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The FIBROID Registry

Report of Structure, Methods, and Initial Results


Chapter 1. Background and Significance
Uterine leiomyomas, or fibroids, are one of the most common conditions affecting
women during their reproductive years. Symptoms attributable to fibroids include heavy
menstrual bleeding, pain either associated with menses or occurring throughout the cycle,
and pressure symptoms associated with increasing uterine size. These symptoms are the
most common indication for hysterectomy in the United States, accounting for 30-40
percent of all hysterectomies, or 150-200,000 hysterectomies annually.3 At least 34,000
myomectomies—surgical procedures in which only the fibroids are removed—are
performed annually (data obtained from the NIS online query system).

The choice of treatment for symptomatic uterine fibroids reflects the severity of
symptoms, the patient's desire for future fertility, and patient and physician preferences.
Medical treatments, such as nonsteroidal anti-inflammatories, oral contraceptive pills,
and progestins, are aimed at minimizing abnormal menstrual bleeding or controlling
pelvic pain. These treatments are associated with minimal cost and risk, but their
effectiveness in women with fibroids is limited.22 Surgical interventions—myomectomy
and hysterectomy—are known to be more effective, but are associated with higher cost
and greater risk of morbidity. Abdominal myomectomy and hysterectomy require general
anesthesia, lengthy hospital stays and lengthy recovery periods. Furthermore,
hysterectomy, the only definitive cure, does not allow a woman to preserve her fertility.

In 2000, there were an estimated 253,000 hospital admissions (surgical and nonsurgical)
with a principal diagnosis of uterine fibroids, resulting in hospital charges of over $2.6
billion. Although there are no data from which to estimate the medical costs incurred in
outpatient settings, or nonmedical costs such as time lost from work, fibroids clearly have
a significant public health impact. For example, total admissions for all gynecological
cancers combined (96,000) are less than half those for fibroids, and the total inpatient
charges ($1.7 billion) are lower than those for uterine fibroids by almost a billion dollars
(NIS online data).

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Prevalence Estimates

Estimating the overall prevalence of fibroids in the population is difficult, since estimates
will vary depending on the population examined, whether asymptomatic women are
included, and the sensitivity and specificity of the methods used to detect fibroids. In
pathological studies of hysterectomy specimens performed for all indications (not limited
to fibroids alone), fibroids have been detected in 45 percent23 to 77 percent24 of
specimens. Prevalence in asymptomatic women is variable, depending on the population
studied and the methods used to diagnose fibroids. Prevalence in asymptomatic pregnant
women undergoing ultrasound is in the range of 1-4 percent.25,26 This low prevalence may
reflect a relatively young age in pregnant women, or a potential adverse effect of fibroids
on fecundity.

Prevalence of fibroids clearly increases with age: for example, a recent Scandinavian
study using ultrasound in a random sample of 335 asymptomatic women aged 25-40
years found an overall prevalence of 5.4 percent, with the prevalence increasing with age
—3.3 percent in women aged 25-32 versus 7.8 percent in women aged 33-40.27
Prevalence in 64 asymptomatic women over 30 years of age in a study from the
University of Iowa was 13 percent,28 while a series of 3,171 women undergoing
laparoscopic sterilization was 10.0 percent; prevalence of previously undiagnosed
fibroids was 6.2 percent.29 The most recent study, in 1,364 women between 35 and 49 in
the Washington, DC, area, found that 35 percent had a previous diagnosis of fibroids and
an additional 51 percent had previously unsuspected fibroids found on ultrasound.2 In that
study, the estimated cumulative incidence of fibroids by age 50 was 80 percent for black
women and 70 percent for white women.

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Incidence of Symptom Development

Of course, the prevalence of asymptomatic fibroids is ultimately less important clinically


than the incidence of symptoms. Unfortunately, incidence is even more difficult to
estimate than prevalence. Most available sources of data are hospital-based; so
determining the number of new cases of symptomatic fibroids is limited by lack of data
on outpatient visits. Data from the Nurses Health Study cohort showed a crude self-
reported incidence rate of 12.8 symptomatic fibroids per 1,000 woman-years in women
aged 25-44; incidence varied significantly by age and race. Estimated cumulative
incidence of a diagnosis between ages 25 and 44 based on these data is approximately 30
percent, and the cumulative risk of hysterectomy for fibroids is 7 percent.1

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Racial Differences

There are clear racial differences in the prevalence and incidence of fibroids. In one
study, the prevalence of fibroids in African-American women undergoing sterilization
procedures was approximately twofold higher than in white women.29 In one large cohort
study of over 53,000 women undergoing hysterectomy in Maryland, uterine fibroids
accounted for 65.4 percent of the hysterectomies in African-American women versus
only 28.5 percent in whites.30 In the Nurses Health Study, incidence among African-
American women was approximately three times that among whites.31

The natural history of fibroids may differ among racial and ethnic groups as well. In the
Nurses Health Study, African-American women had uterine fibroids diagnosed earlier
than their white counterparts, with the highest incidence rate of diagnosis being between
35 and 40, versus 40 and 44 years for whites.31 Similar findings were seen in the
Maryland study, with a mean age of diagnosis of 37.5 ± 7.9 years in African-Americans
versus 41.6 ± 6.6 years for whites.30

In addition to the earlier age of diagnosis noted above, African-American women


undergo surgical procedures for fibroids at younger ages than white women; in the
Nurses Health Study, this was the case despite a longer mean time from diagnosis to
hysterectomy among African-American women.31 Data from the AHRQ's NIS show
younger ages for African-American women for both hysterectomy for fibroids and
myomectomy.1 Recent analysis of a similar independent dataset, the National Hospital
Discharge summary, has found similar results (Myers, unpublished data).

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Severity of Disease

Other studies suggest that the severity of disease at the time of hysterectomy may also
differ. Kjerulff et al reported that African-American women undergoing hysterectomy for
fibroids were more likely to be anemic than white women (56 percent versus 38 percent)
and more likely to complain of severe pelvic pain (59 percent vs. 41 percent)32 at the time
of presentation.

Moreover, at the time of hysterectomy, black women have been shown on average to
have both more myomas and a larger uterine size.32,33 For example, in the Maryland study
of Kjerulff and colleagues, 30 percent of African-American women who underwent
hysterectomy had uterine size greater than 500 grams versus only 15 percent of white
women.32 This differential has potentially important implications because Hillis et al
demonstrated that women undergoing hysterectomy with a uterus of greater than 500
grams were 1.6 (1.0-4.0) times more likely to develop operative or postoperative
complications, particularly cuff cellulitis (relative risk [RR], 2.8 [95% CI, 1.3-6.2]) and
transfusion (RR, 2.4 [95% CI, 1.3-4.3]).33

Analysis of complication rates for both myomectomy and hysterectomy at Duke


University Medical Center has found that African-American women have crude
complication rates more than twice that for white women, but that these rates are largely
explained by larger uterine size and greater number of fibroids among African-American
women.34

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Uterine Artery Embolization

Uterine artery embolization (UAE) is a relatively new procedure for the treatment of
fibroids. Using a catheter advanced from an arterial puncture site, usually the femoral
artery, the physician occludes the arterial supply to fibroids under angiographic guidance
by injecting polyvinyl alcohol particles or spheres, tris-acryl gelatin microspheres, or
gelatin sponge pledgets or slurry. Results from a French center were initially reported in
199535 with the first United States series reported in 1997.36

A survey of the Society of Interventional Radiology (SIR) membership in 2001 found a


doubling of the number of procedures performed from 1999 (4,165 procedures) to 2000
(8,605 procedures). Since its introduction, UAE has been promoted by some as a
"noninvasive" or "minimally invasive" alternative to hysterectomy, one that allows
"preservation of fertility." According to SIR, approximately 25-30,000 UAE procedures
have been performed in the United States.37 In theory, UAE is an attractive alternative to
other invasive procedures, since it preserves the uterus, requires a shorter hospital stay,
and may allow a faster return to work than procedures that require laparotomy.

A number of retrospective and prospective case series have been reported.8,10,12-14,18,38-41


Similar to the case series of myomectomy, these papers report variable short-term
outcomes. Menorrhagia is improved in 82 to 98 percent of patients in the short term (3-4
months) and these results remain stable at a year after therapy. While somewhat less
widely reported, the bulk symptoms of pain and pressure were improved in 64 percent to
97 percent of patients in the short term and these improvements persisted at 1 year.

Of the 1,871 patients included in these series, there were 16 hysterectomies for
complications (0.8 percent of patients treated). The most common complication resulting
in the need for rehospitalization or additional gynecologic therapy appears to be fibroid
expulsion. In a summary of the complications that occurred in 400 consecutive patients,
2.5 percent had fibroid expulsion. In addition, postprocedure amenorrhea occurred in
between 2 and 7 percent of patients in most series10,12 although it was as high as 15
percent in one.42 Whether there is a subclinical effect on ovarian function in most patients
that might affect fertility and/or age at menopause is unknown; 3 of 4 studies using
follicle stimulating hormone (FSH) measures on day 3 of the menstrual cycle have shown
no impact in women under the age of 45.10,43-45

In one published comparison of UAE to other procedures, women undergoing UAE were
more likely to require additional therapy than women undergoing myomectomy46;
however, this study was limited by retrospective collection of data, incomplete followup,
relatively small sample size, and the inability to control for baseline characteristics that
may have led women to choose one procedure over another.

A recent multicenter prospective study reported on outcome to 1 year on cohorts of


patients undergoing UAE or hysterectomy. For embolization patients, there were marked
reductions in blood loss scores (p < 0.001) and menorrhagia questionnaire scores (p <
0.001). At 12 months, a larger proportion of hysterectomy patients had improved pelvic
pain (p = 0.021). There was no difference in other symptoms and both groups had marked
improvement in quality of life (QOL) scores. Complications were more frequent in
hysterectomy patients (50 percent versus 27.5 percent, p = 0.01).
Thus, although the available data suggest that UAE is a viable alternative to other
procedures for management of symptomatic fibroids, that data is derived from mostly
single center studies with outcomes less than 2 years after therapy.

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Overview on the Safety Profile of the UAE Procedure

Uterine artery embolization is very safe method and, like other minimally invasive
procedures, has significant advantages over conventional open surgery. However, there
are some associated risks, as there are with any medical procedure. A small number of
patients have experienced infection, which usually can be controlled by antibiotics. There
also is a less than 1 percent chance of injury to the uterus, potentially leading to a
hysterectomy.13,47,48 These complication rates are lower than those of hysterectomy and
myomectomy.49

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Summary of Background and Significance

There is clear and consistent evidence from a variety of sources that:

• Uterine fibroids are an extremely common condition in reproductive age women.


• Symptoms caused by fibroids frequently lead to hysterectomy.
• The economic impact of fibroids is considerable, with annual inpatient costs alone
greater than the inpatient costs associated with all gynecological cancers
combined.
• There are significant racial differences in the prevalence, incidence and, possibly,
natural history of fibroids; these differences contribute to higher rates of surgery,
and higher complications of surgery, among African-American women.

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Development of a Research Agenda for UAE

In the absence of regulatory requirements for randomized trials, surgical or other invasive
procedures are often introduced and disseminated into practice on the basis of case
reports and series based on the experiences of expert practitioners.50 For example,
laparoscopic methods for performing procedures such as cholecystectomy,
appendectomy, and hysterectomy were being promoted, and taught to practitioners, on
the basis of case series well before randomized trials comparing them to traditional
methods were performed.51-54

The early reports with UAE were similar in many respects, but significant efforts were
made relatively early in the process of development and dissemination of this
intervention to ensure that the evidence supporting its safety and effectiveness was as
strong as possible. In 1999, the SIR Foundation, the research and education foundation of
SIR, commissioned an evidence report from the Rand Corporation, which reached similar
conclusions to the AHRQ report.46 The report recommended four important research
needs: development of a disease-specific quality-of-life instrument, establishment of a
registry for prospective collection of outcomes data, a randomized trial and a comparative
cost analysis. SIR Foundation funded the development of a disease specific quality-of-life
instrument and oversaw the development of the Fibroid Registry for Outcomes Data
(FIBROID).

In addition, the manufacturers of embolic particles conducted comparative clinical trials


and submitted to the FDA to apply for a labeling indication specific for uterine fibroids.
Although the embolic agents were already FDA approved for the embolization of tumors,
the manufactures conducted new trials comparing UAE to hysterectomy (Biosphere
Medical) and myomectomy (Boston Scientific). Both embolic agents received FDA
approval for the specific indication of embolization of uterine fibroids, based on positive
safety and efficacy data.

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Development of a Disease-specific Quality-of-Life Instrument

Until recently, there have been limited tools available for assessing symptom status
associated with uterine fibroids and to determine the impact on health-related quality of
life. Previous research on hysterectomy has used generic health status questionnaires4,55,56
and has noted improved health-related quality of life. Menorrhagia questionnaires have
been developed4,55-58 but these have not considered the pressure symptoms also caused by
fibroids nor the quality-of-life impact.

Spies and colleagues at Georgetown University developed and validated a disease-


specific quality-of-life instrument for symptomatic fibroids, the UFS-QOL.19 The UFS-
QOL was developed from focus groups, clinician opinion and a thorough literature
review, using standard instrument development techniques. The validation study was
conducted in both normal volunteers and women with uterine fibroids. Normal volunteers
were recruited from the Georgetown campus and women with uterine leiomyomas were
recruited from five Washington, DC-area gynecologists' offices and an interventional
radiologist's office to complete the questionnaire packet.

In addition to the UFS-QOL, participants completed several other validated instruments,


including:

• The Medical Outcomes Study Short-Form 36 (SF-36) Health Survey.


• The Ruta Menorrhagia Questionnaire.
• The Revicki-Wu Sexual Function Scale.
• A physician-rated severity scale (1-10).
• Subject self-rated symptom severity (0-10), with 0 being not severe and 10 being
very severe symptoms experienced.
A total of 110 women with uterine leiomyomas and 29 normal volunteers were recruited
into the validation study. African-American women made up 63 percent of the patients
with fibroids and 76 percent of the normal population. Internal consistency was high,
with Cronbach's alpha levels of 0.83-0.97 for individual subscales.

The UFS-QOL was able to discriminate between normal participants and women with
leiomyomas (Table 1). Women with leiomyomas experienced significantly higher levels
of symptom distress and lower health-related quality of life than normal controls. In
addition, the subscale scores were able to discriminate between both patient-reported and
physician-reported symptom severity ratings. The patient-rated severity scores were then
categorized into three groups (< or = 4, > 4 but < 8, and = or > 8) based on distribution of
scores and clinical meaningfulness. The UFS-QOL discriminated between mildly,
moderately and severely symptomatic women, thus indicating sensitivity in the
instrument. Similar results were found with the physician ratings of patient symptom
severity. Test-retest reliability was also good, with intraclass correlation coefficients of
0.76-0.93.

The UFS-QOL demonstrated excellent discriminative validity in distinguishing not only


normals from leiomyoma patients but also among patients with varying self-rated and
physician-rated symptom severities. Women with leiomyomas experienced significant
decrements in health-related quality of life, particularly when experiencing severe
symptoms. Although the subscale score differences were not as pronounced, the subscale
scores differed significantly by physician ratings of patient symptom severity. This
sensitivity in detecting differences in symptom distress and health-related quality of life
impact lends promise for detecting treatment differences in longitudinal studies.

The UFS-QOL subscales of concern and control appear to be the most affected by
symptoms, followed by the subscales of activities and self-consciousness. The concern
subscale focuses on concern regarding soiling garments, the inconvenience of always
carrying sanitary protection, and anxiety about the unpredictable onset of menses. For
women reporting severe leiomyoma symptoms, this concern was particularly detrimental.
This information provides insight into the health-related quality of life impact of
leiomyomas, which had been previously undocumented. The control subscale asks
questions related to feelings of control over one's health, life and future uncertainty. This
was an area that was discussed frequently in the focus groups: women were quite
distressed about their inability to control their symptoms and about the way the
debilitating effects of leiomyoma symptoms could immediately alter all plans for travel,
social engagements, or physical activities.

During the focus group discussions, activities were affected not only by leiomyoma
symptoms but also fatigue. Fatigue, which is captured in the energy/mood subscale, was a
chronic complaint of women in the focus groups, particularly during their menses, but
also as an underlying condition. The importance of this subscale is particularly relevant
for long-term followup of treatments of fibroids because fatigue is a particularly common
complaint after hysterectomy.59
Although the symptom severity scale contains items related to the bulk symptoms of
leiomyoma, the self-consciousness subscale captures the effects of the bulk symptoms on
health-related quality of life as this subscale pertains to appearance related to stomach
appearance and bloating. Dissatisfaction with appearance also had an impact on sexual
function: some women in the focus groups said they "did not feel attractive," although
most stated that they only avoided sexual relations because of menorrhagia related to
their leiomyomas.

The UFS-QOL is a reliable and reproducible measure with evidence of construct and
discriminant validity. The UFS-QOL has been translated into six languages (Spanish,
French, Canadian French, Hebrew, German, and UK English), with equivalent
psychometric properties to the original. The instrument is currently being used in several
prospective cohort studies, including the FIBROID Registry and several industry-
sponsored trials, under licensing agreements with the SIR Foundation.

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Chapter 2. Methods
UAE Registry: Background

The establishment of the FIBROID Registry represents a unique example of collaboration


between a professional medical society, academic investigators, industry and
government. Representatives of the FDA Center for Devices and Radiological Health
(CDRH) were involved in the initial planning of the registry.

Funding for the registry was provided by grants from manufacturers to the SIR
Foundation. Funding was initially planned for 3 years, and investigators intended to apply
for additional funds for long-term followup. Funding was focused on development of a
Web-based data entry system, data management and analysis at the Duke Clinical
Research Institute (DCRI), and 12-24 month followup of patients by the DCRI. No funds
were provided to sites for participation. Additional funds from AHRQ and FDA's Office
of Women's Health have been provided under a contract for analysis and preparation of
this report.

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UAE Registry: Organization

The registry is a cooperative venture between the SIR Foundation and DCRI. The registry
is organized into the following groups:
• The steering committee consists of five interventional radiologists with extensive
experience with UAE, representing the SIR Foundation; a
cardiologist/epidemiologist with extensive experience in design and maintenance
of registries, representing DCRI; a gynecologist/epidemiologist with experience
in clinical epidemiology and clinical trials, also representing DCRI; and an
epidemiologist with prior experience with uterine embolization research. The
steering committee is responsible for all aspects of registry organization,
including final design of all data collection forms, adjudication of adverse events,
and communication with site principal investigators regarding site performance
issues, and establishment of publications and other policies. The Steering
Committee met on a quarterly basis during enrollment, with subsequent meetings
by conference call as needed thereafter.
• The external advisory committee was formed prior to initiation of the registry,
with representation from epidemiologists, gynecologists, and the FDA CDRH to
help pose research questions and to define data points of interest for inclusion of
the study.
• The committee of sponsors provides input, primarily on specific data requests for
sponsors.
• Sites and site investigators are considered either core or participating and are
described in more detail below.

All data management, site data management, data analysis and data reporting are
managed at the DCRI. Longitudinal followup of patients is conducted by DCRI. SIR
Foundation staff are responsible for overall site management, including site
identification, recruitment, training, and monitoring, and serve as the primary liaison with
the investigators, steering committee and external organizations. The SIR Foundation
maintains the registry Web site (www.fibroidregistry.org) and arranges committee and
investigator meetings and conference calls. The SIR Foundation maintains the network of
sites to facilitate investigation and adjudication of adverse events and communications to
sites, access to registry data, and steering committee conference calls and meetings. SIR
Foundation staff and the steering committee also coordinate and participate in data
interpretation and preparation of manuscripts.

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UAE Registry Sites

Recruitment of sites was done through the SIR Foundation and SIR. Sites were classified
as core or participating sites, depending on the amount of data collected. Requirements
for core sites included:

• Membership in the Society of Interventional Radiology.


• Ability to identify a principal investigator and study coordinator at each site.
• Greater than 24 cases of experience, with projected case volume of at least 5 cases
per month.
• Ability to meet all applicable Federal and State regulations, including IRB
oversight.
• Stable Internet access.
• Availability of appropriate research staff.
• Willingness to participate in a voluntary registry, including commitment of
resources for data collection, participation in mandatory site training, and
attendance at investigator meetings. (No funds were available for site-related
research expenses.)
• Agreement to use only agents and devices approved for embolization by the FDA.
• Willingness to collect all baseline and 30-day followup data.

Participating sites had similar requirements, except that they had no prior volume or
experience requirements and fewer data entry requirements, and formal training was not
held (all training materials provided to core sites were provided to participating sites and
sites reviewed materials at their own pace).

Final selection of sites was made by the Registry Steering Committee to ensure diversity
in geographic location, practice type (academic versus community) and practice size and
experience. Although initial plans were for participating sites to submit less data, most
sites have entered complete data, including baseline UFS-QOL scores, on all patients.

Prior to being given access to the Web-based data collection tools, all sites were required
to submit appropriate documentation, including consent forms, IRB protocols, formal
notice of local IRB approval, and number of procedures performed by each investigator
to the DCRI. An executed site agreement between the SIR Foundation and the site was
also required prior to submission of data to the registry.

DCRI and the SIR Foundation publish a joint newsletter for site investigators with
answers to frequently asked questions, reminders about procedures, tips on recruiting,
etc. Initial publication was on a monthly basis; recently, publication has been quarterly, in
conjunction with the quarterly reports. Generic data quality issues are discussed in the
newsletter.

Although sites do not receive direct compensation for participation in the registry, there
are benefits and incentives for participation, including:

• Identification as a participant in the registry on the FIBROID Registry Web site


and on an SIR physician locator.
• Quarterly reports, which provide site-specific statistics on patient demographics,
procedure details and outcomes, as well as aggregate data for the entire registry.
• Longitudinal followup of patients (reports on patient population undergoing
UAE).
• The opportunity to request additional analyses of the data, after approval by the
steering committee.

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Data Collection

All UAE procedures performed at a site for symptomatic fibroids are entered into a Web-
based data collection form. The Web form is designed to minimize data entry errors by
including features like ranges and prompts. Core sites are expected to submit data within
2 days of the procedure, participating sites within 5 days. The exact timing of data entry
relative to the procedure is left to the discretion of the site. For the small percentage of
patients who do not consent to participate, only a date, the performance of the procedure,
and the patient's refusal to consent are entered. In this way, data on site-specific and total
volume is as complete as possible.

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Data Management/Data Quality

Staff at DCRI maintain the database. Monthly checks are run for each site; if data entered
at the time of procedure indicates that the patient is eligible for the registry and has
consented to participate, but no additional data are available, an E-mail is sent to the site.
Each site receives a monthly status report and data quality report, with information on
missing data fields or inconsistencies. In addition, each site receives a quarterly report of
aggregate registry data and site-specific data for each variable.

There is no formal data monitoring by outside review, due to limitations in resources.


Unless specifically required by a regulatory agency, such as those States where registries
are used for quality assurance purposes for procedures such as cardiovascular surgery,
data monitoring of the type that is standard for FDA-regulated trials is not typical of
registry studies.

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Subjects

Subjects enrolled in this study have met the following criteria:

• Presence of symptomatic fibroids prior to undergoing UAE at a registry site.


• Performance of UAE at a registry site from initiation of the registry through
December 31, 2002.
• Signed consent from patient to participate in long-term followup.
• Contact information from patient.

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Data Collected

The following section describes the (a) baseline and 30-day data points, (b) followup data
points, and (c) the rationale for each variable. In general, variables were selected based
on known relationship to the epidemiology of uterine fibroids (such as age and race),
association with severity of disease (such as uterine size and number of fibroids),
documented relationship to outcomes of other therapies for fibroids such as hysterectomy
and myomectomy (body mass index, prior surgery), possible impact on outcomes of UAE
(technical details of the procedure), and relevance to health status or resource utilization
after the procedure (unanticipated emergency room visits or readmission to the hospital).

http://www.ahrq.gov/research/fibroid/fibreg.htm
Agency for Healthcare Research and Quality 540 Gaither Road Rockville, MD 20850
Telephone: (301) 427-1364

Volume 22, Issue 4, Pages 571-588 (August 2008) 3 of 17


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BOOKMARK ARTICLE

Incidence, aetiology and epidemiology of uterine


fibroids
Stanley Okolo, MBBCH, PhD, FWACS, FRCOG (Medical Executive Director and
Professor of Ob-Gyn)

published online 12 May 2008.

Uterine fibroids are the most common benign tumour of the female genital tract.
However, their true prevalence is probably under-estimated, as the incidence at histology
is more than double the clinical incidence. Recent longitudinal studies have estimated
that the lifetime risk of fibroids in a woman over the age of 45 years is more than 60%,
with incidence higher in blacks than in whites. The cause of fibroids remains unclear and
their biology poorly understood. No single candidate gene has been detected for
commonly occurring uterine fibroids. However, the occurrence of rare uterine fibroid
syndromes, such as multiple cutaneous and uterine leiomyomatosis, has been traced to
the gene that codes for the mitochondrial enzyme, fumarate hydratase. Cytogenetic
abnormalities, particularly deletions of chromosome 7, which are found in up to 50% of
fibroid specimens, seem to be secondary rather than primary events, and investigations
into the role of tumour suppressor genes have yielded conflicting results. The key
regulators of fibroid growth are ovarian steroids, both oestrogen and progestogen, growth
factors and angiogenesis, and the process of apoptosis. Black race, heredity, nulliparity,
obesity, polycystic ovary syndrome, diabetes and hypertension are associated with
increased risk of fibroids, and there is emerging evidence that familial predisposition to
fibroids is associated with a distinct pattern of clinical and molecular features compared
with fibroids in families without this prevalence.

http://www.bestpracticeobgyn.com/article/S1521-6934%2808%2900062-X/abstract