and number of subjects at beginning and end of study was not equal.

Description of Dropout Rates.

• Rationale: Dropout rates may reflect differences in clinically important variables, such as side effects or treatment response. Failure to account for dropouts may result in erroneous conclusions similar to those seen with failure to account for loss to followup.

• Operational definition: Criterion met if (a) patients dropping out of the study prior to completion were reported or (b) number of subjects at beginning and end of study were equal. Criterion not met if patients dropping out were not reported and numbers of subjects at beginning and end of study were not equal. Criterion not applicable for studies reporting only hospital-based outcomes.

We made minor modifications to the assessment above by distinguishing among three loss-to-followup rates: <10 percent (++), 10 percent to 20 percent (+), and >20 percent (-). We also distinguished among dropout rates of <5 percent (++), 5 percent to 10 percent (+), and >10 percent (-).

Recognition and Description of Statistical Issues.

• Rationale: Use of inappropriate tests may lead to misleading conclusions. For example, variables such as blood loss, length of stay, or costs are often not normally distributed; use of means instead of medians when data may be affected by outlying observations can be misleading. Many studies, especially case series, may lack sufficient power to detect clinically important differences in outcomes or patient characteristics.

• Operational definition: Criterion met if (a) appropriate statistical tests were used (e.g., nonparametric methods for variables with nonnormal distributions, or survival analysis techniques to account for loss to followup and dropouts) and (b) potential study limitations regarding design and analysis, especially sample size and power issues, were discussed. Criterion not met if (a) inappropriate statistical tests were used or (b) study limitations were not discussed.

We modified this aspect of quality by crediting studies that accounted for crossover and loss to followup in intention-to-treat analysis.

External Validity. We also modeled our assessment of external validity on the earlier review. The criteria for assessing external validity were as follows:^{30 (pp39–42)}

Description of Age of Study Population.

• Rationale: The outcomes of many interventions are affected by patient age. Age is especially important in studies of reproductive disorders in women, since childbearing potential and ovarian hormone production, both key components in decisionmaking regarding management of fibroids, are directly related to age.

• Operational definition: Criterion met if summary statistics of subject age were given. Criterion not met if summary statistics were not given.

Description of Racial/Ethnic Distribution of Population.

• Rationale: The epidemiology, and possibly the biology, of fibroids clearly varies between white and black women. Additionally, there is widespread racial variation in the United States in utilization and outcomes of a wide variety of interventions.³⁹

• Operational definition: Criterion met if (a) racial/ethnic distribution was described or (b) the geographical setting of the study strongly implied the racial/ethnic background of the entire population (e.g., studies of hysterectomy outcomes in Japan or Nigeria). Criterion not met if (a) racial/ethnic distribution was not described and (b) geographic setting was likely to include subjects of diverse racial/ethnic background.

Description of Pregnancy History of Population.

• Rationale: Pregnancy history may affect the natural history or biology of fibroids.⁹ For surgical interventions, pregnancy history may affect the technical difficulty of a procedure; for example, prior vaginal delivery may facilitate vaginal hysterectomy, while prior cesarean section, by increasing the risk of adhesions, may make either abdominal or vaginal hysterectomy more difficult.

• Operational definition: Criterion met if (a) summary statistics on gravidity or parity were given or (b) percentage of women with prior pregnancy was given. Criterion not met if (a) no summary statistics were given and (b) no distribution data on prior pregnancies were given.

Description of Prior Surgery.

• Rationale: A history of prior surgery for fibroids might reflect differences in the natural history or biology between patients. Additionally, previous abdominal surgery might increase the risk of complications by increasing the likelihood of intraperitoneal adhesions.

• Operational definition: Criterion met if (a) any description of history of intra-abdominal surgery was given or (b) proportion of women with prior surgery for fibroids was given. Criterion not met if no description of prior surgery was given.

We modified this criterion for studies of pharmaceutical management and complementary alternative medicine. For these studies, we assigned the category as ‘not applicable’ since surgical history was unlikely to influence the likelihood of complications.

Adequate Characterization of Fibroid and/or Uterine Size.

• Rationale: Individual fibroid size, or aggregate uterine size, may affect the nature or severity of symptoms, the response to various treatments, and the risk of complications of surgical treatments.

• Operational definition: Criterion met if data given on (a) uterine size in weeks of gestational age; (b) uterine volume, area, or length as estimated by radiologic techniques; (c) uterine weight in grams (for hysterectomy specimens); (d) fibroid diameter or volume as estimated by radiologic techniques; or (e) fibroid dimensions or weight based on pathological examinations. Criterion not met if none of the above were provided.

Adequate Characterization of Fibroid Number.

• Rationale: The number of fibroids may affect the nature or severity of symptoms, the response to various treatments, and the risk of complications of surgical treatments.

• Operational definition: Criterion met if summary statistics or distribution of number of fibroids was provided. Criterion not met if no data were provided on number of fibroids.

Adequate Characterization of Fibroid Location.

• Rationale: The location of fibroids may affect the nature or severity of symptoms, the response to various treatments, and the risk of complications of surgical treatments.

• Operational definition: Criterion met if (a) distribution of fibroids by location (subserosal, intramural, submucosal, or pedunculated) was given or (b) other anatomical descriptions were given (e.g., anterior, posterior, fundal, or within the broad ligament). Criterion not met if no anatomical description was given.

Adequate Characterization of Baseline Symptoms.

• Rationale: Because fibroids may present with a variety of symptoms, assessing the effectiveness of therapy requires an adequate description of the nature and severity of symptoms prior to institution of therapy.

• Operational definition: Criterion met if distribution of specific symptoms or symptom classes associated with fibroids were provided. Criterion not met if specific symptoms were not described (e.g., if the only description of inclusion criteria was “symptomatic fibroids”).

Adequate Description of Timing of Outcome Measurement.

• Rationale: Outcome measures may vary depending on when they are obtained. Description of when outcomes were measured facilitates comparison between studies.

• Operational definition: Criterion met if (a) time after initiation of therapy at which outcomes were measured was reported or (b) study was limited to hospital-based outcomes. Criterion not met if (a) time was not reported and (b) study was not strictly hospital-based.

We expanded the measure on adequacy of description of the timing of outcome measures to include appropriateness of the timing of outcome measures. Specifically, we assigned a ‘-’ score to studies that were missing descriptions of the length of followup, a ‘+’ score to studies that had insufficient followup to comment meaningfully on relevant outcomes, and a ‘++’ score to studies that had adequate length of followup.

Adequate Description of Methods Used for Outcome Measurement.

• Rationale: Comparison between studies requires common methods of measurement, which in turn requires adequate description of the methods used to assess comparability.

• Operational definition: Criterion met if (a) methods used to measure outcomes were adequately described or referenced (e.g., pain or bleeding scales), (b) definitions were given (e.g., description of outcomes classified as “complications”), or (c) outcomes were unambiguous (e.g., pregnancy, need for hysterectomy). Criterion not met if (a), (b), or (c) was not present.

Adequate Description of Validity and Reliability of Outcome Measurement.

• Rationale: Measurements of outcomes are only useful if changes in the outcome being measured are reflected in changes in the measurement (validity) and if these changes are reasonably consistent between the same observer measuring at different times or between different observers (reliability). For example, changes in a scale to assess menstrual blood flow should correlate with some other physiological measure of menstrual blood loss, and this correlation should be consistent when different women apply the same scale.

• Operational definition: Criterion met if (a) a description of the methods used to assess validity and reliability of at least one outcome measure was provided, (b) a reference to another article documenting validity and reliability was provided, or (c) only unambiguous outcomes such as pregnancy were included. Criterion not met if (a), (b), or (c) was not present.

Adequate Description of Clinical Care Provided to Subjects.

• Rationale: The ability to replicate study results is dependent on adequate description of methods. Additionally, readers should be aware of aspects of clinical care that might influence outcomes.

• Operational definition: Criterion met if (a) a detailed description of the therapy (dose, dosing schedule, and route of administration for medications and/or techniques for invasive therapies) was provided; (b) a reference to another publication describing the procedure was provided; or (c) statistical adjustment was made for likely sources of variation in clinical care (e.g., site where care was given, type of specialist providing care, individual provider). Criterion not met if (a), (b), or (c) was not provided.

Use of Previously Validated and Standardized Measures.

• Rationale: Use of measures used by other researchers enhances the ability to compare results across studies. Use of measures used with other medical conditions enhances the ability to compare the impact of uterine fibroids to that of other common conditions, which may be important when setting research and resource allocation priorities.

• Operational definition: Criterion met if at least one measure previously used by another group was used. Criterion not met if all measures were internally developed.

We then combined these scores into an aggregate measure of quality for internal and external validity (Table 3). To receive a rating of good overall, the study had receive good scores for both internal and external validity (that is, no negative scores and the lowest level of loss to followup or dropout). To receive a rating of fair overall, the study could receive a fair rating for both internal and external validity, or a mixed rating (good and fair, or good and poor) for internal and external validity. We assigned studies with one negative score for internal validity or intermediate loss to followup (10 percent to 20 percent), or intermediate dropout rate (5 percent to 10 percent) a rating of fair for internal validity. We assigned studies with one to three negative scores for external validity a rating of fair for external validity.

To receive a rating of poor overall, the study could receive a poor rating for both internal and external validity, or a mixed rating of fair and poor for internal and external validity. We considered poor randomization, high loss to followup (> 20 percent), or high dropout rates (> 10 percent) to be in the nature of fatal flaws, and we assigned these studies poor ratings for internal validity. Studies without these flaws that nevertheless received two or more negative scores for internal validity were also rated poor for internal validity. Studies with four or more negative scores for external validity were assigned a poor rating for external validity.

Expectant Management: Overview and Nomenclature

We did not identify any studies that specifically focused on documenting the natural history of uterine fibroids, course of fibroid symptoms, or clinical care received for fibroids over time in a cohort of women with known baseline fibroid status. No studies focused on either outcomes, such as anemia, bleeding patterns, pain, and health-related quality of life, or modifiers of outcomes of expectant management per se as the primary topic of their research. However, RCTs that include a no-treatment comparison group may provide a glimpse of anticipated outcomes in the absence of intervention. With caveats about the limitations of such data, we summarize in this section information about the outcomes of women in trial groups that received no treatment, placebo treatment, or minimal intervention such as multivitamin use (Appendix C ^*, Evidence Table 2).

Thirteen studies included groups that received no treatment or only minimal intervention.⁴²–⁵⁷ Five studies did not include symptoms or fibroid size; instead, they used the comparison group to assess characteristics of specimens of surgical tissue as they related to the anticipated effects of the treatment drug on the fibroids^{42, 43, 45} or to examine other aspects of treatment response such as changes in bone marrow density⁴⁹or hemoglobin⁴⁷in response to medical treatment. Information on these trials can be found in Appendix C ^*, Evidence Table 2.

Eight studies with nine publications provided information about uterine size, fibroid size, or participants' symptoms for the no-treatment comparison groups at baseline and at the end of followup.^{44, 46, 48, 50, 51, 55, 56, 58} All but one⁴⁸ were conducted in Italy by two inter-related groups of investigators whose work on medical management and preoperative management of fibroids was featured in detail in the section on outcomes of pharmaceutical management. In the seven Italian study groups, women were followed for a range of 2 months to 12 months without treatment, with the median duration being 6 months across the studies. The majority of studies used no treatment or placebo; some used a calcium, iron, or multivitamin tablet as the placebo. We do not discuss hemoglobin changes for the studies in which women received iron or multivitamins.

Expectant Management: Results

Shorter treatment spans, of 2 and 3 months, were associated with preoperative studies done most often in premenopausal participants. For those reasons they may be the least informative—all women had symptoms enough to warrant surgery and the followup is extremely brief. In no case was a significant change in uterine size documented. Most studies documented almost identical fibroid volume;^{46, 55, 59} one study, which did not note masking of the individuals conducting the ultrasounds, reported an increase in fibroid volume of 11 percent over 3 months. The longest followup for symptoms was in a group of women using a multivitamin placebo for 6 months. Compared to baseline values, their severity of bleeding, length of bleeding with menses, and hemoglobin levels were unchanged; 72 percent had no change in fibroid size; 24 percent had increases in fibroid size; and 3 percent had a decrease;⁵¹ the increase was not statistically significant.⁴⁴ One other study reported a nonsignificant increase in menorrhagia, pelvic pain, and pressure among women receiving iron tablets only for 2 months.⁵⁹

Longer studies were generally done among postmenopausal women to determine whether a specific medication influenced fibroid size or symptoms. Overall, these untreated comparison groups were the most likely to have less severe presentations and perhaps be more representative. However, they can shed light only on postmenopausal management. In these groups, observed for 12 months, the investigators saw no trend for fibroid growth; they did not, however, document any significant decrease in fibroid or uterine size. Fibroids were consistently reported to be unchanged;^{50, 56, 58} one study noted that 2 of 35 women had a “mild reduction in uterine and fibroid size,”^{56 (p40)} suggesting that fibroid involution (regression in size) may not be marked during menopause.

The last study group was a medical record control group matched to participants in a study of complementary and alternative medicine treatments. The study was conducted in a U.S. academic center. Symptoms at clinical encounters and available radiologic studies were provided for 6 months of followup. Within a group of 37 women (who may have received other clinical care), none had documented worsening of symptoms, three had reduced size or reduced growth of fibroids documented, 20 had no change in fibroid size, and four had documented growth of more than 1 centimeter (cm) per month in diameter of a fibroid.⁴⁸

The size of the comparison groups from these trials is small, from 22 to 60 women, and the time frames are very brief. They offer an initial impression that fibroids may not have a continuous, slow-growth pattern before menopause and that, after menopause, decreases in size may not be as profound as clinical wisdom suggests. However, the total picture provided is insufficient to project what the course of watchful waiting might be for an individual woman with fibroids. Because these studies were not designed for this purpose, the overall quality of the research is too poor to inform the choice of expectant management over other intervention options.

Pharmaceutical Management: Overview and Nomenclature

The etiology of uterine fibroids is not well understood. Pharmaceutical management of fibroids is most commonly done as an adjunctive treatment before surgery. Few medications serve as permanent alternatives to surgery. KQ 2b asks about outcomes from GnRH agonist therapy, menopausal hormone therapy, antiprogestins, oral contraceptives, progesterone-containing IUDs, and NSAIDs among possible medical treatments for uterine fibroids. We did not find any new studies since February 2000 on oral contraceptives, progesterone-containing IUDs, or NSAIDS. The majority of our included studies examined the effect of GnRH agonists on uterine fibroids (Appendix C ^*, Evidence Table 3). Some studies also reported on progestin, estrogen receptor antagonists and modulators, and antiprogestin. We also report on studies that examined the effects of tibolone as adjuvant therapy to GnRH on uterine fibroid growth. For convenience and consistency, we briefly list and define medications evaluated in the studies reviewed below.

GnRH Agonists and Other Adjuvant Therapies. GnRH agonists are often used as preoperative adjunctive therapy to surgery. They cause down-regulation of estrogen receptors, which decreases fibroid growth. GnRH agonist therapy also helps to optimize hematocrit levels that may have declined secondary to menorrhagia from fibroids. Low hematocrit levels can pose a risk for surgical complications. Studies in this review examined leuprolide acetate, triptorelin, and goserelin. One study also reviewed the effect of ipriflavone as adjuvant therapy to prevent osteoporotic side effects of GnRH agonists.⁶⁰

Leuprolide or Leuprolide Acetate. Leuprolide is a potent inhibitor of gonadotropin secretion. Trade names for use with uterine fibroids include Eligard^®, Lupron Depot-Ped^®, Lupron Depot^®, Lupron^®, and Viadur^®. Leuprolide is often used as an alternative to surgery for fibroids or for preoperative adjunctive therapy. Its potent effect on reducing estrogen activity in the uterus can decrease fibroid size and symptoms including menorrhagia. The majority of studies (13, in 15 articles) evaluated a GnRH agonist treatment of uterine fibroids; of these, 10 evaluated leuprolide as the primary intervention.⁴²–^{45, 49, 51}–^{55, 59}–⁶²

Triptorelin. Triptorelin (trade names Decapeptyl^® and Gonapeptyl^®) is generally used in the United States to treat men for advanced prostate carcinoma. Its activity on fibroids and use for fibroid management is similar to that for leuprolide. Two studies from Italy examined the effect of triptorelin on fibroids.^{63, 64}

Goserelin. Goserelin (Zoladex^®) is also a potent inhibitor of gonadotropin secretion. In one study, goserelin was used in one treatment arm of a five-arm study to evaluate fulvestrant (a drug that blocks estrogen in the treatment of breast cancer [see below]).⁴⁶

Ipriflavone. Ipriflavone is a synthetic isoflavone in the herb category of natural products with a structure similar to that for estrogen. It has gained acceptance as an alternative medication for treatment of osteoporosis. One study uses ipriflavone as adjuvant therapy to prevent osteoporotic side effects of GnRH agonists.⁶⁰

Tibolone. Tibolone is an estrogen and progestin combination therapy used for several purposes: to prevent postmenopausal osteoporosis, to treat symptoms such as hot flashes and associated sweating resulting from menopause (surgical or natural), and to improve bone mineral density (BMD) in patients with established postmenopausal osteoporosis. It is used in these studies as adjunctive therapy to GnRH agonists to prevent negative side effects of GnRH agonists or to study whether the addition of tibolone as add-back therapy alters the effect of GnRH on fibroids. Currently this drug is not available in the United States. International brand names include Climatix^®, Livial^®, Tibial^®, and Tibofem^®.

Progestin. Lynestrenol, a progestin, known by international brand names including Endometril^®, Exluton^®, Linestrenol^®, and Orgametril^®, is used to treat endometriosis, prevent pregnancy, and treat symptomatic fibroids in countries other than the United States, where it is not currently available. One study compared lynestrenol to leuprolide in an assessment of preoperative treatment of fibroids.⁶²

Antiprogestin. Mifepristone (Mifeprex ^®; also known as RU-486) is a synthetic steroid that competitively binds to the intracellular progesterone receptor, thereby blocking the effects of progesterone and causing significant shrinkage in fibroids. One study (two articles) evaluated mifepristone as an alternative medical treatment for fibroids.^{65, 66}

Estrogen Receptor Antagonists and Modulators. Raloxifene hydrochloride (Evista ^® ) is a selective estrogen receptor modulator (SERM) that has been reported to cause a significant reduction in fibroid size. One study (three articles) evaluated raloxifene.^{50, 56, 67}

Fulvestrant (Faslodex ^® ) is an estrogen receptor antagonist used to prevent fibroid growth; it is also used for treatment of postmenopausal breast cancer. One study evaluated fulvestrant.⁴⁶

Uterine Artery Embolization: Overview and Nomenclature

This section presents the results of our literature searches and findings about outcomes of fibroids treated with uterine artery embolization (UAE), also known as uterine fibroid embolization. UAE blocks the blood vessels supplying the fibroids by injections of small particles into the arteries feeding the uterus. Because the procedure is minimally invasive, it is an option available to women who wish to avoid surgery, are poor surgical candidates, or wish to retain their uterus. The literature discussed in this section includes studies focusing on UAE only, with the exception of UAE compared with laparoscopic occlusion of the uterine arteries. Studies comparing UAE with myomectomy or hysterectomy are discussed in those respective sections below. For convenience and consistency, we have used uniform terminology and abbreviations to describe the different techniques used to treat uterine fibroids.

Laparoscopic Occlusion of the Uterine Arteries involves a laparoscopic procedure in which the clinician places clips over the uterine arteries at the level of the internal iliac artery. The collateral arteries between the uterus and the ovaries are also coagulated with bipolar forceps. UAE is a technique in which the clinician introduces tiny particles or microspheres into the arteries feeding the uterus. The procedure is based on the theory that occluding blood flow to the muscular portion of the uterus will produce infarction of the fibroids and control symptoms.

Given the relatively new nature of this procedure, very little information was available at the time of the prior review on uterine fibroids; the authors concluded that they could not make estimations of recurrence, persistence, or need for subsequent therapy.³⁰

Studies and Designs. Thirty-one articles report on outcomes of UAE, comparisons of UAE with other procedures, modifiers of UAE outcomes, and related issues (Appendix C ^*, Evidence Table 4).⁷⁰–¹⁰⁰ The 31 publications represent 24 studies and 22 distinct study populations.

The UAE literature consists primarily of studies done at academic centers; at least two-thirds of the studies took place in this setting. One study was done in a community setting, and three combined data from both academic and community hospitals. The majority (13) of the studies was done in the United States; the remaining countries accounted for fewer studies: Canada, 3; United Kingdom, Netherlands, and Japan, 2 each; and Norway, 1. Finally, one study compiled data from studies done in both the United States and abroad.

Study Populations and Outcomes Measured. Twelve of the publications listed here represent five studies and three distinct populations. In the summary tables below, we elected to group articles primarily by study groups and secondarily in alphabetical order by author, owing to the multiplicity of papers from single studies, overlapping samples, and distinct differences in quality of studies across these study groups. We report on multiple studies from a common population source in Table 7 and on single studies from varied populations in Table 8.

One set of five publications, all by Pron and colleagues, on the Canadian Ontario Uterine Fibroid Embolization Trial focused on individual outcomes from the same sample in separate publications; we count all five as a single study, of fair quality.⁸³–⁸⁷

A second population served as the precursor to the FIBROID registry (specifically, the Uterine Artery Embolization Fibroid Registry for Outcomes Data [FIBROID], a U.S. multicenter prospective voluntary registry of patients undergoing uterine embolization for fibroids [www.fibroidregistry.org]). Spies and colleagues published short-term outcomes,⁹² a subanalysis,⁹⁶ and long-term outcomes⁹³ from a case series of 200 women. They subsequently closed enrollment of patients in that protocol, began a new protocol to coincide with participation with the FIBROID registry, and published one study presenting results from both populations.⁹⁷ The studies published from this group are of fair to good quality.

The third, and largest, study population is from the FIBROID registry. Two publications reported on different samples based on eligibility for the outcome considered in the publication (N = 3,041^{82, 100} and N = 2,112⁹⁵), although the articles do not specify whether these two samples overlap completely. We consider the two FIBROID registry papers as two separate studies but, for purposes of tabulating information from the same or similar sources, kept them in Table 7. We rated these studies to be of fair quality.

The other 19 publications that address UAE represent 19 distinct study populations. Of these, the majority (11 studies) are of poor quality.⁷⁰–^{72, 77}–^{80, 89}–^{91, 98, 99}

Outcomes and Modifiers. Among the 24 distinct UAE studies, 17 reported on outcomes or modifiers of UAE. Of these, three were retrospective case series, focusing on outcomes associated with failure or success of UAE.^{77, 78, 88} Twelve studies are prospective case series. Of these, nine reported on short- and/or long-term outcomes;^{79, 80, 82}–^{87, 92, 93, 95}–¹⁰⁰ two reported on imaging modalities associated with UAE;^{71, 81} and one reported on use of a percutaneous closure device during UAE.⁷²

Two cohort studies addressed pain in relation to the UAE procedure. One investigated a prospective sample to compare pain medications,⁸⁹ and the other examined data for a retrospective sample comparing the use of embospheres and polyvinyl alcohol particles.⁹¹

Comparative Studies. Seven studies compared more than one type of procedure. Two were retrospective cohorts, comparing UAE and myomectomy.^{70, 90} Four prospective cohorts were identified; one compared UAE with myomectomy,⁷³ two compared UAE with hysterectomy,^{75, 94} and one compared UAE and laparoscopic occlusion of the uterine arteries.⁷⁴ The only RCT compared UAE with hysterectomy.⁷⁶

UAE Outcomes. This literature comprises nine prospective case series studies (in 15 articles, one of good quality,^{80, 92, 93} four of fair quality,⁸²–^{87, 95, 97, 100} and four of poor quality^{79, 80, 98, 99}) and three retrospective case series (two of poor quality^{77, 78} and one of fair quality⁸⁸) that described either short- or long-term outcomes (or both) (see Table 7 and Table 8).

Satisfaction. All studies reported high levels of satisfaction on the part of the women assessed, measured at various points in time and along varied scales. They reported a range from 87 percent to 97 percent satisfaction with outcomes.

Symptom Improvement. Studies reported high levels of symptom improvement, however longer-term studies appeared to indicate some decline in improvement in symptoms over time. One study found that, at 3 months, the great majority (93 percent) of women had improved symptoms; by 5 years, the proportion reporting improvement in symptoms had declined to 73 percent (of 143 women still in the sample).^{92, 93} Studies also reported some variability in which symptoms were improved: one study found that women reported statistically significant improvement in menorrhagia (83 percent), dysmenorrhea (77 percent), bulk symptoms (84 percent), and urinary symptoms (86 percent) at 3 months.⁸⁶ Improvement in menorrhagia was not related to preprocedure uterine volume or amount of volume reduction. Overall life impact scores (representing the interference of symptoms with everyday or usual activities) were markedly improved after UAE. Before UAE, 72 percent reported impact scores of 7 to 10 (high interference with daily activities); after UAE, this figure dropped to 11 percent.

Pain. In one study, 70 percent of patients reported no pain and 4 percent reported ineffective pain management during the procedure; with respect to postoperative pain, 92 percent reported at least some pain (tolerable pain through unbearable pain) and 10 percent reported ineffective pain management after the procedure.⁸³–⁸⁷

Uterine Volume Reduction. Studies varied in their period of reporting for uterine volume reduction. Studies reported the following percentages of mean uterine volume reduction: at 3 months, 27 percent;⁸³–^{87, 92, 93, 96} at 6 months, 52 percent⁸⁰ and 58 percent;⁹⁹ and at 12 months, 38 percent^{92, 93, 96} and 47 percent.⁷⁹

Mean Recovery Time. Three studies, set in Canada, the United Kingdom, and the United States, were consistent in reporting a 13- to 14-day period for recovery.⁸³–^{87, 98, 100} One U.S. study reported an 8-day period for recovery.^{92, 93, 96}

Complications. Variations in the methods and timing of reporting make the summary evaluation of complication rates across all studies extremely challenging. The largest of these studies, the FIBROID registry, reported a major in-hospital complication rate (e.g., hospitalization, major therapy, unplanned increase in care, or permanent adverse sequelae) of 0.6 percent of the sample; the postdischarge major complication rate was 4.1 percent.¹⁰⁰ The rates of minor complications (nominal or no therapy, no consequences) was 2.1 percent during the admission and 22 percent within 30 days of discharge.

Rate of Subsequent Interventions. As with complication rates, studies vary in the method and timing of reporting rates of subsequent interventions. The FIBROID registry reported that 141 women (9.5 percent of their sample) had experienced at least one gynecological procedure by 12 months; procedures included 49 hysterectomies, 25 myomectomies, and 21 repeat UAEs. The study with the longest period of measurement reported a 25 percent failure (no improvement in symptoms—menstrual bleeding, pain, pressure—or major intervention) by 60 months.^{92, 93, 96}

Modifiers of UAE Outcomes. Demographic Variables and Uterine Characteristics. Nine studies examined modifiers of UAE outcomes,⁷⁷–^{80, 83}–^{88, 95, 96, 100} including two from the FIBROID registry trial.^{95, 100} These studies examined a variety of demographic characteristics including age, race, parity, menopausal status; uterine characteristics, including size and location of the dominant fibroid; health characteristics such as prior surgery and smoking; and UAE characteristics such as UAE particle type and load. Outcomes examined included volume reduction, treatment failure, treatment success, satisfaction, and complications.

Studies that examined age found no association between age and UAE failure⁸⁰ or satisfaction with outcomes.⁹⁶ One of two studies^{96, 100} examining race found it to be a significant predictor of outcomes; the study found that African-American women have a higher risk of adverse events following UAE.¹⁰⁰ Parity and menopausal status were not significant predictors of UAE failure.⁸⁰

Regarding uterine characteristics, four studies that examined baseline uterine characteristics found no relationship between size or volume and UAE failure,^{77, 80} satisfaction with outcomes,⁹⁶ or development of intrauterine infection.⁸⁸ Two of four studies examining fibroid size found no effect on outcomes (failure⁷⁷ or complications⁷⁸). Other studies on volume reduction reported conflicting results: one study reported that larger fibroid size predicted greater decrease in volume,⁸³–⁸⁷ whereas two others reported that size of the dominant fibroid at baseline predicted less volume reduction at both 3^{95, 96} and 12⁹⁶ months after therapy. Studies also found that adjusted for fibroid volume, submucosal dominant fibroids predicted greater volume reduction⁹⁶ and improvement in symptoms⁹⁵ than subserosal fibroids. The location of the fibroid did not predict intrauterine infections.⁸⁸

Regarding health characteristics, one study found that the occurrence of earlier fibroid or pelvic surgery was related to failure^{77, 80} and the risk of adverse events.¹⁰⁰

UAE characteristics such as size of particles used, particle load, and post-UAE complication events did not predict treatment failure at 6 months⁸⁰ or intrauterine infection⁸⁸ in two studies; in a third study, the use of EmboGold^® particles versus Embosphere^® particles resulted in significantly higher risk of skin rash and slower return to usual activities with EmboGold^®, but no difference in volume reduction, fibroid expulsion, or satisfaction.⁷⁹

Modifiers of Pain Associated With UAE. Two studies addressed pain in relation to the UAE procedure.^{89, 91} A prospective case series evaluated the effectiveness of superior hypogastric nerve block (SHNB) in addition to conventional conscious sedation for pain control in 139 patients.⁸⁹ The investigators contacted patients on the third and fifth day after their procedures to elicit pain scores (numeric rating scale from 0 to 10). The first 100 patients had received the standard pre- and postprocedural analgesia. However, after review with the institutional pain management clinic, clinicians had identified a potential for enhanced postprocedural pain and antiemetic treatment, and the last 39 patients received the different regimen, involving SHNB (see Evidence Table 4, Appendix C ^*), which added 8 minutes to 10 minutes to the procedure. All patients could be discharged home by 6 hours after the procedure and had mild pain or no pain at the time of discharge. Readmission rates did not differ significantly between the two regimens (6 percent for conventional vs. 2.6 percent for enhanced intervention). The mean peak pain score did differ significantly between groups; women receiving the enhanced SHNB protocol reported lower pain scores (5.7 ± 2.2 vs. 2.7 ± 2.5; P < 0.01).

Based on animal models, Ryu and colleagues had hypothesized that Embosphere^® would be associated with less pain after UAE than polyvinyl alcohol particles. They compared 29 patients in an Embosphere group with 26 patients in a polyvinyl alcohol particles group in a retrospective analysis.⁹¹ They reported no difference between the groups either in the dosages administered through a patient-controlled analgesia pump that delivered morphine sulfate or in the mean subjective pain scores.

Use of Imaging Techniques in UAE. Two studies evaluated the role of imaging modalities in UAE, such as magnetic resonance imaging (MRI).^{71, 81} One study prospectively followed 111 patients to assess them for the presence of persistent contrast enhancement of fibroids on a routine 6-month follow-up MRI; the investigators specifically tested whether continued gadolinium enhancement (contrast material-enhanced MRI) of the fibroid after failed primary UAE would predict a subsequently successful repeated UAE.⁷¹ Clinical failure was reported in 11 patients (10 percent). Of these 11 patients, eight (73 percent) showed persistent gadolinium enhancement of their dominant treated fibroids on MRI. All eight women were offered a repeat UAE; six accepted. All six had complete resolution of clinical symptoms at 12 months' followup. Additionally, in all six patients, no contrast material enhancement was identified on follow-up MRI at 6 months. The three patients who did not show persistent enhancement demonstrated complete tumor necrosis and were not offered a repeat procedure. Of note, of the 100 clinically successful cases, four had some persistent enhancement of their dominant fibroid with complete necrosis of the remainder.

The second study sought to determine whether Doppler flow measurements are useful in predicting variables associated with UAE, including shrinkage of the uterus and fibroids, adenomyosis, and procedure failure.⁸¹ The investigators evaluated 188 women with Doppler sonography before and 6 months after the procedure. The specific factor analyzed in this study was peak systolic velocity (PSV), an indicator of blood flow. Pre-embolization PSV values were positively correlated with total uterine volume and the diameter of the largest fibroid; that is, stronger blood flow was positively correlated with larger uterine and fibroid volume. In addition, the authors noted a positive correlation between the particle load required to block the vessel and the pre-embolization PSV values (P = 0.009). Higher pre-embolization PSV was associated with greater reduction of the largest uterine fibroid (P = 0.0174) and reduction in uterine volume (P = 0.0440); however, pre-embolization PSV was a significant predictor of failure (P = 0.02). Finally, the authors did not report any association between baseline uterine size or factors related to the procedure and failure of embolization.

Effects of Operator Experience on UAE. One Canadian study examined the effects of the experience of interventional radiologists on procedure and fluoroscopy time through a multicenter prospective design.⁸³ UAE was successful bilaterally (in both uterine arteries) in 97 percent of patients; 94 percent of the procedures were completed on the first attempt. The overall procedural complication rate was 5.3 percent (30 of 570 procedures). Of these 30 procedures with complications, the most common complications were related to angiography; three women required extra care or an extended hospital stay. The article does not provide information on whether complications were influenced by operator experience. The study also found that procedure time and fluoroscopy time differed significantly for early experience (the first 20 consecutive procedures) versus later experience (the next 20 consecutive procedures) (P < 0.001).

Evaluation of Devices Used in UAE. Previous studies have suggested that the use of suture-mediated closure devices (SMCDs) may be associated with a higher rate of complications in patients who are undergoing UAE than in patients who have peripheral vascular disease and/or are undergoing anticoagulation.¹⁰¹ One study assessed the safety and efficacy of SMCDs in UAE through a prospective case series involving attempts to use SMCDs in 328 of 342 consecutive patients.⁷² Device failure occurred in eight patients (2.4 percent; 99% CI, 0.2–4.5 percent). No long-term major complications occurred; however, the rate of minor complications, including thigh pain related to the puncture site and minor hematomas, was 22 percent (72 of 328 women; 99% CI, 16–28 percent).

Comparative Studies. Three studies compared UAE with myomectomy.^{70, 73, 90} Three studies compared UAE with hysterectomy.^{75, 76, 94} The results of these studies are reported in detail in the myomectomy and hysterectomy sections, respectively, later in this chapter.

A single study compared two different methods of UAE: 24 women undergoing UAE and 22 women undergoing laparoscopic occlusion of the uterine arteries; the project was done in a nonrandomized prospective cohort of women with symptomatic fibroids in Norway.⁷⁴ The investigators assigned women to laparoscopic occlusion when the size of the uterus did not exceed the umbilical level and to embolization regardless of fibroid size. They reported no differences between the groups in bulk symptoms or initial pictorial blood loss assessment score. Both groups had a statistically significant decrease in the volume of the dominant fibroid and the uterus from baseline following the procedure, but the groups did not differ significantly from each other. Postoperative pain medication consumption was significantly greater in the UAE group. By the final followup at 6 months, 15 UAE and 14 laparoscopy patients reported a satisfactory reduction in their bleeding. Four hysteroscopies, one dilatation and curettage, and two hysterectomies were performed during the follow-up period.

Endometrial Ablation (With or Without Myomectomy)

The prior evidence review did not identify publications about use of endometrial ablation specifically for the management of uterine fibroids.³⁰ A single study appearing since 2001 reported results on endometrial ablation in comparison with myomectomy.¹⁰² The results are reported in the section on myomectomy (Appendix C ^*, Evidence Table 5).

In Situ Destructive Techniques (MRI-Guided Focused Ultrasound): Overview and Nomenclature

One part of KQ 2 assesses outcomes of interventions to treat fibroids that use techniques to destroy them in situ. Methods previously explored in the research literature include cryoablation (which is freezing the fibroid tissue) and laser ablation (which burns the tissue to destroy the fibroid) via laparoscopy. Neither of these methods is currently available in clinical practice outside research settings. We did not identify any publications on these methods in the timeframe for this review. MRI-guided focused ultrasound, a new technique, is the only in situ destructive technique currently being used outside academic and specialty clinics. This method did not have eligible publications to include in the prior evidence review on management of fibroids. Our search identified two publications of fair quality from a single cohort.^{103, 104}

In MRI-guided focused ultrasound, the clinician uses the MRI to guide the ultrasound energy (i.e., sound waves from the ultrasound) directly to the fibroid. The highly focused ultrasound beam (very different from ultrasound used for imaging studies) causes the temperature in the target tissue to rise. The clinician can monitor the thermal destruction of the fibroid during the procedure with the MRI and avoid damage to nearby tissue or structures. We describe both the conduct of the procedure and the findings of these studies in some detail because the technique is so new.

The treatment is conducted in an MRI suite using an imaging system that integrates real-time MRI and thermometry with an ultrasound unit specially designed to focus the ultrasound waves to create heat; a process like this, which is intended to disrupt biologic materials by use of sound wave energy, is also termed sonication. The woman receives light sedation and is positioned face down on a gantry over a contact pad required for the ultrasound. The gantry, which is a treatment table on a track, is moved to help position her correctly within the MRI machine. The MRI is used to image the fibroids, to finalize positioning of the patient, to help avoid exposing other organs such as the bladder and bowel to the ultrasound, and to define tightly the area of each fibroid for treatment. The clinician uses a “test dose” of ultrasound so that the MRI thermal measurements can confirm that the correct area will receive treatment and then begins the focused ultrasound heating of the target fibroid tissue. Thermal destruction is monitored in real time using MRI estimates of the tissue temperatures achieved. Each fibroid is treated separately, and total treatment times are generally longer than an hour for most women, with a 3-hour total treatment time limit.¹⁰³–¹⁰⁶ The U.S. Food and Drug Administration approved the treatment system in 2004.¹⁰⁷

We identified two publications that present data from the same study population (Appendix C ^*, Evidence Table 6).^{103, 104} This work was undertaken to assess the safety and efficacy of this technique, within a collaborative network of sites including three U.S. centers, two European centers, and one Israeli center, all at academic institutions.

The research collaborative focused on documenting adverse events and identifying the proportion of women who had meaningful improvement in their symptoms as defined by use of the standardized and validated, disease-specific Uterine Fibroid Symptoms Quality-of-Life (UFS-QOL) scale³² in addition to the Medical Outcomes Trust Short Form-36 (SF-36).^{103, 104} The UFS-QOL questionnaire has eight symptom questions and 29 health-related quality-of-life questions (with six subscales), scored on a 100-point scale with higher numbers indicating more severe impairment.

The study population comprised 109 women who were premenopausal and who reported that they had completed childbearing. Eleven percent of the women were African American, African, or Afro-Caribbean. All participants scored above the mean for women with fibroids on the UFS-QOL, reflecting good representation of highly symptomatic women. Each woman was clinically considered a candidate for hysterectomy or myomectomy based on disease severity.

Fifty-five percent had one fibroid treated; the remainder had two or more treated. Overall, 22 percent of fibroids were submucosal, 57 percent intramural, and 21 percent subserosal. The average duration of time within the MRI scanner was 202 minutes (range, 90 to 370 minutes); a portion of this was ascribed to the time required to position the patient correctly. At some point during the procedure, 16 percent of women reported severe pain; 1 percent and 7 percent reported severe or moderate pain, respectively, immediately following the procedure. The majority of women reported mild (33 percent) or moderate (33 percent) pain during the treatment portion of the procedure and no (75 percent) or mild (18 percent) pain immediately afterwards. The single serious complication deemed related to the procedure was a sciatic nerve palsy that fully resolved by 12 months. The injury resulted in a change to pretreatment planning during the balance of the study. One woman had an abdominal skin burn that caused ulceration prior to healing and was traced to incomplete shaving of the abdomen. (Complete shaving in the path of the ultrasound beam is critical because it prevents air pockets that can result in local skin heating.) Six percent of women had febrile morbidity and all six received antibiotics as a precaution. Overall, participants returned to work an average of 1 day after the procedure.

At 6 months after treatment, 77 participants (70.6 percent) reported a 10-point or greater improvement on the UFS-QOL questionnaire. The mean decrease in the score of the women treated was 23.8 points; symptom relief was similar for “bulk symptoms” related to the size and position of fibroids, and for bleeding symptoms. This similarity in levels of improvement for both pressure and bleeding symptoms is notable in the context of a 13.5 percent decrease in the average total volume of fibroids treated; specifically, it suggests possible placebo effects at work because actual volume reduction was quite modest. By 12 months, 51 percent (42 of 82 women who could be evaluated) had sustained improvement of 10 points or more on the UFS-QOL. Scores on the SF-36, which was also administered, indicated improvements at 1, 3, and 6 months compared with baseline scores.

Failure, defined as worsening of symptoms by 6 months, was 11 percent (12 of 109 women); 10 women were classified as unchanged. By 1 year, 23 of 82 evaluable women (28 percent) had sought additional treatment including myomectomy, hysterectomy, or UAE.

The authors noted that the safety protocol requirements of this initial research were highly conservative and required that only a small proportion of the fibroid volume be treated. Clinical practice now successfully targets substantially larger proportions of the total fibroid volume. Future research may yield greater improvements in outcome, but these data do demonstrate the safety and preliminary efficacy of the procedure for improving symptoms.^{103, 104} The need for comparative trials and longer-term followup for this and all fibroid treatment modalities is highlighted in the discussion in Chapter 4.

Myomectomy: Overview and Nomenclature

This section presents the results of our literature search and findings about outcomes of surgical removal of fibroids, termed myomectomy. Myomectomy removes the fibroid(s) that can be surgically removed, repairs the defect in the uterine wall, and does not remove the uterus. For this reason, myomectomy is the surgical option available to women who wish to have future pregnancies or who wish to retain their uterus.

As we briefly describe below, the content of the literature spans the range of surgical approaches currently available in routine clinical practice. We found no publication that described outcomes of robotic surgery, which is becoming available at a limited number of highly specialized sites. Detailed information on all studies relating to myomectomy can be found in Evidence Table 7 in Appendix C ^*.

For convenience and consistency we have used uniform terminology to describe and discuss the different surgical techniques used to remove or destroy uterine fibroids. The groupings that follow—abdominal, laparoscopic, and hysteroscopic—are approximately in the order of “invasiveness” as reflected by the size of the surgical incision to be healed, the degree of disruption of nearby tissue, and, therefore, the amount of healing required after the procedure.

Abdominal Myomectomy and its Variants. Abdominal myomectomy per se is the removal of fibroids through an incision in the skin of the abdomen; this is also called a laparotomy incision. This includes midline incisions made along the line between the umbilicus and the pubic symphysis or “pelvic bone,” as well as incisions made lower on the abdomen at a right angle to that line. The surgeon operates with his or her hands and instruments in direct contact with the abdominal and pelvic organs.

Minilaparotomy is the removal of fibroids through an incision in the skin of the lower abdomen that is smaller than conventional abdominal myomectomy; it is intentionally made to be as small as possible while still allowing the surgery to be performed. Surgeons use several techniques to accomplish this, including raising the uterus through a small incision to operate on the uterus “exteriorized,” meaning elevated out of the pelvis through the skin incision, or raising each fibroid individually up to, or out of, the incision. In our classification of surgical methods, we use this term to refer to myomectomies done by minilaparotomy and accomplished with the surgeon's hands and conventional instruments in direct contact with the abdominal and pelvic organs.

Laparoscopically assisted myomectomy is the removal of fibroids assisted by use of a laparoscope and other instruments inserted through small incisions in the abdominal wall; generally, each incision is less than 1.0 to 1.5 centimeters in size. The laparoscope is attached to a video camera and the surgeon(s) conduct a portion of the procedure while watching the surgery progress on a display screen. In the majority of the cases described in this literature as laparoscopically assisted, the laparoscope was used to augment minilaparotomy to ensure that the skin incision size could be kept small and still allow surgeons to view and operate in areas of the uterus that were more difficult or not possible to reach through the minilaparotomy incision alone; this situation might occur, for instance, low on the posterior aspect of the uterus. Some publications also describe laparoscopic removal of the fibroid followed by closing the defect in the uterus after the fibroid is removed by working through a minilaparotomy incision, in which the surgeon raises the uterine defect up to the incision to close the incision in the uterus using traditional open surgical techniques.

Laparoscopic Myomectomy. Laparoscopic myomectomy is the removal of fibroids using a laparoscope and instruments inserted through “ports” in the abdominal and pelvic wall to accomplish the entire surgery. The surgeon's hands are not directly in contact with the fibroid(s) or pelvic organs during the surgery. The fibroid is removed and the uterine defect is repaired entirely through the laparoscope. During laparoscopic myomectomy, fibroids are generally morcellated (i.e., cut into smaller pieces) to remove them from the abdomen through small openings. This can be accomplished with laparoscopic instruments like scissors or various forms of scalpels or with a specialized device called a morcellator. For this review we have included in this category any myomectomy done via colpotomy, which involves a vaginal incision to remove the fibroid(s) intact or in large pieces from the pelvis.

Hysteroscopic Myomectomy. Hysteroscopic myomectomy is the removal of fibroids using a hysteroscope. This instrument is inserted via the vagina through the cervix, which is dilated to allow the hysteroscope to pass into the uterus. Most often, a camera is attached to the hysteroscope and used to view the procedure on a display screen, although the surgeon may also view the procedure directly through the hysteroscope. Instruments are passed through a single tube that houses the lens for the camera, allows fluid to flow into the uterus to distend it, and provides access for operative instruments, one at a time. The instruments are used to cut, burn, or “shave down” fibroids that can be seen and reached through this interior view of the uterus. As needed, pieces of fibroid are flushed out with the fluid or grasped and removed from the uterus using instruments.

Endometrial ablation, which is the permanent surgical scarring or removal of the lining of the uterus (i.e., the endometrium), is reported in this literature as a concurrent hysteroscopic procedure; in one publication, it is considered as a primary treatment for fibroids associated with abnormal bleeding. To accomplish it, the surgeon inserts the hysteroscope as for hysteroscopic myomectomy and then uses an instrument to resect or cauterize and destroy the endometrium so that it is scarred and unable to support growth of an endometrial lining. When all or a sufficient proportion of the interior of the uterus is ablated, future bleeding decreases or stops altogether. In the literature in this review, all procedures were done with roller-ball or loop ablation techniques. No publications that reported on thermal balloon or wire mesh systems, which are designed to treat the interior surface in a single round of heating, met inclusion criteria.

Myomectomy: Results

The prior evidence review identified 43 studies about myomectomy outcomes, overwhelmingly case series. All studies that included symptom outcomes reported improvements, although measures and follow-up timing were poorly described. Transfusion was the most common short-term complication reported (1.2 percent to 16 percent); uterine perforations and fluid and electrolyte disturbances after hysteroscopy were inconsistently noted.

In summary, our review yielded the following findings. Data were limited on the effect of myomectomy for long-term symptomatic relief. No data supported use of prophylactic myomectomy in women with asymptomatic fibroids. Clear data from multiple studies indicated that myomectomies do have a risk of complications, which appears to increase with increasing number of fibroids removed. Data were insufficient to allow estimation of the cumulative incidence of recurrent symptoms after conservative management of fibroids. Reported recurrence rates ranged up to 50 percent by 5 years after myomectomy, with up to 8 percent of patients undergoing hysterectomy. Data for direct comparison of the risks and benefits of myomectomy and hysterectomy were lacking. The report noted two modifiers of myomectomy outcomes: (1) risk of recurrence of symptoms and fibroids may be lower when only one fibroid is present and removed, and (2) myomectomy may be more effective in perimenopausal women than in premenopausal women. Overall, we judged the quality of the literature about myomectomy to be weak.³⁰

Studies, Designs, and Populations. For this update, we identified 39 unique studies (with 44 publications) that reported on outcomes of myomectomy of any type, including comparisons of myomectomy with other treatments or procedures.^{70, 73, 90, 102, 108}–¹⁴⁸ Some publications dealt with use of GnRH agonist medications to reduce the size of fibroids prior to surgery, either hysterectomy or myomectomy; we summarized these findings above (in pharmaceutical interventions) and do not review them in detail here.

The overall quality of this literature was poor (21 publications) to fair (22 publications); with a single small RCT receiving a quality rating of good.¹⁴⁶ Statistical weaknesses were most common. Six studies either provided an a priori calculation of statistical power and required study size or calculated power achieved. They also included multivariate analysis to adjust for potential confounders or to identify and assess effect modifiers as needed. Nine had either a power calculation or multivariable analysis; the remainder provided neither. Likewise, documentation of inclusion and exclusion criteria was weak, as was documentation of participant characteristics including key information about fibroids such as baseline number and size.

Some study populations are represented more than once in the total number of publications because the authors focused on individual outcomes in separate publications,¹⁰⁸–¹¹⁰ published subanalyses,^{128, 129} followed up participants at a later time in order to report on later outcomes such as satisfaction with surgery or pregnancies,^{125, 126} or expanded on a case series by including the original participants in a larger series in a subsequent publication.^{119, 149}

This literature base included 24 case series studies, which we have operationally defined as descriptive analyses of a sequence of participants having the same type of procedure without a comparison with another type of surgery or treatment. Eighteen of these studies are retrospective case series of a particular type of myomectomy: five report on abdominal myomectomy,^{90, 123, 133, 136, 144} one on minilaparotomy,¹²² six on laparoscopic myomectomy,¹¹⁶–^{119, 134, 147, 149} four on hysteroscopic myomectomy,^{102, 111, 124, 132} and one on myomectomy at the time of cesarean.¹¹⁴ Six studies are prospective case series: four of laparoscopic myomectomy^{115, 125, 127, 150} and two of hysteroscopic myomectomy (one with multiple reports).¹⁰⁸–^{110, 130}

Eight studies are cohort studies that compare outcomes across two or more types of myomectomy procedures. Of these studies, five involve retrospective cohorts: three of fair quality compared abdominal and laparoscopic myomectomy outcomes;^{128, 138, 139} one of poor quality compared abdominal myomectomy with UAE;⁷⁰ and one of fair quality compared myomectomy to expectant management to examine the outcomes of assisted reproductive technology (ART) treatment.¹⁴¹ We identified three prospective cohort studies: one of fair quality compared abdominal and laparoscopic myomectomy;¹²¹ one of fair quality compared abdominal myomectomy and UAE;⁷³ and one of poor quality compared laparoscopic myomectomy and expectant management before in vitro ART treatment.¹¹²

Eight studies were RCTs: one of good quality examined “chemically assisted dissection” with sodium-2-mercaptoethanesulfonate (mesna) to define tissue planes and facilitate fibroid resection during myomectomy;¹⁴⁶ two trials, one poor and one fair, examined interventions to reduce blood loss at the time of myomectomy;^{145, 148} two trials, one fair and one poor, examined products applied at the time of myomectomy to reduce adhesion formation,^{142, 143} two fair-quality studies randomly allocated participants to abdominal or laparoscopic myomectomy;^{135, 137} and one, of fair quality, randomly allocated participants to three arms—abdominal myomectomy, minilaparotomy, and laparoscopically assisted minilaparotomy.¹¹³

The myomectomy literature is dominated by case series from large academic, tertiary care centers and internationally recognized fibroid surgery centers. Studies conducted in Europe outnumber those conducted in the United States or Canada by more than two to one. Among European studies, the majority were conducted in Italy or France. All but one of 11 North American studies were conducted in the United States, including one study that had a study site in Taiwan.

Regardless of country, the majority of studies were conducted in academic centers or specialty fibroid care facilities. Ten studies reflected care in community hospitals or clinics. Two studies relied on large databases, one in a national health care database in Norway and the other in a large private insurer database in the United States.

Outcomes Measured. For each type of surgical procedure, we combed the publications for the outcomes and complications summarized in the analytic framework presented in Chapter 1 (Figure 1). The majority of studies included perioperative outcomes. The clinical outcomes fairly uniformly included the number or size (or both) of fibroids removed, estimated blood loss or change in blood count (e.g., hemoglobin levels), transfusions (number needed or percentage of women receiving at least one), febrile morbidity, and complications. Virtually all studies used conventional clinical measures for these outcomes; some specified operational definitions or specifically timed measurements. Two measures assessed clinical processes including the length of the procedure and length of the entire hospital stay.

Retrospective studies, by definition, rely entirely on existing clinical or administrative data. Such use of clinical data means that measures such as intraoperative blood loss will be biased by documented phenomena such as digit and rounding preferences and by the a priori impressions of the surgical team about how the type of procedure relates to anticipated blood loss. Likewise, clinical practice routines play a large part in determining outcomes such as pain medication strategies or timing of discharge after the procedure. Of note, given the peculiarity of surgical studies, even RCTs are not insulated from these effects of practice patterns and assumptions about likely outcomes. Unless intraoperative details, such as blood volume in the suction canisters and on sponges, were recorded by an observer for whom the group allocation was unknown, and unless postoperative care was coordinated by an individual unaware of type of surgery, the influence of practice patterns on outcomes cannot be avoided. In this literature, such a high level of masking of assessors and care providers is understandably not achieved.

Fourteen studies included some level of detail about the degree to which myomectomy improved symptoms related to recurrence of fibroids or was followed by other surgical interventions after the index myomectomy. None of the identified studies of myomectomy outcomes made use of standardized and validated measures of menstrual bleeding, participant satisfaction, or health-related quality of life.

Eighteen studies provided data about pregnancy outcomes after myomectomy; a large proportion of these focused exclusively on ART outcomes.^{112, 115}–^{117, 119, 123, 125}–^{128, 130, 133, 134, 137, 139, 141, 147, 150}–¹⁵² However, several of these did not meet inclusion criteria for our later discussion of pregnancy outcomes in KQ 3 because they did not track or report the proportion of the women in the original study group who attempted to conceive or because they did not provide denominator data among those who did conceive to allow calculation of the probability of conception, pregnancy loss, or live birth among participants.

Limitations of Study Quality for Reproductive Outcomes. The overall quality of these studies was poor to fair. Because so many of these studies appear low on most study design hierarchies and because quite a few do not meet reasonable quality criteria, we have included in this review even articles and studies that we graded as poor. Quality grading procedures, drawing largely on the original review,³⁰ are explained in Chapter 2. Except for studies in which the myomectomy was done concurrent with evaluation and treatment for infertility, most of the case series and cohorts do not report an approach to data collection that would provide an accurate measure of the proportion of women in the studies who desired a future pregnancy and who attempted conception. Without this information, and without clearly specified lengths of followup, reports of pregnancy, miscarriage, and birth rates are flawed because rates require both an accurate denominator and unit of time over which the outcome was assessed. Likewise, simple proportions of women achieving pregnancy after myomectomy require at minimum an accurate denominator of women attempting to conceive.

Reports of the outcomes of pregnancies achieved can nonetheless be accurately summarized as descriptive data about the proportion of known pregnancies resulting in miscarriage, preterm birth, or cesarean birth and about the proportion associated with complications such as uterine rupture. Miscarriage data will underrepresent true reproductive inefficiency because some pregnancies will be lost before conventional pregnancy testing identifies the pregnancy. No studies of reproductive outcomes after myomectomy used daily urine or serum human chorionic gonadotropin testing to identify pregnancies close to the time of implantation and none, other than those among women receiving care for infertility, tested for pregnancy on a predetermined schedule. If women with one type of treatment for fibroids or without fibroids are differentially likely to conduct pregnancy testing earlier rather than later, the potential for bias caused by differences in very early loss rate is not negligible but cannot be assessed using outcomes reported in these studies.

Abdominal Myomectomy: Perioperative Outcomes. Thirteen publications (eight of poor quality, four of fair, and one of good) provided information about perioperative outcomes of abdominal myomectomy (Table 9).^{90, 113, 121, 122, 128, 133, 136}–^{138, 140, 144, 146, 148} This category includes studies of abdominal surgery and those involving minilaparotomy or laparoscopically assisted myomectomies, as all involve some form of abdominal incision. Four studies presented RCT results.^{113, 137, 146, 148} One study was a prospective cohort;¹²¹ two were retrospective cohorts;^{128, 138} and six were retrospective case series.^{90, 122, 133, 136, 140, 144}

One RCT evaluated use of mesna as a “chemical aid to dissection” of the myoma at the time of abdominal myomectomy.¹⁴⁶ One RCT evaluated techniques for reducing blood loss at the time of myomectomy.¹⁴⁸ In a total study population of 94 women, 31 had vaginal myomectomy. The authors did not provide data separately by myomectomy approach. We present surgical and trial outcomes here (with respect to results for abdominal myomectomy) because this was the only study in the review that included any women who had vaginal myomectomy, which is not a common technique in the United States.

One other trial compared abdominal myomectomy, minilaparotomy, and laparoscopically assisted myomectomy.¹¹³ Data from each arm of this trial and the results of comparisons across arms appear here because each participant had at least a minilaparotomy incision. One RCT compared abdominal with laparoscopic myomectomy;¹³⁷ outcomes for the abdominal group are presented here, and more detailed consideration of direct comparisons are discussed in the next section on laparoscopic myomectomy.

One case series,¹²² one group within a cohort,¹²¹ and one arm of a clinical trial¹¹³ focused exclusively on outcomes of minilaparotomy. Finally, the largest study (N = 1,959), conducted using data in a large private insurance database in the United States, includes some outcomes data, which are presented here.¹⁴⁰ As this work was focused predominantly on costs, and we review those results as part of KQ 4.

Excluding the large insurance database study, the remainder of the publications that include operative outcomes reported on study populations of small to modest size. Populations range from 41 in a clinical trial to 225 in a retrospective cohort formed by hospital record review.

Abdominal myomectomy is a major surgical procedure, as reflected in the data on perioperative outcomes and complications presented in Table 9. We summarize the clinical and utilization measures below.

Fibroids Removed. Seven studies reported some form of data on this outcome. With respect to the number of fibroids removed, the range over five studies was 1.2 to 9, and with respect to weight, the range (three studies) was 170 grams to 286 grams.

Blood Loss and Transfusions. Average operative blood loss, for six studies, ranged from 200 ml to more than a half liter of blood loss (508 ml). Two studies reported decreases in hemoglobin ranging from 1.8 g/dl to 3.1 g/dl. The study that evaluated mesna to assist resection reported the lowest blood loss in the mesna arm (0.9 g/dl) and a more conventional decrease, 1.7 g/dl, in the placebo control group. Finally, one study reported that 31 percent of patients had a blood loss greater than 500 ml. Most of these studies reported mean estimated blood loss without commenting on the handling of extremes of minimal or excessive blood loss. Few authors commented on other measures of centrality such as the median or any skew in the data.

Transfusion risk was reported in eight studies. The percentage of women requiring transfusions ranged from < 1 percent to 21 percent. In four studies, the numbers of transfusions ranged from 1 to 7. Use of intravenous oxytocin (compared with placebo) for reducing blood loss did not provide evidence of advantage when comparing mean blood loss; the study was underpowered to evaluate influence of risk of transfusion.¹⁴⁸ The publications that reported on minilaparotomy and laparoscopically assisted minilaparotomy provided too little detail to determine if these approaches were associated with reports of higher or lower blood loss.

Emergency hysterectomy at the time of abdominal myomectomy is most often a response to excessive bleeding. The two studies that best reflect general practice (including a large number of surgeons at community sites) are one in the United Kingdom and a U.S. insurance database. These studies reported that 4 percent and 3.7 percent (respectively) of women presenting for abdominal myomectomy had their procedure converted to a hysterectomy.^{133, 140}

Fever. Clinicians believe that febrile morbidity is a common occurrence after myomectomy. Definitions of febrile morbidity in this literature ranged from a single temperature recorded at 38° degrees Centigrade (C) or higher, to requiring repeated measures of fever over a number of hours. The three studies that reported low febrile morbidity (2.9 percent,¹³⁶ 3.3 percent,¹²¹) and 12 percent (aggregate of two small study arms with 3 and 20 percent per arm)¹⁴⁶ based their information on undefined “fever” from chart review^{136, 146} or a requirement for temperature of 38° C on two occasions at least 6 hours apart, excluding the first day after surgery.¹²¹ The remainder of studies reporting on febrile morbidity all reported that temperature elevation occurred in 15 percent or more of the study population (15.9, 17, 23.5, 26, 26.2, and 38 percent).

The clinical relevance of a high proportion of postoperative patients having fevers is related to the degree to which clinical examinations and diagnostic testing are done to evaluate the patient and rule out other sources of infection including urinary tract infection, pelvic operative site, and wound infection. Regardless of cost and effort required to evaluate the febrile patient, the occurrence of fever also influences length of stay; virtually all authors reported that a common clinical criterion for discharge is that the patient be afebrile.

Other Complications. Frank infectious complications and wound healing abnormalities are known outcomes of all surgical procedures. Women having myomectomies are generally young and healthy and rates of such complications are low. Endometritis and wound infections were reported at rates below 1 in 100 women. Wound healing complications, which can be difficult to distinguish from wound infection, were more common, affecting between 2 percent and 6 percent of participants in studies of abdominal procedures. Only one minilaparotomy study reported on wound healing complications, which occurred in 2 percent of their participants.¹²² Because wound healing complications such as seromas and hematomas generally require opening the incision and either allowing it to heal by secondary intention with daily wound care and dressing changes or reclosing the incisions with suture or staples after debridement, they present significant morbidity for the patient.

Other complications (data not shown in Table 9) such as intraoperative bowel and bladder injuries were rare. Readmissions were rare as were postoperative bowel and bladder complications such as ileus and urinary retention. No perioperative deaths were reported in these studies.

Utilization Measures. Table 9 also contains information for abdominal myomectomy or its variants on operative times and length of stay. Operative times among the seven studies reporting them all exceeded 1 hour (range from 62 minutes to 180 minutes). Length of stay varied from 13.6 hours to 6.9 days in ten studies.

Abdominal Myomectomy: Longer-Term Outcomes. Nine studies, six of poor quality and three of fair quality, followed up participants months to years after abdominal myomectomy (Table 10).^{70, 90, 122, 123, 128, 133, 135, 137, 140}

The longest followup included women who were contacted an average of 49 months from the initial abdominal myomectomy; shortest follow-up periods were generally 24 months (except for one study that had a range including some women followed for as short a time as 2 months).

Improved Symptoms. After abdominal myomectomy, more than half of women studied had improvements in the symptoms for which they sought care. Outcomes evaluated, most often by survey or telephone interview, included the following: “improved symptoms,” 68 percent; no recurrence of heavy bleeding over 5 years, 50 percent; and “completely” or “significantly” improved menorrhagia in 64 percent of women, pain in 54 percent, and mass effects in 91 percent. One study with 30 participants who had abdominal myomectomies specifically addressed satisfaction with treatment outcomes. At an average follow-up time of 49 months, 10 percent of women had had no improvement or worsening of symptoms and 21 percent were very dissatisfied with the therapy, indicating that 69 percent had satisfactory results.⁷⁰ The investigators for the studies reported here did not carry out formal health-related quality of life, functional status, or detailed satisfaction surveys.

Subsequent Interventions. Incidence of fibroids rises through the late reproductive years. For that reason, recurrence of fibroids after myomectomy is expected, either through growth of small fibroids that could not be identified or removed at the time of first surgery or through appearance of new fibroids.³⁰ In some proportion of such cases, further surgery or other interventions may be advised and carried out.

Two studies of fair quality assessed all participants for recurrence through uniform use of imaging at regular intervals (both were RCTs comparing abdominal myomectomy with other surgeries); they reported that 18 percent of women at 32 months¹³⁷ and 23 percent of women at 40 months¹³⁵ had newly identified fibroids. Hanafi, using data linked to clinical records of ultrasounds done after the index surgery, found that 62 percent of women (followed for an average of 38 months) had fibroids on subsequent ultrasound.¹²³

In studies of longer-term operative outcomes, recurrence is presumed to be the underlying cause for subsequent surgeries; this association, however, is generally not proven by documenting recurrence to the reports of the proportions who have subsequent procedures. In the six studies that sought self-report, medical record evidence, or prospective follow-up data about subsequent intervention, between 1.4 percent and 17 percent of women had another surgery, but we found only limited information to describe what proportion of these procedures were hysterectomy compared to myomectomy.

This literature is limited by the dominance of retrospective case series and cohorts that do not have sufficient opportunity to operationalize outcome definitions and unify measurement for research purposes. As throughout this review, we emphasize that (with the exception of two community-based sources of data) these outcomes reflect the experience of women receiving care in academic centers and specialty clinics with an explicit interest in fibroid care. The community studies suggest higher rates of complications than those observed in academic centers. Outcomes cannot be predictably generalized to all abdominal myomectomies performed in all care settings.

With this concern noted, we can summarize that transfusion and febrile morbidity are expected to be common. Consent for abdominal myomectomy should specifically address the real possibility of transfusion. Exploring autologous blood banking and use of cell-saver and other technologies may be advisable to reduce risks from heterologous transfusion. However, autologous and cell-saver technologies are not without risk themselves. Thus, in general, strategies for minimizing blood loss are preferable to increased use of tools to accommodate high blood loss.

Laparoscopic Myomectomy: Overview. In all, 16 studies (17 articles) dealt with laparoscopic myomectomy alone. Thirteen studies, nine of fair quality and four of poor quality, (14 publications) provided information about perioperative outcomes of laparoscopic myomectomy (Table 11).¹¹⁵–^{117, 119, 121, 125, 127, 128, 134, 137}–^{140, 145} Five publications provided some information about longer-term outcomes that include resolution of symptoms and subsequent surgeries—four already noted^{128, 135, 137, 140} and one additional study.¹¹⁸ Three of the longer-term outcome publications were retrospective analyses; two were RCTs comparing abdominal with laparoscopic myomectomy.^{135, 137} One study reported short-term operative outcomes stratified by whether the participant subsequently achieved a pregnancy; the means and ranges are not provided in aggregate for all participants. The data by pregnancy status are not presented here because the analysis was conducted to examine what characteristics at the time of surgery predicted improved reproductive outcomes. This study is addressed in more detail in KQ 3.¹⁴⁷

In short, the overlap in this literature is small. This lack of continuity is important because it means that the findings of follow-up studies do not reflect the outcomes of the populations studied in the perioperative studies. Overwhelmingly, data were not prospectively gathered to capture details about how surgical events influence long-term outcomes.

Laparoscopic Myomectomy: Perioperative Outcomes. The 13 studies with perioperative outcomes (Table 11) covered essentially the same outcomes as reported for abdominal myomectomy. Complications, however, are different insofar as they can include conversion of this particular operative procedure to one or another form of abdominal myomectomy. These studies involved study populations of small to moderate size with a total of 2,887 participants and an average of 222 participants per study. The range of size was 18 participants to 635 in a European specialty clinic case series.

Fibroids Removed. All but two studies provided some information about fibroids removed. In seven studies, the number of fibroids removed was, on average, fewer than 2; in four others, the number ranged from just over 2 to almost 6; and in one study, the fibroid weight removed was 151 grams.

Blood Loss or Transfusions. Nine studies reported data on average operative blood loss or on postoperative change in hematocrit or hemoglobin. Among those studies that reported estimated blood loss, the mean reported was 235 ml, with a range from 102 ml to 378 ml (in one arm of a trial). When direct comparisons are made within a single study population, laparoscopic myomectomy is statistically associated with lower operative blood loss (data not shown) and decreased length of stay,^{113, 128, 137, 138} though not in each case statistically significant.¹²¹

Transfusion was rare—less than 1 percent across studies. Seven studies reported no transfusions; of the remainder, the number ranged from one to ten.

Fever. Febrile morbidity was variably defined by authors; typically, they did not document operational criteria (such as interval of temperature measurement and duration of elevation). Ten studies had data on febrile morbidity. In terms of numbers of subjects with any fever, the values ranged from 1 (of 28) to 12 (of 368); using percentages as the metric, the values for any febrile morbidity ranged from 1.1 percent to 16 percent.

Complications. The primary adverse outcome was conversion from laparoscopic procedure to abdominal myomectomy, attributed commonly to difficulty with controlling bleeding, accommodating challenging anatomy laparoscopically, or closing the defect in the uterine wall.

Three Italian studies, each with highly specialized laparoscopic surgeons, reported no conversions among a total of 400 participants.^{115, 121, 145} Another large Italian series, also with highly specialized surgeons, reported a conversion rate below 1 percent among 635 procedures.¹¹⁷ Including these studies, the risk of conversion to an open incision, averaged across studies, was 6.1 percent. Excluding these reports, approximately 9 percent of women had conversion to abdominal myomectomy with a range from less than 1 percent to 29 percent.

Conversion in the study based on a large insurance database was 13.3 percent (to abdominal procedures), with an additional 2.8 percent conversion to hysterectomy.¹⁴⁰ In a U.S. retrospective cohort, conversion was 12 percent;¹³⁸ and in a group of 11 Italian university and community hospitals, it was 29 percent.¹²⁸ This spectrum from highly specialized to more generalized practice suggests that, in conventional clinical practice, women and their care providers should anticipate a conversion rate of 10 percent or higher when discussing likely outcomes of laparoscopic myomectomy and planning for postoperative recovery.

Utilization Measures. In the 12 studies reporting on average operative times, all studies reported average times longer than 1 hour (range 62 minutes to 223 minutes) except for one study reporting its own range of 30 minutes to 140 minutes.

Across 11 studies, the length of postoperative admission (i.e., length of stay) generally averaged fewer than 3 days. One study reported a median of 2 days. Most studies apparently discharged their laparoscopic myomectomy patients by the middle of the second postoperative day. European studies tended to report somewhat longer lengths of stay than those done in the United States. This is the case across types of surgery and likely reflects underlying differences in practice styles rather than real differences in the trajectory of postoperative recovery.

Laparoscopic Myomectory: Longer-Term Outcomes. Resolution of symptoms and satisfaction with surgical outcomes were not investigated in the studies that we identified for this review. Five studies did report on recurrence (Table 12). Of these, three of fair quality used regularly repeated ultrasounds for all participants during followup over (on average) 31 months to 47 months;^{118, 135, 137} they documented recurrence rates of 12.7 percent at 1 year (or 16.7 percent by 5 years) to 22 percent or 27 percent (between 10 and 30 months). Contrasted with the estimated 2.5 percent recurrence of fibroids in a poor-quality study based on retrospective documentation of clinical findings and symptoms,¹²⁸ these higher rates document the value of prospective surveillance for presence of uterine fibroids as a research tool.

Three studies, two of fair and one of poor quality, with a total of 637 participants followed for, on average, 24 months to 47 months, sought to document subsequent surgeries.^{118, 137, 140} One Italian group reported that no subsequent procedures were performed over a mean of 31 months; a French study reported that 4.6 percent of women had further surgery (predominantly myomectomies) over an average of 47 months; and the U.S. insurance database study showed that 12.3 percent of women had a subsequent myomectomy or hysterectomy within 2 years.

Hysteroscopic Surgery: Overview. Eight studies, with 10 publications, provided information about perioperative outcomes of hysteroscopic myomectomy. Seven of these also provided some information about longer-term outcomes including subsequent surgeries (Table 13).¹⁰⁸–^{111, 124, 130, 132, 140, 153, 154}

Studies ranged in size from a small comparison of endometrial ablation techniques with 42 participants to a case series of 948 participants. Two studies reported on combining hysteroscopic myomectomy with endometrial ablation during the same hysteroscopic procedure;^{111, 154} a single study reported primarily on use of endometrial ablation as a method of controlling bleeding for women with uterine enlargement from fibroids.¹⁵³

Hysteroscopic Myomectomy: Perioperative Outcomes. The five studies of hysteroscopic resection (myomectomy) without associated endometrial ablation included 2,061 women (top panel of Table 13).^{102, 108}–^{110, 130, 132, 140} Generally, the authors provided relatively little information about operative complexity and perioperative complications.

Fibroids Removed, Blood Loss, and Transfusion. Few authors documented the number of fibroids removed at the time of hysteroscopy. Authors often reported the number of fibroids present on ultrasound (details are recorded on Evidence Table 7 in Appendix C ^*), but the identification of fibroids does not necessarily equate to the number that were able to be resected at the time of surgery. Authors did not routinely report blood loss or transfusion risk; the latter appears to be low but is poorly documented.

Fluid Absorption. Three of five groups reporting on hysteroscopic resection with no other procedure described fluid absorption. This is an important measure because volume imbalances can lead to volume overload and/or hyponatremia, which can be life-threatening. Fluid absorption happens when the fluid used to distend the uterine cavity enters the blood stream via the rich network of blood vessels that serve the endometrium (lining) of the uterus and that can be exposed during hysteroscopic resection. The reported range of fluid absorption is wide, from a mean of 281 ml to a mean of more than 1 liter; one group reported only that they observed no cases of volume overload. Good overall operative technique and low average fluid volumes do not prevent adverse events; for example, the publication reporting a mean of 281 ml fluid absorption also reported one case of volume overload.

Perforations. Perforations of the uterus at the time of the procedure occurred in approximately 1 percent of women who had hysteroscopic myomectomy (10 of 1,009 women for whom data were available in the Agostini and colleagues study and the Munoz et al., study).

Utilization Measures. Length of surgery was not routinely reported by authors.

Other Complications. Seven women (0.7 percent) experienced hemorrhage. Infection was rare, affecting 0.55 percent of women in the two studies that tracked infection risk (data not shown). Incomplete procedures and conversion to other types of procedures were the most common undesired outcomes. In one study, 7.4 percent of cases were converted to abdominal myomectomy and 1.5 percent to hysterectomy. Other studies reported 13.1 percent to 18.3 percent incomplete resections.

This variation in conversion and incomplete procedures likely reflects practice patterns and routines for obtaining preoperative consent of patients. Surgeons who prefer to conduct a second procedure to attempt to complete the hysteroscopic myomectomy are less likely to obtain consent for same-day conversion to abdominal or laparoscopic myomectomy or hysterectomy (unless it is an emergency procedure). In the study that reported conversions, the proportion of these that followed from advanced contingency plans to continue to more definitive surgery in order to have a high level of certainty that symptoms would be resolved is not clear; some may have been responses to operative complications such as hemorrhage or perforations.

In summary, general details are poorly reported in these studies. Serious complications are inconsistently reported for hysteroscopic myomectomy, but they likely occur in fewer than 1 percent of procedures. However, incomplete procedures or immediate conversion to another surgery may occur at rates higher than 5 in 100 women.

Hysteroscopic Myomectomy With Other Procedures: Perioperative Outcomes. Two publications reported on hysteroscopic myomectomy with concurrent endometrial ablation (middle panel of Table 13).^{102, 111} They were both relatively small studies (73 and 149 participants). One reported an average operative time of 43 minutes. Fluid absorption averages were again wide, from 292 to 1,031 ml, with the same study that reported higher fluid absorption for hysteroscopic myomectomy reporting averages over a liter for the combined procedure as well. One study reported a 10 percent perforation rate.¹¹¹

Endometrial Ablation: Perioperative Outcomes. A single small study that included 42 women with uterine size greater than 12 weeks compared two methods of endometrial destruction: using a roller ball versus a resection approach.¹⁵³ It reported mean fluid absorption of 645 ml and an operative time of 29 minutes. Five percent of participants were hospitalized for observation but the reasons were not clearly specified. Fibroids removed, blood loss, perforation, hemorrhage, and other serious complications were not reported.

Hysteroscopic Myomectomy: Long-Term Outcomes. Seven research groups followed up participants at time periods of a year or longer;^{102, 111, 124, 130, 132, 140, 153} the average length of followup was around 2 years, and the longest followup included women who were tracked for 10 years after the initial procedure (with the minimum followup in that cohort being 4 years).

Women who had hysteroscopic myomectomy alone were followed up for satisfaction and symptom control at a minimum of 12 months in one study and at 36 months in another.^{102, 111, 124, 130, 132, 140, 153} Outcomes were poorly operationalized in these studies; the authors gave no definition of how they collected these data. One study reported that 80.8 percent of women achieved “control of bleeding”; the other reported that 81 percent reported “good control” of bleeding with 6 percent reporting return of frank menorrhagia after one or two procedures. In this cohort, 13.1 percent had a second hysteroscopic resection of fibroids.

Across the four studies of hysteroscopic myomectomy reporting such information, between 11 percent and 22 percent of women elected to have subsequent surgical intervention related to fibroids and fibroid symptoms. With the exception of the study in which repeat procedures were common (13.1 percent), myomectomy and hysterectomy were the most common procedures, with hysterectomy being selected by 2 percent to 22 percent of women as definitive management.

Results for women with both hysteroscopic myomectomy and endometrial ablation suggest potential for better control of symptoms. The smaller study group (73 women) was followed up at a minimum of 12 months after their procedure; 95.9 percent reported “control of bleeding.” This study included a comparison group of participants (n = 104) who had hysteroscopic resection only, with 81 percent achieving “control of bleeding.” This difference as well as the rates of hysterectomy by group (22 versus 18 percent) within this cohort favor performance of endometrial ablation at the time of hysteroscopic myomectomy.¹⁰² Istre and Langebrekke studied the largest group (N = 188) and reported that 5 percent of women experienced recurrent fibroids, 4 percent had recurrent bleeding, and 6 percent had recurrent pain (not mutually exclusive) within a minimum follow-up period of 4 years. Eighteen percent of their participants had repeat hysteroscopic resection of the endometrium. Of those who had repeat procedures 36 percent eventually had hysterectomies.

In the single study of endometrial ablation alone, Eskander and colleagues collected more detailed outcomes than other authors reporting on resection and ablation at the time of hysteroscopic myomectomy but had only 42 patients. They reported 67 to 77 percent of women achieved complete absence of menses, 13 percent to 15 percent had light bleeding, and 93 percent to 96 percent were “very satisfied” with their treatment outcomes during 2 years of followup.¹⁵³

Across studies of hysteroscopy with ablation, the rate of eventual selection of hysterectomy for fibroid management is similar to the rate in hysteroscopy alone: 2 percent to 18 percent. None of the studies can clearly delineate whether subsequent surgeries were indicated by the appearance of new fibroids. Several of these studies used survival analysis techniques or other approaches to define the trajectory of time to subsequent procedure. The majority of women who failed treatment in these studies with an average of more than 3 years of followup, did so early, seeking subsequent surgical intervention within 1 to 2 years of the initial procedures. This may reflect the fact that treatment failure is fairly immediately apparent and women choose to act quickly. An additional consideration is that, as women age, some proportion exit the window of chaotic bleeding patterns that can occur in the perimenopause and become frankly menopausal, markedly reducing the need for further fibroid-related treatment.

This literature is limited by a general lack of direct comparisons of intervention methods and by lack of comparison of hysteroscopic approaches to other surgical and medical management methods for outcomes, costs, and risks of harms. With that caveat, the identified case series and cohorts do document that serious complications are rare in the context of hysteroscopic intervention. Expertise and the number of procedures done by a surgeon have been shown to be related to decreased complications. Physicians and clinical care settings that have sufficient participant volume to publish results of case series and cohorts are likely to be more experienced and specialized than some community care settings. They also are likely to accumulate patients, and therefore study participants, who are referred with different expectations for symptom resolution and persistence of intervention to address symptoms than may be the case in general practice. The degree and direction of bias from lack of comparability of surgical skills and patient populations cannot be quantified.

Nonetheless, although repeat procedures and subsequent surgery are not uncommon, more than 80 percent of women followed across hysteroscopy studies for an average of more than 3 years do not have subsequent surgical interventions. Because hysteroscopic interventions are generally outpatient procedures and associated with rapid return to usual activities, these data suggest that the majority of women who have fibroids amenable to hysteroscopic intervention (which is not the case for all) can achieve good outcomes without resorting to more complex and costly procedures that also have a longer recovery time.

Hysterectomy: Overview and Nomenclature

This section presents the results of our literature search and findings about outcomes of hysterectomy, which is surgical removal of the uterus. Hysterectomy does not require removal of the ovaries, which is termed oophorectomy, however both procedures are often done concurrently. Surgery that removes the entire uterus and cervix as well as the ovaries is properly called total hysterectomy with bilateral salpingo-oophorectomy. Surgery that leaves the uterine cervix is called “supracervical” or “subtotal” rather than “total” hysterectomy. Hysterectomy is not a surgical option for women who wish to have future pregnancies or who wish to retain their uterus.

The content of the literature spans the range of surgical approaches currently available in routine clinical practice. These surgical approaches are described below. We did not identify any publication that met inclusion criteria and described outcomes of robotic surgery, which is becoming available at a limited number of highly specialized sites.

For convenience and consistency we have used uniform terminology and abbreviations to describe and discuss hysterectomy. The list that follows is approximately in the order of “invasiveness” as reflected by size and location of the surgical incision to be healed and the degree of disruption of nearby tissue and, therefore, the amount of healing required after the procedure.

Abdominal Hysterectomy. Abdominal hysterectomy consists of removal of uterus (with or without the associated surgery of removing ovaries and fallopian tubes) through an incision in the skin of the abdomen; this is also called a laparotomy incision. This includes midline incisions made along the imaginary line between the umbilicus and the pubic symphysis or “pelvic bone,” as well as incisions made lower on the abdomen at a right angle to that line. The surgeon operates with his or her hands and instruments in direct contact with the abdominal and pelvic organs.

Laparoscopically Assisted Hysterectomy. Laparoscopically assisted hysterectomy is the removal of the uterus assisted by use of a laparoscope and other instruments inserted through small incisions in the abdominal wall. Generally each incision is less than 1.0 to 1.5 centimeters size. The laparoscope is attached to a video camera and the surgeons conduct a portion of the procedure while watching the surgery progress on a display screen. In the majority of the cases described in this literature as laparoscopically assisted, the laparoscope was used to complete the portion of the surgery required to identify and transect the major blood supply to the uterus (and ovaries if they are to be removed), and the procedure, including closing the vaginal incision, was completed through a vaginal approach using conventional vaginal surgical techniques.

Laparoscopic Hysterectomy. Laparoscopic hysterectomy is the removal of the uterus (with or without the ovaries and fallopian tubes) using a laparoscope and instruments inserted through “ports” in the abdominal and pelvic wall to accomplish the entire surgery. The surgeon's hands are not directly in contact with the uterus or pelvic organs during the surgery. The surgery is accomplished and the vaginal incision is closed entirely through the laparoscope. During laparoscopic hysterectomy, the uterus and fibroids may be morcellated (i.e., cut into smaller pieces), to remove them from the abdomen through small openings. This can be accomplished with laparoscopic instruments like scissors or various forms of scalpels or with a specialized device termed a “morcellator.” For the purposes of this review we have indicated when laparoscopic hysterectomy was supracervical or total.

Vaginal Hysterectomy. Vaginal hysterectomy is the removal of the uterus (with or without the ovaries and fallopian tubes) via an exclusively vaginal approach. The operative incisions are made through the upper vagina to allow access to the uterus and pelvis, and the uterus is removed by operating through the vagina.

The approach to hysterectomy is in some part determined by a match between the size of the uterus, the patient's anatomy, the plan to perform or not perform oophorectomy, concerns about potential adhesions (which is scarring) from prior surgery like cesarean, and the surgeon's skill sets via the available approach. Vaginal hysterectomy is more challenging as the size and number of fibroids increases; the very large uterus is generally not compatible with vaginal removal, even when the surgeon uses techniques to divide the uterus or morcellate the segments. Abdominal approaches have traditionally been clinically taught to be appropriate for very large fibroids, i.e., those at and above the umbilicus. However, surgeons continue to compare open and laparoscopic approaches and to examine what size of uterus and fibroids can be safely removed. The influence of pretreatments with medical (pharmaceutical) interventions such as GnRH agonists, to diminish the size of fibroids prior to surgery, was discussed earlier.

The prior review on the management of uterine fibroids found that in prospective studies, hysterectomy resulted in improvement in symptoms and quality of life up to 2 years after the procedure in most women with sufficiently severe symptoms. Type of hysterectomy or short-term outcomes such as complications did not appear to influence longer-term outcomes.³⁰

Studies, Designs, Populations, and Outcomes Measured. Eighteen articles from 17 distinct study populations address hysterectomy (Appendix C ^*, Evidence Table 8).^{47, 75, 76, 94, 144, 155}–¹⁶⁷ Five of these studies are retrospective case series or cohorts;^{144, 159, 161, 166, 167} the remainder are either RCTs^{47, 76, 155}–^{158, 160, 163, 165} or nonrandomized prospective cohorts.^{75, 94, 162, 164}

Five studies were conducted in Italy,^{155, 158, 160, 164, 165} four in the United States,^{94, 161, 166, 167} and the remainder in the United Kingdom,^{162, 163} France,^{156, 157} Sweden,¹⁵⁹ Netherlands,⁷⁶ Greece,^{47, 144} and Canada.⁷⁵ Three were multicenter trials.^{76, 94, 162} One study was based on an inpatient registry,¹⁵⁹ and the others were hospital-based studies.^{75, 144, 156, 157, 160, 161, 163}–¹⁶⁷

With the exception of three studies,^{75, 94, 159} no study examined outcomes beyond the immediate perioperative window. Most studies reported on the length of the procedure, intraoperative and postoperative complications, and length of hospital stay.

Two studies reported outcomes of hysterectomy from large case-series data.^{159, 162} Three studies compared UAE with hysterectomy.^{75, 76, 94} One study compared abdominal myomectomy with abdominal hysterectomy.¹⁴⁴ All other studies compared different types of hysterectomy or modifiers of hysterectomy outcome. Six studies compared different types of hysterectomy: three studies compared vaginal hysterectomy with abdominal hysterectomy,^{94, 155, 161} two studies compared laparoscopically assisted vaginal hysterectomy (LAVH) with abdominal hysterectomy,^{160, 165} and one study compared LAVH with vaginal hysterectomy.^{156, 157} Eight studies addressed modifiers of hysterectomy outcomes.^{47, 76, 94, 158, 160, 163, 164, 167}

Hysterectomy: Outcomes

Our findings are presented in Appendix C ^*, Evidence Table 8 and summary tables below. Two studies reported outcomes of hysterectomy from large case-series data (Table 14).^{159, 162} Of these, one poor-quality study drew upon data from the National Health Service and private hospitals from England, Wales, and Northern Ireland to report a severe operative complication rate of 4.4 percent and a severe postoperative complication rate of 1.2 percent in the 6-week period following surgery from 1994 and 1995.¹⁶² The other study, of fair quality, reported myocardial infarction rates from a national registry of patients from Sweden over an average of 8.9 years of followup.¹⁵⁹ The relative risk of myocardial infarction for women with only fibroids rather than other indications for hysterectomy was not statistically significant (relative risk [RR], 1.1; 95% CI, 0.7–1.7). However, the relative risk of myocardial infarction for naturally menopausal women with fibroids compared with that for all other women was statistically significant but imprecise (RR, 6.2; 95% CI, 1.9–20).

Comparative Studies. Uterine Artery Embolization (UAE) Versus Hysterectomy. Three fair-quality studies compared the outcomes of UAE and hysterectomy (Table 15).^{75, 76, 94} Two were multicenter studies of UAE versus a mixed group of hysterectomies (abdominal, laparoscopic vaginal, LAVH) and focused on symptoms and clinical outcomes.^{76, 94}

These studies consistently demonstrated shorter procedure and hospital times for the UAE group than for the hysterectomy group, but they were not consistent in the rate or direction of complications.^{76, 94} Hehenkamp and colleagues reported a significantly higher rate of minor complications at 6 weeks postprocedure in the UAE group than in the hysterectomy group;⁷⁶ the Spies et al., study reported a significantly lower rate of minor complications and overall morbidity in the UAE group than in the hysterectomy group.⁹⁴ Hehenkamp documented a higher rate of readmissions among UAE patients⁷⁶ whereas Spies et al., did not find any significant differences in rates of readmission.⁹⁴ Spies et al., reported significant differences in days before return to work favoring UAE (UAE: 10.7 days, hysterectomy: 32.5 days; P < 0.001), and significant differences in the proportion reporting improved pelvic pain at 12 months (UAE: 84 percent, hysterectomy: 98 percent; P = 0.021), favoring hysterectomy. They found no differences in other symptoms, quality of life, satisfaction, or overall health assessment.⁹⁴

The third, hospital-based study compared UAE with laparoscopic hysterectomy to assess the risk of damage to ovarian function. The authors reported no differences between the groups in ovarian function between baseline and 6 months following the procedure.⁷⁵

Abdominal Myomectomy Versus Abdominal Hysterectomy. One poor-quality study compared abdominal myomectomy with abdominal hysterectomy, seeking to provide evidence on whether abdominal myomectomy was associated with febrile morbidity.¹⁴⁴ The study's retrospective analysis of 204 patients suggested no difference in the incidence or length of febrile morbidity. The study presented no other outcomes.

Vaginal Versus Abdominal Hysterectomy. Three studies compared vaginal hysterectomy with abdominal hysterectomy (Table 16); two were of fair quality^{155, 161} and one of poor quality.¹⁶⁶ Two of the three were retrospective cohorts^{161, 166} and one was an RCT.¹⁵⁵ All three studies focused on perioperative outcomes.

All three studies reported higher operative times for abdominal hysterectomy, although the difference was statistically significant in only one study.¹⁵⁵ They reported no difference in blood transfusion or intraoperative complications. With regard to postoperative decrease in hemoglobin, the studies yielded inconsistent effects: one study reported no differences in hemoglobin,¹⁵⁵ another reported a higher but nonsignificant decrease in postoperative hemoglobin,¹⁶⁶ and a third reported a significantly lower postoperative decrease in hemoglobin with abdominal hysterectomy than with vaginal hysterectomy.¹⁶¹ All three studies reported higher but nonsignificant rates of blood transfusion among abdominal hysterectomy patients. All three studies reported either no differences in postoperative complication rates or higher rates of postoperative complications among the abdominal hysterectomy patients. These differences are significant for the risk of ileus in one study¹⁶¹ and for postoperative complications in another study.¹⁶⁶ All three studies are consistent in reporting significantly longer hospital stays among abdominal hysterectomy patients.

Laparoscopically Assisted Vaginal Hysterectomy (LAVH) Versus Abdominal Hysterectomy. Two RCTS conducted in Italy reported on comparisons of LAVH and abdominal hysterectomy, one of fair quality¹⁶⁵ and one of poor quality¹⁶⁰ (Table 17). Both trials demonstrated significantly longer hospital stays for the abdominal route. Additionally, one study reported significantly shorter convalescence for the LAVH group (LAVH, 22.0 ± 11.3 days; abdominal hysterectomy, 36.0 ± 12.1 days; P < 0.001),¹⁶⁵ and the other reported significantly reduced use of analgesia for the LAVH group (LAVH, 3 percent of 7 patients; abdominal hysterectomy, 77 percent of 24 patients; P < 0.001).¹⁶⁰ Neither reported significant differences in the rates of blood transfusion or postoperative decrease in hemoglobin.

LAVH Versus Vaginal Hysterectomy. A single fair-quality study (two publications) compared outcomes following LAVH or vaginal hysterectomy (Table 18).^{156, 157} This RCT reported significantly longer operating times, higher rates of total perioperative complications, and longer hospital stays in the LAVH group. The study did not find significant differences in the rates for individual complications, use of paracetamol, use of nonsteroidal anti-inflammatory drugs, use of opioid drugs during hospitalization, or time of passing gas and stool.

Modifiers of Hysterectomy Outcomes. Eight studies reported on a variety of modifiers of outcomes of hysterectomy (Table 19): five of fair quality^{47, 76, 94, 164, 167} and three of poor quality.^{158, 160, 163}

Few studies examined the variety of modifiers identified for KQ 5, such as age, race, or ethnicity, parity, breastfeeding, contraceptive choices, body habitus, insulin resistance, concurrent medical conditions such diabetes, or hormone replacement status. Two studies that compared UAE with hysterectomy found that factors such as uterine volume, previous therapies, age, and race⁹⁴ or radiologists' experience, hospital experience, and type of hysterectomy⁷⁶ did not predict perioperative complication rates.

Another study based on a prospective case series of vaginal hysterectomy found that generally considered contraindications to vaginal hysterectomy, such as large uterus, adnexal pathology, nulliparity, previous pelvic surgery, or more than one contraindication, were not significant predictors of complications.¹⁶⁴

Two studies examined uterine weight as a modifier of outcomes of an RCT of LAVH and total abdominal hysterectomy¹⁶⁰ or retrospective study of abdominal hysterectomy.¹⁶⁷ One study found that uterine weight was a significant predictor of at least one complication (estimated blood loss > 500 mL, perioperative blood transfusion, major organ injury, postoperative antibiotic therapy, readmission);¹⁶⁷ the other study reported that uterine weight was a significant predictor of conversion to laparotomy among LAVH patients.¹⁶⁰

Three RCTs addressed clinical modifiers designed to reduce blood loss; these included use of bipolar electrocautery scissors vs. conventional scissors,¹⁵⁸ vasopressin vs. placebo,¹⁶³ and recombinant human erythropoietin (rHuEPO) plus iron supplementation vs. iron supplementation alone.⁴⁷ Dessole et al., demonstrated lower operating time and number of ligations for the electrocautery group than for the conventional scissors group; they did not find differences in hemoglobin or hematocrit until day 5 following the procedure, when the electrocautery group did better than the conventional scissors group.¹⁵⁸ Okin et al., reported lower estimated blood losses for the vasopressin group than for the placebo group, but they did not demonstrate significant differences in postoperative hemoglobin, change in hemoglobin, intraoperative transfusion, total operating room time, hysterectomy time, or hospital stays of 4 or more days.¹⁶³ Doussias et al., reported improved hemoglobin levels at days 3, 7, and 14 postoperatively in the rHuEPO plus iron group than in the iron-only group. The study also found significantly higher rates of blood transfusion in the iron-only group but not differences in blood loss or length of hospital stay.⁴⁷

Complementary and Alternative Medicine

The prior review on the management of uterine fibroids found a single study on Chinese herbal medicine.³⁰ Similarly, we found a single poor-quality study that met our inclusion criteria for complementary and alternative medicine involving traditional Chinese medicine (Appendix C ^*, Evidence Table 9);⁴⁸ it is also discussed in the section on expectant management. This nonrandomized cohort study compared a group of women who received weekly acupuncture, Chinese herbs, and nutritional therapy (N = 37) to a comparison group (N = 37); patients in the traditional Chinese medicine group also received pelvic bodywork, guided imagery, and meditation. Study investigators selected herbs and nutritional therapies for each patient but standardized them in accordance with traditional Chinese medicine tenets. Patients in the comparison group received progestational agents to stop excessive uterine bleeding, oral contraceptives to control menstrual bleeding, and NSAIDs for pain. Patients in the treatment group had significantly smaller fibroids after 6 month of treatment than in the comparison group (-0.8 cm vs. +1.9 cm; P < 0.01). A greater proportion were improved (that is, cured, reduced in size, stopped growth, or reduced rate of growth) than in the comparison group (22 [60 percent] versus 3 [8 percent]; P < 0.001). The traditional Chinese medicine treatment group was also more likely to be very satisfied with their treatment than the comparison group (14 [38 percent] versus 8 [22 percent]; P < 0.05). The author noted potential biases from the differences in degree of motivation between the two groups: the treatment group was selected from the author's practice or by word-of-mouth referral from current patients; the comparison group, although selected to match the treatment group in age, fibroid size, presenting symptoms, and health insurance status, was entirely drawn from a sample of women who used the emergency room.

KQ 3: Treatment for Goals Other than Symptom Relief

KQ 3 asks about treatment for goals other than symptom relief; specifically, the focus is on enhancing fertility, reducing adverse pregnancy outcomes, preventing further growth, or ruling out uterine malignancy. We found 10 studies relating to reproductive outcomes. We did not find publications about preventing growth of existing fibroids that compared treatment with either no treatment or alternative treatments. Information about fibroid recurrence after myomectomy was presented above for KQ 2. We did, however, find five studies examining uterine fibroid outcomes in postmenopausal women undergoing hormone replacement therapy for postmenopausal symptoms. No studies, in the time frame reviewed, reported on the probability of identifying a uterine malignancy when surgery or biopsy was done for treating or evaluating presumed uterine fibroids. These questions are new to our review, and had not been directly addressed by the prior review on the management of uterine fibroids.³⁰

Pregnancy Outcomes: Overview

We identified 10 studies (10 articles) providing information about objectives for fibroid management other than symptom relief or treating the health consequences of the fibroids (e.g., anemia) (Appendix C ^*, Evidence Table 10). All concerned reproductive outcomes among women after treatment for their fibroids. All studies that contained fertility and pregnancy data and that met the review inclusion criteria of more than 40 women in a trial or cohort or more than 100 women in a case series who desired or achieved a pregnancy were related to outcomes after myomectomy.

Studies, Designs, and Populations. Table 20 provides information on these 10 studies in four blocks with information about specific subgroups; for that reason some studies appear more than once. For example, when authors reported data for both laparoscopic and hysteroscopic myomectomy, these cohort data will be recorded for each intervention group separately; we did not duplicate any study data in this table.

Seven publications focused on laparoscopic myomectomy; two were of poor quality^{112, 151} and five were of fair quality.^{116, 117, 127, 139, 147} Three publications of fair quality included more than one type of myomectomy;^{137, 141, 152} of these, one included a cohort of women who had either laparoscopic or hysteroscopic myomectomy and combined the outcome data;¹⁵² one assessed use of hysteroscopic or abdominal myomectomy as indicated by fibroid type before ART and presented outcomes separately;¹⁴¹ and the third was a randomized trial that examined conception and pregnancy outcomes after laparoscopic or abdominal myomectomy.¹³⁷

This literature is exclusively from large academic, tertiary care centers and internationally recognized fibroid surgery centers. Except for one study conducted in the United States¹⁴¹ and one in Japan,¹⁴⁷ the remainder were performed in Europe, mostly in Italy or France.

Fertility Status. The fertility status of the populations varied widely. One prospective cohort compared women with existing fibroids with those who had had myomectomy before in vitro fertilization and embryo transfer.¹¹² One retrospective cohort made similar comparisons among six groups of women: those who had hysteroscopic myomectomy with and without donor oocytes, those who had laparoscopic myomectomy with or without donor oocytes, and a comparison group of women without fibroids with and without donor oocytes.¹⁴¹ The other retrospective cohort included only women with infertility as an indication for surgery; it compared laparoscopic myomectomy outcomes to those of the small group of women whose procedure was converted to an abdominal myomectomy. This study reported modest subsequent use of ART, which indicated potentially less severe fertility impairment.¹³⁹ One trial compared myomectomy for unexplained infertility with expectant management among women who did not have ART;¹⁵² another randomized trial investigated different myomectomy methods among women with infertility and did not report use of ART;¹³⁷ the remaining four are case series with varied rates of use of ART in their study populations.

Outcomes Measured. The majority of this literature relies on clinical followup, at times with individual contact when records were insufficient. One group conducted annual questionnaires,¹⁵¹ and several specified prospective followup but did not report how this was accomplished. Overall, loss to followup is minimal (< 5 percent) to modest (5 percent to 10 percent), although completeness of data and details about timing of attempted conception is limited by the nature of clinical records.

Ideally, data about ability to conceive would be reported as cycle- or even day-specific probability of conception, or fecundability, and the investigators would do analyses based on comparison of time-to-event across groups or by characteristics. By definition, rates, such as pregnancy rates, require documentation of a time period in which the event occurred among a known population. Overall, the poor quality of outcome assessment is a central challenge of interpreting this literature. Other than the ART studies, which reported outcomes for a group average of embryo transfer cycles, no authors reported per-cycle fecundability. Only one conducted a time-to-event analysis, estimating that 60 percent of women would conceive within 2 years.¹⁴⁷

Several publications reported average time-to-pregnancy as a descriptor and not a focus of the data analysis. These data, however, cannot be equated to fecundability data because we cannot know whether all the elapsed time between the surgical intervention and the pregnancy was associated with cycles in which the women could have conceived or attempted to conceive. Two studies that calculated proportions of women who achieved a pregnancy did not note duration of followup; several reported broad ranges, such as from 12 months to 60 months; and yet others indicated that all participants had a minimum of some fixed time of followup such as 1 year. None adjusted for time attempting conception during or before followup.

Pregnancy Outcomes: Results

Among the three studies, all of fair quality, that included participants or identified a subgroup within the study with predominantly (> 93 percent) spontaneous conceptions (Table 20, first panel), two reported outcomes of laparoscopic myomectomy and one included some proportion of hysteroscopic procedures. In those three studies, the proportions of women attempting to conceive who had a subsequent pregnancy averaged 37 percent (range, 25 percent to 43 percent).^{117, 127, 152} Among spontaneous conceptions, the risk of spontaneous abortion (i.e., miscarriage) was 11 percent, 15 percent, and 37 percent of recognized pregnancies. The proportions of women who achieved a pregnancy and had a live birth in this group of predominantly spontaneous conceptions were 80 percent and 88 percent (not reported in one study). Overall, in this group of studies predominantly reflecting spontaneous conceptions, 20 percent to 36 percent of all women who desired a pregnancy had a live birth.

One study in this group had randomized women with intramural and/or submucous fibroids to receive myomectomy or forego surgery.¹⁵² The investigators reported an increase of more than 15 percent in the proportion of women who achieved a pregnancy among those who had surgery for fibroids with any submucosal component, which is a meaningful, statistically significant improvement. The trend also favored higher numbers of women achieving a pregnancy for intramural fibroids; however, the number of participants was small and the comparison across groups was not significant. This was also the case for comparing miscarriage rates; in each case the miscarriage risk was higher among women without surgery, but the authors did not comment on statistical significance, which was likely not reached given the limited power of this trial.

Among the three studies of fair quality of women who had and who had not had infertility treatment (Table 20, second panel), the proportion of women who achieved pregnancies was 37 percent to 56 percent.^{116, 139, 147} In this subset of studies with a small proportion of women receiving infertility treatment, 40 percent to 82 percent of women who achieved a pregnancy gave birth. Overall, 22 percent to 39 percent of women who desired to conceive after myomectomy were able to conceive and have a live birth. Outcomes were similar to these in the studies that did not specify the proportion of participants who had infertility treatment (Table 20, second and third panels).

Among these studies of fair quality, two compared outcomes by type of myomectomy. Soriano and colleagues compared women who had laparoscopic myomectomy (n = 88) with those who had complications at the time of laparoscopic myomectomy and whose procedure was converted to abdominal myomectomy (n = 18). Noting the small number of conversions, they did not find a statistically significant difference in the proportion of women who became pregnant (50 percent and 56 percent), although time to becoming pregnant was longer by approximately 7 months among those who had a conversion to open procedure (P < 0.001).¹³⁹

Seracchiolli and colleagues randomly assigned participants to either abdominal (n = 65) or laparoscopic (n = 66) myomectomy. They reported similar numbers of pregnancy, miscarriage, preterm births, and cesarean birth across study arms; this finding suggests that the choice of method of myomectomy may exert little influence on outcomes.¹³⁷

In the two studies that included exclusively ART patients, one of poor quality¹¹² and one of fair quality¹⁴¹ (Table 20, bottom panel), the proportions who achieved a clinical pregnancy were 24 percent to 33 percent, with an overall higher miscarriage risk (29 percent, 39 percent, and 48 percent) than other studies had reported. This finding may relate to the very close surveillance of these embryo transfer pregnancies.

Surrey and colleagues retrospectively compared hysteroscopic and laparoscopic myomectomy in a population of women receiving ART.¹⁴¹ The method of myomectomy did not have a statistically meaningful influence on outcomes. Moreover, women who had myomectomy had neither better nor worse outcomes than a comparison group of women with no history of fibroids undergoing similar ART procedures.

Maternal age is a strong predictor of reproductive performance, especially in ART research. In this case, the authors did in effect adjust for some components of maternal age and oocyte quality by comparing groups with similar treatments who did and did not have oocyte donation, which would be from young, healthy donors. The findings were comparable for both those using donor eggs and their own.¹⁴¹ Births are not well reported in these studies, which are oriented toward immediate infertility care outcomes.

Across the other studies with data about route of birth, seven reported on cesarean births; among the women who had had myomectomy, 24 percent of births to 83 percent of births were accomplished by cesarean delivery.^{116, 117, 127, 137, 139, 147, 151}The data are insufficient to understand what proportion of these births were planned as cesarean deliveries or resulted from difficulties during labor. Among the 314 births were three documented cases of uterine rupture; two were at the site of a prior cesarean scar and not in the location of the myomectomy scar. Thus, one rupture is properly attributed as related to the myomectomy.

In summary, the literature about pregnancy outcomes after care for fibroids is quite restricted in scope and of overall fair quality; we did not identify any good-quality studies. The majority of research is descriptive, conducted in clinical settings outside the United States, and is especially limited with respect to representativeness of the population, study size, and statistical analysis. The sole clinical trial with evidence comparing surgical intervention to none, without additional ART care, supports a benefit from removing fibroids that have a submucosal component (i.e., those in which the fibroid is immediately adjacent to or distorts the uterine cavity). The benefit reported in that study is substantial (> 15 percent absolute increase in proportion of women becoming pregnant) but limited, by small study size, to reflecting on only ability to conceive.¹⁵² Other outcomes were promising but not significant. Given how common and concerning fibroids are to women and their care providers, this literature will require expansion beyond infertility care with careful attention to design of large-scale prospective cohorts and intervention trials that shed light on the risks and benefits of intervening with fibroids only for the sake of modifying reproductive outcomes.

Preventing Further Growth: Overview

Despite the widespread use and effectiveness of hormone replacement therapy to reduce symptoms of menopause, clinicians are often hesitant to prescribe hormone therapy to postmenopausal women with fibroids because of the risk of fibroid growth.⁵⁸

Studies, Designs, and Populations. We found five studies (one of good quality,¹⁶⁸ two of fair quality^{58, 169} and two of poor quality^{170, 171}) that evaluated the outcomes associated with menopausal hormone therapy (Table 21).^{58, 169}–¹⁷¹

One of the five studies was an RCT,¹⁷⁰ three were prospective cohorts,^{58, 168, 169} and one was a retrospective case control design.¹⁷¹

Three of the five studies were conducted in Italy,^{58, 169, 170} one in Greece,¹⁶⁸ and one in the United States.¹⁷¹

Preventing Further Growth: Results

Our findings are reported in Appendix C ^*, Evidence Table 11. Four of five studies included only postmenopausal women.^{58, 168}–¹⁷⁰ One study evaluated the risk of a first diagnosis of fibroids in peri- and postmenopausal women associated with prior use of estrogen and progestogen therapy.¹⁷¹ This study reported no statistically significant effects for all women; a subanalysis of women stratified by BMI status, however, demonstrated an increased risk of development of fibroids with prior combined estrogen-progestin therapy among women with a BMI less than 24 (ever-use: OR, 2.3; 95% CI, 1.2–4.3) and hormone therapy use for 5 or more years (OR, 4.0; 95% CI, 1.6–10.3). The remaining four studies reported on size changes.^{58, 168}–¹⁷⁰ One study compared an oral cyclic association of oestradiol valerate and cyproterone acetate with a sequential combination of transdermal E2 and orally administered medroxyprogesterone acetate on 240 postmenopausal women with and without uterine myomas. The study demonstrated a higher risk of uterine growth with the percutaneous-oral schedule of hormone replacement therapy than a single oral combination of oestradiol valerate and cyproterone acetate.¹⁷⁰ The three remaining studies did not report significant increases in uterine volume with hormone therapy.

KQ 1: Incidence and Prevalence of Uterine Fibroids

Two studies, both of fair quality, provided weak evidence (Level III) on the incidence of uterine fibroids. One reported on incidence among black women alone and relied primarily on self-report of ultrasound- or hysterectomy-confirmed diagnosis of uterine fibroids.⁴¹ Although self-reports are likely to be accurate, this study very probably underestimates, perhaps to a considerable degree, the incidence of uterine fibroids because it was not based on ultrasound evidence for all women (diagnosed or undiagnosed). The second study relied primarily on ultrasound-confirmed diagnosis of a random sample of women.² The results suggested cumulative incidence rates by age 50 of nearly 70 percent among white women and more than 80 percent among black women. Black women had earlier onset, and more and larger fibroids, than white women. Black women were more likely to have fibroids than white women, even after controlling for body mass index (BMI) and parity.² Additionally, women who were young at menarche, had no children, or had not had a child within the previous 5 years were more likely to have uterine fibroids.⁴¹

The estimate of cumulative incidence of 70 percent to 80 percent suggests that the vast majority of women will experience uterine fibroids during their lifetimes. Given such high levels of cumulative incidence, the absence of evidence on the proportion of women with uterine fibroids is striking. Currently, the literature provides no guidance on the overall burden of disease posed by uterine fibroids.

KQ 2: Outcomes of Treatment of Uterine Fibroids for Symptoms

Expectant Management. Evidence is lacking (Level IV) to address the subquestion about likely outcomes of expectant management. We identified no literature to document the natural history of uterine fibroid incidence, growth, symptomatology, use of clinical care, or outcomes when women choose watchful waiting over intervention.

Solely as a weak surrogate, we summarized the limited information about outcomes among women who received no intervention, or vitamin supplementation only, in 12 clinical trials and one retrospective clinical comparison group. None had been designed to assess expectant management. The quality of the identified literature for informing this question was poor, and all but one study reflected European populations recruited at specialized fibroid care centers.

Three sets of investigators used imaging to measure fibroids in three small samples (N = 22, 31, and 60) of premenopausal women.^{44, 46, 55} They followed up these women at 2 months to 3 months and documented no clinically meaningful or statistically significant changes in fibroid size as assessed by ultrasound in untreated women. Given that these studies were conducted among women awaiting surgery, this finding suggests an absence of rapid growth even among women in a highly symptomatic population. Another study reported that bleeding severity, pelvic pain, and pressure did not appreciably change in 2 months. The longest followup that addressed symptoms was 6 months, during which severity of bleeding, length of bleeding with menses, and hemoglobin levels remained unchanged.

These results have quite limited implications for clinical care; they provide minimal evidence that, at least among premenopausal women with symptoms, their condition and fibroid characteristics are not likely to change rapidly. This information, with the caveats noted, could be interpreted to mean that decisions about fibroid management do not need to be made with great urgency. Such findings also suggest that some number of months are available in which both women and their clinicians can consider options, continue watchful waiting, and treat discrete symptoms such as pain, with low risk of exacerbation of the condition.

The remaining studies, in postmenopausal women, were done to assess the influence of pharmaceutical agents on fibroids, with the goal of assessing whether use of these medications for menopausal symptoms or to treat other conditions (e.g., bone mineral density) would exacerbate fibroids. The untreated groups were followed for up to a year. The notable finding in the area of expectant management is that these women had little change in fibroid size.

Clinical wisdom reflects a general belief that fibroids undergo involution, or shrinking, after menopause. These findings raise the question about whether and in what circumstances that is the case. The data are poor for asserting the absence of involution for two reasons: (1) the studies had not been designed to assess the natural history of fibroids after menopause and (2) they represented only a cross-sectional sample of women at varied times after menopause and with a broad range of baseline fibroid characteristics that may influence the results observed.

These studies offer two preliminary impressions: (1) fibroids do not have a continuous slow growth pattern before menopause, and (2) after menopause, a decrease in size may not be as profound as believed. Nonetheless, we emphasize that these studies do not provide appropriate information about the growth trajectory or biological behavior of fibroids across the lifespan. The study populations are small, even for the purposes of preliminary descriptive data, and the research was not intended to assess changes in fibroids or related symptoms. In summary, we identified no evidence of sufficient quality to inform the decision to pursue expectant management of uterine fibroids.

Pharmaceutical Management. Although several new randomized controlled trials (RCTs) have been published since the prior review in 2001,³⁰ together they provide moderate to weak evidence about the use of pharmaceutical management on fibroid growth and symptom relief.

Gonadotropin-Releasing Hormone (GnRH) Agonists. Of the 19 studies that we reviewed for pharmaceutical management of fibroids,⁴²–^{46, 49}–^{56, 59}–⁶⁹ 13 addressed the effect of GnRH agonists.⁴²–^{45, 49, 51}–^{55, 59}–^{64, 69} Of these, eight reported on uterine and fibroid size changes in response to GnRH agonists.⁴²–^{45, 55, 61, 63, 64} These studies together provided moderate evidence (Level II) that GnRH agonists were effective in decreasing overall uterine size when used either as preoperative treatment or as an alternative to surgery. A subset of these GnRH agonist studies (six studies) on hemoglobin levels provided weak evidence of increases in hemoglobin levels by 0.9 g/dL to 5.2 g/dL after treatment and before surgery.^{42, 55, 59, 61}–⁶³ The results were statistically significant in two of these studies.^{55, 59, 63}

Three studies provided weak evidence (Level III) on the effect of GnRH agonists on symptom relief. One study reported evidence from a single small nonrandomized study of relief from hot flashes from tibolone.⁶¹ The other two studies together provided no evidence of the effectiveness of raloxifene for dealing with symptomatology alone.⁵¹–^{54, 56}

One study found weak evidence (Level III) that adding raloxifene to leuprolide therapy improves bone mineral density.⁵¹ Two studies compared the effects of leuprolide plus supplemental therapy (ipriflavone or raloxifene) to leuprolide alone on low-density lipoprotein cholesterol (LDL).⁵¹–^{54, 60} The studies found weak evidence (Level III) that levels of LDL increased after therapy for both groups, but leuprolide-only groups had significantly higher levels of LDL than did groups receiving leuprolide plus supplemental therapy.

Progestins. A single small RCT presented weak evidence (Level III) of reduction in fibroid size among women receiving lynestrenol compared with women receiving leuprolide acetate.⁶²

Mifepristone. The literature provided weak evidence (Level III) comparing two different doses of mifepristone. The single study reported significant reductions in uterine volume and menstrual blood loss from baseline values in both groups but no differences between the groups.⁶⁵

Estrogen Receptor Modulators and Antagonists. Three studies^{50, 56, 67} provided weak evidence (Level III) from trials comparing raloxifene with placebo: two reported a significant reduction in uterine and fibroid size compared with baseline values for postmenopausal women on raloxifene and an increase in uterine and fibroid size for premenopausal women on raloxifene.^{50, 56}

Uterine Artery Embolization (UAE). Twenty-four studies examined short- and long-term outcomes following UAE.⁷⁰–¹⁰⁰ Of these, six studies provided evidence on comparisons between UAE and either hysterectomy or myomectomy.^{70, 73, 75, 76, 90, 94}

The comparative studies yielded evidence of moderate strength (Level II) suggesting shorter procedure (operative) times and shorter lengths of hospital stay for UAE than for hysterectomy or myomectomy. However, we found only weak evidence (Level III), either no significant differences or inconsistent direction of effect, concerning the impact of UAE on complications and symptom relief.

Studies of UAE alone were generally case series or cohort studies, of poor or fair quality, ranging from a sample size of 46 to 3,140. They do not provide consistent definitions or time points for measuring key outcomes such as complications. Outcomes included all complications, major and minor complications, perioperative complications, or at least one adverse event; these outcomes are reported from points varying from within the hospital to a 2-year followup window.

The largest of these studies reported an in-hospital complication rate of 2.7 percent, of which 0.6 percent was for major events, and a postdischarge complication rate of 26.1 percent, of which 4.1 percent was for major events.¹⁰⁰

Very few studies reported the rate of subsequent interventions in the long term; of these, only one compared the rate of subsequent interventions between UAE and another procedure. This study reported statistically significant higher rates of subsequent interventions for UAE than for myomectomy (29 percent versus 3 percent, in a follow-up period ranging from 3 to 5 years).⁷⁰ Another study reported a subsequent intervention rate of 20 percent at 5 years.⁹³ The lack of comparable data for other types of treatment limits the value of this information.

Since the formal compilation of this review, the REST trial of Embolization versus Surgical Management was published comparing outcomes for 106 women randomly assigned to UAE compared to surgery (43 hysterectomies and 8 myomectomies). This trial of good quality was designed to evaluate health-related quality of life at 1 year using the Medical Outcomes Study 36-item Short Form General Health Survey. The investigators found no differences between groups in health-related quality of life. UAE patients had shorter hospital stays (1 day compared to 5) and returned to work sooner. At 1 year, symptom scores were superior in the surgical intervention group although the majority of UAE (88 percent) and surgical (93 percent) patients would recommend the treatment they received to a friend. Fifteen and 20 percent of the groups, respectively, had major complications. Twenty percent of women who had UAE subsequently had additional procedures, the majority hysterectomies. Among adverse outcomes were two women who had a hysterectomy immediately due to technical failure of the UAE and one conversion in the operative group, of a myomectomy to an emergency hysterectomy.¹⁷⁴

REST reinforces the general impression of the data in the review: Uterine artery embolization offers documented symptom improvement and a more rapid recovery trajectory. For the majority of women the procedure provides sufficient relief of symptoms that they do not pursue additional intervention. However, more than one in five women who have UAE are likely to seek additional management of their fibroids in the years immediately after UAE. This is important for women and their care providers to understand as is the small but consistently documented risk that women who choose uterus-conserving therapy may have hysterectomy as a complication of either UAE or myomectomy.

Endometrial Ablation. The strength of evidence on endometrial ablation, which is used to treat bleeding symptoms, is weak (Levels III). We found only three studies, all of poor quality. Of these, two combined ablation with hysteroscopic resection (retrospective case series) and one (prospective case series) evaluated ablation only. Operative and longer-term outcomes are poorly documented in each of these publications, such that across the studies they lack enough common data elements to permit any substantive summary of findings. In this and other areas lacking sufficient evidence, it is important to note that absence of evidence is equated not with absence of benefit but rather with lack of data to properly estimate benefit (if any) and potential risks. In these areas women and their health care providers lack meaningful information to guide treatment decisions.

Magnetic Resonance Imaging (MRI) Guided Focused Ultrasound. The strength of evidence about MRI-guided ultrasound ablation of fibroids is weak (Level III). The literature included one carefully conducted prospective case series (N = 109), but it nonetheless ranks as poor for informing clinical decisionmaking. This work had been conducted to support an application for approval from the U.S. Food and Drug Administration (FDA, given in 2004) of the system designed to conduct MRI-guided ultrasound.

Overall, women tolerated the procedure well. Sixteen percent of women reported severe pain at some point during the treatment, but few reported residual pain immediately after it was completed. Patient-reported outcomes were gathered using validated measures; 71 percent of women reported a 10-point or greater improvement on a quality-of-life measure. The investigators also documented improvements in bleeding and pressure. However, the change in fibroid size was modest (13 percent decrease), and 11 percent of women met criteria for treatment failure defined by worsening of symptoms, with 28 percent electing further treatment by other modalities including myomectomy and hysterectomy.

Clinicians need to consider carefully the reality that, now that the systems are in use, care providers are using this new modality to treat fibroids more aggressively than had been allowed during the strict study protocol. The major change in how the systems are now being used is that a greater proportion of the total volume of the fibroid is treated. Therefore, no information exists at present that reflects current practice in terms of procedure-related risks and anticipated outcomes.

Myomectomy. The quality of the evidence to guide decisions about myomectomy for management of uterine fibroids is poor to fair, with limited strength (Level III) because of the dominance of weak study designs, the restricted scope of outcomes studied, and the limited quality of measurements even in the few studies of stronger design. We identified 44 publications that represent 39 distinct study populations; ^{70, 73, 90, 102, 108}–¹⁴⁸ these included 24 case series studies, of which six were prospective; eight cohort studies that compared outcomes across two or more types of myomectomy, of which three were prospective; and five RCTs, of which two compared interventions to reduce blood loss, not broader outcomes of myomectomy.

Short-term outcomes were most robust for immediate measures of operative outcomes (blood loss, length of surgery) and for longer-term outcomes reflecting subsequent care received and fibroid recurrence. Few studies addressed resolution of symptoms, quality of life, sexual function, or satisfaction with treatment outcomes; those that do report such measures did not describe use of validated measures. We summarize here the main findings by type of myomectomy (abdominal, laparoscopic, laparoscopically assisted, and hysteroscopic).

Abdominal Myomectomy. The abdominal myomectomy literature consisted of studies of small to modest size, meaning that they generally lacked precision about risk.^{90, 113, 121, 122, 128, 133, 136}–^{138, 140, 144, 146, 148} For instance, transfusion risk varied widely, from < 1 percent to 21 percent, with higher risk in studies in less specialized surgical settings. A single small trial of good quality reported promising results for using a “chemical aid for dissection” in reducing blood loss and operative time.¹⁴⁶ Across studies 3 percent to 4 percent of women required intraoperative conversion to hysterectomy although myomectomy had originally been intended. Wound healing complications affected 2 percent to 4 percent of women having this form of myomectomy.

When the investigators studied improvement in symptoms, women did report improvements in symptoms for which they sought care, although improvements were not universal: 68 percent reported “improved symptoms”; 64 percent reported “completely” or “significantly” improved menorrhagia; 54 percent reported improved pain; and 91 percent reported resolution of mass effects.

Only one study with 30 participants provided any data about satisfaction, with 69 percent finding their results satisfactory.⁷⁰ Recurrence of fibroids, when defined by identification of new fibroids through imaging, likely affected more than 18 percent of women and may be as high as 62 percent within 3 to 4 years after surgery. Between 1.4 percent and 17 percent of women have additional surgery after myomectomy, but we found only limited information to describe what proportion of these procedures were hysterectomy or another myomectomy.

The nature and strength of this evidence mean that it cannot be used to compare expected outcomes of abdominal myomectomy with those of other types of myomectomy. However, this literature does provide some cautionary data. Women and their surgeons should explicitly discuss risk of transfusion, conversion to hysterectomy, and wound healing complications; although the estimates that might be taken from this body of evidence are imprecise, they indicate that the risks are not negligible. Likewise, when symptoms are attributed to fibroids, a common belief among those seeking treatment is that their removal is a virtual guarantee of resolution of symptoms. Although the majority of women have improvements (poorly measured), that proportion is not likely to be as high as the 8 or 9 of 10 women undergoing this surgery. In the absence of higher quality research, women may still wish to weigh the information that likelihood of complete resolution of symptoms or complete satisfaction is meaningfully less than universal. Clinicians should also share information that emphasizes that myomectomy does not preclude continued appearance of new fibroids and that it is likely that more than 15 percent of women will have recurrence, some of whom will choose additional surgery in the years after myomectomy.

Laparoscopic Myomectomy. With respect to risks, and with the same caveats about study size, design, and generalizability that apply to the entire body of myomectomy literature, summaries of risks from 16 studies offer context for clinical decisionmaking.¹¹⁵–^{117, 119, 121, 125, 127, 128, 134, 137}–^{140, 145} Transfusion ranged from < 1 percent to 8 percent; a single study provided direct comparison between abdominal and laparoscopic myomectomy, reporting statistically significant lower risk among those having laparoscopic procedures. Conversion to open procedures occurred in approximately 9 percent of women, with a range from < 1 percent to 29 percent, among which a small proportion goes to immediate hysterectomy. The less specialized the surgical setting, the more likely conversion appears. Women and their care providers should anticipate a conversion rate of 10 percent or higher when discussing likely outcomes of laparoscopic myomectomy and planning for postoperative recovery. When investigators did make direct comparisons, length of stay in the hospital was shorter after laparoscopy than abdominal procedures, and wound healing complications were rare.

Satisfaction with outcomes and resolution of specific symptoms was poorly studied after laparoscopic procedures. Most of the research emphasized technical and process outcomes, not providing data about how well surgery addressed the key indications for which women elected to have these procedures in the first place. Recurrence of fibroids ranged from 13 percent to 27 percent, and 7 percent to 12 percent of women had additional surgery during the first few years after myomectomy. Although these postoperative risks appear similar to those for abdominal myomectomy, and biologically would be expected to be similar, we found no direct comparisons with power adequate to declare them comparable. The same observations apply about the sole use of these data being cautionary information to provide rough estimates for counseling about probable risks.

Hysteroscopic Myomectomy. Across five studies with 2,061 participants, we found little detail about operative complexity and complications such as transfusions.¹⁰⁸–^{110, 130, 132, 140, 154} The risk of perforations of the uterus, reported in two studies, was consistent with the often clinically cited rate of 1 in 100. Some proportion of resections will be incomplete (13 percent to 18 percent); conversions to abdominal myomectomy (7 percent) and hysterectomy (1 percent) do happen. Repeat procedures and subsequent surgery affect approximately 2 percent to 20 percent of women who are followed for the years immediately after hysteroscopic myomectomy. Because hysteroscopic interventions are generally outpatient procedures and associated with rapid return to usual activities, the limited data available suggest that the majority of women who have fibroids amenable to hysteroscopic intervention (> 80 percent) may achieve good outcomes without resorting to more complex and costly procedures that also have a longer recovery time.

Hysterectomy. A limited number of studies of poor and fair quality provided weak evidence (Level III) on outcomes of hysterectomy, comparisons of types of hysterectomy, and modifiers of hysterectomy.

Outcomes. The literature on hysterectomy is limited largely to short-term outcomes. Most of the studies reporting on comparative studies of hysterectomy did not have sufficient sample sizes to derive estimates of risks of individual operative or postoperative complications. A single study based on large case-series data reported severe operative and postoperative complications up to 6 weeks following surgery,¹⁶² but the time frame (1994-1995) and location of the study (United Kingdom) make generalizations to current U.S.-based practice uncertain.

Long-term outcomes are similarly limited to small studies of comparisons between treatments. These studies together did not have sufficient sample size to derive reliable estimates of long-term outcomes. The few studies that reported long-term outcomes examined a mix of variables, including comparisons of ovarian function 6 months following UAE and hysterectomy;⁷⁵ comparisons of symptoms, quality of life, satisfaction, pain, and overall health 12 months following UAE and hysterectomy;⁹⁴ and rates of myocardial infarction several years following hysterectomy.¹⁵⁹ These studies did not yield sufficiently consistent or statistically significant variables to comment on long-term outcomes following hysterectomy within the first 12 months following the procedure. We found no evidence on quality of life or health outcomes beyond the first 12 months following hysterectomy.

Comparisons of Types of Hysterectomy. Studies comparing hysterectomy with UAE or myomectomy or comparing different types of hysterectomy all reported primarily on short-term outcomes. They were not powered to estimate rates of individual perioperative complications. From a small set of underpowered studies, the direction of effect suggested better outcomes on a limited range of perioperative measures (of which length of hospital stay has the most consistent direction and significance of effect) for vaginal hysterectomy and laparoscopically assisted vaginal hysterectomy (LAVH) compared with abdominal hysterectomy and for vaginal hysterectomy compared with LAVH.

All three studies that reported on vaginal versus abdominal hysterectomy focused on perioperative outcomes.^{155, 161, 166} They consistently reported significantly longer hospital stays with abdominal hysterectomy. Other perioperative outcomes occurred with higher frequency among the abdominal hysterectomy group, with significantly higher risk of ileus reported in one study,¹⁶¹ and significantly higher rates of postoperative outcomes (postoperative transfusion, pelvic hematoma, reoperation, febrile morbidity, and other complications) in another study.¹⁶⁶

The interpretation of these results remains unclear. The studies were not powered to test differences in the occurrence of rare perioperative outcomes. Two of the three studies were not randomized trials; because they did not account for potential differences in baseline fibroid size, selection bias could have potentially influenced outcomes for these two groups.

The two studies reporting on LAVH and abdominal hysterectomy^{160, 165}demonstrated improved outcomes for LAVH on a limited set of perioperative outcomes, namely hospital stay, convalescence, and use of analgesia. These studies were not powered to test differences in perioperative complications: one of the studies noted that the absence of statistically significant differences for wound infection could be attributed to insufficient sample size.¹⁶⁵

The only study reporting outcomes on the comparison between LAVH and vaginal hysterectomy reported significantly worse outcomes for LAVH for hospital stay and total perioperative complications.^{156, 157} Again, the evidence is limited to perioperative outcomes, and the sample size is underpowered to test for differences in individual perioperative complications.

Modifiers of Hysterectomy. We also reviewed the literature for modifiers of hysterectomy outcomes; we sought information on age, race or ethnicity, parity, breastfeeding, contraceptive choices, body habitus, insulin resistance, concurrent medical conditions such diabetes, and hormone replacement status. We found no evidence at all for these variables. We found some evidence of effect of uterine weight and certain procedures on hysterectomy outcomes, described below.

Two studies found worse outcomes with larger uterine weight.^{160, 167} Three studies comparing interventions to reduce postoperative blood loss and improve postoperative hemoglobin found some evidence of effectiveness on an inconsistent group of outcomes such as operating time and number of ligations for bipolar electrocautery scissors compared with conventional scissors,¹⁵⁸ estimated blood losses for vasopressin compared with placebo,¹⁶³ and hemoglobin levels and rates of blood transfusion for preoperative therapy of recombinant human erythropoietin plus iron compared with iron alone.⁴⁷

Complementary and Alternative Medicine. A single study of poor quality compared traditional Chinese medicine with standard medical management (progestational agents, oral contraceptives, or nonsteroidal anti-inflammatory drugs).⁴⁸ The investigator reported significantly smaller fibroid size, greater proportion of women improved, and greater satisfaction with their treatment among women in the traditional Chinese arm. As noted in Chapter 3, the author reported potential biases from the differences in degree of motivation between the two groups. Therefore, we consider the available evidence to be weak (Level III).