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REPOSITÓRIO DA PRODUÇÃO CIENTIFICA E INTELECTUAL DA UNICAMP
Versão do arquivo anexado / Version of attached file:
Versão do Editor / Published Version
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https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013426/full
DOI: 10.1002/14651858.CD013426
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©2019
by John Wiley & Sons. All rights reserved.
DIRETORIA DE TRATAMENTO DA INFORMAÇÃO Cidade Universitária Zeferino Vaz Barão Geraldo
CEP 13083-970 – Campinas SP Fone: (19) 3521-6493
T A B L E O F C O N T E N T S 1 HEADER . . . . 1 ABSTRACT . . . . 1 BACKGROUND . . . . 2 OBJECTIVES . . . . 2 METHODS . . . . 4 ACKNOWLEDGEMENTS . . . . 5 REFERENCES . . . . 5 CONTRIBUTIONS OF AUTHORS . . . . 5 DECLARATIONS OF INTEREST . . . . 6 SOURCES OF SUPPORT . . . . i Interventions for uterine fibroids: an overview of Cochrane Reviews (Protocol)
[Overview of Reviews Protocol]
Interventions for uterine fibroids: an overview of Cochrane
Reviews
Luiz Gustavo Brito1, Elizabeth A Stewart2, Sarah O Olivi Chaim3, Wellington P Martins4, Cindy Farquhar5
1Department of Gynecology and Obstetrics, State University of Campinas (UNICAMP), Campinas, Brazil.2Division of Reproductive
Endocrinology and Infertility, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, USA.3Department of Obstetrics and
Gynaecology CAISM Hospital, State University of Campinas (UNICAMP), Sao Paulo, Brazil.4SEMEAR Fertilidade, Reproductive
Medicine, Ribeirao Preto, Brazil.5Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand
Contact address: Luiz Gustavo Brito, Department of Gynecology and Obstetrics, State University of Campinas (UNICAMP), Rua Alexander Fleming, 101, Cidade Universitária Zeferino Vaz, Campinas, Sao Paulo, 13083-881, Brazil.lbrito@fcm.unicamp.br,
lgobrito@gmail.com.
Editorial group: Cochrane Gynaecology and Fertility Group. Publication status and date: New, published in Issue 9, 2019.
Citation: Brito LG, Stewart EA, Olivi Chaim SO, Martins WP, Farquhar C. Interventions for uterine fibroids: an overview of Cochrane
Reviews. Cochrane Database of Systematic Reviews 2019, Issue 9. Art. No.: CD013426. DOI: 10.1002/14651858.CD013426. Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
This is a protocol for a Cochrane Review (Overview). The objectives are as follows:
The objective is to summarize evidence from Cochrane Reviews on the effectiveness and safety of treatment options available to premenopausal women with uterine fibroid-associated symptoms.
B A C K G R O U N D
Description of the condition
Uterine fibroids (also known as leiomyomas and myomas; UFs) are benign lesions or neoplasms of the uterus that are composed of smooth muscle cells and fibroblasts and are rich in extracellular matrix. They may cause heavy or prolonged menstrual bleeding that can lead to chronic anaemia. Uterine fibroids can also enlarge the uterus and this enlargement can lead to ’bulk symptoms’ - for example, urinary symptoms (such as increased urinary frequency, nocturia, urgency incontinence or urinary retention) or gastroin-testinal symptoms (such as diarrhoea or constipation) - in addition to abdominal distention or acyclic pelvic pain. These symptoms may considerably impair women’s quality of life (Moroni 2014).
Whilst ultrasonography studies show prevalence rates of uterine fibroids to exceed 70%, clinical fibroid symptoms are felt in 25% to 50% of all women; these data represent a self-report diagno-sis of 12.8 per 1000 person-years to 2 per 1000 person-years for hysterectomy-confirmed cases in the USA (Whiteman 2010). The most recurrent risk factor reported to increase the fibroid risk is black race, followed by increasing age (until the perimenopausal transition), premenopausal state, hypertension, family history and others (Stewart 2017). Fibroids may also affect a woman’s fertility; it is known that uterine fibroids may cause cavity distortion and alteration of endometrial receptivity (Whynott 2017), and this may or may not cause symptoms.
Pelvic ultrasonography remains the primary imaging modality for the diagnosis of uterine fibroids, owing to the benefits of wide availability and low cost associated with this test, in addition to
the reliable identification of calcified fibroids and the detection of larger, clinically relevant fibroids. Sensitivity and specificity for ultrasonography are 90% and 87%, respectively, and are improved with the addition of sonohysterography (instilling saline into the uterine cavity through the cervix) (up to 100% and 98%, respec-tively). Magnetic resonance imaging presents the highest sensitiv-ity and specificsensitiv-ity indexes for UF diagnosis (Stewart 2016). Uterine fibroids seem to develop and regulate gene expression in response to menstrual cyclicity and the action of gonadal steroids (mainly oestrogen and progesterone); they induce symptomatol-ogy between first occurrence of menstruation (menarche) and menopause. The fibroid pathogenesis comprises multiple stages, starting with the recruitment of a smooth muscle stem cell from the myometrium that lacks receptors for the gonadal steroids (Bulun 2013). Under the influence of specific driver mutations, in addi-tion to oestrogen, progesterone, and the activaaddi-tion of a protein named beta-catenin within a signalling pathway named wingless-type (WNT), the stem cell differentiates into a preclinical fibroid. Subsequently, four key cell types that comprise fibroids (smooth muscle cells, vascular smooth muscle cells, fibroblasts and fibroid-associated fibroblasts) (Holdsworth-Carson 2014) and the extra-cellular matrix synergize with environmental and molecular stim-uli to undergo growth acceleration and progression into clinical disease (Stewart 2016).
Description of the interventions
There are a number of potential uterine-sparing interventions for uterine fibroids. Choice of a particular intervention will be de-pendent upon the chief complaint, i.e.: heavy menstrual bleeding, pelvic pain, bulk symptoms, infertility or a combination of symp-toms. The following interventions have been studied with regard to their effect on treating uterine fibroids (in alphabetical order).
1. Acupuncture
2. Add-back therapy with gonadotropin-releasing hormone (GnRH) agonists
3. Antifibrinolytics 4. Aromatase inhibitors 5. Combined oral contraceptives 6. Danazol
7. GnRH agonists 8. Herbal preparations
9. High-intensity focused ultrasound
10. Laparoscopic, robotic or hysteroscopic/open myomectomy 11. Mifepristone
12. Non-steroidal anti-inflammatory drugs
13. Progestogens or progestogen-releasing intrauterine systems 14. Radiofrequency (RF) or percutaneous microwave ablation (PMWA)
15. Selective oestrogen receptor modulators (SERMs) 16. Selective progesterone receptor modulators (SPRMs) 17. Uterine artery embolization (UAE)
18. Uterine artery occlusion
How the intervention might work
Surgical interventions and most of the medical treatments aim both to control heavy menstrual bleeding and to improve bulk symptoms. The mechanisms of the control of heavy menstrual bleeding are not well understood but may include physical nor-malization of the endometrial cavity, or may be related to control of angiogenic factors (Stewart 1996). Likewise, bulk symptoms have historically been thought to require volume reduction, and minimally invasive techniques such as uterine artery embolization have brought improvements to quality of life (Keung 2018). More invasive procedures may present more adverse effects. Recently, a selective progesterone receptor modulator (ulipristal acetate) has been extensively studied with regard to relieving moderate to severe symptoms in women with uterine fibroids (Garnock-Jones 2017), however the endometrial safety for extended treatment needs fur-ther investigation (De Milliano 2017).
Why it is important to do this overview
There are now many systematic reviews of interventions available on the medical and surgical treatment of uterine fibroids for im-proving heavy menstrual bleeding, pelvic pain, bulk symptoms or infertility (or a combination of these). In the Cochrane Database of Systematic Reviews, there are 13 systematic reviews available on these topics. It is important to bring these documents together into one coherent review that can be used by clinicians, policy makers and women with fibroids when making decisions about optimal treatment based on the available evidence about uterine fibroids.
O B J E C T I V E S
The objective is to summarize evidence from Cochrane Reviews on the effectiveness and safety of treatment options available to premenopausal women with uterine fibroid-associated symptoms.
M E T H O D S
Criteria for considering reviews for inclusion Only Cochrane Reviews, protocols and titles will be considered for inclusion in this overview. At the time of writing, systematic reviews on the following topics have been published with regard to uterine fibroids (in alphabetical order).
1. Acupuncture
2 Interventions for uterine fibroids: an overview of Cochrane Reviews (Protocol)
2. Add-back therapy with GnRH agonists 3. Aromatase inhibitors
4. Danazol
5. Herbal preparations
6. High-intensity focused ultrasound
7. Laparoscopic or hysteroscopic myomectomy versus open myomectomy
8. Mifepristone
9. Preoperative medical treatment
10. Progestogens or progestogen-releasing intrauterine systems 11. Selective oestrogen receptor modulators (SERMs) 12. Selective progesterone receptor modulators (SPRMs) 13. Uterine artery embolization
We will list in an additional table any titles or protocols that we identify during our searches, and will incorporate data from these in future versions of the overview.
Participants
We will include premenopausal, symptomatic women with a clin-ical or imaging diagnosis (or both) of uterine fibroids, who have sought medical attention for heavy menstrual bleeding, pelvic pain or bulk symptoms (or a combination of these) or for infertility (regardless of symptoms).
Interventions for symptom relief
Interventions for heavy menstrual bleeding
Medical, complementary therapies or surgical interventions will be considered. Medical treatment can be used as a single inter-vention or administered before or after surgery, or both. Eligible comparators include placebo or another treatment.
Interventions for pelvic pain/bulk symptoms
Whilst pelvic pain/bulk symptoms secondary to uterine fibroids might not have been as extensively investigated as those for heavy menstrual bleeding, it is expected that some participants would have presented with both symptoms and it is important to seek the interventions for this specific outcome. Medical/complementary therapies or surgical interventions will be considered in all reviews.
Interventions for infertility
Medical or surgical interventions will be included for this variable.
Outcomes for symptom relief
Heavy menstrual bleeding
Primary outcome measure: improvement, measured by self-report (qualitative measures such as symptom-free, better, the same or worse) or by use of a health-related quality-of-life instrument. One of the quality-of-life measurements mostly used for uterine fibroids is the use of standardized, validated, specific questionnaires such as the UFS-QOL tool (Spies 2002) for measuring improvement of patients after being treated. Other generic questionnaires (e.g. SF-36 -McHorney 1993) could also be used. Measurement by hae-moglobin, haematocrit and ferritin levels, reduction in PBAC (pic-torial blood assessment chart) scores and reduction in the number of bleeding episodes (by number of pads/day) will also be investi-gated.
Pelvic pain
Primary outcome measure: improvement, measured by self-report (yes/no, Likert scales or numeric scales) or by use of a health-related quality-of-life instrument or by a quantitative instrument, such as a visual analogue scale (VAS), or improvement with a specific questionnaire such as UFSQOL.
Bulk symptoms
Primary outcome measures: bloating, pelvic pressure/discomfort, constipation, frequent urination, pain during intercourse mea-sured by qualitative measures (yes/no, or Likert scales).
Secondary outcomes related to any or all symptoms cited above
Reduction in fibroid volume or uterine volume, measured by pelvic ultrasound, computed tomography (CT) or magnetic resonance imaging; presence of adverse effects secondary to treatment (vaso-motor symptoms, bone density, laboratorial changes, acne, weight gain, bloating, breast tenderness, headache, nausea); recurrence rate.
Outcomes for infertility
Primary outcome measures: live birth (number of live births per woman); clinical pregnancies (pregnancy diagnosed by ultrasound visualization of one or more gestational sacs or definitive clinical signs of pregnancy); ongoing pregnancies (pregnancy progressing beyond 12 weeks of gestation).
Secondary outcome: miscarriage (spontaneous loss of a clinical pregnancy before 20 weeks of gestation or less than 400 g of fetal weight).
Search methods for identification of reviews The Cochrane Database of Systematic Reviews will be searched using the keyword “uterine fibroids” (leiomyoma is not a term that is
used in this database). The term will be restricted to title, abstract or keywords. No other databases will be searched.
Data collection and analysis
Selection of reviews
Cochrane Reviews addressing treatment of heavy menstrual bleed-ing, bulk symptoms or for infertility associated with uterine fi-broids will be identified by one overview author (SOC) and checked by a second overview author (LGOB). Any disagreement will be resolved by consensus or discussion with a third party (WPM).
Data extraction and management
Data will be extracted independently by two overview authors (LGOB, SOC) using an Excel spreadsheet. We will follow the methodology for extracting information for overviews of reviews provided by Cochrane (Becker 2011). Disagreements will be re-solved by discussion (CF, ES or WPM). Overview authors who have been involved as authors or co-authors of Cochrane Reviews included in this overview will not be involved in the selection pro-cess and a member outside this group will review the data. Where data are missing, we will contact the original systematic review authors for assistance. For Cochrane Reviews in which the search is more than two years old, we will contact the authors to ascertain if they are able to update their reviews. If the authors are unable to do this, we will update the relevant Cochrane Reviews, if feasible. We will extract information on the following factors.
1. Population demographics: a summary of the participant characteristics
2. Review characteristics: the number of included trials, the number of participants in each review, the date that the systematic review was assessed as up to date, interventions and comparisons, all outcomes, and limitations of the systematic review
3. Statistical summary: the summary effects from relevant comparisons and outcomes
Assessment of methodological quality of included reviews
Quality of included reviews
We will rate the quality of the included Cochrane Reviews using the AMSTAR tool (Shea 2007). We will provide a table to describe whether the authors of each review did the following.
1. Pre-specified their clinical question and inclusion criteria 2. Conducted study selection and data extraction in duplicate 3. Performed a comprehensive literature search
4. Searched grey literature
5. Listed included and excluded studies
6. Described the characteristics of the included studies 7. Assessed study quality
8. Combined the studies using appropriate methods 9. Addressed the risk of reporting bias and conflict of interest Cochrane Reviews that are not recently published will be assessed regarding their last search date as a measure of quality assessment.
Quality of evidence from primary studies in included reviews
We will describe the quality of the evidence for the primary out-comes using GRADE criteria, and will produce GRADEpro GDT ’Summary of findings’ tables for each review to indicate the qual-ity of these included studies (if the systematic reviews have not produced them). These tables will include the following variables, which could influence the quality of the evidence: study limita-tions (risk of bias), inconsistency of results, imprecision, indirect-ness of evidence and publication bias (Balshem 2011).
Data synthesis
We will provide a narrative description of the findings of the in-cluded Cochrane Reviews. Tables will be produced to detail the included studies and their outcomes.
A C K N O W L E D G E M E N T S
The authors wish to acknowledge the support of the Cochrane Gynaecology and Fertility Group for their suggestions in the pre-registration phase and peer-reviewing process before publication of this protocol. They also thank Jane Marjoribanks, Ying Cheong and Roger Hart for supplying referee comments on the draft.
4 Interventions for uterine fibroids: an overview of Cochrane Reviews (Protocol)
R E F E R E N C E S Additional references
Balshem 2011
Balshem H, Helfand M, Schunemmann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011;
64(4):401–6. Becker 2011
Becker LA, Oxman AD. Chapter 22: Overviews of reviews. In: Higgins JPT, Green S editor(s). Cochrane Handbook
for Systematic Reviews of Interventions version 5.1.0.. The
Cochrane Collaboration, March 2011.
Bulun 2013
Bulun SE. Uterine fibroids. New England Journal of
Medicine 2013;369(14):1344–55. De Milliano 2017
De Milliano I, Van Hattum D, Ket JCF, Huirne JAF, Hehenkamp WJK. Endometrial changes during ulipristal acetate use: a systematic review. European Journal of
Obstetrics Gynecology and Reproductive Biology 2017;214:
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Garnock-Jones 2017
Garnock-Jines KP, Duggan ST. Ulipristal acetate: a review in symptomatic uterine fibroids. Drugs 2017;15:1665–75.
Holdsworth-Carson 2014
Holdsworth-Carson SJ, Zaitseva M, Girling JE, Vollenhoven BJ, Rogers PA. Common fibroid-associated genes are differentially expressed in phenotypically dissimilar cell populations isolated from within human fibroids and myometrium. Reproduction 2014;147:683–92.
Keung 2018
Keung JJ, Spies JB, Caridi TM. Uterine artery embolization: a review of current concepts. Best Practice Research Clinical
Obstetrics Gynaecology 2018;46:66–73. McHorney 1993
McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36):II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Medical Care 1993;31(3):247–63.
Moroni 2014
Moroni RM, Vieira CS, Ferriani RA, Candido-dos-Reis FJ, Brito LGO. Pharmacological treatment of uterine fibroids.
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185–92.
Shea 2007
Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007;15:7–10.
Spies 2002
Spies JB, Coyne K, Guaou Guaou N, Boyle D, Skyrnarz-Murphy K, Gonzalves SM. The UFS-QOL, a new disease-specific symptom and health-related quality of life questionnaire for leiomyomata. Obstetrics & Gynecology 2002;99(2):290–300.
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Stewart EA, Nowak RA. Leiomyoma-related bleeding: a classic hypothesis updated for the molecular era. Human
Reproduction Update 1996;2:295–306. Stewart 2016
Stewart EA, Laughlin-Tommaso SK, Catherino WH, Lalitkumar S, Gupta D, Vollenhoven B. Uterine fibroids.
Nature Reviews 2016;2:1–18. Stewart 2017
Stewart EA, Cookson CL, Gandolfo RA, Schulze-Rath R. Epidemiology of uterine fibroids: a systematic review.
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1501–12.
Whiteman 2010
Whiteman JK, Kuklina E, Jamieson DJ, Hillis SD, Marchbanks PA. Inpatient hospitalization for gynecologic disorders in the United States. American Journal of Obstetrics
and Gynecology 2010;202(6):541.e1–6. Whynott 2017
Whynott RM, Vaught KCC, Segars JH. The effect of uterine fibroids on infertility: a systematic review. Seminars
in Reproductive Medicine 2017;35(6):523–32.
∗Indicates the major publication for the study
C O N T R I B U T I O N S O F A U T H O R S
Luiz Gustavo Brito and Sarah Chaim wrote the protocol. Cindy Farquhar, Wellington Martins and Elizabeth Stewart edited the protocol and made final improvements. Advice on statistical matters will be provided by Wellington Martins.
D E C L A R A T I O N S O F I N T E R E S T LGOB: none known
ES: Dr Stewart reports the following: has received consulting fees from Bayer, AbbVie, Allergan and Myovant and serves on a steering committee for a fibroid trial for Myovant. She also received payment for developing an educational presentation from Med Learning Group, receives royalties from UpToDate, and has a patent (6440445) “Methods and Compounds for Treatment of Abnormal Uterine Bleeding” not related to this project.
WPM: none known SOC: none known CF: none known S O U R C E S O F S U P P O R T Internal sources • None, Other. External sources • None, Other. 6 Interventions for uterine fibroids: an overview of Cochrane Reviews (Protocol)
